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CAS No. : | 1334298-90-6 | MDL No. : | MFCD28579595 |
Formula : | C26H23F4N9O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KTBSXLIQKWEBRB-UHFFFAOYSA-N |
M.W : | 553.51 | Pubchem ID : | 53380437 |
Synonyms : |
INCB039110;INCB39110;1334298-96-2
|
Num. heavy atoms : | 40 |
Num. arom. heavy atoms : | 20 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 11.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 141.13 |
TPSA : | 119.62 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -8.55 cm/s |
Log Po/w (iLOGP) : | 2.89 |
Log Po/w (XLOGP3) : | 1.59 |
Log Po/w (WLOGP) : | 4.41 |
Log Po/w (MLOGP) : | 1.52 |
Log Po/w (SILICOS-IT) : | 3.36 |
Consensus Log Po/w : | 2.75 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.18 |
Solubility : | 0.0364 mg/ml ; 0.0000658 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.71 |
Solubility : | 0.107 mg/ml ; 0.000194 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -7.22 |
Solubility : | 0.000033 mg/ml ; 0.0000000596 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | Stage #1: With boron trifluoride diethyl etherate In acetonitrile at 5 - 20℃; for 23 h; Stage #2: With water In acetonitrile at 5 - 20℃; for 2 h; Stage #3: With ammonium hydroxide In water; acetonitrile at 5 - 20℃; for 20 h; |
Example 7. 2-(3-(4-(7H-P rrolo[2,3-rflpyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (22) 21 22 C32H37F4N902Si C26H23F4N9O Mol. Wt: 683.77 Mol. Wt: 553.51 To a 250 mL 4-necked round bottom flask equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 21 (9.25 g, 13.52 mmol, F water content 3.50percent) and acetonitrile (74 mL) at 20 ± 5 °C. The resulting white slurry was cooled to below 5 °C. Boron trifluoride diethyl etherate (BF3-OEt2, 6.46 mL, 51.37 mmol, 3.80 equiv) was then added at a rate while the internal temperature was kept at.below 5.0 °C. The reaction mixture was then warmed to 20 ± 5 °C. After stirring at 20 ± 5 °C for 18 hours, the reaction mixture was cooled to 0 - 5 °C and an additional amount of BF3 OE12 (0.34 mL, 2.70 mmol, 0.2 equiv) was introduced to the reaction mixture at below 5.0 °C. The resulting reaction mixture was warmed to 20 ± 5 °C, and kept stirring at room temperature for an additional 5 hours. The reaction mixture was then cooled to 0 - 5 °C before water (12.17 mL, 0.676 mol, 50 equiv) was added. The internal temperature was kept at below 5.0 °C during addition of water. The resultant mixture was warmed to 20 ± 5 °C and kept stirring at room temperature for 2 hours. The reaction mixture was then cooled to 0 - 5 °C and aqueous ammonium hydroxide (NH4OH, 5 N, 121.7 mmol, 9.0 equiv) was added. During addition of aqueous ammonium hydroxide solution, the internal temperature was kept at below 5.0 °C. The resulting reaction mixture was warmed to 20 ± 5 °C and stirred at room temperature for 20 hours. Once the SEM-deprotection was deemed complete, the reaction mixture was filtered, and the solids were washed with EtOAc (9.25 mL). The filtrates were combined and diluted with EtOAc (74 mL). The diluted organic solution was washed with 13percent aqueous sodium chloride solution (46.2 mL). The organic phase was then diluted with EtOAc (55.5 mL) before being concentrated to a minimum volume under reduced pressure. EtOAc (120 mL) was added to the residue, and the resulting solution was stirred at 20 ± 5 °C for 30 minutes. The solution was then washed with 7percent aqueous sodium bicarbonate solution (2 x 46 mL) and 13percent aqueous sodium bicarbonate solution (46 mL). The resultant organic phase was diluted with EtOAc (46 mL) and treated with water (64 mL) at 50 ± 5 °C for 30 minutes. The mixture was cooled to 20 ± 5 °C and the two phases were separated. The organic phase was treated with water (64 mL) at 50 ± 5 °C for 30 minutes for the second time. The mixture was cooled to 20 ± 5 °C and the two phases were separated. The resultant organic phase was concentrated to afford crude compound 22 (free base), which was further purified by column chromatography (S1O2, 330 g, gradient elution with 0 - 10percent of MeOH in EtOAc) to afford analytically pure free base (22, 7.00 g, 93.5 percent) as an off-white solid. For 22: NMR (400 MHz, (CD3)2SO)812.17 (d, J = 2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, .7=4.7 Hz, 1H), 7.63 (dd, J= 3.6, 2.3 Hz, 1H), 7.09 (dd,J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d,J=7.9Hz, 2H), 3.61 (t,J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t,J= 10.5 Hz, 1H),3.09 (ddd,J= 13.2, 9.5,3.1 Hz, 1H), 2.58 (m, 1H), 1.83- 1.75 (m, 1H), 1.70 - 1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; l3C NMR (101 MHz, (CD3)2SO)5160.28,(153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48,(134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04,(124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4 9O (MW, 553.51), LCMS (EI)m/e 554.1 (M+ + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.6% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 85℃; Inert atmosphere | 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8) [0148] To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stirred at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6percent), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10percent of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C 1.2: 0.17 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 2.2: 1 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2.5 h 2.1: sodium carbonate / water; dichloromethane / 2 h / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2.5 h 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 33 °C 2.2: 1 h / 25 - 35 °C 3.1: sodium carbonate; sodium bromide; trichloroisocyanuric acid; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 2.17 h / 0 - 25 °C 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C |
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2.5 h 2.1: sodium carbonate / water; dichloromethane / 2 h / 0 - 20 °C 3.1: dichloromethane / 20 °C 3.2: 2 h / 20 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 5.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere | ||
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2.5 h 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 33 °C 2.2: 1 h / 25 - 35 °C 3.1: sodium carbonate; sodium bromide; trichloroisocyanuric acid; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 2.17 h / 0 - 25 °C 4.1: dichloromethane / 20 °C 4.2: 2 h / 20 °C 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 6.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | Stage #1: 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile With boron trifluoride diethyl etherate In acetonitrile at 5 - 20℃; for 23h; Stage #2: With water In acetonitrile at 5 - 20℃; for 2h; Stage #3: With ammonium hydroxide In water; acetonitrile at 5 - 20℃; for 20h; | 7 Example 7. 2-(3-(4-(7H-P rrolo[2,3-rflpyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (22) Example 7. 2-(3-(4-(7H-P rrolo[2,3-rflpyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (22) 21 22 C32H37F4N902Si C26H23F4N9O Mol. Wt: 683.77 Mol. Wt: 553.51 To a 250 mL 4-necked round bottom flask equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 21 (9.25 g, 13.52 mmol, F water content 3.50%) and acetonitrile (74 mL) at 20 ± 5 °C. The resulting white slurry was cooled to below 5 °C. Boron trifluoride diethyl etherate (BF3-OEt2, 6.46 mL, 51.37 mmol, 3.80 equiv) was then added at a rate while the internal temperature was kept at.below 5.0 °C. The reaction mixture was then warmed to 20 ± 5 °C. After stirring at 20 ± 5 °C for 18 hours, the reaction mixture was cooled to 0 - 5 °C and an additional amount of BF3 OE12 (0.34 mL, 2.70 mmol, 0.2 equiv) was introduced to the reaction mixture at below 5.0 °C. The resulting reaction mixture was warmed to 20 ± 5 °C, and kept stirring at room temperature for an additional 5 hours. The reaction mixture was then cooled to 0 - 5 °C before water (12.17 mL, 0.676 mol, 50 equiv) was added. The internal temperature was kept at below 5.0 °C during addition of water. The resultant mixture was warmed to 20 ± 5 °C and kept stirring at room temperature for 2 hours. The reaction mixture was then cooled to 0 - 5 °C and aqueous ammonium hydroxide (NH4OH, 5 N, 121.7 mmol, 9.0 equiv) was added. During addition of aqueous ammonium hydroxide solution, the internal temperature was kept at below 5.0 °C. The resulting reaction mixture was warmed to 20 ± 5 °C and stirred at room temperature for 20 hours. Once the SEM-deprotection was deemed complete, the reaction mixture was filtered, and the solids were washed with EtOAc (9.25 mL). The filtrates were combined and diluted with EtOAc (74 mL). The diluted organic solution was washed with 13% aqueous sodium chloride solution (46.2 mL). The organic phase was then diluted with EtOAc (55.5 mL) before being concentrated to a minimum volume under reduced pressure. EtOAc (120 mL) was added to the residue, and the resulting solution was stirred at 20 ± 5 °C for 30 minutes. The solution was then washed with 7% aqueous sodium bicarbonate solution (2 x 46 mL) and 13% aqueous sodium bicarbonate solution (46 mL). The resultant organic phase was diluted with EtOAc (46 mL) and treated with water (64 mL) at 50 ± 5 °C for 30 minutes. The mixture was cooled to 20 ± 5 °C and the two phases were separated. The organic phase was treated with water (64 mL) at 50 ± 5 °C for 30 minutes for the second time. The mixture was cooled to 20 ± 5 °C and the two phases were separated. The resultant organic phase was concentrated to afford crude compound 22 (free base), which was further purified by column chromatography (S1O2, 330 g, gradient elution with 0 - 10% of MeOH in EtOAc) to afford analytically pure free base (22, 7.00 g, 93.5 %) as an off-white solid. For 22: NMR (400 MHz, (CD3)2SO)812.17 (d, J = 2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, .7=4.7 Hz, 1H), 7.63 (dd, J= 3.6, 2.3 Hz, 1H), 7.09 (dd,J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d,J=7.9Hz, 2H), 3.61 (t,J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t,J= 10.5 Hz, 1H),3.09 (ddd,J= 13.2, 9.5,3.1 Hz, 1H), 2.58 (m, 1H), 1.83- 1.75 (m, 1H), 1.70 - 1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; l3C NMR (101 MHz, (CD3)2SO)5160.28,(153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48,(134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04,(124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4 9O (MW, 553.51), LCMS (EI)m/e 554.1 (M+ + H). |
Stage #1: 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile With trifluoroacetic acid In dichloromethane at 20℃; for 2h; Stage #2: With ethylenediamine In methanol at 20℃; for 1h; | 1.J Into a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. After removing the solvents in vacuum, the residue was dissolved in a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the solution was purified by HPLC (method B) to give the title compound. LC-MS: 554.3 (M+H)+; 1H NMR (400 MHz, CDCl3): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J1=3.4 Hz, J2=1.5 Hz, 1H), 6.77 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J1=7.8 Hz, J2=3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H). | |
Stage #1: 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile With trifluoroacetic acid In dichloromethane at 20℃; for 2h; Stage #2: With ethylenediamine In methanol | 5.j Step J. {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile Step J. {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile Into a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. After removing the solvents in vacuum, the residue was dissolved in a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the solution was purified by HPLC (method B) to give the title compound. LC-MS: 554.3 (M+H)+; 1H NMR (400 MHz, CDCl3): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J1=3.4 Hz, J2=1.5 Hz, 1H), 6.77 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J1=7.8 Hz, J2=3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 16 - 30 °C / Large scale 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.4 h / 10 - 20 °C / Large scale 3.1: hydrogenchloride / methanol; isopropyl alcohol / 2 h / 40 °C 4.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 4.2: 2 h / 15 - 30 °C / Large scale 5.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 5.2: 2 h / 5 - 20 °C 5.3: 20 h / 5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.4 h / 10 - 20 °C / Large scale 2.1: hydrogenchloride / methanol; isopropyl alcohol / 2 h / 40 °C 3.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 3.2: 2 h / 15 - 30 °C / Large scale 4.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 4.2: 2 h / 5 - 20 °C 4.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / Reflux; Inert atmosphere 2.1: [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloro palladium(II); cesium fluoride / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 3.1: water; hydrogenchloride / isopropyl alcohol; dichloromethane / Inert atmosphere; Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 4.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 6 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.05 h / 20 °C 2: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 1 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; sodium tris(acetoxy)borohydride / tetrahydrofuran / 20 °C 4: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 2 h / 20 °C 5: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C 6: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol; water; dichloromethane / 18 h / 20 °C 2.1: dichloromethane / 20 °C 2.2: 2 h / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 4.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / Reflux 2.1: cesium fluoride; [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 3.1: hydrogenchloride / isopropyl alcohol; water; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1: hydrogenchloride 2: SiO2 3: hydrazine hydrate | ||
Multi-step reaction with 4 steps 1.1: hydrazine hydrate / acetonitrile / 1.33 h / 20 - 25 °C / Inert atmosphere 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1: hydrogenchloride / isopropyl alcohol; dichloromethane / 18 h / 20 °C 2: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 °C 3: hydrazine hydrate / acetonitrile / 5.5 h / 25 °C / Inert atmosphere 4: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: hydrazine hydrate / acetonitrile / 80 min / 20 - 25 °C / Inert atmosphere 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 30 min / 20 °C 4.2: 125 min / 26 °C | ||
Multi-step reaction with 4 steps 1: hydrogenchloride / isopropyl alcohol; dichloromethane / 18 h / 20 °C 2: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 °C 3: hydrazine hydrate / acetonitrile / 5.5 h / 20 - 25 °C / Inert atmosphere 4: ethanol / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water / 0.5 h / 25 °C / Large scale 2.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 13.3 h / 5 - 20 °C / Large scale 3.1: hydrogenchloride / water; acetonitrile / 8 h / 10 - 20 °C 4.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 4.2: 2 h / 15 - 30 °C / Large scale 5.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 5.2: 2 h / 5 - 20 °C 5.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydroxide / water / 0.5 h / 20 °C / Large scale 2.1: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / water; N,N-dimethyl-formamide / 5 - 20 °C 3.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 4.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 6 steps 1: sodium hydroxide / water / 0.5 h / 20 °C / Large scale 2: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / water; N,N-dimethyl-formamide / 5 - 20 °C 3: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C / Inert atmosphere 4: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 °C / Inert atmosphere 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 6: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Multi-step reaction with 4 steps 1.1: sodium hydroxide / water / 0.5 h / 20 °C / Large scale 2.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.33 h / 20 °C / Large scale 2.2: 13 h / 5 - 20 °C / Large scale 3.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydroxide / water / 0.5 h / 20 °C / Large scale 2.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.33 h / 20 °C / Large scale 2.2: 13 h / 5 - 20 °C / Large scale 3.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C 4.1: dichloromethane / 20 °C 4.2: 2 h / 20 °C 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 6.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 13.3 h / 5 - 20 °C / Large scale 2.1: hydrogenchloride / water; acetonitrile / 8 h / 10 - 20 °C 3.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 3.2: 2 h / 15 - 30 °C / Large scale 4.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 4.2: 2 h / 5 - 20 °C 4.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 3 steps 1.1: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / water; N,N-dimethyl-formamide / 5 - 20 °C 2.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 5 steps 1: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / water; N,N-dimethyl-formamide / 5 - 20 °C 2: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C / Inert atmosphere 3: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 °C / Inert atmosphere 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 5: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Multi-step reaction with 3 steps 1.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.33 h / 20 °C / Large scale 1.2: 13 h / 5 - 20 °C / Large scale 2.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C | ||
Multi-step reaction with 5 steps 1.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 0.33 h / 20 °C / Large scale 1.2: 13 h / 5 - 20 °C / Large scale 2.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C 3.1: dichloromethane / 20 °C 3.2: 2 h / 20 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 5.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; acetonitrile / 8 h / 10 - 20 °C 2.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 2.2: 2 h / 15 - 30 °C / Large scale 3.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 3.2: 2 h / 5 - 20 °C 3.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 2 steps 1.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 2.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 4 steps 1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C / Inert atmosphere 2: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 °C / Inert atmosphere 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 4: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C 2.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: water; hydrogenchloride / acetonitrile / 8 h / 10 - 20 °C 2.1: dichloromethane / 20 °C 2.2: 2 h / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 4.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 1.2: 2 h / 15 - 30 °C / Large scale 2.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 2.2: 2 h / 5 - 20 °C 2.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 3 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 °C / Inert atmosphere 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 3: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: dichloromethane / 20 °C 1.2: 2 h / 20 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 3.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Multi-step reaction with 3 steps 1: SiO2 2: hydrazine hydrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl acetamide; mineral oil / 0.25 h / 0 - 5 °C 1.2: 0.5 h / 0 - 5 °C 2.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; butan-1-ol / 90 °C / Inert atmosphere; Large scale 3.1: hydrogenchloride / water; tetrahydrofuran / 16 - 30 °C / Large scale 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.4 h / 10 - 20 °C / Large scale 5.1: hydrogenchloride / methanol; isopropyl alcohol / 2 h / 40 °C 6.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 6.2: 2 h / 15 - 30 °C / Large scale 7.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 7.2: 2 h / 5 - 20 °C 7.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 3 steps 1.1: [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloro palladium(II); cesium fluoride / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 2.1: water; hydrogenchloride / isopropyl alcohol; dichloromethane / Inert atmosphere; Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydride / N,N-dimethyl acetamide / -5 - 0 °C 1.2: 0 °C 2.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water / 100 °C / Inert atmosphere 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.05 h / 20 °C 4.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 1 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; sodium tris(acetoxy)borohydride / tetrahydrofuran / 20 °C 6.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 2 h / 20 °C 7.1: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C 8.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Multi-step reaction with 3 steps 1.1: cesium fluoride; [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 2.1: hydrogenchloride / isopropyl alcohol; water; dichloromethane / Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 1.2: 0 - 15 °C 2.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 3.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 4.1: oxalyl dichloride / 0.25 h / 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 2 h / 20 - 25 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 0.5 h / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 0.5 h / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 0.5 h / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 8.2: 2.08 h / 26 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 0.5 h / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 8.2: 2.08 h / 26 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 1.2: 0 - 15 °C 2.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 3.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 4.1: oxalyl dichloride / 0.25 h / 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 2 h / 20 - 25 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 8.2: 2.08 h / 26 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 1.2: 0 - 15 °C 2.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 3.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 4.1: oxalyl dichloride / 15 min / 20 - 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 12 h / 20 - 25 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 20 °C 4.1: hydrogenchloride / water; ethanol 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 20 °C 4.1: hydrogenchloride / water; ethanol 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 1.2: 0 - 15 °C 2.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 3.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 4.1: oxalyl dichloride / 15 min / 20 - 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 12 h / 20 - 25 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 20 °C 4.1: hydrogenchloride / water; ethanol 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: sodium hydroxide / water; acetone / 1 h / 20 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 3.1: ethanol; sodium ethanolate / 12 h / 20 °C 4.1: hydrogenchloride / water; ethanol 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / methanol; isopropyl alcohol / 2 h / 40 °C 2.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 2.2: 2 h / 15 - 30 °C / Large scale 3.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 3.2: 2 h / 5 - 20 °C 3.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 5 steps 1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine; sodium tris(acetoxy)borohydride / tetrahydrofuran / 20 °C 3: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 2 h / 20 °C 4: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C 5: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 1.2: 2 h / 15 - 30 °C / Large scale 2.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 2.2: 2 h / 5 - 20 °C 2.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; sodium tris(acetoxy)borohydride / tetrahydrofuran / 20 °C 2: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 2 h / 20 °C 3: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | In acetone Inert atmosphere; Reflux; | 1 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipate (9) 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipate (9) [0143] To a 0.5-L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2×60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (9, 34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 9: 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H). |
In methanol for 2h; Reflux; | 8.1; 8.2 Example 8. 2-(3-(4-(7H-Pyrrolo[2,3-i/]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile a C26H23F4 9O crude sal Example 8. 2-(3-(4-(7H-Pyrrolo[2,3-i/]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile a C26H23F4 9O crude salt Mol. Wt: 553.51 CazH^NgOs Mol. Wt: 699.66 Stepl. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3-fluoro-2' (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate crude salt (24) The process of making compound 22 in Example 7 was followed, except that the final organic phase was concentrated by vacuum distillation to the minimum volume to afford crude compound 22, which was not isolated but was directly used in subsequent adipate salt formation process. To the concentrated residue which containing crude compound 22 was added methanol (200 mL) at room temperature. The mixture was the concentrated by vacuum distillation to a minimum volume. The residue was then added methanol (75 mL) and the resulting solution was heated to reflux for 2 hours. Methyl isobutyl ketone (MIB , 75 mL) was added to the solution and the resulting mixture was distilled under vacuum to about 30 mL while the internal temperature was kept at 40 - 50 °C. Methanol (75 mL) was added and the resulting mixture was heated to reflux for 2 hours. To the solution was added MIBK (75 mL). The mixture was distilled again under vacuum to about 30 mL while the internal temperature was kept at 40 - 50 °C. To the solution was added a solution of adipic acid (23, 2.15 g, 14.77 mmol) in methanol (75 mL). The resultant solution was then heated to reflux for 2 hours. MIBK (75 mL) was added. The mixture was distilled under vacuum to about 60 mL while the internal temperature was kept at 40 - 50 °C. Heating was stopped and heptane (52.5 mL) was added over 1 - 2 hours. The resultant mixture was stirred at 20 ± 5 °C for 3 - 4 hours. The white precipitates were collected by filtration, and the filter cake was washed with heptane (2 x 15 mL). The solid was dried on the filter under nitrogen with a pulling vacuum at 20 ± 5 °C for 12 hours to provide compound 24 (crude adipate salt, 8.98 g, 12.84 mmol., 95.0%). For 24: NMR (400 MHz, (CD3)2SO) δ 12.16 (s, 1 H), 12.05 (brs, 2H), 8.85 (s, 1 H), 8.72 (s, 1H), 8.69 (d, 7 = 4.7 Hz, 1H), 8.45 (s, 1 H), 7.93 (t, 7= 4.7 Hz, 1 H), 7.63 (dd, J= 3.6, 2.3 Hz, 1 H), 7.09 (dd, 7= 3.6, 1.7 Hz, 1H), 8 4.1 1 (dt, 7= 1 1.0, 4.4 Hz, 1 H), 3.77 (d, 7= 7.8 Hz, 2H), 3.60 (t, 7= 7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, 7= 14.4, 4.6 Hz, 1 H), 3.28 (t, 7= 10.4 Hz, 1 H), 3.09 (ddd, 7= 13.2, 9.6, 3.2 Hz, 1 H), 2.58 (tt, 7 = 8.6, 3.5 Hz, 1 H), 2.28 - 2.17 (m, 4H), 1.83 - 1.74 (m, 1 H), 1.67 (d, 7= 1 1.0 Hz, 1 H), 1.59 - 1.46 (m, 4H), 1.37 - 1.21 (m, 2H) ppm; ,3C NMR (101 MHz, (CD3)2SO) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21 , 127.62, 126.84, 122.05, (124.75, 122.02, 1 19.29, 1 16.54), 1 17.39, 1 13.01 , 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (Mol. Wt: 699.66; 24: C26H23F N9O, MW 553.51 ), LCMS (EI) mle 554.0 (M+ + H). Step 2. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-lH^yrazol-l-yl)-l-(l-(3-fluoro-2- (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (25) In a 100 L dried reactor equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 24 (3.40 kg, 4.86 mol) and acetone (23.8 L). The resulting white turbid was heated to 55 - 60 °C to provide a clear solution. The resultant solution was filtered through an in-line filter to another 100 L reactor. Heptane (23.8 L) was filtered through an in-line filter to a separated 50 L reactor. The filtered heptane was then charged to the acetone solution in the 100 L reactor at a rate while the internal temperature was kept at 55 - 60 °C. The reaction mixture in the 100 L reactor was then cooled to 20 ± 5 °C and stirred at 20 ± 5 °C for 16 hours. The white precipitates were collected by filtration and the cake was washed with heptane (2 x 5.1 L) and dried on the filter under nitrogen with a pulling vacuum. The solid was further dried in a vacuum oven at 55 - 65 °C with nitrogen purge to provide compound 25 (3.1 1 kg, 92.2%) as white to off-white powder. For 25: NMR (400 MHz, (CD3)2SO) δ 12.16 (s, 1 H), 12.05 (brs, 2H), 8.85 (s, 1 H), 8.72 (s, 1H), 8.69 (d, J = 4.7 Hz, 1 H), 8.45 (s, 1 H), 7.93 (t, J= 4.7 Hz, 1H), 7.63 (dd, J = 3.6, 2.3 Hz, 1 H), 7.09 (dd, J = 3.6, 1.7 Hz, 1 H), δ 4.1 1 (dt, J= 1 1.0, 4.4 Hz, l H), 3.77 (d, J= 7.8 Hz, 2H), 3.60 (t, J= 7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J= 14.4, 4.6 Hz, 1 H), 3.28 (t, J= 10.4 Hz, 1H), 3.09 (ddd, J= 13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J= 8.6, 3.5 Hz, 1 H), 2.28 - 2.17 (m, 4H), 1.83 - 1.74 (m, 1 H), 1.67 (d, J= 1 1.0 Hz, 1 H), 1.59 - 1.46 (m, 4H), 1.37 - 1.21 (m, 2H) ppm; 13C NMR (101 MHz, (CD3)2SO) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21 , 127.62, 126.84, 122.05, (124.75, 122.02, 1 19.29, 1 16.54), 1 17.39, 1 13.01 , 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4 905( Mol. Wt: 699.66; free base: C26H23F4 9O (MW, 553.51 ), LCMS (EI) mle 554.0 (M+ + H). | |
34 g | In acetone Reflux; | 1 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipate (9) 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipate (9) To a 0.5-L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2*60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (9, 34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 9: 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5(MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H). |
34 g | In n-heptane at 20 - 50℃; for 18h; | 15.5 Step 5. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipic Acid Salt To a 0.5 L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2×60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipic acid salt (34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H). |
In n-heptane; acetone at 0 - 20℃; | 15.5 Step 5. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipic Acid Salt To a 0.5 L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2×60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipic acid salt (34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; butan-1-ol / 90 °C / Inert atmosphere; Large scale 2.1: hydrogenchloride / water; tetrahydrofuran / 16 - 30 °C / Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.4 h / 10 - 20 °C / Large scale 4.1: hydrogenchloride / methanol; isopropyl alcohol / 2 h / 40 °C 5.1: triethylamine / dichloromethane / 0.17 h / 15 - 30 °C / Large scale 5.2: 2 h / 15 - 30 °C / Large scale 6.1: boron trifluoride diethyl etherate / acetonitrile / 23 h / 5 - 20 °C 6.2: 2 h / 5 - 20 °C 6.3: 20 h / 5 - 20 °C | ||
Multi-step reaction with 7 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water / 100 °C / Inert atmosphere 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 3.05 h / 20 °C 3: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 1 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; sodium tris(acetoxy)borohydride / tetrahydrofuran / 20 °C 5: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 2 h / 20 °C 6: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C 7: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen | 15.5 Step 5. Step 5. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipic Acid Salt To a 0.5 L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2*60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipic acid salt (34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H). | |
With nitrogen | 16.5 Step 5. Step 5. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipic Acid Salt To a 0.5-L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. n-Heptane (220 mL) was gradually added to the reaction mixture at 40-50° C. in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with n-heptane (2*60 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipic acid salt (34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (MW 699.66; C26H23F4N9O for free base, MW, 553.51), LCMS (EI) m/e 554.0 (M++H). Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 2: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 2: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: hydrazine hydrate |
Multi-step reaction with 2 steps 1: hydrazine hydrate / acetonitrile / 5.5 h / 25 °C / Inert atmosphere 2: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 2 steps 1: hydrazine hydrate / acetonitrile / 5.5 h / 20 - 25 °C / Inert atmosphere 2: ethanol / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: water; hydrogenchloride / isopropyl alcohol; dichloromethane / Inert atmosphere; Reflux 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 2.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 2 steps 1.1: hydrogenchloride / isopropyl alcohol; water; dichloromethane / Reflux 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C 2.2: 2.08 h / 26 °C | ||
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C 2.2: 2.08 h / 26 °C |
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 2.1: triethylamine / dichloromethane / 30 min / 20 °C 2.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.6% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 85℃; Inert atmosphere; | 2 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8) 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8) [0148] To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stirred at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6%), was obtained as off-white solids by direct silica gel (SiO2) column chromatography (0-10% of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1. |
44.6% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 85℃; Inert atmosphere; | 2 2-(3-(4-(7H-Pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8) To a 25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(1-(1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHCO3, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85° C. The reaction mixture was stired at 85° C. under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6%), was obtained as off-s white solids by direct silica gel (SiO2) column chromatography (0-10% of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one With sodium tris(acetoxy)borohydride In dichloromethane at 20 - 26℃; for 2h; Stage #3: With water; sodium hydrogencarbonate In dichloromethane | 1 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8, Free Base) 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8, Free Base) [0142] To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (6, 20 g, 56.78 mmol), dichloromethane (200 mL) and triethylamine (TEA, 16.62 mL, 119.2 mmol, 2.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes before 1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (7, 17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 113.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26° C.). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as monitored by HPLC, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product (8) in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base) as an off-white solid. For 8: 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). | |
Stage #1: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one With sodium tris(acetoxy)borohydride In dichloromethane at 26℃; for 2.08h; | 1 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8, Free Base) To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (6, 20 g, 56.78 mmol), dichloromethane (200 mL) and triethylamine (TEA, 16.62 mL, 119.2 mmol, 2.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes before 1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (7, 17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 113.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26° C.). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as monitored by HPLC, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product (8) in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base) as an off-white solid. For 8: 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). | |
With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; SiO2 | 16.4 Step 4. Step 4. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile To a 0.5 L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (20 g, 56.78 mmol), dichloromethane (200 mL), and triethylamine (TEA, 16.62 mL, 119.2 mmol, 2.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes before 1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 113.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26° C.). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as monitored by HPLC, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile as an off-white solid. The 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile obtained by this synthetic method is identical in every comparable aspect with the compound obtained by Example 15 and previously reported synthetic methods (see e.g., U.S. Publication No.: 2011/0224190, the disclosure of which is incorporated herein by reference in its entirety). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). |
Stage #1: 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one; 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one With sodium tris(acetoxy)borohydride In dichloromethane at 26℃; for 2.08333h; | 16.4-16.5 Step 4. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile To a 0.5 L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (20 g, 56.78 mmol), dichloromethane (200 mL), and triethylamine (TEA, 16.62 mL, 119.2 mmol, 2.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes before 1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 113.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26° C.). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as monitored by HPLC, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile as an off-white solid. The 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile obtained by this synthetic method is identical in every comparable aspect with the compound obtained by Example 15 and previously reported synthetic methods (see e.g., U.S. Publication No.: 2011/0224190, the disclosure of which is incorporated herein by reference in its entirety). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). |
|
Stage #1: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt With triethylamine In dichloromethane at 20℃; Stage #2: 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one With sodium tris(acetoxy)borohydride In dichloromethane at 26℃; | 16.4-16.5 Step 4. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile To a 0.5 L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (20 g, 56.78 mmol), dichloromethane (200 mL), and triethylamine (TEA, 16.62 mL, 119.2 mmol, 2.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature for 30 minutes before 1-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 113.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26° C.). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as monitored by HPLC, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (SiO2, 0-10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile as an off-white solid. The 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile obtained by this synthetic method is identical in every comparable aspect with the compound obtained by Example 15 and previously reported synthetic methods (see e.g., U.S. Publication No.: 2011/0224190, the disclosure of which is incorporated herein by reference in its entirety). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / 20 °C / Reflux 2: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / 20 °C / Reflux 2.1: [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloro palladium(II); cesium fluoride / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 3.1: water; hydrogenchloride / isopropyl alcohol; dichloromethane / Inert atmosphere; Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 4.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 2 steps 1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: cesium fluoride; [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 3.1: hydrogenchloride / isopropyl alcohol; water; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 7 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 0.25 h / 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 2 h / 20 - 25 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.2: 2.08 h / 26 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.2: 2.08 h / 26 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 0.25 h / 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 2 h / 20 - 25 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.2: 2.08 h / 26 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 7 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 15 min / 20 - 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 12 h / 20 - 25 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water; tetrahydrofuran / 7.5 h / Reflux 2.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 15 min / 20 - 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 12 h / 20 - 25 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloro palladium(II); cesium fluoride / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 2.1: water; hydrogenchloride / isopropyl alcohol; dichloromethane / Inert atmosphere; Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 - 26 °C | ||
Multi-step reaction with 3 steps 1.1: cesium fluoride; [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) / <i>tert</i>-butyl alcohol; water / Inert atmosphere; Reflux 2.1: hydrogenchloride / isopropyl alcohol; water; dichloromethane / Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 2 h / 20 °C 2: triethylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium carbonate / water; dichloromethane / 2 h / 0 - 20 °C 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C 2.2: 2.08 h / 26 °C | ||
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 33 °C 1.2: 1 h / 25 - 35 °C 2.1: sodium carbonate; sodium bromide; trichloroisocyanuric acid; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 2.17 h / 0 - 25 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: sodium carbonate / water; dichloromethane / 2 h / 0 - 20 °C 2.1: dichloromethane / 20 °C 2.2: 2 h / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 4.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 33 °C 1.2: 1 h / 25 - 35 °C 2.1: sodium carbonate; sodium bromide; trichloroisocyanuric acid; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 2.17 h / 0 - 25 °C 3.1: dichloromethane / 20 °C 3.2: 2 h / 20 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 5.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium carbonate; sodium bromide; trichloroisocyanuric acid; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 2.17 h / 0 - 25 °C 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C 2.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: sodium carbonate; sodium bromide; trichloroisocyanuric acid; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 2.17 h / 0 - 25 °C 2.1: dichloromethane / 20 °C 2.2: 2 h / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C 4.1: sodium hydrogencarbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | 15.4 Step 4. Step 4. 2-(3-(4-(7H-Pyrrolo[2,3-c]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile To a solution of 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-hydrazineylazetidin-3-yl)acetonitrile (0.606 g, 1.51 mmol, 1.30 equiv) in ethanol (3 mL) was added vinamidinium perchlorate (0.40 g, 1.16 mmol) in one portion. The resulting reaction mixture was stirred at ambient temperature for 16 hours. Upon completion, the reaction solvent was evaporated in vacuo. The residual reaction mixture was diluted by DCM (10 ml) and washed by brine (5 mL). The organic layer was separated and collected. The aqueous layer was extracted by another portion of DCM (10 mL), and the combined organic layer was evaporated in vacuo. The crude desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (0.58 g, 95%) was obtained as a yellow gel, which was directly used in the next salt formation step without further purification. The free base obtained by this synthetic method is identical in every comparable aspect with the compound obtained by the previously reported synthetic methods (see e.g. U.S. Publication No.: 2011/0224190, the disclosure of which is incorporated herein by reference in its entirety). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 0.25 h / 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 2 h / 20 - 25 °C 7.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.2: 2.08 h / 26 °C | ||
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 0.5 h / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.2: 2.08 h / 26 °C | ||
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 0.25 h / 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 2 h / 20 - 25 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 0.5 h / 20 °C 9.2: 2.08 h / 26 °C | ||
Multi-step reaction with 10 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 10 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 15 min / 20 - 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 12 h / 20 - 25 °C 7.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 20 °C 5.1: hydrogenchloride / water; ethanol 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydroxide / water; acetone / 1 h / 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 4.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 5.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 6.1: trichlorophosphate / 30 min / 15 - 90 °C 6.2: 2 h / 0 - 20 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 2.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 2.2: 0 - 15 °C 3.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 4.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 5.1: oxalyl dichloride / 15 min / 20 - 50 °C 5.2: 21.5 h / 20 - 50 °C 6.1: sodium perchlorate / water / 12 h / 20 - 25 °C 7.1: ethanol / 4 h / 20 °C 8.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 9.1: triethylamine / dichloromethane / 30 min / 20 °C 9.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 2.1: hydrogenchloride / water; isopropyl alcohol / 72 h / 20 °C 3.1: oxalyl dichloride / 0.25 h / 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 2 h / 20 - 25 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 2.1: hydrogenchloride / water; isopropyl alcohol / 72 h / 20 °C 3.1: oxalyl dichloride / 0.25 h / 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 2 h / 20 - 25 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C | ||
Multi-step reaction with 5 steps 1.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 2.1: hydrogenchloride / water; isopropyl alcohol / 3 d / 20 °C 3.1: oxalyl dichloride / 15 min / 20 - 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 12 h / 20 - 25 °C 5.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 7 steps 1.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 2.1: hydrogenchloride / water; isopropyl alcohol / 3 d / 20 °C 3.1: oxalyl dichloride / 15 min / 20 - 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 12 h / 20 - 25 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 72 h / 20 °C 4.1: oxalyl dichloride / 0.25 h / 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 2 h / 20 - 25 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 72 h / 20 °C 4.1: oxalyl dichloride / 0.25 h / 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 2 h / 20 - 25 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 0.5 h / 20 °C 8.2: 2.08 h / 26 °C | ||
Multi-step reaction with 6 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 3 d / 20 °C 4.1: oxalyl dichloride / 15 min / 20 - 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 12 h / 20 - 25 °C 6.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 8 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: orthoformic acid triethyl ester / tetrahydrofuran; butan-1-ol / 65 h / 110 - 120 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 3 d / 20 °C 4.1: oxalyl dichloride / 15 min / 20 - 50 °C 4.2: 21.5 h / 20 - 50 °C 5.1: sodium perchlorate / water / 12 h / 20 - 25 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / -5 - 5 °C / Inert atmosphere 1.2: 0.5 h / -5 - 5 °C 1.3: 1 h / -5 - 5 °C 2.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 3.1: bis(trichloromethyl) carbonate / acetonitrile / 0.67 h / 0 - 40 °C 3.2: 1 h / 20 - 90 °C 4.1: sodium perchlorate / water / 2 h / 20 - 25 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / -5 - 5 °C / Inert atmosphere 1.2: 0.5 h / -5 - 5 °C 1.3: 1 h / -5 - 5 °C 2.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 3.1: bis(trichloromethyl) carbonate / acetonitrile / 0.67 h / 0 - 40 °C 3.2: 1 h / 20 - 90 °C 4.1: sodium perchlorate / water / 2 h / 20 - 25 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C | ||
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / -5 - 5 °C / Inert atmosphere 1.2: 30 min / -5 - 5 °C 1.3: 1 h / -5 - 5 °C 2.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 3.1: bis(trichloromethyl) carbonate / acetonitrile / 0 - 40 °C 3.2: 1 h / 20 - 90 °C 4.1: sodium perchlorate / water / 12 h / 20 - 25 °C 5.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 7 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / -5 - 5 °C / Inert atmosphere 1.2: 30 min / -5 - 5 °C 1.3: 1 h / -5 - 5 °C 2.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 3.1: bis(trichloromethyl) carbonate / acetonitrile / 0 - 40 °C 3.2: 1 h / 20 - 90 °C 4.1: sodium perchlorate / water / 12 h / 20 - 25 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 2.1: bis(trichloromethyl) carbonate / acetonitrile / 0.67 h / 0 - 40 °C 2.2: 1 h / 20 - 90 °C 3.1: sodium perchlorate / water / 2 h / 20 - 25 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 2.1: bis(trichloromethyl) carbonate / acetonitrile / 0.67 h / 0 - 40 °C 2.2: 1 h / 20 - 90 °C 3.1: sodium perchlorate / water / 2 h / 20 - 25 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 0.5 h / 20 °C 6.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 2.1: bis(trichloromethyl) carbonate / acetonitrile / 0 - 40 °C 2.2: 1 h / 20 - 90 °C 3.1: sodium perchlorate / water / 12 h / 20 - 25 °C 4.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 6 steps 1.1: palladium-carbon; hydrogen / methanol / 3 h / 50 - 55 °C / 760.05 Torr 2.1: bis(trichloromethyl) carbonate / acetonitrile / 0 - 40 °C 2.2: 1 h / 20 - 90 °C 3.1: sodium perchlorate / water / 12 h / 20 - 25 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: bis(trichloromethyl) carbonate / acetonitrile / 0.67 h / 0 - 40 °C 1.2: 1 h / 20 - 90 °C 2.1: sodium perchlorate / water / 2 h / 20 - 25 °C 3.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: bis(trichloromethyl) carbonate / acetonitrile / 0.67 h / 0 - 40 °C 1.2: 1 h / 20 - 90 °C 2.1: sodium perchlorate / water / 2 h / 20 - 25 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 0.5 h / 20 °C 5.2: 2.08 h / 26 °C | ||
Multi-step reaction with 3 steps 1.1: bis(trichloromethyl) carbonate / acetonitrile / 0 - 40 °C 1.2: 1 h / 20 - 90 °C 2.1: sodium perchlorate / water / 12 h / 20 - 25 °C 3.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 5 steps 1.1: bis(trichloromethyl) carbonate / acetonitrile / 0 - 40 °C 1.2: 1 h / 20 - 90 °C 2.1: sodium perchlorate / water / 12 h / 20 - 25 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 30 min / 20 °C 5.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C |
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 0.5 h / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C | ||
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C | ||
Multi-step reaction with 7 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 2.1: ethanol; sodium ethanolate / 12 h / 20 °C 3.1: hydrogenchloride / water; ethanol 4.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 5.1: trichlorophosphate / 30 min / 15 - 90 °C 5.2: 2 h / 0 - 20 °C 6.1: ethanol / 4 h / 20 °C 7.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 8.1: triethylamine / dichloromethane / 30 min / 20 °C 8.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 0.5 h / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 0.5 h / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 0.5 h / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 0.5 h / 20 °C 6.2: 2.08 h / 26 °C |
Multi-step reaction with 6 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 0.5 h / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 0.5 h / 20 °C 6.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: ethanol; sodium ethanolate / 12 h / 20 °C 2.1: hydrogenchloride / water; ethanol 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: ethanol; sodium ethanolate / 12 h / 20 °C 2.1: hydrogenchloride / water; ethanol 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C | ||
Multi-step reaction with 6 steps 1.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 2.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C | ||
Multi-step reaction with 7 steps 1.1: ethanol; sodium ethanolate / 12 h / 20 °C 2.1: hydrogenchloride / water; ethanol 3.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C | ||
Multi-step reaction with 7 steps 1.1: ethanol; sodium ethanolate / 12 h / 20 °C 2.1: hydrogenchloride / water; ethanol 3.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 4.1: trichlorophosphate / 30 min / 15 - 90 °C 4.2: 2 h / 0 - 20 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 0.5 h / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 0.5 h / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 0.5 h / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 0.5 h / 20 °C 5.2: 2.08 h / 26 °C |
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 0.5 h / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 0.5 h / 20 °C 5.2: 2.08 h / 26 °C | ||
Multi-step reaction with 3 steps 1.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 30 min / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 30 min / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 30 min / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 30 min / 20 °C 5.2: 125 min / 26 °C | ||
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 2.1: trichlorophosphate / 30 min / 15 - 90 °C 2.2: 2 h / 0 - 20 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 30 min / 20 °C 5.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 20℃; for 16h; | 15.4 Step 4. 2-(3-(4-(7H-Pyrrolo[2,3-c]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile To a solution of 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-hydrazineylazetidin-3-yl)acetonitrile (0.606 g, 1.51 mmol, 1.30 equiv) in ethanol (3 mL) was added vinamidinium perchlorate (0.40 g, 1.16 mmol) in one portion. The resulting reaction mixture was stirred at ambient temperature for 16 hours. Upon completion, the reaction solvent was evaporated in vacuo. The residual reaction mixture was diluted by DCM (10 ml) and washed by brine (5 mL). The organic layer was separated and collected. The aqueous layer was extracted by another portion of DCM (10 mL), and the combined organic layer was evaporated in vacuo. The crude desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (0.58 g, 95%) was obtained as a yellow gel, which was directly used in the next salt formation step without further purification. The free base obtained by this synthetic method is identical in every comparable aspect with the compound obtained by the previously reported synthetic methods (see e.g. U.S. Publication No.: 2011/0224190, the disclosure of which is incorporated herein by reference in its entirety). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). |
|
In ethanol at 20℃; | 15.4 Step 4. 2-(3-(4-(7H-Pyrrolo[2,3-c]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile To a solution of 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-hydrazineylazetidin-3-yl)acetonitrile (0.606 g, 1.51 mmol, 1.30 equiv) in ethanol (3 mL) was added vinamidinium perchlorate (0.40 g, 1.16 mmol) in one portion. The resulting reaction mixture was stirred at ambient temperature for 16 hours. Upon completion, the reaction solvent was evaporated in vacuo. The residual reaction mixture was diluted by DCM (10 ml) and washed by brine (5 mL). The organic layer was separated and collected. The aqueous layer was extracted by another portion of DCM (10 mL), and the combined organic layer was evaporated in vacuo. The crude desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (0.58 g, 95%) was obtained as a yellow gel, which was directly used in the next salt formation step without further purification. The free base obtained by this synthetic method is identical in every comparable aspect with the compound obtained by the previously reported synthetic methods (see e.g. U.S. Publication No.: 2011/0224190, the disclosure of which is incorporated herein by reference in its entirety). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm; C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: ethanol / 4 h / 20 °C 2.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C | ||
Multi-step reaction with 3 steps 1.1: ethanol / 4 h / 20 °C 2.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 3.1: triethylamine / dichloromethane / 30 min / 20 °C 3.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 2.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 3.1: oxalyl dichloride / 0.25 h / 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 2 h / 20 - 25 °C 5.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 2.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 3.1: oxalyl dichloride / 0.25 h / 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 2 h / 20 - 25 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 0.5 h / 20 °C 7.2: 2.08 h / 26 °C | ||
Multi-step reaction with 5 steps 1.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 2.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 3.1: oxalyl dichloride / 15 min / 20 - 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 12 h / 20 - 25 °C 5.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 7 steps 1.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 2.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 3.1: oxalyl dichloride / 15 min / 20 - 50 °C 3.2: 21.5 h / 20 - 50 °C 4.1: sodium perchlorate / water / 12 h / 20 - 25 °C 5.1: ethanol / 4 h / 20 °C 6.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 7.1: triethylamine / dichloromethane / 30 min / 20 °C 7.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 0.5 h / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 10.2: 2.08 h / 26 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 0.5 h / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 10.2: 2.08 h / 26 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 3.2: 0 - 15 °C 4.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 5.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 6.1: oxalyl dichloride / 0.25 h / 50 °C 6.2: 21.5 h / 20 - 50 °C 7.1: sodium perchlorate / water / 2 h / 20 - 25 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 0.5 h / 20 °C 10.2: 2.08 h / 26 °C |
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 0.5 h / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 0.5 h / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 3.2: 0 - 15 °C 4.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 5.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 6.1: oxalyl dichloride / 0.25 h / 50 °C 6.2: 21.5 h / 20 - 50 °C 7.1: sodium perchlorate / water / 2 h / 20 - 25 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 3.2: 0 - 15 °C 4.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 5.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 6.1: oxalyl dichloride / 15 min / 20 - 50 °C 6.2: 21.5 h / 20 - 50 °C 7.1: sodium perchlorate / water / 12 h / 20 - 25 °C 8.1: ethanol / 4 h / 20 °C 9.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 10.1: triethylamine / dichloromethane / 30 min / 20 °C 10.2: 125 min / 26 °C | ||
Multi-step reaction with 11 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 20 °C 6.1: hydrogenchloride / water; ethanol 7.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 30 min / 20 °C 11.2: 125 min / 26 °C | ||
Multi-step reaction with 11 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 20 °C 6.1: hydrogenchloride / water; ethanol 7.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 30 min / 20 °C 11.2: 125 min / 26 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 6.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 7.1: trichlorophosphate / 30 min / 15 - 90 °C 7.2: 2 h / 0 - 20 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 8 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 3.2: 0 - 15 °C 4.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 5.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 6.1: oxalyl dichloride / 15 min / 20 - 50 °C 6.2: 21.5 h / 20 - 50 °C 7.1: sodium perchlorate / water / 12 h / 20 - 25 °C 8.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 20 °C 6.1: hydrogenchloride / water; ethanol 7.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: hydrogenchloride / water / 20 - 30 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 3.1: sodium hydroxide / water; acetone / 1 h / 20 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 5.1: ethanol; sodium ethanolate / 12 h / 20 °C 6.1: hydrogenchloride / water; ethanol 7.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 2.1: oxalyl dichloride / 0.25 h / 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 2 h / 20 - 25 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 2.1: oxalyl dichloride / 0.25 h / 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 2 h / 20 - 25 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 0.5 h / 20 °C 6.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 2.1: oxalyl dichloride / 15 min / 20 - 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 12 h / 20 - 25 °C 4.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 6 steps 1.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 2.1: oxalyl dichloride / 15 min / 20 - 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 12 h / 20 - 25 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; isopropyl alcohol / 72 h / 20 °C 2.1: oxalyl dichloride / 0.25 h / 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 2 h / 20 - 25 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: hydrogenchloride / water; isopropyl alcohol / 72 h / 20 °C 2.1: oxalyl dichloride / 0.25 h / 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 2 h / 20 - 25 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 0.5 h / 20 °C 6.2: 2.08 h / 26 °C | ||
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; isopropyl alcohol / 3 d / 20 °C 2.1: oxalyl dichloride / 15 min / 20 - 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 12 h / 20 - 25 °C 4.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 6 steps 1.1: hydrogenchloride / water; isopropyl alcohol / 3 d / 20 °C 2.1: oxalyl dichloride / 15 min / 20 - 50 °C 2.2: 21.5 h / 20 - 50 °C 3.1: sodium perchlorate / water / 12 h / 20 - 25 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium perchlorate / water / 2 h / 20 - 25 °C 2: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium perchlorate / water / 2 h / 20 - 25 °C 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 2 steps 1: sodium perchlorate / water / 12 h / 20 - 25 °C 2: ethanol / 16 h / 20 °C |
Multi-step reaction with 4 steps 1.1: sodium perchlorate / water / 12 h / 20 - 25 °C 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 30 min / 20 °C 4.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: ethanol / 4 h / 20 °C 2.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 2.08 h / 26 °C | ||
Multi-step reaction with 3 steps 1.1: ethanol / 4 h / 20 °C 2.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 3.1: triethylamine / dichloromethane / 30 min / 20 °C 3.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: trichlorophosphate / 0.5 h / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 0.5 h / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 2 steps 1.1: trichlorophosphate / 30 min / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 30 min / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 30 min / 20 °C 4.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: trichlorophosphate / 0.5 h / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 0.5 h / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 0.5 h / 20 °C 4.2: 2.08 h / 26 °C | ||
Multi-step reaction with 2 steps 1.1: trichlorophosphate / 30 min / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 30 min / 15 - 90 °C 1.2: 2 h / 0 - 20 °C 2.1: ethanol / 4 h / 20 °C 3.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 4.1: triethylamine / dichloromethane / 30 min / 20 °C 4.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / 0.25 h / 50 °C 1.2: 21.5 h / 20 - 50 °C 2.1: sodium perchlorate / water / 2 h / 20 - 25 °C 3.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / 0.25 h / 50 °C 1.2: 21.5 h / 20 - 50 °C 2.1: sodium perchlorate / water / 2 h / 20 - 25 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 0.5 h / 20 °C 5.2: 2.08 h / 26 °C | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / 15 min / 20 - 50 °C 1.2: 21.5 h / 20 - 50 °C 2.1: sodium perchlorate / water / 12 h / 20 - 25 °C 3.1: ethanol / 16 h / 20 °C |
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / 15 min / 20 - 50 °C 1.2: 21.5 h / 20 - 50 °C 2.1: sodium perchlorate / water / 12 h / 20 - 25 °C 3.1: ethanol / 4 h / 20 °C 4.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 5.1: triethylamine / dichloromethane / 30 min / 20 °C 5.2: 125 min / 26 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: sodium ethanolate / ethanol / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 0.5 h / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.2: 2.08 h / 26 °C | ||
Multi-step reaction with 11 steps 1.1: sodium ethanolate / ethanol / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 0.5 h / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.2: 2.08 h / 26 °C | ||
Multi-step reaction with 11 steps 1.1: sodium ethanolate / ethanol / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 4.2: 0 - 15 °C 5.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 6.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 7.1: oxalyl dichloride / 0.25 h / 50 °C 7.2: 21.5 h / 20 - 50 °C 8.1: sodium perchlorate / water / 2 h / 20 - 25 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 0.5 h / 20 °C 11.2: 2.08 h / 26 °C |
Multi-step reaction with 9 steps 1.1: sodium ethanolate / ethanol / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 0.5 h / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: sodium ethanolate / ethanol / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 0.5 h / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: sodium ethanolate / ethanol / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 15 °C 4.2: 0 - 15 °C 5.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 6.1: ammonium hydroxide / water / 16 h / 15 - 40 °C 7.1: oxalyl dichloride / 0.25 h / 50 °C 7.2: 21.5 h / 20 - 50 °C 8.1: sodium perchlorate / water / 2 h / 20 - 25 °C 9.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 10 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 20 °C 7.1: hydrogenchloride / water; ethanol 8.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 9.1: trichlorophosphate / 30 min / 15 - 90 °C 9.2: 2 h / 0 - 20 °C 10.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 10 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 20 °C 7.1: hydrogenchloride / water; ethanol 8.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 9.1: trichlorophosphate / 30 min / 15 - 90 °C 9.2: 2 h / 0 - 20 °C 10.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 11 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 30 min / 20 °C 11.2: 125 min / 26 °C | ||
Multi-step reaction with 11 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 30 min / 20 °C 11.2: 125 min / 26 °C | ||
Multi-step reaction with 11 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 4.2: 0 - 15 °C 5.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 6.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 7.1: oxalyl dichloride / 15 min / 20 - 50 °C 7.2: 21.5 h / 20 - 50 °C 8.1: sodium perchlorate / water / 12 h / 20 - 25 °C 9.1: ethanol / 4 h / 20 °C 10.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 11.1: triethylamine / dichloromethane / 30 min / 20 °C 11.2: 125 min / 26 °C | ||
Multi-step reaction with 12 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 20 °C 7.1: hydrogenchloride / water; ethanol 8.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 9.1: trichlorophosphate / 30 min / 15 - 90 °C 9.2: 2 h / 0 - 20 °C 10.1: ethanol / 4 h / 20 °C 11.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 12.1: triethylamine / dichloromethane / 30 min / 20 °C 12.2: 125 min / 26 °C | ||
Multi-step reaction with 12 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 20 °C 7.1: hydrogenchloride / water; ethanol 8.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 9.1: trichlorophosphate / 30 min / 15 - 90 °C 9.2: 2 h / 0 - 20 °C 10.1: ethanol / 4 h / 20 °C 11.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 12.1: triethylamine / dichloromethane / 30 min / 20 °C 12.2: 125 min / 26 °C | ||
Multi-step reaction with 9 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydroxide / water; acetone / 1 h / 20 °C 5.1: caesium carbonate / N,N-dimethyl-formamide / 50 - 60 °C 6.1: ethanol; sodium ethanolate / 12 h / 65 - 75 °C 7.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 8.1: trichlorophosphate / 30 min / 15 - 90 °C 8.2: 2 h / 0 - 20 °C 9.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: sodium ethanolate / methanol; ethanol / 1 h / 20 - 75 °C / Large scale 2.1: hydrogenchloride / water / 20 - 30 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 0 - 70 °C / Large scale 4.1: sodium hydride / tetrahydrofuran; mineral oil / 30 min / 0 - 15 °C 4.2: 0 - 15 °C 5.1: iron(III)-acetylacetonate / tetrahydrofuran; mineral oil / 2 h / 0 - 30 °C 6.1: ammonium hydroxide / water; methanol / 16 h / 15 - 40 °C 7.1: oxalyl dichloride / 15 min / 20 - 50 °C 7.2: 21.5 h / 20 - 50 °C 8.1: sodium perchlorate / water / 12 h / 20 - 25 °C 9.1: ethanol / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; ethanol 2.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; ethanol 2.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 16 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: hydrogenchloride / water; ethanol 2.1: water; sodium hydroxide / tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C |
Multi-step reaction with 6 steps 1.1: hydrogenchloride / water; ethanol 2.1: sodium hydroxide / water; tetrahydrofuran; acetone / 5 h / 20 °C 3.1: trichlorophosphate / 30 min / 15 - 90 °C 3.2: 2 h / 0 - 20 °C 4.1: ethanol / 4 h / 20 °C 5.1: hydrogenchloride / water; isopropyl alcohol; dichloromethane / Reflux 6.1: triethylamine / dichloromethane / 30 min / 20 °C 6.2: 125 min / 26 °C |
Tags: 1334298-90-6 synthesis path| 1334298-90-6 SDS| 1334298-90-6 COA| 1334298-90-6 purity| 1334298-90-6 application| 1334298-90-6 NMR| 1334298-90-6 COA| 1334298-90-6 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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