There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 591769-05-0 | MDL No. : | MFCD11857755 |
Formula : | C8H11N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VMELXYJYSXXORF-ZZXKWVIFSA-N |
M.W : | 121.18 | Pubchem ID : | 21427952 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.62 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.73 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.31 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 2.43 |
Log Po/w (WLOGP) : | 2.26 |
Log Po/w (MLOGP) : | 1.58 |
Log Po/w (SILICOS-IT) : | 2.1 |
Consensus Log Po/w : | 2.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.06 |
Solubility : | 1.06 mg/ml ; 0.00879 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.57 |
Solubility : | 0.324 mg/ml ; 0.00268 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.17 |
Solubility : | 8.29 mg/ml ; 0.0684 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.56 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P301+P310-P405-P501 | UN#: | 3276 |
Hazard Statements: | H301 | Packing Group: | Ⅲ |
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 |
---|---|---|
89% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; Stage #2: at 0 - 20℃; for 64 h; |
Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 °C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by recooling to 0 °C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g of olefin isomers which was used without further purification (89percent). 1H NMR (400 MHz, CDCl3): δ 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26 (m, 16H). |
67% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 3 h; Cooling with ice Stage #2: at 0 - 20℃; |
Under ice-cooling conditions, 5.9g of diethyl cyanomethylphosphonate was dissolved in 100mL anhydrous tetrahydrofuran. 5.6g of potassium tert-butoxide was added portionwise in the solution and was stirred at room temperature for three hours. The temperature was reduced to 0°C and cyclopentanecarbaldehyde was added dropwise to the reaction solution and reacted overnight at room temperature. TLC was used to monitor reaction completion. 100ml of saturated ammonium chloride solution was added to quench the reaction. After distilling off the solvent, the residue was extracted with ethyl acetate then washed with water. The organic phase was washed with 100mL each of saturated sodium chloride solution 3 times. The organic phase was dried over anhydrous anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 2.5g of intermediate 5a as a colorless liquid, yield: 67percent. |
46% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 49 h; | To a solution of Potassium t-butoxide (1.23 g, 10.37 mmol) in THF (20 mL) at 0 °C was added diethyl cyanomethylphosphonate 34b (1.96 g, 10.87 mmol) dropwise over a period of 10 mins. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and added a solution ofcyclopentanecarbaldehyde 34a (0.97 g, 9.88 mmol) in THF (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was diluted with water (10 mL and extracted with ethyl acetate (3 x 30 ml). The ethyl acetate layers were combined and washed with brine (25 ml), dried concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 20 g, eluting with 0-50percent ethyl acetate in hexane) to furnish 3-cyclopentylacrylonitrile 34c (0.55 g, 46percent) as a colorless oil; 1HNMR (300 MHz, DMSO) δ 6.85 (dd, J= 8.1, 16.3, 0.4H), 6.66 - 6.51 (m, 0.6H), 5.67 (dd, J= 1.2, 16.3, 0.4H), 5.56 (dd, J= 0.6, 10.8, 0.6H), 2.86 (dq, J= 8.1, 16.5, 0.6H), 2.60 (dt, J= 8.3, 16.7, 0.4H), 1.79 (m, 2H), 1.70 - 1.50 (m, 4H), 1.42 - 1.29 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.2% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere |
Under nitrogen, a suspension of (cyanomethyl)triphenylphosphanium bromide (12 g, 31.49 mmol) in anhydrous THF (100 mL) was cooled to 0° C., a solution of 2.5 M n-BuLi in n-hexane (13 mL, 34.64 mmol) was added dropwise. The mixture was stirred at 0° C. for another 30 minutes, then cyclopentane-carbaldehyde (3.1 g, 31.49 mmol) was added, and the mixture was warmed to the room temperature and stirred for further 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (60 mL×3) and saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate. The mixture was filtrated, the filtrate was concentrated in vacuum, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give colorless oil 3-b (1.0 g, yield: 26.2percent). LC-MS (ESI): m/z=122 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 °C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by recooling to 0 °C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g of olefin isomers which was used without further purification (89percent). 1H NMR (400 MHz, CDCl3): delta 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26 (m, 16H). | |
67% | Under ice-cooling conditions, 5.9g of diethyl cyanomethylphosphonate was dissolved in 100mL anhydrous tetrahydrofuran. 5.6g of potassium tert-butoxide was added portionwise in the solution and was stirred at room temperature for three hours. The temperature was reduced to 0°C and cyclopentanecarbaldehyde was added dropwise to the reaction solution and reacted overnight at room temperature. TLC was used to monitor reaction completion. 100ml of saturated ammonium chloride solution was added to quench the reaction. After distilling off the solvent, the residue was extracted with ethyl acetate then washed with water. The organic phase was washed with 100mL each of saturated sodium chloride solution 3 times. The organic phase was dried over anhydrous anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 2.5g of intermediate 5a as a colorless liquid, yield: 67percent. | |
46% | With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 49h; | To a solution of Potassium t-butoxide (1.23 g, 10.37 mmol) in THF (20 mL) at 0 °C was added diethyl cyanomethylphosphonate 34b (1.96 g, 10.87 mmol) dropwise over a period of 10 mins. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and added a solution ofcyclopentanecarbaldehyde 34a (0.97 g, 9.88 mmol) in THF (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was diluted with water (10 mL and extracted with ethyl acetate (3 x 30 ml). The ethyl acetate layers were combined and washed with brine (25 ml), dried concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 20 g, eluting with 0-50percent ethyl acetate in hexane) to furnish 3-cyclopentylacrylonitrile 34c (0.55 g, 46percent) as a colorless oil; 1HNMR (300 MHz, DMSO) delta 6.85 (dd, J= 8.1, 16.3, 0.4H), 6.66 - 6.51 (m, 0.6H), 5.67 (dd, J= 1.2, 16.3, 0.4H), 5.56 (dd, J= 0.6, 10.8, 0.6H), 2.86 (dq, J= 8.1, 16.5, 0.6H), 2.60 (dt, J= 8.3, 16.7, 0.4H), 1.79 (m, 2H), 1.70 - 1.50 (m, 4H), 1.42 - 1.29 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;Inert atmosphere; Reflux; | Racemic 3-Cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (23).; To a 500 mL round bottom flask equipped with a stir bar, condenser and nitrogen inlet was charged <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (8, a mixture of E and Z isomers, 8.46 g, 0.067 mol, 1.3 equiv), acetonitrile (242 mL, 4.64 mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4, 10.0 g, 0.0515 mol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 16.2 ml, 0.108 mol, 2.1 equiv) at room temperature. The resulting solution was then warmed to reflux, and the reaction mixture was stirred at reflux for 18 hours. When the reaction was deemed complete, the reaction mixture was allowed to cool to room temperature followed by concentration under reduced pressure. The residue was purified directly by flash column chromatography (SiO2, 0percent to 30percent ethyl acetate/hexane gradient elution) to afford 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 13.1 g, 16.2 g theoretical, 81percent) as off-white solids. This racemic mixture was directly used for subsequent chiral column separation with out further purification. For 23: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.07 (d, 1H, J=0.53 Hz), 7.65 (s, 1H), 4.42 (td, 1H, J=19.2, 4.5 Hz), 3.14 (dd, 1H, J=9.39, 17.2 Hz), 3.08 (dd, 1H, J=4.58, 17.2 Hz), 2.31 (m, 1H), 1.75 (m, 1H), 1.62-1.32 (m, 4H), 1.29-1.01 (m, 15H); C17H26BN3O2 (MW, 315.22) LCMS (EI) m/e 316 [M++H]. |
73% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60℃; | To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.00 g, 0.0103 mol) in acetonitrile (30 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (1.25 g, 0.0103 mol), followed by 1,8- diazabicyclo[5.4.0]undec-7-ene (1.54 mL, 0.0103 mol). The resulting mixture was stirred at 60 0C <n="54"/>overnight, then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50percent EtOAc in hexanes, to give the desired product (2.36 g, 73percent). LCMS (M+H) 316.1. |
27.5% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60℃; for 18h; | To a solution of compound 3-b (1 g, 8.26 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.4 g, 12.39 mmol) in acetonitril (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 g, 16.52 mmol). The mixture was stirred at 60° C. for 18 hours. The mixture was concentrated in vacuum. To the residue was added water (50 mL), then the mixture was extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (60 mL×3) and saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate. The mixture was filtrated, the filtrate was concentrated in vacuum, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=3:1) to give yellow oil 3-a (715 mg, yield: 27.5percent). LC-MS (ESI): m/z=316 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.7% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 80℃; for 25h; | Racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound).; Method A.; 3-Cyclopentylacrylonitrile (8, 273.5 g, 2.257 mol, 1.20 equiv) and DBU (28 mL, 0.187 mol, 0.10 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 591.8 g, 1.876 mol) in acetonitrile (4.7 L) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to 70-80° C. for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was cooled to room temperature. The cooled solution was then concentrated under reduced pressure to give the crude product (9) as a thick amber oil. The crude product was dissolved in dichloromethane (DCM) and absorbed onto silica gel then dry-loaded onto a silica column (3 Kg) packed in 33percent EtOAc/heptanes. The column was eluted with 33percent EtOAc/heptanes (21 L), 50percent EtOAc/heptanes (28 L), 60percent EtOAc/heptanes (12 L) and 75percent EtOAc/heptanes (8 L). The fractions containing the desired product (9) were combined and concentrated under reduced pressure to generate a yellow oil, which was transferred to a 3 L flask with EtOAc. The solvent was removed under reduced pressure and the residual EtOAc by co-evaporating with heptanes. The residue was further dried under high vacuum for overnight to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 800 g, 819.1 g theoretical, 97.7percent yield) as an extremely viscous yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and 459 (M++Na). |
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | To a solution of 4-(lH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added 3- cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HC1. The aqueous layer was back- extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). |
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | Step 2. (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile. To a solution of 4-(1H-pyrazol- 4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layer was back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H column, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. The products may be isolated by preparative HPLC or other means known to those of skill in the art for use in Step 3 below. 1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03- 1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H),?0.06 (s, 9H); MS(ES): 437 (M+1). |
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | Step 2. (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile. To a solution of 4-(1H-pyrazol- 4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layer was back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H column, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. The products may be isolated by preparative HPLC or other means known to those of skill in the art for use in Step 3 below. 1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03- 1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), 0.06 (s, 9H); MS(ES): 437 (M+1). |
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; | To a solution of 4-(1 H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g,0.0476 mol) mACN (300 mE) was added 3-cyclopentylacry-lonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mE, 0.10 mol). The resultingmixture was stirred at room temperature overnight. The ACNwas evaporated. The mixture was diluted with ethyl acetate,and the solution was washed with 1.0 N HC1. The aqueouslayer was back-extracted with three portions of ethyl acetate.The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The crudeproduct was purified by silica gel chromatography (gradientof ethyl acetate/hexanes) to yield a viscous clear syrup, whichwas dissolved in ethanol and evaporated several times toremove ethyl acetate, to afford 19.4 g of racemic adduct(93percent). The enantiomers were separated by preparativeHPEC, (OD-H, 15percent ethanol/hexanes) and used separately inthe next step to generate their corresponding final product.The final products (see Step 3) stemming from each of theseparated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the secondpeak to elute from the preparative-HPEC was more activethan its enantiomer.?H NMR (300 MHz, CDC13): oe 8.85 (s, 1H), 8.32 (s, 2H),7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t,2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), ?0.06 (s, 9H);MS (ES): 437 (M+1). |
With potassium carbonate; In dimethyl sulfoxide; at 43 - 45℃; for 24h; | 3-Cyclopentylacrylonitrile (76.06 g) (prepared as per the procedure disclosed in U.S. Patent No. 7,598,257) was added to a mixture of 4-(lH-pyrazol-4-yl)-7-[2- (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-£/]pyrimidine (165 g, as prepared in Step b) in dimethylsulfoxide (825 mL). Powdered potassium carbonate (16.58 g) was added to the reaction mixture and the temperature of the reaction mixture was raised to 43 °C to 45 °C. The reaction mixture was stirred for 24 hours. The reaction mixture was cooled to 20°C to 25°C and DI water (3300 mL) was added to the reaction mixture at 10°C to 25°C. The aqueous layer was extracted with ethyl acetate (825 mL) and the organic layer was collected. The aqueous layer was again extracted with ethyl acetate (825 mL) and the organic layer was collected. The combined organic layers were washed with DI water (825 mL) and concentrated under reduced pressure at 45°C to 50°C to obtain title compound, which was used as such for next step. | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60 - 80℃; for 26h;Inert atmosphere; | 231.67 g (1.90 mol) 3-Cyclopentyl-acrylonitrile and 23.70 ml ( 0.16 mol) 1,8- Diazabicyclo[5.4.0]undec-7-en (DBU) were added to a suspension of the starting material (1) (500 g, 1.56 mol) in 4000 ml acetonitrile (MeCN) at room temperature under stirring and nitrogen atmosphere. The reaction mixture was heated to 60°C for -22 hours, then to 80°C for 4 hours. The reaction mixture was cooled to room temperature. The cooled reaction mixture was evaporated under reduced pressure at 42°C to yield a viscous black oil. The oil was dissolved in 1300 ml dichloromethane (DCM) and 650 g silica (63-200 tim) were added. The suspension was evaporated under reduced pressure at 44°C. The obtained crude product on silica was dry loaded on a silica column (1.25 kg (2.5 1) silica 63-200 jim, diameter of column 7 cm length 92 cm). The whole separation was accomplished via flash system (companion ?combi flash?) with a solvent flow of 100 ml/min. (pressure 5-15 bar). Elution was accomplished with EtOAc (ethylacetate)/n-hexane 1/2. The solvent was evaporated at 50°C to yield the product as highly viscous yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 5h;Product distribution / selectivity; | Method B.; To a stirred suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 158 mg, 0.50 mmol) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (8, 122 mg, 1.0 mmol, 2.0 equiv) in dimethyl sulfoxide (DMSO, 1.0 mL, 14 mmol) at room temperature was added powder potassium carbonate (K2CO3, 10.4 mg, 0.075 mmol, 0.15 equiv). The reaction mixture was then stirred at room temperature for 5 h. The reaction mixture became a clear solution in 2 h. When LCMS showed the reaction was deemed complete, the reaction was quenched with water (H2O, 5 mL) and extracted with ethyl acetate (EtOAc, 3.x.15 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-50percent EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 172.6 mg, 210 mg theoretical, 82percent yield) as a white solid. For 20: 1H NMR (CDCl3, 400 MHz) delta ppm 8.87 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 7.47 (d, 1H, J=3.9 Hz), 6.75 (d, 1H, J=3.9 Hz), 6.24 (s, 2H), 4.25 (m, 1H), 3.12 (dd, 1H, J=17.0, 8.7 Hz), 2.95 (dd, 1H, J=17.0, 3.9 Hz), 2.58 (m, 1H), 1.95 (m, 1H), 1.72-1.52 (m, 5H), 1.25 (m, 2H), 1.14 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.8% | caesium carbonate; In acetonitrile; at 20 - 65℃;Inert atmosphere; | Racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound).; Method B.; Into a four-neck 250 mL round bottom flask equipped with a stir bar, thermocouple, condenser and nitrogen inlet was charged (3S)-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 13.9 g, 31.5 mmol), acetonitrile (84 mL) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (8, a mixture of E and Z isomers, 3.82 g, 31.5 mmol, 1.0 equiv) at room temperature. The resulting mixture was then treated with cesium carbonate (Cs2CO3, 2.57 g, 7.88 mmol, 0.25 equiv) at room temperature. The reaction mixture was warmed to 65° C. and checked after 12 hours by chiral HPLC to determine the enantiomeric ratio of compound (R)-10 to compound (S)-10. When the ratio of compound (R)-10 to compound (S)-10 reached to one to one, the reaction mixture was then allowed to cool to room temperature gradually and stirred at room temperature for 24 to 48 h. The reaction mixture was monitored by HPLC to determine the level of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5). The reaction was considered complete when the level of compound 5 was found to be 2percent by HPLC area percent. The reaction mixture was then filtered through a Celite pad to remove insoluble solids present in the reaction solution. The filtrates were then concentrated under reduced pressure to remove about 40 mL of solvent. The concentrated solution was diluted with ethyl acetate (40 mL) and washed with 1 N aqueous HCl solution (40 mL). The two layers were separated, and the aqueous acid wash solution was back extracted with ethyl acetate (20 mL). The combined organic fractions were washed with 1 M aqueous sodium bicarbonate (NaHCO3) solution (45 mL) and 20percent (w/w) brine solution (40 mL). The organic fraction was dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to afford the crude racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 13.6 g, 13.9 g theoretical, 97.8percent) as an amber oil, which was found to be identical to the material made by Method A. This crude product was found to be pure enough (>96 area percent by HPLC) and was directly used in the subsequent chiral separation without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | To a solution of 4-iodo-lH-pyrazole 34e (0.72 g, 3.75 mmol) in acetonitrile (10 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> 34c (0.5 g, 4.12 mmol) and DBU (0.57 g, 3.75 mmol). The reaction mixture was stirred at room temperature and concentrated in vacuum. The residue obtained was dissolved in ethyl acetate washed with 1 N aqueous HC1, brine, dried and concentrated in vacuum to furnish crude as oil. The crude was purified by flash column chromatography (silica gel 24 g, eluting with 0-50percent ethyl acetate in hexane) to furnish 3- cyclopentyl-3-(4-iodo-lH-pyrazol-l-yl)propanenitrile 34f (0.845 g, 72percent) as a colorless oil;1HNMR (300 MHz, DMSO) delta 8.06 (d, J= 0.6, 1H), 7.61 (s, 1H), 4.40 (td, J= 5.2, 9.0, 1H), 3.20 - 3.04 (m, 2H), 2.39 - 2.21 (m, 1H), 1.74 (m, 1H), 1.63 - 1.36 (m, 4H), 1.33 - 1.18 (m, 2H), 1.13 - 1.02 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.2% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; | Step B: Preparation of 3 -cyclopentyl-3 -(3 -methyl-4-(7-f 4-morpholinophenyl) imidazor 1 ,2-c1pyrimidin-5 -yl)- 1 H-pyrazol- 1 -vDpropanenitrile : 4-(4-(5-(3-methyl-lH- pyrazol-4-yl)imidazo[l,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0690 g, 0.191 mmol), 3- cyclopentylacrylonitrile (Table 1, compound g; 0.0696 g, 0.574 mmol) and DBU 0.0661 mL, 0.479 mmol) were suspended in DMF (3 mL) and stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCC>3 and EtOAc. The organics were washed with brine, dried, MgS04 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5 - 2 percent (9:1, MeOH:NH4OH)/DCM) to furnish 3-cyclopentyl-3-(3-methyl-4-(7-(4-mophiholinophenyl) imidazo[l,2-c]pyrimidin-5-yl)-lH-pyrazol-l-yl)propanenitrile (0.0380 g, 0.078905 mmol, 41.2percent yield). MS (apci) m/z = 482.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.19% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; for 66h; | Step G: Preparation of 3-cvclopentyl-3-(4-(7-(4-(l-methylpiperidin-4- yl)phenyl)imidazo [ 1.2-clpyrimidin-5-yl)- 1 H-pyrazol- 1 -yDpropanenitrile : 7-(4-(l- Methylpiperidin-4-yl)phenyl)-5-(lH-pyrazol-4-yl)imidazo[l ,2-c]pyrimidine (0.130 g, 0.363 mmol) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (Table 1, compound g; 0.220 g, 1.81 mmol) were suspended in DMF (10 mL) and 2,3,4,6, 7,8, 9, 10-octahydropyrimido[l,2-a]azepine (0.2169 mL, 1.451 mmol) added in one portion. The reaction mixture was stirred at ambient temperature for 66 hours. The reaction mixture was partitioned between saturated aqueous 1 N NaOH and EtOAc. The organics were washed with brine, dried over MgS04 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 2 - 6 percent (9: 1 , MeOH:NH4OH) / DCM) to furnish 3- cyclopentyl-3-(4-(7-(4-(l -methylpiperidin-4-yl)phenyl)imidazo[ 1 ,2-c]pyrimidin-5-yl)-lH- pyrazol-l-yl)propanenitrile (0.096 g, 0.200 mmol, 55.19percent yield). MS (apci) m/z = 480.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.9% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; | Step E: Preparation of 3-cyclopentyl-3-(4-(7-(4-morpholinophenyl imidazor 1 ,2-c1pyrimidin-5 -yl)- 1 H-pyrazol- 1 -vDpropanenitrile : 4-(4-(5-(lH-Pyrazol-4- yl)imidazo[l,2-c]pyrimidin-7-yl)phenyl)morprioline (0.0300 g, 0.0866 mmol) and 3- cyclopentylacrylonitrile (Table 1 , compound g; 0.0175 g, 0.144 mmol) were suspended in DMF (3 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[l ,2-a]azepine (0.0324 mL, 0.217 mmol) added in one portion. The reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was partitioned between saturated aqueous 1 N NaOH and EtOAc. The solids were isolated by filtration. The organics were washed with brine, dried over MgS04 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5 - 3 percent (9: 1 , MeOH:NH4OH)/DCM) to provide 3-cyclopentyl-3-(4-(7-(4-morpholinophenyl)imidazo[l ,2- c]pyrimidin-5-yl)-lH-pyrazol-l-yl)propanenitrile (0.0190 g, 0.04064 mmol, 46.9percent yield). MS (apci) m/z = 468.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃; for 3h; | To a solution of 4-(lH-pyrazol-4-yl)pyrrolo[l,2-b]pyridazine-3-carboxamide 14c (30 mg, 0.13 mmol) in acetonitrile was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (0.33 mol), DBU (0.020 mL, 0.13 mmol) and heated at 50 °C for 3 h. The reaction mixture was concentrated in vacuum and the residue obtained was purified by flash column chromatography [silica gel 4g, eluting with hexanes/10percent MeOH in ethyl acetate, 1 :0 to 1 : 1 , (Rf = 0.40 with hexanes/ethylacetate/methanol = 10:10:1)] to give 4-(l-(2-cyano-l-cyclopentylethyl)-lH-pyrazol-4- yl)pyrrolo[l,2-b]pyridazine-3-carboxamide 14d, (38 mg, 84percent) as a yellow film. 1H NMR (300 MHz, DMSO) delta 8.43 (bs, 1H), 8.15 (s, 1H), 7.97 - 7.92 (m, 2H), 7.75 (s, 1H), 7.58 (s, 1H), 6.95 (dd, J= 2.7, 4.4 Hz, 1H), 6.74 (dd, J= 1.5, 4.4 Hz, 1H), 4.55 (td, J= 4.5, 9.2, 1H), 3.26 - 3.10 (m, 2H), 2.47-2.30 (m, 1H), 1.87 - 1.72 (m, 1H), 1.67 - 1.24 (m, 7H); MS (ES+): 371.1 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 50℃; for 3h; | To a solution of 4-(lH-pyrazol-4-yl)pynOlo[l,2-b]pyridazine-3-carbonitrile 16a (60 mg, 0.287 mmol) in DMF (1.5 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (109 mg, 0.717 mmol), 2,3,4,6,7,8,9, 10-octahydropyrimido[l,2-a]azepine (0.270 mL, 1.772 mmol) and heated with stirring at 50 °C for 3 h. The reaction mixture was cooled to RT and concentrated in vacuum to dryness. The residue obtained was purified by combiflash column chromatography [silica gel, 4 g eluting with hexanes/ethyl acetate (1 :0 to 2:1)] to give 4-(l-(2-cyano-l-cyclopentylethyl)-lH- pyrazol-4-yl)pyrrolo[l,2-b]pyridazine-3-carbonitrile 16b (56 mg, 59percent, Rf = 0.42 with hexanes/ethyl acetate = 2:1) as a yellow solid; 1H NMR (300 MHz, OMSO-d6) delta 8.80 (d, J= 0.6 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 8.19 (t, J= 2.1 Hz, 1H), 7.13 (d, J= 2.0 Hz, 2H), 4.64 (td, J = 9.0, 4.8 Hz, 1H), 3.29 - 3.21 (m, 2H), 2.48 - 2.37 (m, 1H), 1.91 - 1.11 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 mg; 40 mg | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 72h; | To a stirred solution of 4,5, 10,12-tetraazatetracyclo[6.6.1. O^.O11,15]pentadeca- l(15),2,5,8,l l,13-hexaen-7-one (0.15 g, 0.71mmol) in DMSO (2 mL) was added 3- cyclopentylacrylonitrile (0.09 g, 0.71 mmol), K2C03 (15 mg, 0.15 equiv). The reaction mixture was stirred at room temperature for 3 days. When TLC showed completion of reaction, water was added. The mixture was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2S04, and concentrated under vacuum. [0255] The resulting residue was purified by prep-TLC, eluting with Hexanes: EtOAc (10: 1) to give 80 mg of 3-cyclopentyl-3-{7-oxo-4,5,10,12- tetraazatetracyclo[6.6.1.02'6.0u'15]pentadeca-l(15),2,5,8,l l,13-hexaen-4-yl}propanenitrile, [M+H] found 332; and 40 mg of 3-cyclopentyl-3-{7-oxo-4,5,10,12- tetraazatetracyclo[6.6.1.02'6.0n'15]pentadeca-l(15),2(6),3,8,l l,13-hexaen-5- yl}propanenitrile, [M+H] found 332. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10%; 4% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 20℃; for 48h; | To a stirred solution of Compound 7c (0.21 g, 1.0 mmol) in DMSO (8 mL) was added 3-cyclopentylprop-2-enenitrile (0.24 g, 2.0 mmol) and DBU (15 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 48 hours. 10 mL of water was added. The mixture was extracted with ethyl acetate (6 X 100 mL), and the combined organic extracts were washed with brine, dried by Na2S04, filtered, and concentrated under vacuum at below 50 °C. The crude product was purified by flash chromatography (3percent Methanol/DCM) to give 33 mg of Compound 7 (Yield: 10percent>) and 14 mg of Compound 8 (Yield: 4percent) as light yellow solids. [M+H] found 318.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.2% | Under nitrogen, a suspension of (cyanomethyl)triphenylphosphanium bromide (12 g, 31.49 mmol) in anhydrous THF (100 mL) was cooled to 0° C., a solution of 2.5 M n-BuLi in n-hexane (13 mL, 34.64 mmol) was added dropwise. The mixture was stirred at 0° C. for another 30 minutes, then cyclopentane-carbaldehyde (3.1 g, 31.49 mmol) was added, and the mixture was warmed to the room temperature and stirred for further 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (60 mL×3) and saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate. The mixture was filtrated, the filtrate was concentrated in vacuum, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give colorless oil 3-b (1.0 g, yield: 26.2percent). LC-MS (ESI): m/z=122 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of -4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (15.0 g,0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers),followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN wasevaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layerwas back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradientof ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several timesto remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product.The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors;however, the final product stemming from the second peak to elute from the preparative-HPLC was more active thanits enantiomer.1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H),3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), -0.06(s, 9H); MS(ES):437 (M+1). | ||
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | (3R)- and (3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile[0112] To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cisand trans isomers), followed by DBU (15 mL, 0.10 mol).The resulting mixture was stirred at room temperatureovernight. The ACN was evaporated. The mixture wasdiluted with ethyl acetate, and the solution was washedwith 1.0 N HCl. The aqueous layer was back-extractedwith three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude product waspurified by silica gel chromatography (gradient of ethylacetate/hexanes) to yield a viscous clear syrup, whichwas dissolved in ethanol and evaporated several timesto remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H, 15percent ethanol/hexanes) and usedseparately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were foundto be active JAK inhibitors; however, the final productstemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer.1H NMR (300 MHz, CDCl3): delta8.85 (s, 1H), 8.32 (s, 2H),7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54(t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H),2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), -0.06(s, 9H); MS(ES):437 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | To a solution of 4-(1H-pyrazol- 4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The aqueous layer was back-extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93percent). The enantiomers were separated by preparative-HPLC, (OD-H column, 15percent ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. The products may be isolated by preparative HPLC or other means known to those of skill in the art for use in Step 3 below. 1H NMR (300 MHz, CDCl3): delta 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03- 1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H),?0.06 (s, 9H); MS(ES): 437 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 65℃; | 0.15g of compound 3 and 0.14g of compound 5a were dissolved in 30mL acetonitrile. To the above solution, 0.10g of 1,8-diazabicyclo undec-7-ene was added and reacted at 65°C for 5-6 days. After distilling off the solvent, it was dissolved in ethyl acetate then water and aqueous citric acid solution was added. 100mL saturated sodium chloride solution was washed 3 times each. The organic phase was dried over anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by column chromatography (methylene chloride/methanol 80:1) to give 0.10g of intermediate 6a as a yellow solid, yield: 37percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 65℃; for 48h; | 3.0g of compound 9 and 2.9g of compound 5a were dissolved in 150mL acetonitrile. To the above solution, 0.10g of 1,8-diazabicyclo undec-7-ene was added and reacted at 65°C for 2 days. TLC was used to determine reaction completion. After distilling off the solvent, it was dissolved in ethyl acetate then water and aqueous citric acid solution was added. 100mL saturated sodium chloride solution was washed 3 times each. The organic phase was dried over anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by column chromatography (methylene chloride/methanol 80:1) to give 2.4g of intermediate 10a as a white solid, yield: 48percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | Compound 17 (190mg, 0.7mmol) and Compound 2 (169mg, 1.4mmol) placed in 50mL single-neck flask under nitrogen, a solution of DBU (425mg, 2.8mmol) at room temperature and mix well. Then heated to 80 , reaction 8h. After completion of the reaction, the solvent spin dry column chromatography (ethyl acetate: petroleum ether = 5: 1) to give a colorless oil 60mg, 17percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | Compound 2 (250mg, 2.1mmol) and the compound 10 (400mg, 2.1mmol) placed in 50mL single-neck flask under nitrogen, a solution of DBU at room temperature (1g, 4.2mmol), stir. Then heated to 80 , reaction 8h. After completion of the reaction, the solvent spin dry column chromatography (ethyl acetate: petroleum ether = 5: 1) to give a white solid 250mg, 36percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 72h; | To a solution of 4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin -4-yl)-1H-pyrazol-3-formamide (79 mg, 0.22 mmol, 1.0 eq.) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (67 mg, 0.55 mmol, 2.5 eq., prepared from the step A of Example 1) in acetonitrile was added 1,8-diazabicyclo[5.4.0]undec-7-ene (70 mg, 0.46 mmol, 2.1 eq.) at room temperature. The reaction liquid was stirred for 3 days at room temperature, diluted with brine and ethyl acetate, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give the titled compound (76 mg, 72percent yield). 1H NMR (CDCl3) delta 10.93 (1H, s), 8.90 (1H, s), 8.29 (1H, s), 7.47 (1H, d, J = 3.6 Hz), 6.78 (1H, d, J = 3.6 Hz), 5.93 (1H, s), 5.71 (2H, s), 4.40-4.45 (1H, m), 3.58 (2H, t, J = 8.4 Hz), 3.17 (1H, dd, J = 17.2 Hz, 7.2 Hz), 3.06 (1H, dd, J = 17.2 Hz, 3.6 Hz), 2.75-2.82 (1H, m), 2.01-2.06 (1H, m), 1.54-1.82 (4H, m), 1.32-1.36 (3H, m), 0.95 (2H, t, J = 8.4 Hz), -0.02 (9H, s). m/z=480[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 60℃; | To a solution of ethyl 4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-3-formate (173 mg, 0.446 mmol, 1.0 eq.) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (135 mg, 1.11 mmol, 2.5 eq., prepared from the step A of Example 1) in acetonitrile (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (142 mg, 0.94 mmol, 2.1 eq.) at room temperature. The reaction liquid was stirred overnight at room temperature, then heated to 60°C and reacted for 5 hrs. After the mixture was cooled to room temperature, the mixture was diluted with brine and ethyl acetate, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give the titled compound (79 mg, 35percent yield), as a off-white solid. 1H NMR (CDCl3) delta 8.88 (1H, s), 7.98 (1H, s), 7.32 (1H, d, J = 3.6 Hz), 6.46 (1H, d, J = 3.6 Hz), 5.65 (2H, s), 4.27-4.35 (1H, m), 4.23 (2H, q, J = 7.2 Hz), 3.53 (2H, t, J = 8.4 Hz), 3.11 (1H, dd, J = 17.2 Hz, 7.6 Hz), 2.97 (1H, dd, J = 17.2 Hz, 4.0 Hz), 2.58-2.69 (1H, m), 1.88-1.99 (1H, m), 1.51-1.74 (4H, m), 1.22-1.30 (3H, m), 1.08 (3H, t, J = 7.2 Hz), 0.90 (2H, t, J = 8.4 Hz), -0.05 (9H, s). m/z=509[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 60℃; | To a solution of [4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-3-yl]methanol (40 mg, 0.12 mmol, 1.0 eq.) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (35 mg, 0.29 mmol, 2.5 eq., prepared from the step A of Example 1) in acetonitrile was added 1,8-diazabicyclo[5.4.0]undec-7-ene (35 mg, 0.23 mmol, 2.0 eq.) at room temperature. The reaction liquid was stirred for 5 hrs at room temperature, then warmed to 60°C and stirred overnight. After the reaction liquid was cooled to room temperature, the reaction liquid was diluted with brine and ethyl acetate, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give the titled compound (13 mg, 24percent yield). 1H NMR (CDCl3) delta 8.86 (1H, s), 8.24 (1H, s), 7.42 (1H, d, J = 3.6 Hz), 7.10-7.19 (1H, brs), 6.77 (1H, d, J = 3.6 Hz), 5.69 (2H, s), 4.80 (2H, s), 4.20-4.28 (1H, m), 3.55 (2H, t, J = 8.4 Hz), 3.11 (1H, dd, J = 17.2 Hz, 8.0 Hz), 2.95 (1H, dd, J = 17.2 Hz, 4.0 Hz), 2.61-2.69 (1H, m), 1.93-2.02 (1H, m), 1.58-1.79 (4H, m), 1.28-1.33 (3H, m), 0.93 (2H, t, J = 8.4 Hz), -0.05 (9H, s). m/z=467[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 5h; | To a solution of 4-[3-(fluoromethyl)-1H-pyrazol-4-yl)-7-[2-(trimethylsilyl) ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq.) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (2.5 eq., prepared from the step A of Example 1) in acetonitrile was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.0 eq.) at room temperature. The reaction liquid was stirred for 5 hrs at room temperature, then warmed to 60°C and stirred overnight. After the reaction liquid was cooled to room temperature, the reaction liquid was diluted with brine and ethyl acetate, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give the titled compound. m/z=469[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 60℃; | To a solution of 4-[3-(difluoromethyl)-1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq.) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (2.5 eq., prepared from the step A of Example 1) in acetonitrile was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.0 eq.) at room temperature. The reaction liquid was stirred for 5 hrs at room temperature, then warmed to 60°C and stirred overnight. After the reaction liquid was cooled to room temperature, the reaction liquid was diluted with brine and ethyl acetate, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give the titled compound. m/z=487[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59%; 21% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 70℃;Inert atmosphere; | 3-[5-amino-4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopentylpropanenitrile To a solution of 4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin -4-yl)-3-amino-1H-pyrazole (5.6 g, 16.95 mmol, 1.0 eq.) in acetonitrile was added <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (5.176 g, 42.71 mmol, 2.52 eq.) under stirring at room temperature, and then DBU (5.42 g, 35.60 mmol, 2.1 eq.) was added. The reaction liquid was protected with nitrogen gas and stirred overnight at 70°C. After the reaction liquid was cooled to room temperature, the reaction was quenched by adding water, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give 3-[3-amino-4-(7-[2-(trimethylsilyl) ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopentylpropanenitrile (4.49 g, 59percent yield) and 3-[5-amino-4-(7-[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] -3-cyclopentylpropanenitrile (1.60 g, 21percent yield). G1: 1HNMR (400MHz, CDCl3) delta 8.79 (s, 1H), 8.01 (s, 1H), 7.34 (d, J =3.6 Hz, 1H), 6.68 (d, J =3.6 Hz, 1H), 5.66 (brs, 4H), 4.00 (t, J =2.0 Hz, 1H), 3.53 (t, J =8 Hz, 2H), 3.08 (dd, J =16.8 Hz, J =8.4 Hz, 1H), 2.89 (dd, J =16.8 Hz, J =3.6 Hz, 1H), 2.53 (s, 1H), 1.95-1.93 (m, 1H), 1.74-1.57 (m, 5H), 1.28-1.22 (m, 2H), 0.92 (dd, J =14 Hz, J =8.4 Hz, 2H), 0.00 (s, 9H). m/z=452[M+1]+. G2: 1HNMR (400MHz, CDCl3) delta 8.74 (s, 1H), 8.13 (s, 1H), 7.33 (d, J =3.6 Hz, 1H), 6.80 (d, J =3.6 Hz, 1H), 6.12 (brs, 2H), 5.30 (s, 2H), 4.12-4.07 (m, 1H), 3.53 (t, J =8.4 Hz, 2H), 3.14 (dd, J =16.8 Hz, J =9.6 Hz, 1H), 2.90 (dd, J =16.8 Hz, J =4.0 Hz, 1H), 2.60-2.57 (m, 1H), 1.94-1.91 (m, 1H), 1.74-1.54 (m, 5H), 1.34-1.22 (m, 2H), 0.92 (t, J =8.0 Hz, 2H), 0.00 (s, 9H). m/z=452[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 60℃; | To a solution of N-methyl-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-yl]methylamine (1.0 eq.) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (2.5 eq., prepared from the step A of Example 1) in acetonitrile was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.0 eq.) at room temperature. The reaction liquid was stirred for 5 hrs at room temperature, then warmed to 60°C and stirred overnight. After the reaction liquid was cooled to room temperature, the reaction liquid was diluted with brine and ethyl acetate, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was separated by column chromatography on silica gel column to give the titled compound. m/z=480[M+1]+. |
Tags: 591769-05-0 synthesis path| 591769-05-0 SDS| 591769-05-0 COA| 591769-05-0 purity| 591769-05-0 application| 591769-05-0 NMR| 591769-05-0 COA| 591769-05-0 structure
[ 1146629-77-7 ]
(4-(1H-Pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate
[ 4354-73-8 ]
2-Cyclohexylidenemalononitrile
Similarity: 0.58
[ 95-12-5 ]
Bicyclo[2.2.1]hept-5-en-2-ylmethanol
Similarity: 0.54
[ 15760-35-7 ]
3-Methylenecyclobutanecarbonitrile
Similarity: 0.52
[ 7785-70-8 ]
(1R,5R)-2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene
Similarity: 0.52
[ 4354-73-8 ]
2-Cyclohexylidenemalononitrile
Similarity: 0.58
[ 95-12-5 ]
Bicyclo[2.2.1]hept-5-en-2-ylmethanol
Similarity: 0.54
[ 15760-35-7 ]
3-Methylenecyclobutanecarbonitrile
Similarity: 0.52
[ 7785-70-8 ]
(1R,5R)-2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene
Similarity: 0.52
[ 94412-40-5 ]
4'-(trans-4-propylcyclohexyl)-[1,1'-biphenyl]-4-carbonitrile
Similarity: 0.58
[ 4354-73-8 ]
2-Cyclohexylidenemalononitrile
Similarity: 0.58
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 |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :