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CAS No. : | 1314910-43-4 | MDL No. : | MFCD19227479 |
Formula : | C5H7ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XELKWDFNWRGTLX-UHFFFAOYSA-N |
M.W : | 130.58 | Pubchem ID : | 55300440 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.99 |
TPSA : | 35.82 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) : | -7.23 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -0.19 |
Log Po/w (WLOGP) : | 0.46 |
Log Po/w (MLOGP) : | -0.04 |
Log Po/w (SILICOS-IT) : | 0.9 |
Consensus Log Po/w : | 0.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.53 |
Solubility : | 38.5 mg/ml ; 0.295 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.11 |
Solubility : | 102.0 mg/ml ; 0.783 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.79 |
Solubility : | 21.3 mg/ml ; 0.163 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
98.59% | Stage #1: With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 10℃; for 0.166667 h; Stage #2: at 0 - 25℃; for 16 h; |
N,N-Diisopropylethylamine (4.5 mL) was added into a reaction vessel containing acetonitrile (50 mL) and 3-(cyanomethylene)azetidine hydrochloride (1.5 g; Formula VII) at about 0°C to about 10°C. The reaction mixture was stirred for about 10 minutes. Ethanesulfonyl chloride (2.22 g) was added into the reaction mixture at about 0°C to about 5°C over about 5 minutes. The temperature of the reaction mixture was raised to about 20°C to about 25 °C, and then the reaction mixture was stirred for about 16 hours. On completion of the reaction, acetonitrile was recovered from the reaction mixture under reduced pressure at about 40°C to about 45°C to obtain an oily residue. Dichloromethane (50 mL) was added into the residue. The contents were washed with a saturated sodium chloride solution (30 mL), followed by complete recovery of dichloromethane under reduced pressure at about 40°C to obtain 2-(l-(ethylsulfonyl)azetidin-3- ylidene)acetonitrile . Yield: 98.59percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In 1,4-dioxane for 2.5 h; Inert atmosphere; Cooling with ice | General procedure: Compound 1d (1.0 g, 5.15 mmol) and a 4M solution of HCI in dioxane (10 mL) were added to a 50 mL reaction flask, argon atmosphere protection was applied, and the reaction was stirred in an ice bath for 2.5 h, while white solid gradually precipitated. The reaction was monitored by thin layer chromatography. After the reaction was complete, the reaction solution was filtered with suction, and the filter cake was washed with anhydrous ether and dried, to afford 2-(azetidin-3-ylidene) acetonitrile hydrochloride salt (1e) (600 mg, yield: 90.0percent, white solid), which was used directly in the next reaction. |
75% | With hydrogenchloride In methanol; waterReflux | Aqueous hydrochloric acid (6N, 10 mL) and montmorillonite K-10 (2 g) were added into a reaction vessel at ambient temperature. The contents were stirred for 1 hour, and then filtered under reduced pressure to obtain activated montmorillonite K-10. The activated montmorillonite K-10 was added into another reaction vessel containing tert- butyl 3-(cyanomethylidene)azetidine-l-carboxylate (2 g; Formula VI) and methanol (20 mL) at ambient temperature. The reaction mixture was refluxed for about 12 hours to about 15 hours. On completion, the reaction mixture was filtered under reduced pressure followed by recovery of methanol under reduced pressure at about 40°C to about 45°C to obtain 3-(cyanomethylene)azetidine hydrochloride. Yield: 75percent |
67.8% | With hydrogenchloride In isopropyl alcohol at 20℃; for 18 h; Inert atmosphere | 2-(Azetidin-3-ylidene)acetonitrile hydrochloride (2a) [0145] To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 30 g, 154.46 mmol) and methylenechloride (300 mL) at ambient temperature. The solution was then treated with a solution of 5 M hydrogen chloride (HCl) in isopropanol solution (294.2 mL, 1.54 mol, 10 equiv) at ambient temperature and the resulting reaction mixture was stirred at ambient temperature for 18 hours. After the reaction was complete as monitored by HPLC, the suspension was added tert-butyl methyl ether (TBME, 150 mL), and the mixture was stirred at ambient temperature for 2 hours. The solids was collected by filtration, washed with n-heptane (2×100 mL), and dried on the filtration funnel at ambient temperature for 3 hours to afford 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 13.7 g, 20.2 g theoretical, 67.8percent) as a white solid. For 2a: 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 2H), 5.94 (p, J=2.5 Hz, 1H), 4.85-4.80 (m, 2H), 4.77-4.71 (m, 2H) ppm; 13C NMR (126 MHz, DMSO-d6) δ 155.65, 114.54, 94.78, 55.26, 54.63 ppm; C5H7ClN2 (MW 130.58; C5H6N2 for free base, MW 94.11), LCMS (EI) m/e 95 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.59% | N,N-Diisopropylethylamine (4.5 mL) was added into a reaction vessel containing acetonitrile (50 mL) and <strong>[1314910-43-4]3-(cyanomethylene)azetidine hydrochloride</strong> (1.5 g; Formula VII) at about 0C to about 10C. The reaction mixture was stirred for about 10 minutes. Ethanesulfonyl chloride (2.22 g) was added into the reaction mixture at about 0C to about 5C over about 5 minutes. The temperature of the reaction mixture was raised to about 20C to about 25 C, and then the reaction mixture was stirred for about 16 hours. On completion of the reaction, acetonitrile was recovered from the reaction mixture under reduced pressure at about 40C to about 45C to obtain an oily residue. Dichloromethane (50 mL) was added into the residue. The contents were washed with a saturated sodium chloride solution (30 mL), followed by complete recovery of dichloromethane under reduced pressure at about 40C to obtain 2-(l-(ethylsulfonyl)azetidin-3- ylidene)acetonitrile . Yield: 98.59% | |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃;Product distribution / selectivity; | A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5 C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5 C. The resulting homogeneous solution was allowed to cool down to 0 C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5 C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45 C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45 C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60 % ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) delta 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H). | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; for 7h; | Intermediate No.33Step A-B. ll-(Ethylsulfonv0azetidin-3-ylidenelacetonitriletert-Butyl 3-(cyanomethylidene)azetidine-l-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HC1 in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to -10 C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrousNa2S04, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtO Ac/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C7H10N2O2S [M+H]+: 187, Found: 187. |
Dissolving raw material CF0726Y (0.4 g, 0.0021 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spinning solvent dry after raw material disappears, adding THF (10 mE) to dissolve it, then dropwise adding DIPEA (0.8 g, 6.18 mmol, 3 eq), stirring for 10 mi dropwise adding ethylsulfonyl chloride (0.32 g, 0.0025 mol, 1.2 eq), performing room-temperature stirring and ECMS tracking, spinning it dry after the reaction, using EAH20 for extraction, washing it once with NaHCO3 and washing with saturated saline solution, spuming it dry to obtain 0.3 g of yellow oily crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; | tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 82 g, 0.42 mol) was added to THF (850 mL) and the resulting solution was cooled to 0 C. before a 4 M HCl solution in 1,4-dioxane (850 mL, 3.38 mol, 8.0 equiv) was added over 1 h while keeping the temperature<5 C. The resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was placed under high vacuum for an additional 3 h before being treated with THF (900 mL) and diisopropylethyl amine (183 mL, 1.06 mol, 2.5 equiv) at room temperature. The resulting solution was then cooled to 0 C. and ethanesulfonyl chloride (56 mL, 0.59 mol, 1.4 equiv) was added while keeping the reaction temperature<5 C. The ice bath was removed and the reaction was stirred at room temperature for 18 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with ethyl acetate (1 L) and washed with saturated brine (1 L). The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was diluted with dichloromethane and absorbed onto silica gel (150 g). This mixture was purified by column chromatography (1.5 Kg silica gel) eluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8L), 30% EtOAc in heptane (12 L), and finally with 40% EtOAc in heptane (12 L) to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4) and 2-(3-chloro-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (4B) as a off-white solid (58.1 g, 68% yield), which was found to be an approximately one to one mixture of compound 4 and 4B. For 4: 1H NMR (300 MHz, CDCl3) delta 1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05; found: 187.1. For 4B: 1H NMR (300 MHz, CDCl3) delta 1.38 (t, 3H), 3.05 (q, 2H), 3.1 (s, 2H), 4.15 (d, 2H), 4.37 (d, 2H); MS: m/z calcd. 222.9; found: 222.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In 1,4-dioxane; for 2.5h;Inert atmosphere; Cooling with ice; | General procedure: Compound 1d (1.0 g, 5.15 mmol) and a 4M solution of HCI in dioxane (10 mL) were added to a 50 mL reaction flask, argon atmosphere protection was applied, and the reaction was stirred in an ice bath for 2.5 h, while white solid gradually precipitated. The reaction was monitored by thin layer chromatography. After the reaction was complete, the reaction solution was filtered with suction, and the filter cake was washed with anhydrous ether and dried, to afford 2-(azetidin-3-ylidene) acetonitrile hydrochloride salt (1e) (600 mg, yield: 90.0%, white solid), which was used directly in the next reaction. |
89% | With hydrogenchloride; In dichloromethane; isopropyl alcohol; at 20℃; for 4h; | To a solution of tert-butyl 3-(cyanomethylene) azetidine-1-carboxylate (150.0 g, 772 mmol) in dichloromethane (1.48 L) was added a 5.25 M solution of HCl in isopropyl alcohol (1.47 L, 7723 mmol) with an addition funnel. After the reaction mixture was stirred at room temperature for 4 h, heptane (3.0 L) was added. The mixture was stirred for 1 hour, filtered and dried by pulling air through the resulting cake to give 89.5 g of the title compound (yield: 89%, white solid). 1H NMR (400 MHz, DMSO) delta 9.96 (s, 2H), 6.25-5.66 (m, 1H), 5.13-4.47 (m, 4H). |
75% | With hydrogenchloride; In methanol; water;Reflux; | Aqueous hydrochloric acid (6N, 10 mL) and montmorillonite K-10 (2 g) were added into a reaction vessel at ambient temperature. The contents were stirred for 1 hour, and then filtered under reduced pressure to obtain activated montmorillonite K-10. The activated montmorillonite K-10 was added into another reaction vessel containing tert- butyl 3-(cyanomethylidene)azetidine-l-carboxylate (2 g; Formula VI) and methanol (20 mL) at ambient temperature. The reaction mixture was refluxed for about 12 hours to about 15 hours. On completion, the reaction mixture was filtered under reduced pressure followed by recovery of methanol under reduced pressure at about 40C to about 45C to obtain 3-(cyanomethylene)azetidine hydrochloride. Yield: 75% |
67.8% | With hydrogenchloride; In isopropyl alcohol; at 20℃; for 18h;Inert atmosphere; | 2-(Azetidin-3-ylidene)acetonitrile hydrochloride (2a) [0145] To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 30 g, 154.46 mmol) and methylenechloride (300 mL) at ambient temperature. The solution was then treated with a solution of 5 M hydrogen chloride (HCl) in isopropanol solution (294.2 mL, 1.54 mol, 10 equiv) at ambient temperature and the resulting reaction mixture was stirred at ambient temperature for 18 hours. After the reaction was complete as monitored by HPLC, the suspension was added tert-butyl methyl ether (TBME, 150 mL), and the mixture was stirred at ambient temperature for 2 hours. The solids was collected by filtration, washed with n-heptane (2×100 mL), and dried on the filtration funnel at ambient temperature for 3 hours to afford 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 13.7 g, 20.2 g theoretical, 67.8%) as a white solid. For 2a: 1H NMR (500 MHz, DMSO-d6) delta 9.99 (s, 2H), 5.94 (p, J=2.5 Hz, 1H), 4.85-4.80 (m, 2H), 4.77-4.71 (m, 2H) ppm; 13C NMR (126 MHz, DMSO-d6) delta 155.65, 114.54, 94.78, 55.26, 54.63 ppm; C5H7ClN2 (MW 130.58; C5H6N2 for free base, MW 94.11), LCMS (EI) m/e 95 (M++H). |
67.8% | With hydrogenchloride; In dichloromethane; water; isopropyl alcohol; at 20℃; for 18h; | 2-(Azetidin-3-ylidene)acetonitrile hydrochloride (2a) To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 30 g, 154.46 mmol) and methylenechloride (300 mL) at ambient temperature. The solution was then treated with a solution of 5 M hydrogen chloride (HCl) in isopropanol solution (294.2 mL, 1.54 mol, 10 equiv) at ambient temperature and the resulting reaction mixture was stirred at ambient temperature for 18 hours. After the reaction was complete as monitored by HPLC, the suspension was added tert-butyl methyl ether (TBME, 150 mL), and the mixture was stirred at ambient temperature for 2 hours. The solids was collected by filtration, washed with n-heptane (2*100 mL), and dried on the filtration funnel at ambient temperature for 3 hours to afford 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 13.7 g, 20.2 g theoretical, 67.8%) as a white solid. For 2a: 1H NMR (500 MHz, DMSO-d6) delta 9.99 (s, 2H), 5.94 (p, J=2.5 Hz, 1H), 4.85-4.80 (m, 2H), 4.77-4.71 (m, 2H) ppm; 13C NMR (126 MHz, DMSO-d6) delta 155.65, 114.54, 94.78, 55.26, 54.63 ppm; C5H7ClN2 (MW 130.58; C5H6N2 for free base, MW 94.11), LCMS (EI) m/e 95 (M++H). |
With hydrogenchloride; water; In acetonitrile; at 20℃; for 18h;Product distribution / selectivity; | A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5 C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5 C. The resulting homogeneous solution was allowed to cool down to 0 C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5 C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45 C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45 C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60 % ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) delta 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H). | |
With hydrogenchloride; In 1,4-dioxane; at 15 - 25℃; for 16h; | Intermediate No.33Step A-B. ll-(Ethylsulfonv0azetidin-3-ylidenelacetonitriletert-Butyl 3-(cyanomethylidene)azetidine-l-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HC1 in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to -10 C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrousNa2S04, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtO Ac/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C7H10N2O2S [M+H]+: 187, Found: 187. | |
With hydrogenchloride; In 1,4-dioxane; | Dissolving raw material CF0726Y (0.4 g, 0.0021 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spinning solvent dry after raw material disappears, adding THF (10 mE) to dissolve it, then dropwise adding DIPEA (0.8 g, 6.18 mmol, 3 eq), stirring for 10 mi dropwise adding ethylsulfonyl chloride (0.32 g, 0.0025 mol, 1.2 eq), performing room-temperature stirring and ECMS tracking, spinning it dry after the reaction, using EAH20 for extraction, washing it once with NaHCO3 and washing with saturated saline solution, spuming it dry to obtain 0.3 g of yellow oily crude product. Dissolving raw material CF0726Y (0.5 g, 0.0026 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spinning solvent dry after raw material disappears, adding THF (10 mE) to dissolve it, then dropwise adding DIPEA (1.0 g, 7.75 mmol, 3 eq), stirring for 10 mi dropwise adding N,N-dimethylsulfamoyl chloride (0.4 g, 0.0028 mol, 1.1 eq), performing room-temperature stirring and ECMS tracking, spinning it dry after the reaction, using EAH20 for extraction, washing it once with NaHCO3 and washing with saturated saline solution, spinning it dry to obtain 0.55 g of yellow oily crude product. Dissolving CF0726Y (0.5 g, 0.0026 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spuming solvent dry afier raw material disappears, adding DCM (10 mE) to dissolve it, and then adding TEA (1.51 g, 14.9 mmol, 5.8 eq), stirring for 10 mm, adding EDCI (0.62 g, 3.2 mmol,1.25 eq), HOST (0.43 g, 3.2 mmol, 1.25 eq), stirring for 15 mm and then adding N-Soc-E-proline (0.56 g, 2.6 mmol, 1.0 eq), performing room-temperature stirring overnight. Performing ECMS tracking, adding DCMJH2O for extraction afier the reaction, washing it with saturated NaHCO3 solution and spuming it dry to obtain brown oily substance (0.7g). Dissolving raw material CF0726Y (0.4 g, 0.002 1 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spinning solvent dry after raw material disappears, adding THF (10 mE) to dissolve it, then dropwise adding DIPEA (0.8 g, 6.18 mmol, 3 eq), stirring for 10 mi dropwise adding ethylsulfonyl chloride (0.32 g, 0.0025 mol, 1.2 eq), performing room-temperature stirring and ECMS tracking, spinning it dry afier the reaction, using EAH20 for extraction, washing it once with NaHCO3 and washing with saturated saline solution, spinning it dry to obtain 0.3 g of yellow oily crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrahydrofuran; 1,4-dioxane; at 0 - 20℃; | tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 82 g, 0.42 mol) was added to THF (850 mL) and the resulting solution was cooled to 0 C. before a 4 M HCl solution in 1,4-dioxane (850 mL, 3.38 mol, 8.0 equiv) was added over 1 h while keeping the temperature<5 C. The resulting reaction mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was placed under high vacuum for an additional 3 h before being treated with THF (900 mL) and diisopropylethyl amine (183 mL, 1.06 mol, 2.5 equiv) at room temperature. The resulting solution was then cooled to 0 C. and ethanesulfonyl chloride (56 mL, 0.59 mol, 1.4 equiv) was added while keeping the reaction temperature<5 C. The ice bath was removed and the reaction was stirred at room temperature for 18 h. When TLC indicated the reaction was complete, the reaction mixture was diluted with ethyl acetate (1 L) and washed with saturated brine (1 L). The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was diluted with dichloromethane and absorbed onto silica gel (150 g). This mixture was purified by column chromatography (1.5 Kg silica gel) eluting with heptane (4 L), 10% EtOAc in heptane (4 L), 20% EtOAc in heptane (8L), 30% EtOAc in heptane (12 L), and finally with 40% EtOAc in heptane (12 L) to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4) and 2-(3-chloro-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (4B) as a off-white solid (58.1 g, 68% yield), which was found to be an approximately one to one mixture of compound 4 and 4B. For 4: 1H NMR (300 MHz, CDCl3) delta 1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05; found: 187.1. For 4B: 1H NMR (300 MHz, CDCl3) delta 1.38 (t, 3H), 3.05 (q, 2H), 3.1 (s, 2H), 4.15 (d, 2H), 4.37 (d, 2H); MS: m/z calcd. 222.9; found: 222.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.8% | 2-(1-(1-(3-Fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10) [0146] To a 0.25-L flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added <strong>[1314910-43-4]2-(azetidin-3-ylidene)acetonitrile hydrochloride</strong> (2a, 4.5 g, 34.46 mmol), 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one (7, 10 g, 34.46 mmol, 1.0 equiv), and methylenechloride (100 mL) at ambient temperature and the resulting mixture was then treated with sodium triacetoxyborohydride (14.6 g, 68.93 mmol, 2.0 equiv) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours before being quenched with saturated sodium bicarbonate (NaHCO3) aqueous solution (50 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phase was washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to afford the crude desired product ( 10), which was purified by column chromatography (SiO2, O-10% of ethyl acetate in hexane gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 9.5 g, 12.7 g theoretical, 74.8%) as a white solid. For 10: 1H NMR (400 MHz, CDCl3) delta 8.57 (d, J=4.7 Hz, 1H), 7.54 (t, J=4.6 Hz, 1H), 5.29 (p, J=2.4 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-4.03 (m, 2H), 3.98-3.94 (m, 2H), 3.57-3.39 (m, 2H), 3.17-3.04 (m, 1H), 2.56 (tt, J=7.4, 3.5 Hz, 1H), 1.86-1.77 (m, 1H), 1.75-1.64 (m, 1H), 1.54-1.43 (m, 1H), 1.43-1.31 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3) delta 161.34, 160.73, 152.62 (d, J=269.1 Hz), 145.75 (d, J=6.1 Hz), 136.73 (qd, J=36.1, 12.0 Hz), 134.56 (d, J=16.9 Hz), 126.89, 120.58 (qd, J=275.0, 4.9 Hz), 115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm; C17H16F4N4O (MW 368.33), LCMS (EI) m/e 369 (M++H). | |
74.8% | 2-(1-(1-(3-Fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10) To a 0.25-L flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added <strong>[1314910-43-4]2-(azetidin-3-ylidene)acetonitrile hydrochloride</strong> (2a, 4.5 g, 34.46 mmol), 1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-one (7, 10 g, 34.46 mmol, 1.0 equiv), and methylenechloride (100 mL) at ambient temperature and the resulting mixture was then treated with sodium triacetoxyborohydride (14.6 g, 68.93 mmol, 2.0 equiv) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours before being quenched with saturated sodium bicarbonate (NaHCO3) aqueous solution (50 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phase was washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to afford the crude desired product (10), which was purified by column chromatography (SiO2, 0-10% of ethyl acetate in hexane gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 9.5 g, 12.7 g theoretical, 74.8%) as a white solid. For 10: 1H NMR (400 MHz, CDCl3) delta 8.57 (d, J=4.7 Hz, 1H), 7.54 (t, J=4.6 Hz, 1H), 5.29 (p, J=2.4 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-4.03 (m, 2H), 3.98-3.94 (m, 2H), 3.57-3.39 (m, 2H), 3.17-3.04 (m, 1H), 2.56 (tt, J=7.4, 3.5 Hz, 1H), 1.86-1.77 (m, 1H), 1.75-1.64 (m, 1H), 1.54-1.43 (m, 1H), 1.43-1.31 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3) delta 161.34, 160.73, 152.62 (d, J=269.1 Hz), 145.75 (d, J=6.1 Hz), 136.73 (qd, J=36.1, 12.0 Hz), 134.56 (d, J=16.9 Hz), 126.89, 120.58 (qd, J=275.0, 4.9 Hz), 115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm; C17H16F4N4O (MW 368.33), LCMS (EI) m/e 369 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dmap; triethylamine; In dichloromethane; for 1h;Cooling with ice; | Under cooling with an ice bath, compound 14e (300 mg, 2.31 mmol), dichloromethane (15 mL), triethylamine (1.6 mL, 11.55 mmol) and DMAP (5.7 mg, 0.05 mmol) were sequentially added to a 50 mL reaction flask, and after the reaction was stirred until homogeneous, a solution of dimethylsulfamoyl chloride (431 mg, 3.00 mmol) in dichloromethane (15 mL) was slowly added dropwise to the reaction system. After the addition, the reaction was stirred for 1 h, quenched with water, and extracted with dichloromethane. The organic phase was washed with water, a solution of citric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to afford 3-(cyanomethylene)-N,N-dimethylazetidine-1-sulfonamide (14f) (311 mg, yield: 67.0%, brown solid). MS (ESI, m/z): 201.1 [M+H]+. |
Dissolving raw material CF0726Y (0.5 g, 0.0026 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spinning solvent dry after raw material disappears, adding THF (10 mE) to dissolve it, then dropwise adding DIPEA (1.0 g, 7.75 mmol, 3 eq), stirring for 10 mi dropwise adding N,N-dimethylsulfamoyl chloride (0.4 g, 0.0028 mol, 1.1 eq), performing room-temperature stirring and ECMS tracking, spinning it dry after the reaction, using EAH20 for extraction, washing it once with NaHCO3 and washing with saturated saline solution, spinning it dry to obtain 0.55 g of yellow oily crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.7 g | Dissolving CF0726Y (0.5 g, 0.0026 mol) in dioxane solution (10 mE) of saturated hydrogen chloride, clearly dissolving it and separating white solid out, spuming solvent dry afier raw material disappears, adding DCM (10 mE) to dissolve it, and then adding TEA (1.51 g, 14.9 mmol, 5.8 eq), stirring for 10 mm, adding EDCI (0.62 g, 3.2 mmol,1.25 eq), HOST (0.43 g, 3.2 mmol, 1.25 eq), stirring for 15 mm and then adding N-Soc-E-proline (0.56 g, 2.6 mmol, 1.0 eq), performing room-temperature stirring overnight. Performing ECMS tracking, adding DCMJH2O for extraction afier the reaction, washing it with saturated NaHCO3 solution and spuming it dry to obtain brown oily substance (0.7g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With dmap; triethylamine; In dichloromethane; for 1h;Cooling with ice; | Under cooling with an ice bath, compound 15e (160 mg, 1.23 mmol), dichloromethane (8 mL), triethylamine (0.8 mL, 5.78 mmol) and DMAP (2.5 mg, 0.02 mmol) were sequentially added to a 50 mL reaction flask, and after the reaction was stirred until homogeneous, a solution of propionyl chloride (134 mg, 1.45 mmol) in dichloromethane (8 mL) was dropwise added slowly to the reaction system. After the addition, the reaction solution was stirred for 1 h, quenched with water, and extracted with dichloromethane. The organic phase was washed with water, a solution of citric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to afford 2-(1-propionylazetidin-3-ylidene)acetonitrile (15f) (116 mg, yield: 80.2%, yellow oil). MS (ESI, m/z): 150.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | With dmap; triethylamine; In dichloromethane; for 1h;Cooling with ice; | Under cooling with an ice bath, compound 16e (160 mg, 1.23 mmol), dichloromethane (8 mL), triethylamine (0.8 mL, 5.78 mmol) and DMAP (2.5 mg, 0.02 mmol) were sequentially added to a 50 mL reaction flask, and after the reaction was stirred until homogeneous, a solution of cyclopropanecarbonyl chloride (151 mg, 1.45 mmol) in dichloromethane (8 mL) was dropwise added slowly to the reaction system. After the addition, the reaction solution was stirred for 1 h, quenched with water, and extracted with dichloromethane. The organic phase was washed with water, a solution of citric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to afford 2-(1-(cyclopropanecarbonyl)azetidin-3-ylidene)acetonitrile (16f) (130 mg, yield: 83.2%, off-white solid). MS (ESI, m/z): 162.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.6% | With dmap; triethylamine; In dichloromethane; for 1h;Cooling with ice; | Under cooling with an ice bath, compound 37e (200 mg, 1.54 mmol), dichloromethane (10 mL), triethylamine (1.3 mL, 9.24 mmol) and DMAP (3.8 mg, 0.03 mmol) were added to a reaction flask, and after the reaction was stirred until homogeneous, a solution of propionylsulfonyl chloride (212 mg, 2.3 mmol) in dichloromethane (10 mL) was slowly added dropwise to the reaction system, and the reaction solution was stirred for 1 h. After the reaction was complete, the reaction was quenched with water, and extracted with dichloromethane. The organic phase was collected, washed with water, a solution of citric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, to afford 2-(1-propionylazetidin-3-ylidene)acetonitrile (37f) (140 mg, yield: 60.6%, brown solid). MS (ESI, m/z): 150.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | With dmap; triethylamine; In dichloromethane; for 1h; | Under cooling with an ice bath, compound 1e (200 mg, 1.54 mmol), dichloromethane (10 mL), triethylamine (1.3 mL, 9.24 mmol) and DMAP (3.8 mg, 0.03 mmol) were sequentially added to a 50 mL reaction flask, and after the reaction was stirred until homogeneous, a solution of <strong>[923032-55-7]1-methylcyclopropane-1-sulfonyl chloride</strong> (357 mg, 2.31 mmol) in dichloromethane (10 mL) was slowly dropwise added to the reaction system. After the addition, the reaction solution was stirred for 1 h, quenched with water, and extracted with dichloromethane. The organic phase was washed with water, a solution of citric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to afford 2-(1-((1-methylcyclopropyl)sulfonyl)azetidin-3-ylidene) acetonitrile (1f) (272 mg, yield: 83.4%, brown solid). MS (ESI, m/z): 213.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; for 5h;Cooling with ice; | In an ice-water bath, the white solid obtained in step 1 (30b) (500 mg) was added to dichloromethane (20mL), a solution of (3,3,3-trifluoropropane)sulfonyl chloride (1.126 g) and TEA (1.16 g) in DCM (15 mL) was added, and the reaction solution was stirred for 5 h. After the reaction was complete, the reaction was added with water (10 mL), and stirred for 10 min. The organic phase was separated, concentrated, and the residue was used directly in the next reaction. MS (ESI, m/z): 255 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium tetrahydroborate; In dichloromethane; at 0℃;Inert atmosphere; | 40 g (0.3 mol, 1.0 eq) of <strong>[1314910-43-4]2-(azetidin-3-ylidene)acetonitrile hydrochloride</strong> (prepared by reference to US2014/256941 A1 Paragraph 0145) and 61 g (0.3 mol, 1.0 eq), N-tert-butoxycarbonyl-4-piperidone was dissolved in 500 mL of dichloromethane, and the ice water bath was cooled to 0 C under nitrogen protection. 130 g (0.6 mol, 2.0 eq) of sodium borohydride hydride was slowly added in batches. After the addition, the reaction was kept in an ice bath, and the reaction was monitored by TLC. The reaction solution was slowly poured into water, and the aqueous phase was extracted with dichloromethane. The combined organic phases, the organic phase washed with water and saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, the residue was purified by column chromatography to give the product (40g, yield = 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In dichloromethane; at 20℃; | 300 mg (2.3 mmol, 1.0 eq) of <strong>[1314910-43-4]2-(azetidin-3-ylidene)acetonitrile hydrochloride</strong> and 700 mg (6.9 mmol, 3.0 eq) of triethylamine were dissolved in 20 mL of dichloromethane, 387 mg ( 2.7 mmol, 1.2 eq) benzoyl chloride was slowly added dropwise to the above reaction solution. The reaction system was allowed to stand at room temperature overnight. Quench the reaction with 30 mL of saturated aqueous sodium bicarbonate solution with dichloromethane the aqueous phase was extracted, and the organic phase was dried over anhydrous sodium sulfate and evaporated.The title compound (397 mg, yield = 87%) was obtained by column chromatography (PE: EA=2:1 to 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of tert-butyl alcohol (123 g, 1660 mmol) in dichloromethane (660 mL, 6V) was allowed to stir and cooled via a salt/ice bath. To this solution, sulfurisocyanatidic chloride (128 mL, 1468 mmol) dissolved in dichloromethane (660 mL, 6V) was added slowly via addition funnel, as the temperature of the solution was held from 1.2 C. to 5.5 C.). The solution was stirred for 1 h at 3 C., providing a solution of tert-butyl chlorosulfonylcarbamate. To a suspension of 2-(azetidin-3-ylidene) acetonitrile hydrochloride (Step 1, 166.7 g, 1277 mmol) in dichloromethane (1660 mL, 10V) was added triethylamine (445 mL, 3192 mmol). After stirring for 30 minutes, the reaction mixture was cooled down to 0 C. To this mixture was slowly added the prepared solution of tert-butyl chlorosulfonylcarbamate with an addition funnel, holding the temperature between 2 and 13 C. The reaction mixture was then stirred at 0 C. for 1 h. The reaction mixture was diluted with dichloromethane (300 mL). The reaction mixture was partitioned between dichloromethane and 0.2N HCl in water (3.55 L). The organics were dried over MgSO4 and concentrated to give the title compound (352 g, 101%). LC-MS calculated for C10H15N3O4S [M+H]+ m/z: 274.0; found 296.0 (M+Na). 1H NMR (400 MHz, CDCl3) delta 7.14 (s, 1H), 5.46 (s, 1H), 3.74 (s, 2H), 3.24 (s, 2H), 1.56 (s, 9H). |
Tags: 1314910-43-4 synthesis path| 1314910-43-4 SDS| 1314910-43-4 COA| 1314910-43-4 purity| 1314910-43-4 application| 1314910-43-4 NMR| 1314910-43-4 COA| 1314910-43-4 structure
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