* 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.
With copper(l) cyanide In 1-methyl-pyrrolidin-2-one at 195℃; for 1.5 h; Inert atmosphere
Example 123Exam le 123 a Methyl 2-Cyano-4-fluorobenzoate 123a123aA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 °C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under CGIPHARM60WO reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73percent yield (6.99 g) as a white solid: mp 92-93 °C; ]H NMR (500 MHz, CDC13) δ 8.18 (dd, 1H, / = 9.0, 5.5 Hz), 7.50 (dd, 1H, / = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Stage #1: for 1.25 h; Heating / reflux Stage #2: With sodium cyanide In DMF (N,N-dimethyl-formamide); water
(b) Methyl 2-cyano-4-fluorobenzoate; Methyl 2-bromo-4-fluorobenzoate (1.0 g, 4.29 mmol; see step (a) above) was dissolved in dry DMF (5 mL) and degassed with N2-gas for 5 minutes. CuCN (769 mg, 8.58 mmol) was added and mixture was degassed again before the temperature was raised. The reaction mixture was refluxed for 75 minutes. NaCN (aq, 10percent) was added and the mixture was extracted with DCM. The DCM phase was dried through a phase separator and the solvent was removed in vacuo. The crude product was dissolved in toluene and washed once with water. The organic phase was dried over MgS04 and filtered. The solvent was removed in vacuo to give the product (in 94percent yield), which was used without further purification. 'H NMR (500 MHz, CDC13) 5 4.01 (s, 3H), 7.35-7. 42 (m, 1H), 7.52 (dd, 1H), 8.15-8. 23 (m, 1H)
To a 250-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen, was added methyl2-bromo-4-fluorobenzoate 101 b (4 g, 17.16 mmol, 1.0 equiv.)andN';N-dimethylformamide (20 mL). Solid CuCN (2.3 g, 25.84 mmol, 1.5 equiv.) wasadded in several batches. The resulting mixture vvas stirred at l40°C overnight. Upon coolingto room temperature, the mixture '.vas quenched with water. The aqueous mixture was15 extracted with ethyl acetate (100 mL x 3), and the combined organic extracts were washedwith t-hO (50 mL x 2) and brine (80 mL x 2) Removal of solvents gave a residue which waspmitl.ed by silica gel column chromatography eluting with ethyl acetate/petroleum ether(lOpercent) to provide methyl2-cyano-4-t1uorobenzoate 101c (1.2g, 39percent) as a white solid
850 mg
at 120℃; for 1.5 h; Inert atmosphere
To a solution of methyl 2-bromo-4-fluorobenzoate (1.2 g, 5.15 mmol) in DMF (5 mL) was added cyanocopper (0.92 g, 10.3 mmol) under N2. The reaction was stirred at 120 °C for 1.5 h under N2. Then, the reaction was cooled to room temperature.10percent NaCN (10 mL) was added to the reaction. The mixture was extracted with DCM (3 x 30 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (3 x 50 mL) .The combined organic layers were dried over Na2SO4. After filtration, 850 mg of product was obtained as a white solid.
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 °C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73percent yield (6.99 g) as a white solid: mp 92-93 °C; ]H NMR (500 MHz, CDC13) δ 8.18 (dd, 1H, J = 9.0, 5.5 Hz), 7.50 (dd, 1H, J = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4613 - 4627
6
[ 1006-41-3 ]
[ 127510-96-7 ]
Reference：
[1] Patent: WO2018/39386, 2018, A1,
7
[ 127510-96-7 ]
[ 1260666-80-5 ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrogen In ethanol for 16 h; Inert atmosphere
A 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 106a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76percent yield of 106b (1.29 g) as a colorless oil: ]H NMR (500 MHz, CDC13) δ 7.85 (dd, 1H, / = 8.5, 5.5 Hz), 7.21- 7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H).
76%
With hydrogen; nickel In ethanol for 16 h; Inert atmosphere
Exam le 123b 5-Fluoroisoindolin-l-one 123bA 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 123a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76percent yield of 123b (1.29 g) as a colorless oil: ]H NMR (500 MHz, CDC13) δ 7.85 (dd, 1H, / = 8.5, 5.5 Hz), 7.21- 7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H).
1.2 g
With hydrogen In methanol
2-cyano-4-fluorophenyl-carboxylate (1.5g, 8.4mmoL) was dissolved with 30ml of methanol was added 1g of Raney-Ni catalyst, under hydrogen and stirred overnight.The reaction mixture was filtered, the filter cake with ethyl acetate (200ml) washed and the combined filtrate was concentrated to dryness to give the crude product.Flash column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the intermediate 18 (1.2g, white solid)
50 mg
With hydrogen In ethanol at 20℃; for 16 h;
To a solution of methyl 2-cyano-4-fluorobenzoate (850 mg, 4.74 mmol) in ethanol (30 mL) was added Raney Nickel (1 g). The reaction was stirred at ambient temperature for 16 h under H2 (50 psi). LCMS showed the desired product. After purification by silica gel chromatography eluted with DCM: MeOH= 150: 1→80: 1 to give the product 500 mg as white solid.
a) 2-Cyano-4-dimethylamino-benzoic acid methyl ester (9a) To a stirred solution of 4,03 g (22.5 mmol) <strong>[127510-96-7]2-Cyano-4-fluoro-benzoic acid methyl ester</strong> () and 60.0 ml dimethylsulphoxid are added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture is stirred for 9h at 60C in an autoclave and is concentrated with high vacuum rotation evaporator at 65C. The residue is diluted with dichloromethane, washed twice with water. The combined water phases are extracted with dichloromethane. The combined dichloromethane phases are washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude is purified by column chromatography and the desired product 9a is obtained in 85% yield (3,90 g, 19.1 mmol). MS-ESI: 205 (M+ +1, 81).
With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; for 9h;Autoclave;
Example 9a) 2-Cyano-4-dimethylamino-benzoic acid methyl ester (9a)To a stirred solution of 4,03 g (22.5 mmol) <strong>[127510-96-7]2-Cyano-4-fluoro-benzoic acid methyl ester</strong> (J. Med. Chem., 35; 24; (1992); 4613-4627) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 9h at 600C in an autoclave and was concentrated with high vacuum rotation evaporator at 65C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 9a was obtained in 85% yield (3,90 g, 19.1 mmol). <n="106"/>MS-ESI: 205 (M+ +1 , 81).Elementary analysis: C 64.69% H 5.92% N 13.72%Determined: C 64.72% H 5.95% N 13,70%
(b) Methyl 2-cyano-4-fluorobenzoate; Methyl 2-bromo-4-fluorobenzoate (1.0 g, 4.29 mmol; see step (a) above) was dissolved in dry DMF (5 mL) and degassed with N2-gas for 5 minutes. CuCN (769 mg, 8.58 mmol) was added and mixture was degassed again before the temperature was raised. The reaction mixture was refluxed for 75 minutes. NaCN (aq, 10%) was added and the mixture was extracted with DCM. The DCM phase was dried through a phase separator and the solvent was removed in vacuo. The crude product was dissolved in toluene and washed once with water. The organic phase was dried over MgS04 and filtered. The solvent was removed in vacuo to give the product (in 94% yield), which was used without further purification. 'H NMR (500 MHz, CDC13) 5 4.01 (s, 3H), 7.35-7. 42 (m, 1H), 7.52 (dd, 1H), 8.15-8. 23 (m, 1H)
(c) r2- (AminomethYl)-4-fluorophenyllmethanol; LiAlH4 (357 g, 9.41 mmol) was suspended in dry THF (5 mL) and the resulting mixture cooled with an ice bath. Methyl 2-cyano-4-fluoro- benzoate (562mg, 3.14 mmol; see step (b) above) was dissolved in THF (5+3 mL) and added to the reducing agent. The reaction mixture was stirred for 10 minutes and then the ice bath was removed. After 2 hours, the reaction was quenched with water (2 mL), NaOH (2 M, 2 mL) and more water (2 mL) and the resulting mixture was stirred for 10 minutes. The mixture was diluted with diethyl ether (30 mL) and filtered. The organic phase was dried over MgS04 and filtered. The solvent was removed in vacuo and the residue was then purified by Prep-HPLC, which provided the title compound inl6% yield. 1H NMR (500 MHz, CDC13) 8 4.25 (s, 2H), 4.74 (s, 2H), 7.14-7. 20 (m, 1H), 7. 28 (dd, 1H), 7.43-7. 48 (m, 1H)
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93 C; ]H NMR (500 MHz, CDC13) delta 8.18 (dd, 1H, J = 9.0, 5.5 Hz), 7.50 (dd, 1H, J = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
With hydrogen;Raney Nickel; In ethanol; under 2585.81 Torr; for 16h;Inert atmosphere;
A 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 106a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76% yield of 106b (1.29 g) as a colorless oil: ]H NMR (500 MHz, CDC13) delta 7.85 (dd, 1H, / = 8.5, 5.5 Hz), 7.21- 7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H).
76%
With hydrogen; nickel; In ethanol; under 2585.81 Torr; for 16h;Inert atmosphere;
Exam le 123b 5-Fluoroisoindolin-l-one 123bA 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 123a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76% yield of 123b (1.29 g) as a colorless oil: ]H NMR (500 MHz, CDC13) delta 7.85 (dd, 1H, / = 8.5, 5.5 Hz), 7.21- 7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H).
1.2 g
With hydrogen; In methanol;
2-cyano-4-fluorophenyl-carboxylate (1.5g, 8.4mmoL) was dissolved with 30ml of methanol was added 1g of Raney-Ni catalyst, under hydrogen and stirred overnight.The reaction mixture was filtered, the filter cake with ethyl acetate (200ml) washed and the combined filtrate was concentrated to dryness to give the crude product.Flash column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the intermediate 18 (1.2g, white solid)
50 mg
With hydrogen; In ethanol; at 20.0℃; under 2585.81 Torr; for 16h;
To a solution of <strong>[127510-96-7]methyl 2-cyano-4-fluorobenzoate</strong> (850 mg, 4.74 mmol) in ethanol (30 mL) was added Raney Nickel (1 g). The reaction was stirred at ambient temperature for 16 h under H2 (50 psi). LCMS showed the desired product. After purification by silica gel chromatography eluted with DCM: MeOH= 150: 1?80: 1 to give the product 500 mg as white solid.
With copper(l) cyanide; In 1-methyl-pyrrolidin-2-one; at 195.0℃; for 1.5h;Inert atmosphere;
Example 123Exam le 123 a Methyl 2-Cyano-4-fluorobenzoate 123a123aA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with <strong>[85953-29-3]methyl 2-chloro-4-fluorobenzoate</strong> (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under CGIPHARM60WO reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73% yield (6.99 g) as a white solid: mp 92-93 C; ]H NMR (500 MHz, CDC13) delta 8.18 (dd, 1H, / = 9.0, 5.5 Hz), 7.50 (dd, 1H, / = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
In N,N-dimethyl-formamide; at 140.0℃;Inert atmosphere;
To a 250-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen, was added methyl2-bromo-4-fluorobenzoate 101 b (4 g, 17.16 mmol, 1.0 equiv.)andN';N-dimethylformamide (20 mL). Solid CuCN (2.3 g, 25.84 mmol, 1.5 equiv.) wasadded in several batches. The resulting mixture vvas stirred at l40C overnight. Upon coolingto room temperature, the mixture '.vas quenched with water. The aqueous mixture was15 extracted with ethyl acetate (100 mL x 3), and the combined organic extracts were washedwith t-hO (50 mL x 2) and brine (80 mL x 2) Removal of solvents gave a residue which waspmitl.ed by silica gel column chromatography eluting with ethyl acetate/petroleum ether(lO%) to provide methyl2-cyano-4-t1uorobenzoate 101c (1.2g, 39%) as a white solid
850 mg
In N,N-dimethyl-formamide; at 120.0℃; for 1.5h;Inert atmosphere;
To a solution of methyl 2-bromo-4-fluorobenzoate (1.2 g, 5.15 mmol) in DMF (5 mL) was added cyanocopper (0.92 g, 10.3 mmol) under N2. The reaction was stirred at 120 C for 1.5 h under N2. Then, the reaction was cooled to room temperature.10% NaCN (10 mL) was added to the reaction. The mixture was extracted with DCM (3 x 30 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (3 x 50 mL) .The combined organic layers were dried over Na2SO4. After filtration, 850 mg of product was obtained as a white solid.
(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane hydroiodide salt[ No CAS ]
[ 127510-96-7 ]
methyl 2-cyano-4-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
250 mg
With potassium carbonate; In dimethyl sulfoxide; at 120.0℃;Sealed tube;
To a 8 mL sealed tube was added (lS,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichloropheny 1)-l ,2-oxazol-4-y 1 ]methoxy l-2-azabicyd o[ 2. 2. 1 ]heptane hydroiodide salt 12dd(200 mg, 0.394 mmol, 1.0 equiv.), methyl2-cyano-4-fluorohenzoate lOlc (104 mg, 0.582.5 mmol, 1.49 equiv.), potassium carbonate (144 mg, 1.04 mmol, 2.67 equiv.) and DMSO (2mL). The resulting rnixture was stirred at l20C overnight. After cooling, v.·ater was added,the mixture was extracted with ethyl acetate (150 mL x 2). The combined organic extractswere washed with brine (l 00 mL x 5), dried over anhydrous sodium sulfate and concentratedunder vacuum to afford methyl2-cyano-4-[(1S,4S,5R)-5-[[5-cydopropyl-3-(2,6-30 dichloropheny 1)-1,2-oxazol-4-yl]methoxy l-2-azabicydo[2.2.1 ]heptan-2-yl]benzoate lOld(250 mg) as a greenish yellow solid.
7-(6-((1r,3r)-3-(3-(3-(azetidin-3-yloxy)propoxy)propoxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole[ No CAS ]
[ 127510-96-7 ]
[ 7087-68-5 ]
5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
Step 1: 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione A mixture of 7-(6-((1r,3r)-3-(3-(3-(azetidin-3-yloxy)propoxy)propoxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (crude, 0.390 mmol) [prepared as described for Compound 104], N-ethyl-N-isopropylpropan-2-amine (86 mg, 1.17 mmol) and <strong>[127510-96-7]methyl 2-cyano-4-fluorobenzoate</strong> (90 mg, 0.468 mmol) in 1-methyl-2-pyrrolidinone (3 ml) was stirred at 90 C. for 16 hour. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 2-4% methanol in dichloromethane) to afford 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (160 mg, yield 61%) as light yellow oil.
6-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-6-azaspiro[3.4]octan-2-amine hydrochloride[ No CAS ]
[ 127510-96-7 ]
C24H22F3N5O2S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; for 12h;
A stir bar, 6-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-6-azaspiro[3.4]octan-2-amine hydrochloride (intermediate 3a) (S00 mg, HCIsalt, 1.32 mmol), <strong>[127510-96-7]methyl 2-cyano-4-fluorobenzoate</strong> (284 mg, 1.59 mmol), potassium carbonate (365 mg, 2.64 mmol) and dimethylsulfoxide (6 mL) were added to a 25 mL round-bottomed flask, the resultant mixture was heated and stirred at 60 C for 12 h. The mixture was cooled to room temperature and suspended into dichloromethane (40 mL) and washed with water (20 mL x 3). The combined organic layers were dried over anhydrous NagSOxg,filtered and concentrated under reduced pressure to give the crude which was purified by prep. HPLC (Column: Xtimate C18 150*25mm*Sum, Mobile Phase A: water (0.04%NH;3H,0 + 10 mM NH4HCQ;), Mobile Phase B: acetonitrile, Flow rate: 30 mL/min, gradient condition from 40% B to 70%). The pure fractions were collected and the solvent was evaporated under vacuum to give a residue. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to give intermediate 296 as a white powder.
methyl 2-cyano-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 110.0℃; for 2h;
Into a 100-mL round-bottom flask, was placed <strong>[127510-96-7]methyl 2-cyano-4-fluorobenzoate</strong> (3.58 g, 19.983 mmol, 1 equiv), (piperidin-4-yl)methanol (3.45 g, 29.954 mmol, 1.50 equiv), DIEA (9.9 mL, 56.837 mmol, 2.84 equiv), DMSO (40 mL). The resulting mixture was stirred for 2h at 110 in an oil bath. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 2) and the organic layers combined. The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 5.21 g (95%) of methyl 2-cyano-4-[4-(hydroxymethyl)piperidin-1-yl]benzoate as a yellow green semi-solid. LC/MS (ESI) m/z: 274.95 [M+1] +.
tert-butyl 6-(3-cyano-4-(methoxycarbonyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 110.0℃; for 2h;
Into a 30-mL sealed tube, was placed <strong>[127510-96-7]methyl 2-cyano-4-fluorobenzoate</strong> (896.00 mg, 5.001 mmol, 1.00 equiv), oxalic acid; tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.59 g, 5.515 mmol, 1.10 equiv), DIEA (4.20 mL, 24.113 mmol, 4.82 equiv), DMSO (12.00 mL). The resulting mixture was stirred for 2h at 110 in an oil bath. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 2) and the organic layers combined. The organic was washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 1.75 g (98%) of tert-butyl 6-[3-cyano-4-(methoxycarbonyl)phenyl]-2,6-diazaspiro[3.3]heptane- 2-carboxylate as a yellow green solid. LC/MS (ESI) m/z: 358.00 [M+1] +.
(3R)-N-(3-(5-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide[ No CAS ]
(3R)-N-(3-(5-(4-(6-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide[ No CAS ]
(3R)-N-(3-(5-(4-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide[ No CAS ]
With platinum(IV) oxide; formic acid; water; at 80.0℃; for 4h;
Into a 250-mL round-bottom flask, was placed <strong>[127510-96-7]methyl 2-cyano-4-fluorobenzoate</strong> (5.38 g, 30.031 mmol, 1.00 equiv), formic acid (50.00 mL, 88%), H2O (5.00 mL), PtO2 (1.36 g, 5.989 mmol, 0.20 equiv). The resulting mixture was stirred for 2 h at 80 in an oil bath. The rest of PtO2 (0.10 equiv) was added and the resulting mixture was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at 80 in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL) and ethyl acetate (200 mL). The solids were filtered out. The aqueous layer was back extracted with ethyl acetate (100 mL). The organic layers were combined and washed with brine (150 mL x 2). The organic was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/25). This resulted in 2.17 g (40%) of methyl 4-fluoro-2-formylbenzoate as a white crystal. LC/MS (ESI) m/z: 182.95 [M+1] +; 1H-NMR (300MHz, CDCl3) d 10.68-10.65 (m, 1H), 8.10-8.03 (m, 1H), 7.64-7.60 (m, 1H), 7.36-7.28 (m, 1H), 3.99 (s, 3H).
tert-butyl 3-(2,6-difluoro-3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)benzoyl)-5-(4-(((1R,3S)-3-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)oxy)cyclohexyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate[ No CAS ]
(3R)-N-(3-(5-(4-(((1R,3S)-3-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)oxy)cyclohexyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide[ No CAS ]
methyl 2-cyano-4-(3-(hydroxymethyl)azetidin-1-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.4%
With potassium carbonate In dimethyl sulfoxide at 110℃;
Step 1: methyl 2-cyano-4-(3-(hydroxymethyl)azetidin-l-yl)benzoate
A solution of methyl 2-cyano-4-fluorobenzoate (2.70 g, 15.1 mmol), K2CO3 (7.80 g, 60.3 mmol) and azetidin-3-ylmethanol hydrochloride (2.05 g, 16.6 mmol) in DMSO (30 mL) was stirred at 110 °C overnight. The mixture was diluted with water and extracted with EA (50 mL x 2). The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography (PE / EA=5 / 1) to afford methyl 2-cyano-4-[3- (hydroxymethyl)azetidin-l-yl]benzoate (2.80 g, 11.4 mmol, 75.4% yield) as ayellow solid. LCMS calculated for C13H15N2O3 (M+H)+ m/z =247.1; found: 247.2.
55%
Stage #1: 3-(hydroxymethyl)azetidine hydrochloride With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 15℃; for 0.5h;
Stage #2: methyl 2-cyano-4-fluorobenzoate In dimethyl sulfoxide at 120℃; for 11.5h;
R Step R: methyl 2-cyano-4-[3-(hydroxymethyl) azetidin-1-yl]benzoate
To a solution of azetidin-3-ylmethanol hydrochloride (18.0 g, 145.7 mmol) in dimethylsulfoxide (300 mL) was added diisopropylethylamine (126.85 mL, 728.27 mmo). The mixture was stirred at 15 °C for 0.5 h. Then methyl 2-cyano-4-fluoro-benzoate (20.87 g, 116.5 mmol) was added and the reaction stirred at 120 °C for 11.5 h. The mixture was diluted with water (2000 mL) and extracted with ethyl acetate (5 x 1000 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (3 x 2000 mL), dried over sodium sulfate, filtered, and concentrated. The residue was triturated with 1:2 ethyl acetate:petroleum ether (300 mL) to afford methyl 2-cyano-4-[3-(hydroxymethyl)azetidin-1-yl]benzoate (60 g, 55%) as a light yellow solid. MS (ESI): m/z 247.2 [M+H]+.
55%
Stage #1: 3-(hydroxymethyl)azetidine hydrochloride With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 15℃; for 0.5h;
Stage #2: methyl 2-cyano-4-fluorobenzoate In dimethyl sulfoxide at 120℃; for 11.5h;
R Step R: methyl 2-cyano-4-[3-(hydroxymethyl) azetidin-1-yl]benzoate
To a solution of azetidin-3-ylmethanol hydrochloride (18.0 g, 145.7 mmol) in dimethylsulfoxide (300 mL) was added diisopropylethylamine (126.85 mL, 728.27 mmo). The mixture was stirred at 15 °C for 0.5 h. Then methyl 2-cyano-4-fluoro-benzoate (20.87 g, 116.5 mmol) was added and the reaction stirred at 120 °C for 11.5 h. The mixture was diluted with water (2000 mL) and extracted with ethyl acetate (5 x 1000 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (3 x 2000 mL), dried over sodium sulfate, filtered, and concentrated. The residue was triturated with 1:2 ethyl acetate:petroleum ether (300 mL) to afford methyl 2-cyano-4-[3-(hydroxymethyl)azetidin-1-yl]benzoate (60 g, 55%) as a light yellow solid. MS (ESI): m/z 247.2 [M+H]+.
Chemistry
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