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Into a 250-mE round-bottom flask, was placed methyl 4-bromo-2-iodobenzoate (5.8 g, 17.01 mmol, 1.00 equiv), NMP (60 mE), CuCN (1.82 g, 20.45 mmol, 1.20 equiv). The resulting solution was stirred for 2 hours at 60 C. in an oil bath. The resulting solution was extracted with ethyl acetate (50 mEx2) and the organic layers combined. The resulting mixture was washed with Fe504 (aq.) (50 mEx2). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel colunm with ethyl acetate/petroleum ether (1/3). This resulted in 3.68 g (90%) of methyl 4-bromo-2-cyanobenzoate as a white solid.
2.39 g
In 1-methyl-pyrrolidin-2-one; at 60℃; for 1h;
[0363] Preparation Example 75: Preparation of methyl 4-bromo-2-cyanobenzoate[0364][0365] To a mixture of methyl 4-bromo-2-iodobenzoate (3.52 g) described in Preparation Example 74 and coppercyanide (1.16 g) was added N-methylpyrrolidone (21 mL), and the mixture was stirred at 60C for 1 hr. The reactionmixture was cooled, a solution of saturated aqueous ammonium chloride solution and aqueous ammonia (1:1) wasadded, and the mixture was extracted with ethyl acetate. The organic layer was washed with a solution of saturatedaqueous ammonium chloride solution and aqueous ammonia (1:1), saturated aqueous ammonium chloride solution,and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the titlecompound (2.39 g).MS (ESI) m/z:240(M+H)+.
[0366] Preparation Example 76: Preparation of 4-bromo-2-cyanobenzoic acid[0367][0368] Methyl 4-bromo-2-cyanobenzoate (8.53 g) described in Preparation Example 75 was dissolved in dimethoxyethane(140 mL), a solution of lithium hydroxide 1 hydrate (2.24 g) in water (54 mL) was added dropwise underice-cooling, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added dropwise1N hydrochloric acid (60 mL) under ice-cooling, saturated brine was added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporatedto give the title compound (7.97 g).MS (ESI) m/z:226(M+H)+
808 mg
With water; lithium hydroxide; In methanol; at 20℃; for 4h;
A mixture of Compound II (980 mg), 2N aqueous lithium hydroxide solution (6.1 mL) and methanol (18 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with 4N hydrochloric acid, and then extracted with chloroform. The chloroform layer was dried over sodium sulfate, and then concentrated under reduced pressure to give Compound III (808 mg).
To an ice-cooled mixture of Compound I (1.5 g) and 2N hydrochloric acid was added a mixture of sodium nitrite (540 mg) and water (6.5 mL), and the mixture was stirred for 1 hour. The reaction mixture was neutralized by the addition of sodium carbonate. Then, to an ice-cooled mixture of copper cyanide (759 mg), potassium cyanide (637 mg), ethyl acetate (8 mL) and water (4 mL) was added the reaction mixture of Compound I which was prepared above, and the mixture was stirred for 1 hour. The reaction mixture was filtered through Celite, and to the filtrate was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 10/0 to 8/2) to give Compound II (980 mg).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 60℃; for 5h;
General procedure: A mixture of V-01 (922 mg, 4.292 mmol), ethynyltrimethylsilane (506 mg, 5.153 mmol), Pd(PPh3)2Cl2 (150 mg, 0.214 mmol), CuI (25 mg, 0.131 mmol), TEA (1.73 g, 17.16 mmol) was dissolved in anhydrous THF (20 mL). The mixture was stirred at 60 for 5 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and then the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (50/1-20/1) to give 0.9 g (90.4%) of V-13 as a brown oil.
( 1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane[ No CAS ]
methyl 2-cyano-4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium carbonate; In dimethyl sulfoxide; at 110℃;
To a 50 mL round-bottorn flask was added (1 S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-( 1-Huorocyclopropyl)-1 ,2-oxazol-4-yl]methoxy ]-2-azabicyclo[2.2.1 ]heptane 24d (120 mg,0.30 mmol, 1.0 equiv.), methyl4-bromo-2-cyanobenzoate (55 mg, 0.23 mmol, 1.0 equiv.),pota;;;sium carbonate (83 mg, 0.60 mmol, 2.0 equiv.), and DMSO (1 mL). The resultingrnix ture was stirred at ll 0C overnight After cooling to room temperature, the mixture Vas30 diluted '.vith of ethyl acetate and added with H20. The pH value of the solution '.Vas adjusted to 6 using a lM hydrogen chloride aqueous solution. The aqueous mixture was extracted withethyl acetate (1 00 mL x 2). l11e combined organic extracts were ·washed with brine (50 mL x4), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :3)5 to give methyl 2-cyano-4-[( l S,4S,5R)-5-UJ-(2,6-dichloropheny l)-5-(J -iluorocyclopropy l)L2-oxazol-4-yl]methoxy ]-2-azabicyclo[2.2.1]heptan-2-yl]benzoate 123a (90 mg, 54~~) as anoff-white solid.
rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-methylene-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide[ No CAS ]
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