* 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 dimethylsulfide borane complex; In tetrahydrofuran; at 20℃;Cooling with ice;
To a solution of 5-bromo-2, 4-difluoro-benzoic acid (45.2 g, 190 mmol) in anhydrous THF (500 mL) cooled in an ice-bath was added (CH3) 2S BH3 (57 mL, 570 mmol) . The resulting mixture was allowed to stir at room temperature overnight. Then methanol (500 mL) was carefully added to quench the reaction, and the mixture was stirred at 60for 1 h. The mixture was then acidified with HCl (1N) to pH5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified via silica gel chromatography (PE/EtOAc8/1) to give the title compound. 1H NMR (400 MHz, CDCl3) delta: 4.77 (br. s. , 2 H) , 6.95 (t, J8.78 Hz, 1 H) , 7.71 (t, J7.53 Hz, 1 H) .
With dimethylsulfide borane complex; In tetrahydrofuran; at 20℃;Cooling with ice;
To a solution of <strong>[28314-83-2]5-bromo-2,4-difluoro-benzoic acid</strong> (45.2 g, 190 mmol) in anhydrous THF (500 mL) cooled in an ice-bath was added (CH3)25.BH3 (57 mL, 570 mmol). The resulting mixturewas allowed to stir at room temperature overnight. Then methanol (500 mL) was carefully added to quench the reaction, and the mixture was stirred at 60C for 1 h. The mixture was acidified with HC1 (iN) to pH?-5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2504 and concentrated. The resulting residue was purified via silica gel chromatography (PE/EtOAc = 8/1) to give the title compound. ?HNMR (400 MHz, CDC13) oe: 4.77 (br. s., 2 H), 6.95 (t, J= 8.78 Hz, 1 H), 7.71 (t, J= 7.53 Hz, 1H).
2-(5-bromo-2,4-difluorobenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylmethylamino)acrylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 2-2: Production of crystal form II of the compound A; Step 1; 5-Bromo-2,4-difluorobenzoic acid (82.7 kg, 349 mol) was dissolved in toluene (420 L), thionyl chloride (62.3 kg, 523 mol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at 70C for 6 hr. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and azeotroped again with toluene (420 L). The residue was dissolved in toluene (220 L), this solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (55.0 kg, 384 mol) and diisopropylethylamine (58.6 kg, 523 mol) in toluene (220 L), and the mixture was stirred with heating at 70C for 21 hr. The reaction mixture was allowed to cool to room temperature, (S) - (+) -valinol (36.0 kg, 349 mol) was added, and the mixture was stirred at room temperature for 1.5 hr. Water (420 L) was added to the reaction mixture to allow partitioning, and the organic layer was washed successively with 1N hydrochloric acid (250 L, twice), water (420 L), 5% aqueous sodium hydrogen carbonate (250 L, twice), water (420 L) and 10% brine (250 L). The extract was concentrated under reduced pressure and azeotroped with dimethylformamide (420 L) to give a concentration residue (330 L) containing a crude product of 2- (5-bromo-2,4-difluorobenzoyl)-3-((S)-l-hydroxymethyl-2- methylpropylmethylamino) acrylic acid ethyl ester.
To a solution of <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (400 mg, 1.688 mmol) in methanol (8.44 mL) was added thionyl chloride (0.493 mL, 6.75 mmol), and the reaction mixture was stirred at 65 C for 1 hour. The reaction mixture was poured into 50 mL ice-water and thenpartitioned with ethyl acetate (3 x 30 mL). The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes) to provide the title compound (0.269 g, 1.05 mmol, 62.3 % yield).
With hydrogenchloride; In water; at 95℃; for 18h;
Preparation 18 (Proyl Prep 10)Methyl 5-bromo-2,4-difluorobenzoate; Concentrated hydrochloric acid (10.4 mL, 127 mmol) was slowly added to a mixture of <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (0.999 g, 4.21 mmol) in methanol (26 mL). The mixture was heated at 95 C for 18 hours. The reaction was cooled and then concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extract was washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil (0.847 g). The crude product was purified by silica gel chromatography (Biotage, 100g SNAP cartridge, 5 to 50% EtOAc in Heptane) to afford the title compound as clear crystalline solid (0.544 g).1H NMR (400 MHz, CDCI3): delta 3.95 (s, 3H), 6.98 (m, 1 H), 8.21 (t, 1 H). LCMS Rt = 2.95 minutes
(5aR,6S,6aS)-tert-butyl 3-((2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4'-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4'-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4'-(3-hydroxy-2-(2-hydroxypropan-2-yl)-3-methylbutoxy)-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4,6-difluoro-4'-(3-hydroxy-2-(2-hydroxypropaN-2-yl)-3-methylbutoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa-[4,5]cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4'-(3,4-dihydroxy-3-methylbutyl)-4,6-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4'-(3,4-dihydroxy-3-methylbutyl)-4,6-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4'-((S)-3,4-dihydroxybutoxy)-4,6-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
sodium (5aR,6S,6aS)-3-((4'-((S)-3,4-dihydroxybutoxy)-4,6-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-2’,6’-dimethyl-4’-((1r,3r)-3-(methylsulfonyl)cyclobutoxy)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa-[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4,6-difloro-2’,6’-dimethyl-4’-((1r,3r)-3-(methylsulfonyl)cyclobutoxy)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4’-(2-(2-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa-[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4,6-difluoro-4’-(2-(2-hydroxy-2-methylpropyl)-2H-tetrazol-5yl)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4’-(1-(2-hydroxy-2-methylpropyl)-1H-1,2,4-triazol-3-yl)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo-propa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4,6-difluoro-4’-(1-(2-hydroxy-2-methylpropyl)-1H-1,2,4-triazol-3-yl)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclo-penta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4’-(((1s,3R,4S)-3,4-dihydroxy-3,4-dimethyl-cyclopentyl)methoxy)-4,6-difluoro-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4’-(((1S,3R,4S)-3,4-dihydroxy-3,4-dimethylcyclopentyl)-methoxy)-4,6-difluoro-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo-propa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4’-((1s,3s)-3-(1,2-dihydroxypropan-2-yl)cyclobutoxy)-4,6-difluoro-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-3-((4’-((1S,3s)-3-((R)-1,2-dihydroxypropan-2-yl)cyclobutoxy)-4,6-difluoro-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo-propa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-3-((4’-((1R,3s)-3-((S)-1,2-dihydroxypropan-2-yl)cyclobutoxy)-4,6-difluoro-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo-propa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylic acid[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((2’-chloro-4,6-difluoro-4’-((3-hydroxy-3-(hydroxyl-methyl)cyclobutyl)methoxy)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa-[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((2’-chloro-4,6-difluoro-4’-(((1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)methoxy)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((2’-chloro-4,6-difluoro-4’-(((1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)methoxy)-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4’-((3-hydroxy-3-(hydroxymethyl)cyclobutyl)methoxy)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4’-(((1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)methoxy)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4’-(((1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)methoxy)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate[ No CAS ]
With thionyl chloride; N,N-dimethyl-formamide; at 15 - 70℃; for 4h;Inert atmosphere;
Intermediate A8: 5-Bromo-2,4-difluoro-benzoyl chloride Thionyl chloride (55.4 mL, 759.50 mmol) was added portionwise to a mixture of DMF (7.84 mL, 101.27 mmol) and <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (120 g, 506.33 mmol) in toluene (600 mL) at 15C over a period of 5 minutes under an inert atmosphere. The resulting mixture was stirred at 70C for 4 h then evaporated to dryness and the residue was azeotroped with toluene to afford the desired material as a brown oil (129 g, 100 %) which was used directly in the next step without purification. NMR Spectrum: lH NMR (400MHz, CDCh) delta 7.04-7.09 (1H, m), 8.34-8.42 (1H, m)
100%
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 15 - 70℃; for 4.08333h;Inert atmosphere;
Thionyl chloride (55.4 mL, 759.50 mmol) was added portionwise to a mixture of DMF (7.84 mL, 101.27 mmol) and <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (120 g, 506.33 mmol) in toluene (600 mL) at 15C over a period of 5 minutes under an inert atmosphere. The resulting mixture was stirred at 70C for 4 h then evaporated to dryness and the residuewas azeotroped with toluene to afford the desired material as a brown oil (129 g, 100 %) which was used directly in the next step without purification. NMR Spectrum: ?H NMR(400MHz, CDC13) oe 7.04-7.09 (1H, m), 8.34-8.42 (1H, m).
100%
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 15 - 70℃; for 4.08333h;Inert atmosphere;
Thionyl chloride (55.4 mL, 759.50 mmol) was added portionwise to a mixture of DMF (7.84 mL, 101.27 mmol) and <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (120 g, 506.33 mmol) in toluene (600 mL) at 15C over a period of 5 minutes under an inert atmosphere. The resulting mixture was stirred at 70C for 4 h then evaporated to dryness and the residue was azeotroped with toluene to afford the desired material as a brown oil (129 g, 100 %) which was used directly in the next step without purification. NMR Spectrum: 1H NMR (400MHz, CDCI3) delta 7.04-7.09 (1H, m), 8.34-8.42 (1H, m).
With thionyl chloride; In N,N-dimethyl-formamide; at 15 - 70℃; for 4h;Inert atmosphere;
Thionyl chloride (55.4 mL, 759.50 mmol) was added portionwise to a mixture of DMF (7.84 mL, 101.27 mmol) and <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (120 g, 506.33 mmol) in toluene (600 mL) at 15C over a period of 5 minutes under an inert atmosphere. The resulting mixture was stirred at 70C for 4 h then evaporated to dryness and the residue was azeotroped with toluene to afford the desired material as a brown oil (129 g, 100 %) which was used directly in the next step without purification. NMR Spectrum: lH NMR (400MHz, CDCls) delta 7.04-7.09 (1H, m), 8.34-8.42 (1H, m).
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 15 - 70℃; for 4.08333h;Inert atmosphere;
Thionyl chloride (55.4 mL, 759.50 mmol) was added portionwise to a mixture of DMF (7.84 mL, 101.27 mmol) and <strong>[28314-83-2]5-bromo-2,4-difluorobenzoic acid</strong> (120 g, 506.33 mmol) in toluene (600 mL) at 15C over a period of 5 minutes under an inert atmosphere. The resulting mixture was stirred at 70C for 4 h then evaporated to dryness and the residue was azeotroped with toluene to afford the desired material as a brown oil (129 g, 100 %) which was used directly in the next step without purification. NMR Spectrum: lH NMR (400MHz, CDCb) delta 7.04-7.09 (1H, m), 8.34-8.42 (1H, m).
N-(2',4'-difluoro-5'-((2,4,4-trimethylpentan-2-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide[ No CAS ]
N-(2',4'-difluoro-5'-((2,4,4-trimethylpentan-2-yl)carbamoyl)-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide trifluoroacetate[ No CAS ]
N-(5'-carbamoyl-2,4'-difluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide trifluoroacetate[ No CAS ]
5-bromo-2,4-difluoro-N-(2,4,4-trimethylpentan-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;
A 250 mL round bottom flask was charged with 5-bromo-2,4- difluorobenzoic acid (1 g, 4.22 mmol), HATU (2.407 g, 6.33 mmol) and tert- octylamine (1.023 mL, 6.33 mmol). NN-Dimethylformamide (10 mL) was then added and the mixture was stirred at RT for 5 min. NN-Diisopropylethylamine (2.94 mL, 16.88 mmol) was added and the reaction mixture was stirred for 16 hours at RT. The mixture was then diluted with EtOAc, washed with water (3 X 10 mL) and brine, dried over Na2S04 and concentrated in vacuo. The crude residue was loaded onto celite and purified by purified by flash column chromatography on silica gel (0-40% Hexane/EtOAc). The title compound was obtained as a light grey solid (1.275 g, 87 % yield); LCMS [M+H]+ = 348 g/mol.
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