| 30% |
With diethylamino-sulfur trifluoride In cis-1,2-Dichloroethylene at 40℃; for 16h; Inert atmosphere; |
Intermediate 332B: Benzyl 3,3-difluorocyclopentanecarboxylate
Intermediate 332B: Benzyl 3,3-difluorocyclopentanecarboxylate To a stirred ice-cooled solution of Intermediate 332A (0.2 g, 0.916 mmol) in anhydrous DCE (4 mL) was added DAST (0.303 mL, 2.291 mmol) under nitrogen. The reaction mixture was then allowed to heat to 40° C. and stir for 16 h. The reaction mixture was quenched with an aq. solution of NaHCO3 at 0° C. and extracted with DCM (2*50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP column, eluting with 10% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 332B as a colorless oil (0.07 g, 30% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.41-7.31 (m, 5H), 5.15 (s, 2H), 3.05 (m, 1H), 2.49-2.33 (m, 2H), 2.26-2.00 (m, 4H). |
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With (bis-(2-methoxyethyl)amino)sulfur trufluoride In 1,2-dichloro-ethane at 50℃; for 20h; |
39
EXAMPLE 39; N-((lR)-l-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-3,3- difluoro- 1 -hydroxycyclopentanecarboxamide; To a solution of 3-carboxycyclopentanone (640 mg, 5.0 mmol) in 8 mL of degassedDMF was added potassium carbonate (828 mg, 5.99 mmol) and benzyl bromide (0.65 mL, 5.49 mmol). After 4 hours at room temperature, the reaction mixture was poured into 50 mL of water and extracted 3 times with EtOAc. The combined organic layers were washed with water and dried over sodium sulfate. Filtration and solvent removal provided material that was subjected to silica gel chromatography eluting with 10% EtOAc in hexanes to yield benzyl 3-oxocyclopentanecarboxylate.To a solution of benzyl 3-oxocyclopentanecarboxylate (1.03 g, 4.72 mmol) in 8 ml of 1,2-dichloroethane was added 3.34 g (7.55 mmol) of bis(2-methoxymethyl)amino-sulfur trifluoride. The mixture was heated at 50 0C for 20 hours and then slowly poured into 50 ml of saturated aqueous sodium bicarbonate solution. The mixture was extracted with one portion of chloroform and then two portions of ethyl acetate. The combined organic extracts were dried, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-10% EtOAc in hexanes to yield benzyl 3,3-difluorocyclopentane- carboxylate.A solution of benzyl 3,3-difluorocyclopentanecarboxylate (13.1 g, 54.7 mmol) in 274 ml of TΗF was cooled to -78 0C under nitrogen. Potassium bis(trimethylsilyl)amide (175 ml of 0.5 M toluene solution, 87.5 mmol) was added via syringe over 15 minutes. The mixture was stirred for one hour, and then a solution of 3-phenyl-2-(phenylsulfonyl)oxaziridine (17.1 g, 65.6 mmol) in 50 ml of TBDF was added dropwise over 2 minutes. After 30 minutes at -78 0C, the reaction was quenched with the addition of 300 ml of saturated aqueous ammonium chloride solution. The reaction mixture was then warmed to room temperature, diluted with 100 ml of water, and extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, and dried over sodium sulfate. Filtration and evaporation of solvent gave 35 g of an oily solid. The oily solid was stirred with 150 ml of chloroform and then filtered to remove the insoluble material. The filtrate was concentrated in vacuo and the residue EPO was subjected to chromatrography on silica gel eluting with 5 to 30% EtOAc in hexane to afford 8.2 g of racemic benzyl S^-difluoro-l-hydroxycyclopentanecarboxylate.The racemic material (5.3 g) was then applied to a ChiralPak AD column (5 cm x 50 cm, 20 μ ) to effect separation of enantiomers. The mobile phase gradient was 100 % hexane to 15% ethanol in hexane over 1 hour, and the flow rate was 100 ml per minute. The ultraviolet detector was set at 250 run. The (+)-enantiomer eluted first (retention time, 33.66 min) and the (-)-enantiomer eluted at 39.16 minutes.To a solution of (+)-benzyl 3,3-difluoro-l-hydroxycyclopentanecarboxylate (1.8 g, 7.0 mmol) in 45 ml of EtOAc was added a suspension of 10% Palladium on Carbon (720 mg) in 5 ml of EtOAc. The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour (balloon). The reaction mixture was filtered through a glass micropore filter to remove the catalyst and the filtrate was concentrated under vacuum to give (+)-3,3-difluoro-l-hydroxycyclopentanecarboxylic acid.To a solution of the compound of Reference Example 4 (0.766 g, 2.18 mmol), (+)-3,3- difluoro-1-hydroxycyclopentanecarboxylic acid (0.454 g, 2.73 mmol), (lH-l,2,3-benzotriazol~l~yloxy)- [tris(dimethylamino)]phosphonium hexafluorophosphate (1.35 g, 3.06 mmol) in anhydrous dichloromethane (43 mL), was added triethylamine (0.553 g, 5.46 mmol). This reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc, washed with water, 0.25 NΗC1 and saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide the title compound as a foam, which gave proton ΝMR spectra consistent with theory and a mass ion (ES+) of 499.2 for M+Η+: 1H ΝMR (500 MHz, CDCI3) δ 8.13 (s, IH), 7.96 (bd, NH), 7.34 (d, J= 8.8 Hz, IH), 7.26 (m, 2H), 5.41 (m, IH),4.342 (s, 3H), 2.82 (m, IH), 2.46-2.25 (m, 4H), 1.92 (m, IH), 1.45 (d, J= 6.8 Hz, 3H). |
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