1-(1,1-Dimethylethyl) (2S)-4,4-difluoro-1,2-pyrrolidinedicarboxylate

solid

PREPARATION 63CS^-l -iiert-ButoxycarbonylJ^^-difluoropyrrolidine^-carboxylic acid1.08 g (4.08 mmol) of (S)^ -ferf-butyl 2-methyl 4, 4-difluoropyrrolidine-1 , 2-dicarboxylate (purchased from AldrichTo a solution of compound 14-3 (5.0 g. 18.86 mmol) in THF (40 mL) at 0 °C was added LiOH aqueous solution (1.5 g, 20 mL). and the mixture was stirred at rt for 2 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous NaTo a solution of compound 12-2 (5.0 g, 18.86 mmol) in THF (40 mL) was added LiOH aqueous solution (1.5 g, 20 mL) at 0 °C, and the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and then the THF solvent was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaTo a solution of compound 12-7 (5.0 g.18.86 mmol) in THF (40.0 mL) was added LiOH aqueous solution (1.5 g, 20 mL) at 0 'C, and the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M). and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous NaTo a solution of compound 5-10 (5.0 g, 18.86 mmol) in THF (40 mL) at 0 °C was added an aqueous solution of lithium hydroxide (1.5 g, 20 mL) dropwise. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (1 M) till pH = 5 and then the THF was removed in vacuo. The aqueous layers were acidified with aqueous HC1 (1 M) till pH = 2 and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SC>4 and concentrated in vacuo to give the title compound as a white solid (4.54 g, 94percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 252.3 [M+H]+; and NMR (400 MHz, CDC13): δ 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.11125] To a solution of compound 14-3 (5.0 g, 18.86 mmol) in THF (40 mE) at 0° C. was added EiOH aqueous solution (1.5 g, 20 mE), and the mixture was stirred at it for 2 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to give the title compound as a white solid (4.54 g, 94percent). The compound was characterized by the following spectroscopic data:11126] MS (ESI, pos.ion) mlz: 252.23 [M+H]11127] ‘H NMR (400 MHz, CDC13) ö (ppm): 9.60 (brs, 1H), 4.94-4.72, 4.60-4.57 (m, m, 1H), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J=16 Hz).Compound 26-4 (5.0 g, 18.86 mmol) was dissolved in THF (40 mL) and an aqueouslithium hydroxide solution (1.5 g, 20 mL) was added to the system at 0 ° C. The mixturewas reacted at room temperature for 2.0 hours. After the reaction was completed, thereaction mixture was adjusted to pH 5 with dilute hydrochloric acid (1 M) to remove theTHF. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) andextracted with EtOAc (80 mL x 3). The organic phases were combined, Wash with saturatedbrine, anhydrous Na 2SO 4Drying and concentration gave 4.54 g of white solid, yield: 94percent.c. ) TERT-BUTYL (2S)-2- (AMINOCARBONYL)-4, 4-DIFLUOROPYRROLIDINE-1-CARBOXYLATE; In general formula (VII) Z stands for the group of formula (A) 5.7 g (22.7 mmole) of (2USD)-1-(TERT-BUTOXYCARBONYL)-4, 4-difluoroproline (Tetrahedron Lett. 1998, 39, 1169) are dissolved in 57 ml of dichloromethane and to the solution 3. 8 ml (27.2 mmole) of triethylamine are added. To the resulting mixture AT-15C 3 ml (25 mmole) of pivaloyl chloride is added, the reaction mixture is stirred at that temperature for 1 hour, then 7 ml of 25 % aqueous ammonia solution is added to it dropwise and stirring is continued for an additional hour. The reaction mixture is washed with water, with 1 N sodium hydroxide solution, and with water, dried over sodium sulphate and evaporated. The product is crystallised from diethyl ether to obtain 3.94 g (69%) of the title product. M. p.: 136-138C. LH-NMR (CDCL3) : 1.48 (s, 9H); 2.3-2. 9 (M, 3- CH2), 3.69 (br, minor) + 3. 86 (M, MAJOR) (5-CH2), 4.53 (br, 2-CH), 6.0 (br, major) + 6. 81 (br, minor) (NH2).c. ) tert-butyl) (2-2- (aminocarbonyl)-4, 4-difluoro-1-pvrrolidinecarboxylate of the general formula (VII) wherein R2 and R3 mean fluorine atom; 5.7 g (22.7 mmol) of tert-butyl (2S)-2- (aminocarbonyl)-4, 4-difluoro-2- pyrrolidinecarboxylic acid (Tetraheron Lett. 1998, 39, 1169) are dissolved in 57 ml of dichloromethane and to the solution 3.8 ml (27.2 mmol) of triethylamine are added. To the resulting mixture dropwise, at-15 C 3 ml (25 mmol) of pivaloyl chloride are added and the mixture is stirred at that temperature for 1 hour, then 7 ml of 25 % aqueous ammonia solution are added drop wise and the mixture is stirred for 1 hour. The reaction mixture is washed with water, 1 N NaOH solution, then with water, dried over sodium sulphate and evaporated. On addition of diethyl ether 3.94 g (69%) of the above product crystallize. M. p.: 136-138C. 1H-NMR (400 MHz, CDC13) : 8 1.48 (s, 9H); 2.3-2. 9 (m, 3-CH2), 3.69 (br, minor) + 3.86 (m, major) (5-CH2), 4.53 (br, 2-CH). 6.0 (br, major) + 6.81 (br, minor) (NH2).Example 3D 2S-CARBAMOYL-4, 4-DIFLUORO-PYRROLIDINE-L-CARBOXYLIC acid TERT-BUTYL ester The compound from Example 3C and triethylamine (1.7 mL) were mixed with 15 mL of THF and cooled to 0 C. Isobutyl CHLOROFORMATE (1.14 mL) was added via syringe. After 30 minutes, 27.1 mL of 0.5 N NH3 in dioxane were added. After stirring overnight, the mixture was concentrated in vacuo and extracted with ethyl acetate. The combined organic extracts were dried with NA2S04, concentrated and purified by flash chromatography (70% ethyl acetate/hexane) to provide the title amide (0.82 g, 48%). MS (ESI) M/Z 251 (M+H) +.EXAMPLE 3D 2S-Carbamoyl-4, 4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester The compound from Example 3C and triethylamine (1.7 mL) were mixed with 15 mL of THF and cooled to 0 C. Isobutyl chloroformate (1.14 mL) was added via syringe. After 30 minutes, 27.1 mL of 0.5 N NH3 in dioxane were added. After stirring overnight, the mixture was concentrated in vacuo and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4, concentrated and purified by flash chromatography (70% ethyl acetate/hexane) to provide the title amide (0.82 g, 48%). MS (ESI) m/z 251 (M+H)+.(1) Synthesis of (2S)-2-(aminocarbonyl)-1-(tert-butoxycarbonyl)-4, 4-difluoropyrrolidine According to the manner similar to that of Example 1(1), the title compound (2.8 g) was obtained as a colorless powder from (2S)-1-(tert-butoxycarbonyl)-4, 4-difluoropyrrolidine-2-carboxylic acid (3.2 g). MS(ESI pos.)m/z: 273([M+Na]+), (ESI neg.)m/z: 249([M-H]-).To a solution of (2S)-L- (TERT-BUTOXYCARBONYL)-4, 4- difluoro-2-pyrrolidinecarboxylic acid obtained in Example 8-3 in acetonitrile (30mL), were added 1-HYDROXYBENZOTRIAZOLEHYDRATE (1.98g) ANDWATERSOLUBLE carbodiimide (3. 11g) with cooling on an ice bath. After stirred for 20min, 28% aqueous NH3 (2mL) was added at the same temperature and the resulting mixture was stirred for lhr. The reaction mixture was filtered and the filtration was evaporated in vacuo. After dilution with ethyl acetate, the resulting mixture was washed with water and saturated aqueous NaCl, dried over MGS04, and filtered. After removal of the solvent, the target compound was obtained as a yellow oil (3.2g). H-NMR (in CDCL3) : D 1.48 (9H, s), 3.10-2. 44 (2H, M), 4.02-3. 54 (2H, m), 4.65-4. 41 (1H, m), 5.71-5. 40 (1H, m), 6.97-6. 64 (1H, m). MS (ESI+) : m/z 251.22 (M+H).Step 4: (S)-ferf-butyl 2-carbamoyl-4, 4-difluoropyrrolidine-1-carboxylate In a 50 m L round-bottomed flask (S)-1 -(ieri-butoxycarbonyl)-4, 4-difluoropyrrolidine-2-carboxylic acid (1 .6 g, 6.37 mmol), obtained from step 4, was dissolved in 10 mL of dichloromethane at 15C. Then 1 -hydroxypyrrolidine-2, 5-dione (0.806 g, 7.01 mmol) was added. To the formed suspension Lambda/, /V-dicyclohexylcarbodiimide (1 .445 g, 7.01 mmol) was added at vigorous stirring. In a few seconds a cloudy white suspension forms. The mixture was allowed to reach RT and stirred for 30 min, followed by the addition of 7N ammonia in methanol (2.002 ml, 14.01 mmol) and stirring for another 20 min. Before evaporation of volatile components 1 spoon of Celite was added to the flask. Cold ethyl acetate was added to the residue and filtered over Celite. The filtrate was washed with saturated sodium bicarbonate. The formed slightly yellowish crystals were used without further purification. Yield: 1 .15g, 72% - - 1 H NMR (400 MHz, CDCI3) : delta 1 .45 (s, 9H), 2.77 - 2.44 (m , 1 H), 2.82 - 3.02 (m , 1 H), 3.56 - 3.78 (m, 1 H), 3.80 - 4.00 (m, 1 H), 4.52 (br_s, 1 H), 5.54 (br s, 1 H), 6.77 (br_s, 1 H). LC-MS(I) Rt 1 .34 min, m/z 251 .5 [M+H]+ (89%). MS (ESI) m/z 251 .2 [M + H]+Into a solution of

Molecular Weight:251.23
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:251.09691428
Monoisotopic Mass:251.09691428
Topological Polar Surface Area:66.8
Heavy Atom Count:17
Complexity:338
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes