(2S,5S)-N-Boc-5-methylpyrrolidine-2-carboxylic aci

(2S, 5S)-1-(Tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (2S, 5S)-1-(Tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (Compound 1-6) [001651 To a solution of compound 1-5 (9.11 g, 35.45 mmol) in EtOH (80 mL) was added a solution of Lithium hydroxide hydrate (2.5 g, 59.67 mmol) in 20 mL of H20 at 25 °C. The mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the mixture was extracted with EtOAc (150 mL), then the EtOAc phase was discarded. The aqueous phase was adjusted to pH 2 with 6percent hydrochloric acid, then the resulting mixture was extracted with EtOAc (80 mLx3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated /n vacuo to give the title compound as a white solid (8.0 g, 98.5percent).The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 230.3 [M+Hfb; and‘H NMR (400 MHz, CD3OD): 4.24 (m, 1H), 3.56 (m, 1H), 1.75-1.97 (m, 2H), 1.45-1.69 (m, 2H), 1.40 (s, 9H), 1.32-1.34 (m, 3H) ppm.Step 5) the Preparation of Compound 1-6 (0231) To a solution of compound 1-5 (9.11 g, 35.45 mmol) in EtOH (80 mL) was added a solution of Lithium hydroxide hydrate (2.5 g, 59.67 mmol) in 20 mL of HIn the 12g ii-5 prepared in the previous step, add 30ml of ethanol and stir to dissolve.2 g of lithium hydroxide monohydrate and 12 ml of deionized water are added. The mixture was stirred for 16 hours, Add 100ml of saturated sodium chloride solution and acidify with 1N hydrochloric acid;Then add 100ml of ethyl acetate to extract;It is extracted once more with 50 ml of ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate overnight. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure.(9.1 g) of a white solid of (2S, 5S)-N-(tert-butoxycarbonyl)-5-methyl-pyrrolidine-2-carboxylic acid (II) was obtained.Step 5: In 12 g of ii-5 prepared in the previous step, add 30 ml of ethanol, stir to dissolve, add 2 g of lithium hydroxide monohydrate and12ml of deionized water. The mixture was stirred for 16 hours, Add 100ml of saturated sodium chloride solution and acidify with 1N hydrochloric acid; Then add 100ml of ethyl acetate to extract;It is extracted once more with 50 ml of ethyl acetate.The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate overnight.The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure.9.1 g of white solid II was obtained.General procedure: Trifluoroacetic acid (10ml) was added to a solution of compound4a(4.7g, 0.014mol) in dichloromethane (30ml). The reaction mixture was stirred for 3h at room temperature. The solvent was removed in vacuo, and the residue was azeotroped with toluene to afford the crude product. To a solution of the product in methanol (50ml) was added 10percent Pd/C (500mg, 50percent wetted, type AD). The resulting mixture was stirred under a hydrogen atmosphere (1atm) for 16h at room temperature. The mixture was filtered to remove the catalyst, and the filtrate was concentrated in vacuo to afford the crude product. To a solution of the product in acetonitrile (60ml) with water (10ml) was added di-tert-butyl dicarbonate (4.58g, 21mmol) and 1N aqueous sodium hydroxide solution (35ml, 35mmol). The resulting solution was stirred for 1h at room temperature. After removing the solvent in vacuo, the residue was diluted with chloroform, and extracted with water. The aqueous layer was diluted with saturated aqueous NHCompound 4 (35.98 g, 50 mmol), compound 9 (12.04 g, 52.5 mmol), N, N-dimethylformamide (180 mL) was added to a three-necked flask, and the mixture was stirred, and then cesium carbonate (32.58 g, 100 mmol) was added.Heat to 50 C for 4-6 hours, then cool to room temperature and add saturated ammonium chloride (360 mL).Ethyl acetate (360 mL), liquid separation, The aqueous layer was extracted once more with ethyl acetate (180 mL).The combined organic phase was washed with water (180 mL) twice.Dry over anhydrous sodium sulfate, filter, Concentrated to remove most of the ethyl acetate.Add petroleum ether (360mL) to beat and filterVacuum drying to obtain intermediate 10(31.96 g, yield 72%).Compound 16 (3.19 kg, 4.71 mol, 1.0 eq)And compound 7 (1.13 kg, 1.05 eq)Was dissolved in N, N-dimethylformamide (DMF)Potassium carbonate (682.3 g, 1.05 eq) was added, the mixture was replaced with nitrogen three times in vacuo, Heat to 20-40 ° C for 16 hours.TLC showed compound 16 completely reacted. Dropped to 5-10 ° C, dropped into water, 5-10 ° C, Stirred for 2-3 hours, filtered, the filter cake washed with water, dried, 3.79 kg of compound 15 was obtained in a yield of 95.0percent and an HPLC purity of 98.57percent.Compound 8 (1.96 kg, 2.73 mol, 1.0 eq)And compound 7 (659 g, 1.05 eq)Was dissolved in N, N-dimethylformamide (DMF)Potassium carbonate (376.3 g, 1.05 eq) was added, the mixture was replaced with nitrogen three times in vacuo, Heat to 20-40 ° C for 16 hours.TLC showed complete reaction of compound 8. Down to 5-10 ° C, Dropping water, 5-10 ° C, stirring for 2-3 hours, filtering, washing the filter cake with water, drying, 2.25 kg of compound 6 was obtained with a yield of 95.0percent and an HPLC purity of 98.46percent.a. (2S, 5S)-2-[N?-(5-Fluoro-pyridin-2-yl)-hydrazinocarbonyl]-5-methyl pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 7a) (0182) (0183) A solution of

Molecular Weight:229.27
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:229.13140809
Monoisotopic Mass:229.13140809
Topological Polar Surface Area:66.8
Heavy Atom Count:16
Complexity:295
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes