1,1-Dimethylethyl (3S)-3-(methylamino)-1-pyrrolidinecarboxylate

To a solution of tert-butyl (3S)-3-(formylamino)pyrrolidine-1-carboxylate (2.29g, lOJmmol) (from preparation 27), in tetrahydrofuran (35ml), stirring at OStep 1:Mesylate 20 (1.33 g, 5 mmol) and 2 M solution of MeNHTo a solution of To a solution of tert-butyl (3S)-3-[methyl-(2-nitrophenyl)sulfonyl-amino]pyrrolidine-1-carboxylate (5.10 g, 13.2 mmol) in acetonitrile (120 mL), potassium carbonate (5.49 g, 39.7 mmol) and 2-fluorobenzenethiol (2.83 mL, 26.5 mmol) were added. The mixture was stirred at room temperature for 12 h. Ethyl acetate was added to the mixture. The solution was washed with saturated aqueous sodium hydrogen carbonate, water, and brine, dried over anhydrous sodium sulfate salt, and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (80 g) and eluted with 0-20% ethyl acetate in hexane to obtain the title compound (2.65 g, 100%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) delta: 3.57-3.33 (3H, m), 3.20-3.10 (2H, m), 2.44 (3H, s), 2.09-2.00 (1H, m), 1.73-1.70 (1H, m), 1.44 (9H, s); 13C NMR (100 MHz, DMSO-d6) delta: 153.58, 77.94, 59.06, 58.21, 51.23, 50.99, 44.17, 43.94, 34.23, 28.15; HRMS(Positive ESI) m/z 201.1594 (201.1598 calcd for C10H20N2O2 + H); EA Anal. calcd for C10H20N2O2: C, 59.97; H, 10.07; N, 13.99. Found: C, 57.59; H, 9.94; N, 13.33; [alpha]D20: -14.45 (c=1.002, CHCl3).A degassed mixture of (R)-6-bromo-2-(3-(l-(4-methyl- 4H-l, 2, 4-triazol-3-yl)propan-2-yl)phenyl)-4-(trifluoromethyl)isoindolin-l-one (200 mg, 0.42 mmol), tert-butyl (S)-3-(methylamino)pyrrolidine-l-carboxylate (84 mg, 0.42 mmol), XPhos (20 mg, 0.04 mmol), XPhos Pd G3 (35 mg, 0.04 mmol) and CS2CO3 (273 mg, 0.84 mmol) in dioxane (4 mL) was stirred at 90 C for 16 h under nitrogen. When the reaction was completed, the reaction was quenched by the addition of 20 mL water. The aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic solution was dried, and concentrated to give the residue, which was purified by chromatography B to afford the title compound (129 mg, 65% purity) as a yellow oil, which was used without purification. MS (ESI) calculated for (C3 IH37F3N603) [M+Hf, 599.3; found, 599.3.c. Add 300 g of water to the reaction kettle at normal temperature.Additional compound 3 (88 g, 1.00 eq) was added and stirred for 10 min.Then cool to 5 C, adjust the pH to 8 with 25% aqueous sodium hydroxide solution.Slowly drip acetyl chloride (1.60 eq) and simultaneously add 25% aqueous sodium hydroxide solution.Control the pH to 8-10, react for 2h, then add MTBE to extract the organic phase.The organic phase was washed with saturated brine; then anhydrous sodium sulfate and activated carbon were added for 3 hours.Filtration gave Compound 4.Step 2. Preparation of te/f-butyl (S)-3-((5-fluoro-2-formyl-4-(/V-(4-methoxybenzyl)-//-(thiazol-4-yl)sulfamoyl)phenyl)(methyl)amino)pyrrolidine-1-carboxylate To a solution of 2, 4-difluoro-5-formyl-A/-(4-methoxybenzyl)-A/-(thiazol-4- yl)benzenesulfonamide (1.07 g, 2.52 mmol) in anhydrous dimethyl sulfoxide (20 ml_) was added te/f-butyl (S)-3-(methylamino)pyrrolidine-1-carboxylate (1.01 g, 5.04 mmol). The reaction mixture was heated to 80 C for 30 minutes. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (80 ml_). The organic layer washed with saturated ammonium chloride (2 chi 50 ml_), brine (50 ml_), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo afforded the title compound as a beige oil (1.45 g, 95% yield): H NMR (300 MHz, CDCI3) delta 9.89 (s, 1 H), 8.56 (d, J = 2.3 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.25-7.21 (m, 3H), 6.81- 6.71 (m, 3H), 5.02 (s, 2H), 4.15-4.09 (m, 1 H), 3.76 (s, 3H), 3.64-3.59 (m, 1 H), 3.46- 3.32 (m, 2H), 2.92 (s, 3H), 2.21-2.12 (m, 2H), 1.72-1.70 (m, 1 H), 1.49 (s, 9H); MS (ES+) m/z 605.5 (M + 1).Step 1:Mesylate 20 (1.33 g, 5 mmol) and 2 M solution of MeNH2 in THF (25 mL, 50 mmol) were loaded to a sealed tube and aged at 95 C for 60 h, then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give the desired amine 38 (0.85 g, 85%).1H NMR (CDC13, 400 MHz): delta 3.58 - 3.28 (m, 3H), 3.26 - 3.02 (m, 2H), 2.43 (s, 3H), 2.08 - 1.98 (m, 1H), 1.76 - 1.63 (m, 1H), 1.45 (s, 9H).b. At room temperature, add 660 g of methylamine methanol solution to the autoclave.Further, 82 g of Compound 2 was added, and the autoclave was sealed, and the temperature was raised to 80 C for 28 hours.After being cooled to room temperature, it was concentrated under reduced pressure to a substantially solvent-free distillation.320 g of dichloromethane and 82 g of water were added, the organic phase was separated, the aqueous phase was extracted with 100 g of dichloromethane, and the organic phases were combined, washed with 30 g of water and 30 g of 15% brine.Then add a proper amount of acid and 250g MTBE and stir for a few minutes, filter and dry.The compound 3 was obtained in a yield of 88 g.

Molecular Weight:200.28
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:200.152477885
Monoisotopic Mass:200.152477885
Topological Polar Surface Area:41.6
Heavy Atom Count:14
Complexity:211
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes