(2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride

[TRANS-4-HYDROXY-L-PROLINE] (1; 10 g, 76.3 mmol) was dissolved in 200 ml of methanol, acetyl chloride (7.6 ml, 106.8 mmol) was added therein and the mixture was refluxed with stirring up for overnight. The mixture was cooled to RT (room temperature) and 500 ml of ether was added to form white crystal followed by filtration and drying under vacuum to yield the compound 2 (12.7 g, 87.6 percent):General procedure: 20 g (150 mmol) of (2S, 4S) -4-hydroxypyrrolidine-2-carboxylic acid (manufactured by Sigma- Aldrich) was dissolved in methanol and 12.2 mL (170 mmol) of thionyl chloride was added dropwise at 0 ° C., And stirred for a while. The resulting white suspension was heated as it was to 70 ° C. and heated under reflux for 24 hours. After the reaction, the solvent of the reaction liquid was distilled off under reduced pressure, 20 mL of methanol was added to the obtained mixture, and the azeotropic distillation of impurities was repeated three times under reduced pressure to obtain a solid of Compound A1 (30 g) as a crude product Obtained.Example 65B[840] (2R, 45)-methyl 1 -(2-chloroacetyl)-4-hydroxypyrrolidine-2-carboxylate[841] To a suspension of Example 65 A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetylchloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25 °C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50 °C to afford the title compound. XH NMR (300 MHz, DMSO-i?) ' ppm 2.06 -2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=l l. lHz), 3.76 (s, 3H), 3.76-3.86 (m, 2 H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).Example 17B[0835] (2R, 45)-methyl 1 -(2-chloroacetyl)-4-hydroxypyrrolidine-2-carboxylate[0836] To a suspension of Example 17A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetyl chloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25 °C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50 °C to afford the title compound. XH NMR (300 MHz, DMSO-i/6) delta ppm 2.06 -2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=l l . lHz), 3.76 (s, 3H), 3.76-3.86 (m, 2 H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).Example 65A[838] (2R, 45)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride[839] To a suspension of iraws-4-hydroxy-D-proline hydrochloride (150 g, 0.89 mol, 1 equivalent) in methanol (1.25 L), thionyl chloride (130 mL, 1.79 mol, 2 equivalents) was added drop-wise at 0-5 °C. Then the reaction mixture was stirred for 4 hours at 20- 25 °C. The reaction mixture was concentrated under reduced pressure. This crude material was stirred in a mixture of ethanol-methyl tert-butyl ether (1:4, 750 mL) for 30 minutes and the solid was collected by filtration. The wet cake was dried in a vacuum tray dryer for 8 hours at about 50 °C to afford the title compound. lR NMR (300 MHz, DMSO-i?) ' ppm 2.03 -2.23 (m, 2H), 3.06 (d, 1H, J=12.0Hz), 3.37 (dd, 2H, J=4.5Hz, J=12.0Hz), 3.75 (s, 3H), 4.41- 4.48 (m, 2H), 5.64 (bs, 1H), 9.43 (bs, 1H), 10.48 (bs, 1H).Example 17A[0833] (2R, 45)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride[0834] To a suspension of iraws-4-hydroxy-D-proline hydrochloride (150 g, 0.89 mol, 1 equivalent) in methanol (1.25 L), thionyl chloride (130 mL, 1.79 mol, 2 equivalents) was added drop-wise at 0-5 °C. Then the reaction mixture was stirred for 4 hours at 20-25 °C. The reaction mixture was concentrated under reduced pressure. This crude material was stirred in a mixture of ethanol-methyl tert-butyl ether (1 :4, 750 mL) for 30 minutes and the solid was collected by filtration. The wet cake was dried in a vacuum tray dryer for 8 hours at about 50 °C to afford the title compound. XH NMR (300 MHz, DMSO-i¾) delta ppm 2.03 -2.23 (m, 2H), 3.06 (d, 1H, J=12.0Hz), 3.37 (dd, 2H, J=4.5Hz, J=12.0Hz), 3.75 (s, 3H), 4.41- 4.48 (m, 2H), 5.64 (bs, 1H), 9.43 (bs, 1H), 10.48 (bs, 1H).

Molecular Weight:181.62
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:181.0505709
Monoisotopic Mass:181.0505709
Topological Polar Surface Area:58.6
Heavy Atom Count:11
Complexity:137
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes