4-Hydroxy-L-proline methyl ester hydrochloride

White Solid

methyl (To a solution of (2S, 4R)-4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride (1.0 g, 7.6 mmol) in methanol (25 mL) at 0° C. was added thionyl chloride (0.83 mL, 11.4 mmol). To a stirred solution of (2S, 4i?)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooled to 0°C was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was triturated with ether several times to get methyl (25', 4/?)-4-hydroxypyrrolidine-2- carboxylate hydrochloride salt as a white powder (14.5 g) in 100percent yield, m/z (M+l) 145; A solution of trans-4-hydroxy-ι-proline (10.0 g, 76.3 mmol) in MeOH (80 mL) was cooled to 0 °C andthionyl chloride (11.1 mL, 152 mmol) was added dropwise. The mixture was allowed to stir at roomtemperature for 1 h before being heated under reflux for a further 17 h. The resulting solution wasconcentrated and the residue azeotroped with MeOH (3 × 200 mL) to give the desired compound14·HCl (13.6 g, 100percent) as a colourless solid; mp 169–171 °C;−21.6 (c 1.0, EtOH); νmax/cm-1 3317, 2952, 2707, 1740, 1439, 1240, 1074, 1025, 956, 901, 625; δH (500 MHz; MeOD) 4.63–4.59 (2 H, m), 3.86 (3 H, s), 3.46 (1 H, dd, J 3.2, 10.0 Hz), 3.34–3.30 (1 H, m), 2.45–2.41 (1 H, m), 2.21 (1 H, ddd, J2.4, 8.0, 11.2 Hz); δC (125 MHz; CDCl3) 170.6, 70.6, 59.4, 55.0, 54.0, 38.6; m/z (+ESI) 146 ([M - Cl], 100).At room temperature, Trans-4-hydroxy-L-proline 2A (20.0 g, 152.6 mmol) was dissolved in anhydrous methanol (200 mL)Cooling to 0 , Dichloro sulfoxide (20.6g, 172.4mmol), The temperature was raised to 64 ° C and the reaction was refluxed for 8 hours.The reaction solution was lowered to -20 ° C, and a white solid was precipitated. Methyl tertiary butyl ether (50 mL) was added and the reaction was continued for 30 minutes.The filter cake was washed with methyl tertiary butyl ether (50 mL x 2) and dried to give white solid 4A (28 g, yield 100percent).Acetyl chloride (4.14 g, 52.8 mmol) is dropped into a three neck round bottom flask containing anhydrous methanol (33 ml) in ice bath and under N4-Hydroxy proline (10.0 g, 76.33 m mol)dissolved in dry methanol (150 ml) and stirred for 10 minutes under nitrogen atmosphere.The reaction mixture cooled to 0°C by ice bath and thionyl chloride (152.6 mmol, 11.07 ml)added dropwise under nitrogen atmosphere .The ice bath removed and the reaction mixturerefluxed for six hours. The solvents were removed under reduced pressure to obtain a whitesolid which was dissolved in methanol and again evapourated to dryness to yield 13.54 g ofthe title compound in 98percent yield.To a stirred solution of (25, 4R)-4-hydroxypyrrolidine-2-carboxylic acid (75.0 g, 572 mmol) in MeOH (800 mL), SOCIStep 1 : (2S, 4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2). Thionyl chloride (11.6 ml, 160 mmol) was added to a stirred solution of (2S, 4R)-4- hydroxypyrrolidine-2-carboxylic acid (10.0 g, 76.26 mmol) (1) in methanol (150 ml) at - 78SOClAbsolute methanol (8.0 equiv) was poured into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and a drop funnel. L-hydroxyproline (1 equiv) was placed into the flask with stirring. To the suspension obtained was added dropwise at 10-15 0C distilled thionyl chloride (1.1 equiv). Then the mixture was stirred at 45 0C until TLC indicated completion (5 h) of the reaction. The suspension was cooled to 5-10 0C and then filtered and washed with dry diethyl ether. The mother liquor was evaporated in vacuo and the residue was recrystallized from dry methanol to give the title compound in 92-97percent yield.26.2 g (200 mmol) trans-4-hydroxy-L-proline (1) in methanol(300 ml) was treated with dry hydrogen chloride until homogeneous.The solution was heated to the reflux temperature for 2 h and concentrated in vacuo. Upon cooling, the product was crystallizedfrom the solvent, collected by filtration, washed with acetoneand ether, and dried to yield trans-4-hydroxy-L-proline methylesterhydrochloride (2) as white crystal (32.7 g, 90percent), mp 159–162 C.Acetyl chloride (14 mL, 198 mmol) was slowly added into the anhydrous methanol (100 mL) in an ice bath. Trans-4-hydroxy-L-proline (15.0 g, 114.3 mmol) in dry methanol (250 mL) at 0 - 4 °C, was added dropwise thionyl chloride (17 ml .. 231 mmol). The resulting mixture was sl irrcd for at RT overnight, concentrated, crystallized with EtOH/hexane to provide the title compound (18.0 g, 87percent yield), ESI MS m//+ 168.2 (M + Na).To a solution of trans-4-hydroxy-L-proline (15.0 g, 114.3 mmol) in dry methanol (250 mL) was added thionyl chloride (17 mL, 231 mmol) dropwise at 0 to 4 °C. The resulting mixture was stirred for at r.t. overnight, concentrated, crystallized with EtOH/hexane to provide the title compound (18.0 g, 87percent yield). ESI MS m/z 168.2 ([M+Na]Step-1: Step C-1. Compound 20r (2 g, 8.6 mmol) was taken up with a solution of HC1 (g) in methanol (4 M, 40 mL). The mixture was stirred at ambient temperature for 12 hrs. After that, the reaction mixture was concentrated under reduced pressure to afford compound 20s (1.6 g, yield 99percent) as a white solid.

Trans-4-Hydroxy-L-proline (H952376) derivative. A natural constituent of animal structural proteins such as collagen and elastin.

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