L-Proline, methyl ester, hydrochloride (1:1)

Crystalline

Methyl (S)-pyrrolidine-2-carboxylate was preparedTo a solution of L-proline (10 g, 86.9 mmol) in MeOH (100 mL) was added SOClTo a solution of L-proline (10 g, 86.9 mmol) in MeOH (100 mL) was added SOCl2 (12.6 mL, 174 mmol) at 0°C. The mixture was stirred at 80 °C for 1.5 hours and concentrated in vacuo to afford the title compound 26-1 as a whitesolid (14.3 g, 100percent). The compound was characterized by the following spectroscopic data:MS-ESI: m/z 130.2 [M+H]+; and1H NMR (400 MHz, CD3OD): δ 4.45 (m, 1H), 3.85 (s, 1H), 3.40 (m, 2H), 2.42 (m, 1H), 2.12 (m, 1H), 2.07 (m, 1H).To the solution L-proline (15.0 g, 130.3 mmol, 1.0 equiv) in MeOH (200 mL) at 0 °C, was added thionyl chloride (12.3 mL, 156.4 mmol, 1.2 equiv) over a period of 10 minutes. Thereaction mixture was slowly warm to room temperature and stirred it for 12 h. The resultedmixture was concentrated under reduced pressure by using KOH trapper attached rotaryevaporator and then the flask was connected with vacuum pump over a period of 1 h to affordcompound (14b) as colorless oil., 11.5 g (0.1 mol) of proline, 20 ml of dichloroethane and step 2)The resulting mother liquor (i.e., step 2) was sprinkled with 20 ml of filtrate) into a 250 ml three-necked flask, A hydrogen chloride gas was introduced at a rate of 1.25 ml / s, Reaction at room temperature for 0.5 h, Consumption of HCl 0.1mol., then 4.16 g (0.13 mol) of methanol was put into a three-necked flask, Continue to pass hydrogen chloride gas (0.05ml / s) under reflux conditions, The aqueous dichloroethane was distilled off, And anhydrous dichloroethane was added dropwise to the reaction system at the same rate (using step 2)The dichloroethane obtained after the water treatment) was maintained so that the amount of dichloroethane in the reaction remained substantially unchanged. After 3 hours of reaction, Consumption of HCl 0.024 mol, co-distillation of azeotrope (water-containing dichloroethane) about 140ml.The resulting reaction solution was cooled to room temperature, and then the remaining dichloroethane (solvent) and methanol were removed by vacuum distillation (10 mmHg pressure, 40C). The reaction mixture was recrystallized at -10C to precipitate a solid, Washed with 20 ml of 0 ° C ice dichloroethane and filtered to obtain a filtrate and a filter cake, respectively, The filter cake was dried at 40 ° C for 5 hours to give a yield of 99.6percent of 16.5 g (0.0996 mol) of proline methyl ester hydrochloride.The distilled azeotrope (aqueous dichloroethane) was subjected to water removal to give anhydrous dichloroethane, The anhydrous dichloroethane can be used in the presence of anhydrous dichloroethane in the following cyclic application (thereby enabling recycling).The filtrate was steamed (40 ° C) to 20 ml as the next circulating mother liquor (i.e., as a starting materialIn the middle).The total amount of HCl in step 3) was 0.124 mol.SOCl2 (76 mL, 1.04 mol) was added dropwise to a solution of (S)-proline (28.64 g, 0.25 mol)in MeOH (500 mL) at 0 °C. When the addition was complete, the mixture was refluxed for2.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure.The resultant (S)-1’ was obtained in 99percent yield (42 g, 0.25 mol) as a pale-yellow oil and wasused in the alkylation step without further purification.Optically active L-proline amino acid was purchased from LOBA Chemie and was commercial grade and used without further purification for thesynthesis of methyl L-prolinate hydrochloride. About1.0 g (6.0379 mmol) of L-proline was treated with methanol in the presence of 0.7183 g (6.0379 mmol)of SOCl2 to form this ester. It was synthetically an effective and well-known acid-catalyzed method for this esterification process.[11] Since the addition ofSOCl2 was an exothermic reaction, the entire reactionsystem was maintained under ice bath for about24 hr in a fume hood chamber. The completion ofthe reaction and purity of the product were checkedduring reasonable intervals using precoated Merckgraded thin layer chromatographic (TLC) plates inthe mixture of the hexane and ethyl acetate solventsystem. Finally, the formed ester was separated usinga Roto Vacuum Evaporator branded from BucheLabortechnike AG with appropriate temperatureand pressure. The percentage of yield was >98percent.The scheme of the reaction is shown in Fig.To a solution of proline (5.00 g, 43.5 mmol) in MeOH (250 mL) at 0 °C was added thionyl chloride (10.3 mL, 86.9 mmol) (dropwise). The reaction was warmed to 50 °C and stirred for 20 h. Cooled the reaction to room temperature and concentrated under vacuum to afford methyl ester 6 as a clear yellow oil (6.88 g, 96percent); To a stirring solution of L-proline (SMI) (100 g, 0.87 mol) in methanol (800 mL) was slowly added thionyl chloride (76.9 mL, 1.04 mol) at 0°C. The reaction mixture was slowly warmed to RT and heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure to afford A (143.9 g, HCl salt). H-NMR: (400 MHz, CDC1To a stirred solution of L-proline 1 (100 g, 0.87 mol) in methanol (800 mL) was added thionyl chloride (76.9 mL, 1.04 mol) slowly drop wise at 0°C. The reaction mixture was heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure. The residue was washed with w-hexane to afford 2 (143.9 g, HC1 salt). 1H-NMR: (400 MHz, CDC1To a solution of (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.50 g, 6.97 mmol) in methanol (20 mL) was added sulfoxide chloride (0.51 mL, 6.97 mmol) dropwise in an ice-bath. The mixture was stirred in the ice-bath for 30 min, and then stirred at 70 for 7 h. The reaction mixture was concentrated, and DCM (8 mL) and a HCl in EtOAc solution (4 M, 6 mL) were added. The resulting mixture was stirred at rt for 5 min, and then concentrated to give the title compound as white thick oil (800 mg, 88) .To Boc-L- proline (1.50g, 6.97mmol) in methanol (20 mL) was added dropwise thionyl chloride (0.51 mL underice-cooling, 6.97mmol), The reaction under ice 30min, 70 ° C 7H reaction, the solvent is removed, dichloromethane (8mL) and HCl in ethyl acetate Solution (4M, 6mL), stirred at rt for 5min, the solvent wasremoved to give 800mg of white viscous material, yield: 88percent.Dissolve 333mg of fluorescein and 1mmol of DIEA HBTU HOBt in 20ml of DMF.The temperature was lowered to 5 C for 15 minutes; 1 mmol of proline methyl ester hydrochloride and 1 mmol of DIEA were dissolved in 10 ml of DMF and stirred, and then the previous solution was added and reacted at normal temperature for 10 hours.After the reaction was completed, 200 ml of water was added and extracted twice with 100 ml of ethyl acetate.The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and separated by column chromatography.273 mg of product was obtained with a yield of 61.5%.

Used in biochemical reagents and pharmaceutical intermediates.

Molecular Weight:165.62
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:165.0556563
Monoisotopic Mass:165.0556563
Topological Polar Surface Area:38.3
Heavy Atom Count:10
Complexity:114
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes