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A kind of preparation method of l-prolineamide

The technology of prolineamide and proline is applied in the field of preparation of pharmaceutical intermediates, which can solve the problems of weak alkalinity and low effective content of products, and achieves the effects of mild conditions, easy control of conditions and simple process.

Active Publication Date: 2022-07-29
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainly contain two kinds of impurities of ammonium chloride and L-prolineamide hydrochloride in the synthetic solution of L-prolineamide that this preparation process obtains, the crude product of L-prolineamide after the purification is in order to remove by-product ammonium chloride, needs After several times of recrystallization, and because the alkalinity of ammonia gas is weaker than that of L-prolinamide, the resulting L-prolinamide product still contains more than 20% undissociated L-prolinamide hydrochloride , the effective content of the product is not high

Method used

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  • A kind of preparation method of l-prolineamide

Examples

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preparation example Construction

[0030] The reagents and raw materials used in the preparation examples, examples and comparative examples of the present invention are all commercially available products unless otherwise specified.

[0031] The external standard content of L-prolineamide was measured by Metrohm ECO automatic potentiometric titrator, and the L-prolineamide reference substance was purchased from the National Standard Material Center; solvent: glacial acetic acid; indicator: crystal violet indicator; titration solution : Perchloric acid titration solution (0.1mol / L).

[0032] L-prolineamide adopts gas chromatography (GC) to measure volatile related substances, adopts high performance liquid chromatography (HPLC) method of pre-column derivatization to measure non-volatile related substances, and the chromatographic conditions are as follows:

[0033] GC chromatographic conditions: Gas chromatograph: Agilent 7890B; Column: DB-624 30m×0.53mm×3.0μm; Sampler: Autosampler or microinjector; Column flow...

preparation example

[0039] (1) Preparation of L-proline methyl ester hydrochloride

[0040]The dry 500ml reaction flask was replaced by nitrogen three times and then added 150g (1.30mol) of L-proline and 300ml (2v / w) of methanol, cooled to 5.0-10.0°C, and 157g (1.56mol) of thionyl chloride was added dropwise under temperature control. ). The dropwise addition time is about 6 to 8 hours. After the dropwise addition is completed, the temperature is raised to 15.0 to 20.0 ° C and the reaction is incubated for 10 to 15 hours. The specific reaction endpoint is controlled by TLC until the raw material spots basically disappear. 1:3, add 2 drops of glacial acetic acid, ninhydrin develops color). After the reaction, the temperature of the water bath is controlled to be 15.0~20.0°C, and the vacuum degree is -0.085~-0.095MPa for methanol precipitation, until no solvent flows out from the condenser receiving tube, and the precipitation is stopped to obtain L-proline methyl ester concentrated oil.

[0041]...

Embodiment L

[0043] Embodiment L-prolineamide synthetic liquid is purified to prepare L-prolineamide

[0044] Take the above-mentioned L-prolineamide synthesis solution, first control the vacuum degree to be -0.06~-0.09MPa to remove ammonia gas, slowly heat up to an internal temperature of 15.0~20.0°C, remove to the point where no bubbles are generated in the kettle, and stop degassing. The feed liquid was filtered, the filter cake was rinsed with 0.5v / w methanol, the filtrates were combined, and the filter cake was discarded. The filtrate was adjusted to pH=9.5-10.0 with solid sodium hydroxide at 20-30°C, and then hydroxide was added dropwise. Methanol solution of sodium (2mol / L), adjust pH=10.5, heat up to 30.0-35.0°C and stir for 1 hour, the pH remains unchanged after re-measurement. The feed liquid was filtered, the filter cake was rinsed with 15ml (0.1v / w) methanol, the filtrates were combined, and the filtrate was desolvated under reduced pressure at 50.0-55.0°C and a vacuum degree o...

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Abstract

The invention provides a preparation method of L-prolineamide. L-proline is used as a starting material, firstly forming L-proline methyl ester hydrochloride, and then performing aminolysis to obtain L-proline amide containing L-proline The synthesis solution is obtained, and the residual L-prolineamide hydrochloride in the synthesis solution is dissociated into L-prolineamide by an inorganic base in a non-aqueous environment, and by-products are simultaneously removed by a non-aqueous solvent system. The preparation method provided by the invention can fully free L-prolineamide hydrochloride, and can also effectively remove by-products and impurities, thereby significantly improving the yield and purity of the target product, and the preparation method of the invention has a simple and convenient process. , the conditions are mild and easy to control, no expensive reagents are needed, the production efficiency of L-prolineamide can be improved, it is suitable for large-scale industrial production, and has important economic and social value.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a preparation method of L-prolineamide. Background technique [0002] L-prolineamide is an important intermediate in the synthesis of vildagliptin, an oral hypoglycemic drug belonging to the cyanopyrrolidine class of DPP-4 inhibitors. [0003] [0004] At present, the preparation process of L-prolineamide mainly uses L-proline as the starting material. First, it undergoes an esterification reaction with methanol to obtain L-proline methyl ester hydrochloride. Ammonolysis of hydrochloride gives L-prolineamide. The L-prolineamide synthesis solution obtained by the preparation process mainly contains two impurities, ammonium chloride and L-prolineamide hydrochloride. In order to remove the by-product ammonium chloride, the purified L-prolineamide crude product needs to be After several recrystallizations, and because the alkalinity of ammonia gas is we...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 吕华成杨会林王臻朱国荣屠勇军
Owner ZHEJIANG TIANYU PHARMA