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Stereomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid and preparation method for salt thereof

A phenyl and aryl technology, applied in the field of preparation of isomers and their salts, can solve the problems of high price, high preparation cost, and low optical purity of products

Inactive Publication Date: 2012-02-08
WUHAN QR PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the literature reports the direct absolute configuration preparation method of related impurities. The literature (J.Med.Chem.1988, 31, 1148-1160) reports the preparation of one of the diastereomers with (2S)-4-oxoproline Construct (2S, 4R)-4-phenylpyrrolidine-2-carboxylic acid (the route is as follows), but the price of (2S)-4-oxoproline in this route is higher, the preparation cost is high, and the preparation The optical purity of the product is low

Method used

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  • Stereomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid and preparation method for salt thereof
  • Stereomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid and preparation method for salt thereof
  • Stereomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid and preparation method for salt thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of embodiment 1.D-hydroxyproline methyl ester hydrochloride

[0043] Add 100ml of anhydrous methanol to a 250ml three-necked flask, and stir for 0.5h under ice bath. Acetyl chloride (8.67g, 0.11mol) was dripped into the reaction solution, stirred at this reaction temperature for 1h, D-hydroxyproline hydrochloride (10g, 0.06mol) was added in batches, and the reaction solution was slowly heated to Reflux, reaction about 10h. TLC detects that the reaction is complete. The solvent was evaporated to dryness to obtain 11.2 g of a light yellow oil, which was then slurried with 30 ml of anhydrous ether for 5 hrs, filtered, and vacuum-dried to obtain 10.3 g of white solid D-hydroxyproline methyl ester hydrochloride with a yield of 95%.

Embodiment 2

[0044] The preparation of embodiment 2.1-benzoyl-D-hydroxyproline methyl ester

[0045] 60ml of water and 30ml of dioxane were added to a 250ml three-necked flask, and D-hydroxyproline methyl ester hydrochloride (10.3g, 0.057mol) was added in batches, stirred for 0.5h under ice bath, and triethylamine ( 12.6g, 0.125mol), complete, slowly add dropwise benzoyl chloride (8.13g, 0.0578mol) diluted with 30ml dioxane, move to normal temperature after stirring for 3h, TLC detection (DCM:MeOH=5:1, Ninhydrin color development) reaction is complete. Evaporate the solvent to dryness, add 200ml ethyl acetate and 100ml water, let stand to separate the layers, extract the aqueous layer with ethyl acetate (100ml×3), combine the ethyl acetate layers, and wash with saturated NaHCO3 (50ml×2), 10% Citric acid (50ml×2), finally dried with 20g of anhydrous sodium sulfate for 5h, evaporated to dryness to obtain 19.5g of off-white viscous substance, added 30ml of ethyl acetate, beat for 5h, filtere...

Embodiment 3

[0046] Preparation of Example 3.1-benzoyl-4-trans-(methylsulfonyloxy)-D-proline

[0047] Add toluene (64ml) and methanesulfonic acid (2.5ml, 0.038mol) to 250mL three-hole round bottom burner, add triethylamine (5.6ml, 0.038mol) under mechanical stirring, heat up to 55°C, add triphenylphosphine (10.5 g, 0.04mol), 1-benzoyl-D-hydroxyproline methyl ester (8.0g, 0.032mol), under the protection of nitrogen, add diisopropyl azodicarboxylate (8ml, 0.04mol) dropwise, and add , heated up to 75-85°C, and reacted for 5h. TLC detected that the reaction was complete, stopped heating, controlled the internal temperature to 0-5°C under ice bath, added dropwise sodium hydroxide aqueous solution (2g sodium hydroxide dissolved in 58mL water, 1.5eq), stirred at 0-5°C for 5-6h, Use concentrated hydrochloric acid to adjust pH=6~7 (9mL of concentrated hydrochloric acid is consumed), and stir at 0~5°C for 1h. Filter, wash the reaction bottle and filter cake with ice water (12ml×2), let the filtrat...

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Abstract

The invention discloses isomers of (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid (D) and a preparation method for salt thereof, and particularly discloses diastereoisomers [(2R,4S)-4-phenylpyrrolidine-2-carboxylic acid (A) and (2S, 4R)-4-phenylpyrrolidine-2-carboxylic acid (B)] and an enantiomer (C) of the (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid (D) and a preparation method for the salt thereof. In the preparation method disclosed by the invention, the corresponding isomers A, B and C are obtained by taking D-hydroxyproline or L-hydroxyproline as a starting material through esterification, hydroxyl protection, sulphur esterification, Friedel-Craft alkylation, hydrolysis and deprotection reaction. The compounds are used for preparing anti-cardiovascular disease drugs and controlling the quality of the drugs.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a preparation method of an isomer of (2S, 4S)-4-phenylpyrrolidine-2-carboxylic acid and a salt thereof. Background technique [0002] Fosinopril is a new type of angiotensin-converting enzyme inhibitor, which can reduce the content of angiotensin II and dilate blood vessels, thereby lowering blood pressure. The impurity D mentioned in the USP standard for fosinopril sodium involves the corresponding isomer. The current literature reports the direct absolute configuration preparation method of related impurities. The literature (J.Med.Chem.1988, 31, 1148-1160) reports the preparation of one of the diastereomers with (2S)-4-oxoproline Construct (2S, 4R)-4-phenylpyrrolidine-2-carboxylic acid (the route is as follows), but the price of (2S)-4-oxoproline in this route is higher, the preparation cost is high, and the preparation The optical purity of the product is low. [000...

Claims

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Application Information

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IPC IPC(8): C07D207/16
Inventor 许全胜刘勇潘新周晓丽王朝东
Owner WUHAN QR PHARMA CO LTD
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