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(S)-N-methoxy-methyl-2-(pyrrolidine) propionamide and preparation method and application thereof

A technology of tetrahydropyrrolyl and methoxy, which is applied in the field of synthesis of efavirenz chiral ligands, can solve the problems of difficulty in obtaining and limiting the preparation of chiral ligands, and achieve simple operation, great implementation value and Socioeconomic benefits, the effect of mild reaction conditions

Active Publication Date: 2014-12-17
HANGZHOU OULIAN MEDICINE SCI & TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] There are not many reports about its synthesis, and the literature (J.Org.Chem.1998,63,8536-8543) has reported that taking norephedrine hydrochloride as a starting material, under alkaline conditions with 1,4-dibromo Butane reaction makes this chiral ligand (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl) propan-1-alcohol, and this method needs to use norephedrine as starting material, because norephedrine Ephedrine is a precursor raw material, which is controlled by the public security department according to the "Regulations on the Safety Management of Hazardous Chemicals" and "Regulations on the Administration of Precursor Chemicals", and is not easy to obtain, thus limiting the preparation of the chiral ligand

Method used

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  • (S)-N-methoxy-methyl-2-(pyrrolidine) propionamide and preparation method and application thereof
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  • (S)-N-methoxy-methyl-2-(pyrrolidine) propionamide and preparation method and application thereof

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Experimental program
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Embodiment 1

[0036] Embodiment 1: the preparation of (S)-tert-butoxycarbonylalanine

[0037] Will K 2 CO 3(30.1g, 217.8mmol) and L-alanine (10g, 112.3mmol) were dissolved in water (80mL), under nitrogen protection, a THF solution of di-tert-butyl dicarbonate (25.7g, 118mmol) was dissolved at 0°C ( 40 mL) was slowly added dropwise to the above solution to maintain the pH at 10-12. Stirring was continued at room temperature for 8 h. TLC showed that there was no remaining raw material. After the reaction was complete, the reaction was concentrated under reduced pressure to remove the solvent, and acidified with citric acid until pH = 2. Extracted with ethyl acetate (100 mL×3), dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure to obtain 18.5 g of (S)-tert-butoxycarbonylalanine as a white solid, with a yield of 86%. Melting point: 75-77°C.

Embodiment 2

[0038] Embodiment 2: the preparation of (S)-benzyloxycarbonylalanine

[0039] Sodium hydroxide (4.48g, 112mmol) and L-alanine (5g, 56.2mmol) were dissolved in water (40mL), under nitrogen protection, benzyl chloroformate (10.3g, 60mmol) was slowly added dropwise at 0°C Into the above solution, maintain the pH at 10-12. Stirring was continued at room temperature for 6 h. TLC showed that there was no raw material remaining. The reaction was completed, and citric acid was added to adjust the pH to 2. Extracted with ethyl acetate (50 mL×3), dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure to obtain (S)-benzyloxycarbonylalanine as a white solid 9.1 g, yield 73%. Melting point: 83-85°C.

Embodiment 3

[0040] Embodiment 3: Preparation of (S)-tert-butoxycarbonyl amino-1-methyl (methoxy) amino-propionamide

[0041] Dissolve (S)-tert-butoxycarbonylalanine (15g, 79.3mmol) in dichloromethane (200mL), slowly add carbonyldiimidazole (14.2g, 87.3mmol), and stir at room temperature for 1 hour. Then N,O-dimethylhydroxylamine hydrochloride (8.5 g, 87.3 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Ethyl acetate (100mL×3) was added for extraction, and the combined organic phases were washed with 1mol / L HCl aqueous solution (20mL×2), saturated NaHCO 3 Aqueous solution (30mL×2), washed with saturated brine (40mL×2). The organic phase was dried over anhydrous sodium sulfate. Concentrate under reduced pressure and evaporate the solvent to obtain 18.3 g of (S)-tert-butoxycarbonylamino-1-methyl(methoxy)amino-propionamide as a white solid, with a yield of 99%. m.p.: 144.5°C, literature 144±5°C.

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Abstract

The invention discloses a (S)-N-methoxy-methyl-2-(pyrrolidine) propionamide shown as a formula (5). A preparation method is as follows: subjecting a starting material L-alanine to amino protection, reaction with N,O-dimethyl hydroxylamine hydrochloride, removal of amino protecting group, and alkylation; and subjecting the prepared compound shown as (5) to addition elimination and reduction to obtain an Efavirenz chiral ligand shown as the formula (7). The synthetic method of Efavirenz chiral ligand provided by the invention has the advantages of mild reaction conditions, simple operation, high yield and low production cost, and is suitable for industrialized production.

Description

(1) Technical field [0001] The invention relates to (S)-N-methoxy-methyl-2-(tetrahydropyrrolyl)propionamide, a preparation method thereof, and an application in the synthesis of efavirenz chiral ligands. (2) Background technology [0002] Efavirenz, English: Efavirenz, is a specific drug against HIV. It is a drug belonging to the category of non-nucleoside reverse transcriptase inhibitor (NNRTI--non-nucleoside reverse transcriptase inhibitor), which can be used in highly active antiretroviral therapy for the treatment of class A human immune virus (HIV type1) . (1R,2S)-1-Phenyl-2-(1-pyrrolidinyl)propan-1-ol, English name: (1R,2S)-1-Phenyl-2-(1-pyrrolidinyl)propan-1- ol (CAS: 127641-25-2) is an important chiral ligand for the synthesis of efavirenz, and its structural formula is as follows: [0003] [0004] There are not many reports about its synthesis, and the literature (J.Org.Chem.1998,63,8536-8543) has reported that taking norephedrine hydrochloride as a starting ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/15C07D295/092
CPCY02P20/55C07D295/15C07D295/092
Inventor 张兴贤
Owner HANGZHOU OULIAN MEDICINE SCI & TECH CO LTD
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