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The preparation method of (s)-azetidine-2-carboxylic acid

A technology for azetidine and tetracyclobutane, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as difficult and low-cost target compounds, and achieves the effects of low cost of raw materials, improved splitting effect and short synthesis route.

Inactive Publication Date: 2015-10-07
中国科学院嘉兴应用化学工程中心
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] As mentioned above, the methods reported in the literature all have different shortcomings, and it is difficult to obtain optically pure target compounds at low cost and easily.

Method used

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  • The preparation method of (s)-azetidine-2-carboxylic acid
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  • The preparation method of (s)-azetidine-2-carboxylic acid

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Embodiment 1

[0033] Heat 500g of 1-benzylcyclobutane-2-carboxylic acid (synthesized according to Tetrahedron:Asymmetry, 1998, 9:429-435) in 3L of ethanol, then add 200g of D-α-phenylethylamine dropwise to form a salt, After dripping, continue to reflux for 0.5 hours. Then slowly lower to room temperature, stand still, precipitate crystals and filter, dissolve in 1L of water, then adjust the pH value to 10 with 10% NaOH solution, extract and recover D-α-phenylethylamine with dichloromethane; Adjust the pH value to 2 with hydrochloric acid, then extract with ethyl acetate, spin dry the solvent, and recrystallize the obtained solid with ethanol to obtain 189 g of white crystals (S)-1-benzylazetidine-2-carboxylic acid, HPLC>99%, ee>98%, yield 37.8%.

[0034] 1 H NMR (D 2 O,500MHz):δ2.39-2.43(m,1H,Aze-CH 2 ),2.60-2.64(m,1H,Aze-CH 2 ),3.81-3.85(m,1H,Aze-CH 2 ),3.96-4.00(m,1H,Aze-CH 2 ),3.3(q,J=13Hz,2H,Bn-CH 2 ), 4.727 (t, J=9.5Hz, 1H, Aze-CH), 7.408-7.412 (m, 5H, Bz-H).

[0035] Add 150...

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Abstract

The invention provides a method for preparing (S)-azetidine-2-carboxylic acid, which is an important intermediate for synthesizing a plurality of inhibitors. The method comprises the following steps of: (1) reacting 1-benzyl-azetidine-2-carboxylic acid and D-alpha-phenylethylamine in a solvent to form a salt, cooling, crystallizing and filtering, and carrying out pH value regulation and salt removing on the obtained solid to obtain a (S)-1-benzyl-azetidine-2-carboxylic acid coarse product; (2) re-crystallizing the coarse product by a solvent to obtain pure (S)-1-benzyl-azetidine-2-carboxylic acid; (3) performing debenzylation on the product in the second step to obtain (S)-azetidine-2-carboxylic acid. The preparation method provided by the invention has low-price and easily available raw materials, is convenient to operate, is low in cost and high in product purity, and has a great implementation value.

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of (S)-azetidine-2-carboxylic acid, which has strong biological activity and is an important intermediate for the synthesis of various inhibitors body. Background technique [0002] (S)-azetidine-2-carboxylic acid (L-Aze for short) is a special amino acid with a four-membered ring structure, which is an analog of proline. It was first discovered in 1955 by French scientist Fowden from the European plant Boll Convallaria Majalis (Convallaria Majalis) and Polygonatum (Polygonatum) are extracted and isolated, and it is the first confirmed compound containing azetidine structure in plants. Since then, many natural products such as Mugineic Acid and Nicotianamine have been found to contain this amino acid structure in their molecules. The compound has a wide range of bactericidal effects. Recently, some molecules with important pha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/04
Inventor 李佶辉费雅君张建荣常东亮
Owner 中国科学院嘉兴应用化学工程中心
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