Preparation method of caine drug intermediate (S)-2-piperidinecarboxylic acid

A technology of piperidinecarboxylic acid and cyanopiperidine is applied in the field of preparation of caine-type drug intermediate-2-piperidinecarboxylic acid, which can solve the problems such as difficulty in obtaining starting materials, high production cost, complicated steps, etc. Mild conditions, improved safety, and good reaction yield

Active Publication Date: 2021-06-18
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In summary, the synthetic methods of (S)-2-piperidinecarboxylic acid reported in the literature have disadvantages such as difficult availability of starting materials, expensive noble metal catalysts, cumbersome steps, low yields, and high production costs.

Method used

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  • Preparation method of caine drug intermediate (S)-2-piperidinecarboxylic acid
  • Preparation method of caine drug intermediate (S)-2-piperidinecarboxylic acid
  • Preparation method of caine drug intermediate (S)-2-piperidinecarboxylic acid

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Experimental program
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Embodiment 1

[0044] The synthesis of embodiment 1 compound I

[0045] Add 1g (8.3mmol) of 5-chlorovaleraldehyde, 1.25g (9.13mmol) of L-phenylglycinol, and 1g (10mmol) of trimethylsilylcyanide into the reaction flask, and then add 115mg (0.415mmol) of magnesium diiodide , Stir the reaction at room temperature (25° C.) for 4 h. TLC monitors the reaction process. After the reaction is completed, the reaction solution is purified by silica gel column chromatography. The eluent is sherwood oil: ethyl acetate (volume ratio: 5: 1), and after concentration, 209 mg of light yellow oily product I is obtained. The yield is 95%. HPLC area normalization method detection purity is 98% [chromatographic condition: chromatographic column Kromasil C 18Column (4.6mm×250mm, 5μm), mobile phase: acetonitrile-water (volume ratio 70:30), detection wavelength: 254nm, column temperature: 25°C, flow rate: 1.0mL·min -1 ]. Optical purity 98% [chromatographic conditions: chiral chromatographic column CHIRALPAK AD-H...

Embodiment 2

[0046] The synthesis of embodiment 2 compound I

[0047] Add 1g (8.3mmol) of 5-chlorovaleraldehyde, 1.25g (9.13mmol) of L-phenylglycinol, and 1g (10mmol) of trimethylsilylcyanide into the reaction flask, and then add 76mg (0.415mmol) of magnesium dibromide , Stir the reaction at room temperature (25° C.) for 6 h. TLC monitors the reaction process. After the reaction is completed, the reaction solution is purified by silica gel column chromatography. The eluent is sherwood oil: ethyl acetate (volume ratio: 5: 1). After concentration, 171 mg of the light yellow oily product I is obtained. The yield is 78%. HPLC area normalization method detection purity is 98% [chromatographic condition: chromatographic column Kromasil C 18 Column (4.6mm×250mm, 5μm), mobile phase: acetonitrile-water (volume ratio 70:30), detection wavelength: 254nm, column temperature: 25°C, flow rate: 1.0mL·min -1 ]. Optical purity 98% [chromatographic conditions: chiral chromatographic column CHIRALPAK AD-...

Embodiment 3

[0048] The synthesis of embodiment 3 compound I

[0049] Add 1g (8.3mmol) of 5-chlorovaleraldehyde, 1.25g (9.13mmol) of L-phenylglycinol, and 1.2g (12mmol) of trimethylsilylcyanide into the reaction flask, and then add 186mg (0.8mmol) of magnesium perchlorate ), stirred at room temperature (25° C.) for 8 h. TLC monitors the reaction process. After the reaction is completed, the reaction solution is purified by silica gel column chromatography. The eluent is sherwood oil: ethyl acetate (volume ratio: 5: 1), and after concentration, 158 mg of light yellow oily product I is obtained. 72%. HPLC area normalization method detection purity is 98% [chromatographic condition: chromatographic column Kromasil C 18 Column (4.6mm×250mm, 5μm), mobile phase: acetonitrile-water (volume ratio 70:30), detection wavelength: 254nm, column temperature: 25°C, flow rate: 1.0mL·min -1 ]. Optical purity 97% [chromatographic conditions: chiral chromatographic column CHIRALPAK AD-H (250mm×4.6mm, 5μm...

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Abstract

The invention discloses a preparation method of a caine drug intermediate (S)-2-piperidinecarboxylic acid. The preparation method specifically comprises the following steps of a) carrying out a one-pot reaction on 5-chlorovaleraldehyde, L-phenylglycinol and trimethylsilyl cyanide under the action of a catalyst A to obtain a compound as shown in a formula (I), wherein the catalyst A is magnesium diiodide, magnesium dibromide and magnesium perchlorate, (b) carrying out catalytic hydrogenation reaction on the compound as shown in the formula (I) to obtain (S)-2-cyano piperidine as shown in a formula (II), and (c) hydrolyzing the compound as shown in the formula (II) to obtain (S)-2-piperidinecarboxylic acid as shown in a formula (III). The preparation method utilizes cheap and easily available organic raw materials, and has the advantages of simple operation, mild reaction conditions, good stereoselectivity, high yield and the like.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of (S)-2-piperidinecarboxylic acid, an intermediate of caine drugs. Background technique [0002] (S)-2-piperidinecarboxylic acid is an unnatural amino acid that widely exists in plants, animals, and microorganisms, and it is also the main component of several secondary metabolites in plants and fungi. (S)-2-piperidinecarboxylic acid is an important fragment of many drugs or natural products, such as immunosuppressant rapamycin, FK506, or anti-tumor antibiotic sandamycin, etc., in which (S)-2-piperidine Formic acid is a key intermediate of local anesthetics ropivacaine, bupivacaine and mepivacaine. [0003] [0004] The synthetic method of (S)-2-piperidinecarboxylic acid mainly contains following several kinds: [0005] The literature (The Journal of organic chemistry, 2010, 75(6): 2077-2080) uses chiral amides as raw materials ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 杨玉燕张兴贤游中林
Owner ZHEJIANG UNIV OF TECH
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