Process for preparing bepotastine and intermediates used therein

A technology of bepotastine and intermediates, applied in the preparation of bepotastine and the field of intermediates used therein, can solve problems such as not being effective

Inactive Publication Date: 2010-03-24
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this racemization process requires high temperature conditions in butanol in the presence of base, which is not efficient

Method used

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  • Process for preparing bepotastine and intermediates used therein
  • Process for preparing bepotastine and intermediates used therein
  • Process for preparing bepotastine and intermediates used therein

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0031] Step 5) preparation of bepotastine

[0032] In reaction step 5), bepotastine l-menthyl ester of formula (IV) is hydrolyzed in the presence of a base to produce bepotastine.

[0033] Sodium hydroxide, potassium hydroxide, or the like can be used in an amount of 1 to 5 equivalents based on bepotastine l-menthyl ester.

[0034] This hydrolysis reaction is carried out in a mixture of water and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran at a temperature between 10°C and 60°C. Preferably, the mixing ratio of water and organic solvent is 1:0.05-1:20.

[0035] In addition, the present invention may further comprise the following step: after filtering the bepotastine l-menthyl ester N-benzyloxycarbonyl L-aspartic acid of the formula (III) precipitated in the reaction step 2), recovering rich Bepotastine l-menthyl ester containing (R)-isomer and treatment of recovered material with acid to...

preparation example 1

[0059] Preparation Example 1: Preparation of l-menthyl 4-bromobutyrate

[0060] 14.6g of 1-menthol and 14.8ml of pyridine were dissolved in 150ml of dichloromethane, and the solution obtained by dissolving 17.0g of 4-bromobutyryl chloride in 20ml of dichloromethane was slowly added dropwise to it, and the resulting mixture was cooled to room temperature. Stir for 1 hour. The reaction mixture was washed with 100 ml of water and the solvent was removed under reduced pressure to afford 27 g (97%) of the title compound as an oil.

[0061] 1 H-NMR (DMSO-d 6 , ppm): δ4.7(m, 1H), 3.5(t, 2H), 2.5(t, 2H), 2.2(m, 2H), 2.0(m, 1H), 1.9(m, 1H), 1.7( m, 2H), 1.5 (m, 1H), 1.3 (m, 1H), 1.1 (m, 3H), 0.9 (d, 6H), 0.7 (d, 3H).

[0062] IR (KBr, cm -1 ): 2956, 2928, 2870, 1729, 1456, 1370, 1251, 1205, 1177, 1129, 984.

preparation example 2

[0063] Preparation Example 2: Preparation of l-menthyl 4-chlorobutyrate

[0064] 1.0g of 1-menthol and 1.0ml of pyridine were dissolved in 5.0ml of dichloromethane, and the solution obtained by dissolving 0.7ml of 4-chlorobutyryl chloride in 5.0ml of dichloromethane was slowly added dropwise to it, and the resulting The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 20 ml of water, and the solvent was removed under reduced pressure to obtain 1.6 g (99%) of the title compound as an oil.

[0065] 1 H-NMR (DMSO-d 6 , ppm): δ4.7(m, 1H), 3.6(t, 2H), 2.5(t, 2H), 2.1(m, 2H), 2.0(m, 1H), 1.9(m, 1H), 1.7( m, 2H), 1.5(m, 1H), 1.4(m, 1H), 1.2(m, 3H), 0.9(d, 6H), 0.8(d, 3H).

[0066] IR (KBr, cm -1 ): 2956, 2929, 2869, 1729, 1456, 1386, 1371, 1308, 1204, 1177, 1010, 984, 964, 913.

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Abstract

A process for stereospecific preparation of bepotastine of formula (I) and novel intermediates used therein having formulae (II) to (IV) are provided. The inventive process comprises subjecting (RS)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine to a reaction with a 4-halobutanoic acid l-menthyl ester, halo being chloro, bromo or iodo, in an organic solvent in the presence of a base to produce (RS)-bepotastine l-menthyl ester of formula (II), conducting a reaction of the compound of formula (II) with N-benzyloxycarbonyl L-aspartic acid in an organic solvent to induce selective precipitationof bepotastine l-menthyl ester.N-benzyloxycarbonyl L-aspartate of formula (III), filtering the precipitates formed in step 2) to isolate the compound of formula (III), treating the compound of formula(III) with a base to liberate bepotastine l-menthyl ester of formula (IV), and hydrolyzing the compound of formula (IV) in the presence of a base. The inventive process can provide bepotastine havinga high optical purity of not less than 99.5% in a high yield, and thus, is useful in the development of anti-histamines and anti-allergic agents.

Description

technical field [0001] The invention relates to a stereospecific preparation method of bepotastine and an intermediate used therein. Background technique [0002] Optically active bepotastine in formula (I), (+)-(S)-4-{4-[(4-chlorophenyl)-(pyridin-2-yl)methoxy]piperidine Base} butyric acid, is a selective antihistamine, as disclosed in JP 1998-237070. [0003] [0004] JP1998-237070 and JP2000-198784 disclose the preparation method of bepotastine as shown in reaction formula 1, it comprises by making (RS)-4-[(4-chlorophenyl) (pyridin-2-yl) Methoxy]piperidine (compound a) and the optically active (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitro-5-chlorophenylthio base) propionic acid (compound b) for optical resolution, via compound c to obtain the left-handed isomer (S)-(-)-4-[(4-chlorophenyl)(pyridin-2-yl)methoxy base] piperidine (compound d); and thereby prepare bepotastine. [0005] Reaction 1 [0006] [0007] However, the above method is complicated and uneco...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 河泰曦朴昌熙金元政赵秀花金汉卿徐贵贤
Owner HANMI SCI CO LTD
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