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Method for preparing olopatadine hydrochloride

A technology of olopatadine hydrochloride and hydrochloric acid, which is applied in the field of preparation of olopatadine hydrochloride, can solve the problems of low yield, waste phosphoric acid, and unsuitability for industrial production, and achieve high yield, high total yield, low cost effect

Active Publication Date: 2015-01-07
仁合益康集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above two processes also have the disadvantages of low yield, a large amount of waste phosphoric acid, and not suitable for industrial production.

Method used

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  • Method for preparing olopatadine hydrochloride
  • Method for preparing olopatadine hydrochloride
  • Method for preparing olopatadine hydrochloride

Examples

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Comparison scheme
Effect test

Embodiment 1

[0035] Step 1. Preparation of Intermediate I

[0036] Methyl 2-chloromethylbenzoate (100g, 0.54mol) and methyl p-hydroxyphenylacetate (90g, 0.54mol) were dissolved in 1L of ethanol, and 1.08mol of acid-binding agent (see the table below for dosage) was added, heated to reflux, according to TLC (petroleum ether: ethyl acetate = 5:1) monitored the reaction end point, cooled to room temperature, vacuum filtered, the filter cake was washed with ethanol (200mL*2), and the filtrate was concentrated under reduced pressure to obtain a yellow oil, which was the intermediate I. Wherein, acid-binding agent dosage and test result are shown in the following table:

[0037]

[0038] Step 2. Preparation of Intermediate II

[0039] Intermediate I (160g, 0.51mol) and 3.2g TEBA were dissolved in ethanol, stirred, potassium hydroxide (60g, 1.07mol) was added, heated to reflux for 3h, ethanol was distilled off, and the residue was dissolved in 1L of water. Acidify with concentrated HCl to p...

Embodiment 2

[0051] Step 1. Preparation of Intermediate I

[0052] Methyl 2-chloromethylbenzoate (2kg, 10.8mol) and methyl p-hydroxyphenylacetate (1.8kg, 10.8mol) were dissolved in 20L ethanol, and potassium carbonate (3kg, 21.6mol) was added, heated to reflux for 24h, cooled to Suction filtration under reduced pressure at room temperature, the filter cake was washed with ethanol (4L*2), and the filtrate was concentrated under reduced pressure to obtain 3.26kg of intermediate I as a yellow oil, with a yield of 95.6%.

[0053] Step 2. Preparation of Intermediate II

[0054] Dissolve intermediate I (3.2kg, 10.2mol) and 34g TEBA in ethanol, stir, add potassium hydroxide (1.2kg, 21.4mol), heat to reflux for 3h, distill off ethanol, and dissolve the residue with 20L of water. Acidify with concentrated HCl to pH = 1-2 to generate a large amount of light yellow solid, filter with suction, wash the filter cake with water until neutral, and dry to obtain 2.42kg of light yellow solid, which is Inte...

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Abstract

The invention relates to a method for preparing a compound, namely, olopatadine hydrochloride. The method specifically comprises the following steps: by taking 2-chloromethyl methyl benzoate and methyl 4-hydroxyphenylacetate as initial raw materials, performing etherification, hydrolysis and cyclization, further performing wittig reaction, and salifying, thereby synthesizing olopatadine hydrochloride. The process is gentle in process reaction condition, acetic anhydride is adopted to replace polyphosphoric acid, a hydrochloric acid organic solvent is adopted to effectively split Z / E type olopatadine so as to obtain olopatadine hydrochloride, conversion of Z / E configuration is effectively achieved after an E configuration byproduct is treated by using concentrated hydrochloric acid, the yield of olopatadine hydrochloride is increased, the product purity is good, and the feasibility of industrialization production is greatly improved.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of olopatadine hydrochloride. Background technique [0002] Olopatadine hydrochloride is a highly selective inhibitor of H1 receptors and a mast cell membrane stabilizer. It has no effect on a-adrenergic receptors, dopamine receptors, M1 and M2 receptors, and has low side effects. The chemical name of olopatadine hydrochloride is: (Z)-11-(3-dimethylaminopropenyl)-6,11-dihydrodibenzo[b,e]oxazone-2-acetic acid hydrochloride , the structural formula is as follows: [0003] [0004] There are many methods for preparing olopatadine hydrochloride in the prior art, but there are many disadvantages such as complex process, low yield, high cost, serious environmental pollution, and difficulty in realizing industrialized production. [0005] For example, EP0235796 reports the synthesis method of olopatadine hydrochloride: the carboxyl group of isoket acid is protected and ...

Claims

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Application Information

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IPC IPC(8): C07D313/12
CPCC07D313/12
Inventor 何镭
Owner 仁合益康集团有限公司
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