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Preparation method of bilastine intermediate

A compound and reaction technology, applied in the field of preparation of bilastine intermediates, can solve the problems of increasing the amount of catalyst, severe reaction exotherm, affecting the reaction efficiency, etc., so as to improve experimental safety, reduce extraction times, and mild reaction conditions. Effect

Inactive Publication Date: 2020-04-21
厦门云凡医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] There are following defects in these two steps of reaction: 1, the first step quenches reaction with water, emits a large amount of heat, increases the danger of experiment on the one hand, produces a large amount of aluminum hydroxide after aluminum trichloride is quenched with water, gives back Great inconvenience to deal with
The second step uses titanium tetrachloride and triethylsilane. Because titanium tetrachloride is highly hygroscopic, it is necessary to keep the reaction system dry. For example, the product compound 4 of the first step needs to be dried, and the reaction vessel also needs to be dried, otherwise Affect the activity of titanium tetrachloride, increase the amount of catalyst and affect the reaction efficiency
[0011] It can be said that the method reported in the prior art has a strong reaction exotherm, and there is a large safety hazard; and the demanding anhydrous operation is not suitable for industrial production

Method used

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  • Preparation method of bilastine intermediate
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  • Preparation method of bilastine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1 A kind of new preparation method of compound 2

[0030]

[0031] 1. Add 1000mL dichloromethane, 230.00g, 1.73mol anhydrous aluminum trichloride to the flask in turn;

[0032] 2. At -5°C, slowly drop 100.00 g, 0.56 mol of compound 3 (dissolved in a small amount of dichloromethane) into the flask; then slowly drop 76.00 g, 0.67 mol of chloroacetyl chloride, and raise the temperature to 20 ℃ reaction, TCL monitors the reaction, and the reaction is completed in 3 hours;

[0033] 3. Cool the reaction solution to -5°C, slowly add 75.50 g, 0.56 mol 1,1,3,3-tetramethyldisiloxane dropwise, monitor the reaction with TCL, and complete the reaction in 1 hour;

[0034] 4. Cool down to -5°C, slowly drop the reaction solution into water to quench; separate the liquid, wash the organic phase once with saturated NaCl solution, dry, and distill off the solvent under reduced pressure to obtain a crude product; the crude product is distilled under reduced pressure again to...

Embodiment 2

[0037] Embodiment 2 A kind of new preparation method of compound 2

[0038] 1. Add 1000mL dichloromethane, 230.00g, 1.73mol anhydrous aluminum tribromide to the flask in turn;

[0039] 2. At -5°C, slowly drop 100.00g, 0.56mol of compound 3 (dissolved in a small amount of methylene chloride) into the flask; ℃ reaction, TCL monitors the reaction, and the reaction is completed in 3 hours;

[0040] 3. Cool the reaction liquid to -5°C, slowly add 75.50 g, 0.56 mol 1,1,3,3-tetramethyldisiloxane dropwise, monitor the reaction with TCL, and the reaction is completed in 1 hour;

[0041] 4. Cool down to -5°C, slowly drop the reaction solution into water to quench; separate the liquid, wash the organic phase once with saturated NaCl solution, dry, and distill off the solvent under reduced pressure to obtain a crude product; the crude product is distilled under reduced pressure again to obtain compound 2 The refined product 106.50g, GC detection purity 96.2%.

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Abstract

The invention discloses a preparation method of a bilastine intermediate, and relates to the technical field of organic matter synthesis. The bilastine intermediate is a compound 2. The preparation method comprises the following steps: carrying out a substitution reaction on a compound 3, halogenated acetyl halide and aluminum trihalide in an organic solvent, directly adding 1,1,3,3-tetramethyldisiloxane (TMDS) into a reaction solution after the reaction is finished, carrying out a reduction reaction, and dropwise adding the reaction solution into water after the reaction is finished in orderto carry out a quenching reaction. The substitution reaction of the compound 3 and chloroacetyl chloride and the carbonyl reduction reaction of the compound 4 can be carried out by a one-pot method, the TMDS is directly added after the reaction of the first step is finished, the quenching reaction is carried out after the reaction of the second step is finished, the heat release of the quenching reaction is not obvious, and the experiment safety is improved; and in the second-step reaction, 1,1,3,3-tetramethyldisiloxane is adopted, strict anhydrous conditions are not needed, the operation is simple and convenient, and the reaction conditions are mild.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing a bilastine intermediate. Background technique [0002] The chemical name of bilastine is 2-[4-[2-[4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]piperidin-1-yl]ethyl ]phenyl]-2-methylpropionic acid, the structural formula is: [0003] [0004] It is an antihistamine with a new chemical structure developed by Spain's FAES Pharmaceutical Company. The drug has no sedative effect, no cardiotoxicity, does not interact with cytochrome P450 enzyme substrates, and has the characteristics of a strong antihistamine, which meets the current standards of the European Society of Allergy and Clinical Immunology and the impact of allergic rhinitis on asthma Standard requirements for therapeutic drugs for the treatment of allergic diseases. Bilastine is now approved in the EU for the treatment of allergy, urticaria and allergic rhinitis in adults and adolescent...

Claims

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Application Information

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IPC IPC(8): C07C67/317C07C69/65
CPCC07C67/313C07C67/317C07C69/65C07C69/738
Inventor 叶兆宝李科翁善晖罗善梅
Owner 厦门云凡医药科技有限公司
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