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Synthetic method of bilastine intermediate

A synthesis method, the technology of bilastine, applied in the field of synthesis of bilastine intermediates, can solve the problems of difficult industrial operation, large pollution in the synthesis process, long synthesis process, etc., to achieve convenient operation and avoid isomers The effect of too much, too little solvent

Active Publication Date: 2021-05-11
湖北英纳氏生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In the synthesis process, methyl iodide, sodium cyanide, and ethylene oxide react with bromobenzene under the action of Grignard reagent or n-butyllithium. The whole synthesis process is long and difficult for industrialization.
[0017] α,α-Dimethylphenylacetic acid methyl ester generally adopts a method similar to the methylation method. Under the action of methylating reagents such as methyl iodide or dimethyl sulfate, phenylacetonitrile has two methyl groups through sodium amide or sodium hydride. Then it is hydrolyzed into carboxylic acid, and then esterified. The synthesis process is very polluting, flammable and explosive, and not easy to industrialize.

Method used

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  • Synthetic method of bilastine intermediate
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  • Synthetic method of bilastine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 α, the preparation of α-dimethylphenylacetic acid methyl ester

[0042] 200g of benzene, add 40g of hexafluoroisopropanol, stir at room temperature, dropwise add 100g of α-methyl methacrylate, stir at room temperature for 10-15 hours to complete the reaction, recover excess benzene under reduced pressure at 30-40°C, and recover hexafluoroisopropanol Wash with propanol, adjust the water phase to pH=7-9, separate the liquid, dry the organic phase, and distill to obtain 125g of intermediate compound A with a purity of 98% and a yield of 70%.

Embodiment 2

[0043] Example 2 Preparation of α, α-dimethylphenylacetyl diisopropylamine

[0044] 100g of compound A and 200g of diisopropylamine were mixed and stirred at room temperature. After the reaction was complete, the diisopropylamine was recovered by distillation under reduced pressure, washed with water, and dried to obtain 160g of intermediate compound B with a yield of 92%.

Embodiment 3

[0045] Example 3 Preparation of α,α-dimethyl-4-(2-hydroxyethyl)phenylacetyldiisopropylamine

[0046] Cool down 100g of compound B to 0°C, add 50g of ethylene oxide, dropwise add 200g of hexafluoroisopropanol, and stir at 0-5°C to complete the reaction. After the reaction, recover hexafluoroisopropanol under reduced pressure at 30-40°C, wash and dry 106 g of α,α-dimethyl-4-(2-hydroxyethyl)phenylacetyldiisopropylamine was obtained with a purity of 99% and a yield of 90%.

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Abstract

The invention discloses a synthetic method of a bilastine intermediate, and belongs to the technical field of organic synthesis. The method comprises the steps of (1) carrying out Friedel-Crafts reaction on benzene and alpha-methyl methacrylate in fluoroalcohol A at the temperature of -15 to 25 DEG C to obtain a compound A; (2) carrying out amine ester exchange reaction on the compound A and diisopropylamine at the temperature of 20-50 DEG C to obtain a compound B; and (3) carrying out Friedel-Crafts reaction on the compound B and ethylene oxide in fluoroalcohol B at the temperature of -15 to 25 DEG C to obtain the bilastine intermediate. According to the method, cheap benzene is taken as a raw material, and the intermediate alpha, alpha-dimethyl-4-(2-ethoxyl) phenylacetyldiisopropylamine is obtained through Friedel-Crafts alkylation, amine ester exchange and further Friedel-Crafts alkylation. In the step (2), a diisopropyl group is relatively large, so that the positioning effect is changed, and the problem of excessive isomers in the Friedel-Crafts alkylation process is avoided. The proportion of Friedel-Crafts alkylation para-position and meta-position products can be 95% or above.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a bilastine intermediate. Background technique [0002] Bilastine (Bilst for short), the chemical name is 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzimidazol-2-yl}B base)-phenyl]2-methyl-propionic acid, cas number 202189-78-4. Bilastine is an oral second-generation histamine H1 receptor antagonist developed by Spanish FAES Pharmaceutical Company. It was registered as a new drug in the European Union in 2009, and was first approved for marketing in the UK and Ireland in 2011, and then successively marketed in Italy, Japan, Canada and other countries. It is used for the treatment of seasonal allergic rhinitis and perennial allergic rhinitis. The dosage specification is 20mg / piece. Other approved indications include pruritus, eczema and hives. This product is safe, without the sedative effect and cardiotoxicity of commonly used antihistamines. ...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C235/34C07C231/02C07C233/11C07C67/343C07C69/612
CPCC07C231/12C07C231/02C07C67/343C07C69/612C07C233/11C07C235/34
Inventor 王海李健雄
Owner 湖北英纳氏生物科技有限公司
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