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Bilastine intermediate compound and preparation method thereof

A bilastine and compound technology, applied in the field of drug synthesis, can solve problems such as complex operation, long reaction route, and difficult purification of products, and achieve the effects of simple synthesis process, high yield and purity, and simple preparation method

Pending Publication Date: 2022-06-07
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] This reaction mainly has three disadvantages: ① raw material 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propene and catalyst bis(dibenzylideneacetone) palladium and tri-tert-butyl Phosphorous bases are extremely expensive, difficult to buy, and difficult to store; 2. This reaction requires extremely strict anhydrous and oxygen-free conditions, the operation is complicated, and the resulting product is difficult to purify; 3. After the reaction is completed, the remaining palladium and phosphorus will serious pollution of the environment
[0037] But compound 4-formylpiperidine-1-carboxylate tert-butyl ester and 2-methyl-2-(4-(2-(tosyloxy) ethyl) phenyl) sodium propionate in this reaction scheme All can not be purchased from the market, so the reaction route is longer, in addition, in the bilastine synthesis process, need to carry out 20 hours of purification, prolong the processing time greatly, reduce industrial production efficiency

Method used

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  • Bilastine intermediate compound and preparation method thereof
  • Bilastine intermediate compound and preparation method thereof
  • Bilastine intermediate compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083]At room temperature, 1-(2-ethoxyethyl)-2-(piperidine-4-yl)-1H-benzo[d]imidazole (54.68g, 0.20mol), triethylamine (44.52g, 0.44mol) was added to N, N-dimethylformamide (300ml), added (E)-1,2-dibromoethylene (39.03g, 0.21mol) of N, N-dimethylformamide (100ml) solution, temperature control 80 ~ 85 ° C reaction, after the detection of the reaction, will The reaction liquid was cooled to room temperature, filtered, the filtrate was added to purified water (2000ml), dichloromethane (600ml×3) extracted, combined organic phase, saturated brine (500ml×2) washed, anhydrous sodium sulfate dried, filtered filtrate was concentrated to dry I-1, yield 85.3%, HPLC purity 99.63%.

[0084] Synthesis of compound I-2

Embodiment 2

[0086] Argon protects the room temperature, the compounds I-1 (37.83g, 0.10 mol), binborate pinaol ester (SM-1, 33.01 g, 0.13 mol), potassium acetate (15.70 g, 0.16 mol), Pd (PPh 3 ) 4 (5.78g, 5.0mmol) was added to dimethyl sulfoxide (250ml), the temperature control was 100 ~ 105 °C reaction, after the detection of the reaction, the reaction solution was reduced to room temperature, add K 3 PO 4 (33.96g, 0.16mol) purified water (110ml) solution, 2-(4-bromophenyl)-2-methylpropionate methyl ester (SM-2,51.42g, 0.20mol), temperature control 95~ 100 °C reaction, after the detection of the reaction, filtration, the filtrate was added to purified water (500ml), ethyl acetate (200ml×3) extraction, combined organic phase, anhydrous sodium sulfate dried, filtered, filtrate decompression concentration to dry intermediate I-2, Yield 86.6%, HPLC purity 99.66%.

Embodiment 3

[0088] Under argon protection at room temperature, compoundSY-1 (37.83g, 0.10mol), pinnacol biborate (25.39g, 0.1 mol), K 2 CO 3 (22.11g，0.16mol)、Pd(PPh 3 ) 4(5.78g, 5.0mmol) added to dimethyl sulfoxide (250ml), temperature control 105 ~ 110 °C reaction, after the detection of the reaction, the reaction solution dropped to room temperature, addED KOAc (15.70g, 0.16mol) purified water (110ml) solution, 2-(4-bromophenyl)-2-methylpropionate methyl ester (SM-2,38.57g, 0.15mol), temperature control 95 ~ 100 °C reaction, after the detection of the reaction, filtered, The filtrate was added to purified water (500ml), ethyl acetate (200ml×3) was extracted, combined with the organic phase, anhydrous sodium sulfate dried, filtered, and the filtrate was concentrated to dry after the intermediate I-2 was prepared, with a yield of 82.5% and a PURITy of 99.32% hplc.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a bilastine intermediate compound and a preparation method thereof. According to the invention, (E)-2-(1-(2-bromovinyl) piperidine-4-yl)-1-(2-ethoxy ethyl)-1H-benzo [d] imidazole as a starting material reacts with bis (pinacolato) diboron and 2-(4-bromophenyl)-2-methyl propionate to obtain a new intermediate compound methyl (E)-2-(4-(2-(4-(1-(2-ethoxy ethyl)-1H-benzo [d] imidazole-2-yl) piperidine-1-yl) vinyl) and phenyl)-2-alpha, alpha methyl propionate. Meanwhile, the invention provides a method for preparing an important bilastine intermediate 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-alpha, alpha-dimethyl methyl phenylacetate by reducing the novel intermediate compound. The synthesis method of the novel intermediate is simple, the synthesized important bilastine intermediate has higher yield and purity compared with the prior art, and the synthesis method is simple, convenient and safe to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a bilastine intermediate compound and a preparation method thereof. Background technique [0002] Bilastine, the chemical name is 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-B Base]-α,α-dimethylphenylacetic acid, CAS No. 202189-78-4, is an oral second-generation non-sedating histamine H developed by Spanish FAES pharmaceutical company 1 Receptor antagonist, approved by the European Union in August 2012 for the treatment of allergic rhinitis and urticaria. This product selectively acts on peripheral histamine receptors, has no effect on other histamine receptors, has no cardiotoxicity, is rapidly absorbed after oral administration, and has good tolerance, safety and high bioavailability. [0003] Its chemical structural formula is: [0004] [0005] For the synthesis of bilastine, the most commonly used method is to first synthesize ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 张贵民刘加成刘统
Owner LUNAN PHARMA GROUP CORPORATION
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