阅读说明：本技术 比拉斯汀中间体的制备方法 (Preparation method of bilastine intermediate ) 是由 王坚 李彬 李朝阳 林浩 任国宝 吴彦 于 2019-10-10 设计创作，主要内容包括：本发明公开了一种比拉斯汀中间体的制备方法,利用硫酸乙烯酯的特殊活性构建Bilastine关键的季碳单元,避免了高毒性物料的使用,改善了可操作性,降低了工业化的生产成本。同时本发明利用中间体的独特性质和Bilastine原始合成策略相结合,设计了新的合成路线,一步同时脱除了两个保护剂,减少了合成步骤,降低了生产成本,同时避免了现有技术中的昂贵催化剂。(The invention discloses a preparation method of a Bilastine intermediate, which utilizes the special activity of vinyl sulfate to construct a Bilastine key quaternary carbon unit, avoids the use of high-toxicity materials, improves the operability and reduces the industrial production cost. Meanwhile, the unique property of the intermediate is combined with the original Bilastine synthesis strategy, a new synthesis route is designed, two protective agents are removed in one step, the synthesis steps are reduced, the production cost is reduced, and the expensive catalyst in the prior art is avoided.)

1. A preparation method of a bilastine intermediate is characterized in that the bilastine intermediate is a compound shown in a formula II, and the preparation method comprises the following steps:

wherein X is halogen, S1, S2 and S3 are reaction solvents, and Acid is Acid;

(1) carrying out lithium halide exchange on the compound III and a lithium reagent to obtain a corresponding phenyllithium compound;

(2) the phenyl lithium compound reacts with the vinyl sulfate of the formula IV in situ to obtain a compound V;

(3) reacting the compound V with acid to obtain a compound II.

2. The method of claim 1, wherein: the halogen is Cl, Br or I.

3. The method of claim 1, wherein: the reaction temperature of the compound III for lithium halide exchange with the lithium reagent is controlled to be-80 ℃ to-50 ℃.

4. The method of claim 1, wherein: the lithium reagent is n-butyllithium or sec-butyllithium.

5. The method of claim 1, wherein: the S1 is one or more selected from methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, n-hexane and toluene.

6. The method of claim 1, wherein: the S2 is one or more selected from methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, n-hexane and toluene.

7. The method of claim 1, wherein: the reaction temperature of the in situ reaction of the phenyllithium compound with the vinyl sulfate of formula IV is controlled to be from-80 ℃ to-20 ℃.

8. The method of claim 1, wherein: the S3 is selected from water or ethanol.

9. The method of claim 1, wherein: the reaction temperature of the reaction of the compound V with the acid is controlled to be 60 ℃ to 100 ℃.

10. The method of claim 1, wherein: the acid is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid, trifluoroacetic acid and methanesulfonic acid.

Technical Field

The invention relates to the technical field of medicine production, and particularly relates to a preparation method of a bilastine intermediate.

Background

Bilastine (English name Bilastine) bulk drug and tablet are the second generation of anti-histamine H1 receptor antagonists developed by Spanish FAES pharmacy, which were approved by the European Union for the treatment of allergic rhinitis and urtica at 26.8.2012, and clinical phase II trials are underway in the United states.

The synthesis of bilastine is not easy, and the difficulty mainly lies in the construction method and construction time of quaternary carbon in the compound II. Aiming at the core structure of bilastine, researchers continuously design a synthetic route and a synthetic method to solve the problem of industrial production. The FAES company reports the following route in patent ES2151442a 1:

according to the route, a quaternary carbon structure is firstly constructed by carrying out double methylation on methyl p-bromophenylacetate through α, then saponification and carboxyl protection are carried out, magnesium metallization or lithium metallization is carried out on bromine atoms, and then the obtained product is reacted with ethylene oxide to obtain an intermediate.

WO2009/102155a2 and US2011/9636a1 report the construction of very unstable tmsenol silyl ethers starting from isobutyrate at low temperatures, noble metal-catalyzed coupling reactions with p-bromophenyl ethanol under anhydrous and oxygen-free conditions, and finally hydrolysis to give the above structure II:

the method is novel, and a quaternary carbon and carboxylic acid structure is constructed in one step through a coupling reaction from a substrate containing a phenethyl alcohol structure, so that the method is efficient and novel. However, noble metal coupling reaction catalysts are expensive, the reaction conditions are harsh, the amplification effect is strong, the yield is low, and the application of the route in actual production is limited due to the difficulty in purification.

A Synthetic route to the construction of quaternary carbon para-phenylethanol structures using Still coupling with a vinyl tin reagent followed by hydroboration oxidation was reported by Collier et al in the academic paper of Synthetic Communications 2011 vol.41Page1394-1402:

the organotin reagent, the boron reagent and the palladium tetratriphenylphosphine catalyst adopted by the route are expensive and harsh in use conditions, and the organotin reagent has strong toxicity, borane dimethylsulfide is extremely toxic and has strong odor, and the environment is greatly polluted, so that the amplification risk is huge. This route is difficult to apply industrially.

CN104326909 reports a strategy for constructing a key structure starting from dimethyl phenylacetate by friedel-crafts reaction-carbonyl reduction:

the route reduces the cost of raw materials, but the application of the route in the industrial field is limited by the catalyst of the Friedel-crafts reaction and the harsh reduction conditions of the Huang-Minlon reaction which must be used for carbonyl reduction.

CN106146459A reports a strategy for constructing quaternary carbon units by the Suzuki european union reaction:

the route is expensive, and the main raw material and the catalyst are very expensive, so that the route is not suitable for industrial production.

CN103788003A reports the following synthetic strategy:

although the strategy avoids using ethylene oxide, dibromoethane with strong toxicity still needs to be used, which brings risks to production. In addition, the format reaction initiation requires higher temperature and has a greater risk.

As can be seen from the above review, the current synthesis strategies for the bilastine key intermediate II all have the disadvantages of high risk, high cost and high toxicity.

Disclosure of Invention

The invention aims to provide a preparation method of a Bilastine intermediate, which utilizes the special activity of vinyl sulfate to construct a critical quaternary carbon unit of Bilastine, avoids the use of high-toxicity materials, improves the operability and reduces the industrial production cost. Meanwhile, the unique property of the intermediate is combined with the original Bilastine synthesis strategy, a new synthesis route is designed, two protective agents are removed in one step, the synthesis steps are reduced, the production cost is reduced, and the expensive catalyst in the prior art is avoided.

The technical scheme adopted by the invention for solving the technical problems is as follows:

a preparation method of a bilastine intermediate is characterized in that the bilastine intermediate is a compound shown in a formula II, and the preparation method comprises the following steps:

wherein X is halogen, S1, S2 and S3 are reaction solvents, and Acid is Acid;

(1) carrying out lithium halide exchange on the compound III and a lithium reagent to obtain a corresponding phenyllithium compound;

(2) the phenyl lithium compound reacts with the vinyl sulfate of the formula IV in situ to obtain a compound V;

(3) reacting the compound V with acid to obtain a compound II.

The adopted vinyl sulfate is solid, has high safety compared with ethylene oxide, is convenient to feed, and is more suitable for industrial production.

The preferable mode of the step (3) is as follows: the compound V directly reacts with acid without separation to obtain a compound II.

The halogen is Cl, Br or I.

The reaction temperature of the compound III for lithium halide exchange with the lithium reagent is controlled to be-80 ℃ to-50 ℃.

The lithium reagent is n-butyllithium or sec-butyllithium.

The S1 is one or more selected from methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, n-hexane and toluene.

The S2 is one or more selected from methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, n-hexane and toluene.

The reaction temperature of the in situ reaction of the phenyllithium compound with the vinyl sulfate of formula IV is controlled to be from-80 ℃ to-20 ℃.

The S3 is selected from water or ethanol.

The reaction temperature of the reaction of the compound V with the acid is controlled to be 60 ℃ to 100 ℃.

The acid is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid, trifluoroacetic acid and methanesulfonic acid.

The mass concentration of the concentrated hydrochloric acid is 36-38%, and the mass concentration of the concentrated sulfuric acid is not less than 96%.

The invention has the beneficial effects that: the use of toxic reagents is reduced, the cost is reduced, the operation steps are reduced, the operation convenience is improved, and the method is suitable for large-scale production.

Detailed Description

The technical solution of the present invention will be further specifically described below by way of specific examples.

In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.

The bilastine intermediate is a compound shown in a formula II, and the process route is as follows:

(1) carrying out lithium halide exchange on the compound III and n-butyl lithium to obtain a corresponding phenyllithium compound;

(2) the phenyl lithium compound reacts with the vinyl sulfate of the formula IV in situ to obtain a compound V;

(3) reacting the compound V with acid to obtain a compound II;

the synthesis of compound III can refer to Tetrahedron 2008 vol.64#29 p.6979-6987.

In a preferred embodiment, the present invention provides the following synthetic routes: