阅读说明：本技术 一种基于绿色环保的替格瑞洛中间体的制备方法 (Green and environment-friendly ticagrelor intermediate preparation method ) 是由 祝莉 李天赋 徐硕 周彬 于 2019-11-25 设计创作，主要内容包括：本发明公开了一种基于绿色环保的替格瑞洛中间体的制备方法,以3,4-二氟苯甲醛为原料,依次通过缩合反应、酰氯化反应、酯化反应得到具有手性薄荷醇基团的(E)-3-(3,4-二氟苯基)丙烯酸薄荷酯,三步反应过程所用试剂廉价易得,并且通过催化剂的使用,减少了反应副产物提高反应收率；将(E)-3-(3,4-二氟苯基)丙烯酸薄荷酯与硫叶立德试剂反应,在溶剂、手性辅基、碱存在条件下,反应生成2-(3,4-二氟苯基)-环丙烷甲酸薄荷酯,通过选用具有手性结构的硫叶立德试剂,并配合L-薄荷醇基以及手性辅基的空间定位作用,提高了2-(3,4-二氟苯基)-环丙烷甲酸薄荷酯的立体选择性,同时也提高了产物的收率。(The invention discloses a preparation method of a ticagrelor intermediate based on green environmental protection, which takes 3, 4-difluorobenzaldehyde as a raw material, and sequentially carries out condensation reaction, acyl chlorination reaction and esterification reaction to obtain (E) -3- (3, 4-difluorophenyl) menthyl acrylate with chiral menthol groups, wherein reagents used in the three-step reaction process are cheap and easy to obtain, and by using a catalyst, reaction byproducts are reduced, and the reaction yield is improved; the method comprises the steps of reacting (E) -3- (3, 4-difluorophenyl) menthyl acrylate with a thioylide reagent, reacting in the presence of a solvent, a chiral auxiliary group and alkali to generate 2- (3, 4-difluorophenyl) -cyclopropane menthyl formate, and improving the stereoselectivity of the 2- (3, 4-difluorophenyl) -cyclopropane menthyl formate and the yield of the product by selecting the thioylide reagent with a chiral structure and matching with the space positioning effect of an L-menthol group and the chiral auxiliary group.)

1. The preparation method of the ticagrelor intermediate based on green environmental protection is characterized by comprising the following reaction steps:

in the first step, pyridine is used as a solvent, piperidine is used for catalyzing the condensation reaction of 3, 4-difluorobenzaldehyde and malonic acid to generate (E) -3- (3, 4-difluorophenyl) acrylic acid, and the reaction formula is as follows:

and step two, using toluene as a solvent, and reacting (E) -3- (3, 4-difluorophenyl) acrylic acid with thionyl chloride under the catalysis of pyridine to generate (E) -3- (3, 4-difluorophenyl) acryloyl chloride, wherein the reaction formula is as follows:

and step three, using toluene as a solvent, and carrying out esterification reaction on (E) -3- (3, 4-difluorophenyl) acryloyl chloride and L-menthol in the presence of pyridine to generate (E) -3- (3, 4-difluorophenyl) menthyl acrylate, wherein the reaction formula is as follows:

step four, reacting (E) -menthyl 3- (3, 4-difluorophenyl) acrylate with a thioylide reagent in a solvent in the presence of a chiral auxiliary group and a base to generate 2- (3, 4-difluorophenyl) -cyclopropane-menthyl formate, wherein the reaction formula is as follows:

2. the method for preparing the ticagrelor intermediate based on green environmental protection, according to claim 1, wherein in the first step, the molar ratio of the 3, 4-difluorobenzaldehyde, the malonic acid, the pyridine and the piperidine is 1: 1-3: 2-8: 0.01 to 0.5, the reaction temperature is 50 to 110 ℃, and the reaction time is 1 to 5 hours.

3. The method for preparing a ticagrelor intermediate based on green environmental protection according to claim 1, wherein in the second step, the molar ratio of the (E) -3- (3, 4-difluorophenyl) acrylic acid to the thionyl chloride to the pyridine to the toluene is 1: 1-3: 0.01-0.5: 2-8 ℃, the reaction temperature is 40-90 ℃, and the reaction time is 1-5 h.

4. The method for preparing ticagrelor intermediate based on green environmental protection according to claim 1, wherein in the third step, the molar ratio of (E) -3- (3, 4-difluorophenyl) acryloyl chloride, L-menthol, pyridine and toluene is 1: 1-3: 0.01-0.2: 2-8 ℃, the reaction temperature is 40-100 ℃, and the reaction time is 2-10 h.

5. The method for preparing ticagrelor intermediate based on green environmental protection according to claim 1, wherein in the fourth step, the solvent is one of toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran, the base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the molar ratio of the (E) -menthyl 3- (3, 4-difluorophenyl) acrylate, the thioylide reagent, the base, the chiral prosthetic group and the solvent is 1: 0.5-2: 1-3: 0.01-0.5: 2-8, and the reaction temperature is-10-50 ℃.

6. The method for preparing a ticagrelor intermediate based on green environmental protection according to claim 1, wherein in the fourth step, the chiral prosthetic group is R-binaphthol or S-binaphthol.

7. The method for preparing a ticagrelor intermediate based on green environmental protection according to claim 1, wherein in the fourth step, the thioylide reagent is one of the compounds with the following structure:

Technical Field

The invention relates to the field of synthesis of ticagrelor intermediates, and in particular relates to a preparation method of a ticagrelor intermediate based on green environmental protection.

Background

Ticagrelor is a novel oral anti-platelet drug of cyclopentyl triazolopyrimidine (CPTP), is a key drug for treating acute coronary syndrome, and the (1R, 2S) -2- (3, 4-difluorophenyl) cyclopropylamine is a key intermediate for synthesizing ticagrelor, wherein the key of the synthesis research is to improve the stereoselectivity of a three-membered ring structure in the synthesis process;

chinese patent CN 106905182A discloses that 3, 4-difluorostyrene is used as a raw material and reacts asymmetrically with azide under the action of a rhodium catalyst to prepare a ticagrelor intermediate compound with a chiral cyclopropane structure, and the rhodium catalyst used in the reaction is a noble metal catalyst, so that the price is high and the product selectivity is low; chinese patent CN 106854158A discloses that 3, 4-difluorobromobenzene is used as a raw material, 3, 4-difluorobromobenzene is prepared into a Grignard reagent, and then the Grignard reagent and 4-chlorobutyl-2-ethyl enoate are subjected to asymmetric addition reaction to obtain an intermediate with a chiral cyclopropane structure.

Disclosure of Invention

The invention aims to provide a preparation method of a ticagrelor intermediate based on green environmental protection, which avoids using expensive reagents, reduces the use of thionyl chloride, avoids the pollution of a large amount of hydrogen chloride gas generated during experimental treatment to the environment, and provides a synthesis method of the ticagrelor intermediate with low consumption, low pollution, cleanness and high efficiency; and simultaneously improves the stereoselectivity of the product with the chiral cyclopropane structure.

The purpose of the invention can be realized by the following technical scheme:

a preparation method of a ticagrelor intermediate based on green environmental protection comprises the following reaction steps:

in the first step, pyridine is used as a solvent, and piperidine is used for catalyzing the condensation reaction of 3, 4-difluorobenzaldehyde and malonic acid to generate (E) -3- (3, 4-difluorophenyl) acrylic acid, wherein the reaction formula is as follows:

the possible reaction mechanisms are: the method comprises the steps of using piperidine as a catalyst, enabling unpaired electrons of amino nitrogen in piperidine molecules to activate carbonyl carbon of 3, 4-difluorobenzaldehyde and methylene carbon of malonic acid, enabling the carbonyl carbon to react with the amino nitrogen to carry out deoxygenation to generate imine ions, enabling the methylene carbon to be subjected to proton abstraction to generate carbanion, enabling the carbanion to attack the imine ions and form covalent bonds with original carbonyl carbon, then carrying out intramolecular hydrogen migration, removing the amino to form a carbon-carbon double bond, carrying out molecular hydrolysis under an alkaline condition, and then carrying out acid treatment and decarboxylation to obtain the product (E) -3- (3, 4-difluorophenyl) acrylic acid.

The reaction rate can be improved by activating reactants through piperidine in the reaction, pyridine is selected as a reaction solvent, on one hand, the pyridine can provide an alkaline environment and provide negative ions in the reaction process, on the other hand, the pyridine is taken as amine and can play a synergistic catalytic role in the reaction with the piperidine, in addition, the piperidine and the pyridine are both easily soluble in water, can be removed by washing during the reaction post-treatment and then are rectified and recovered from water, aldehyde groups and carboxyl groups are condensed to generate acrylic acid through the reaction, the reaction speed is high, the side reaction is less, the product yield is high, meanwhile, the solvent and the catalyst can be recovered, and the reaction is green and environment-friendly.

And step two, using toluene as a solvent, and reacting (E) -3- (3, 4-difluorophenyl) acrylic acid with thionyl chloride under the catalysis of pyridine to generate (E) -3- (3, 4-difluorophenyl) acryloyl chloride, wherein the reaction formula is as follows:

the possible reaction mechanisms are: the unshared electron pair on the pyridine nitrogen atom can accept protons to show alkalinity, one chlorine atom is removed by thionyl chloride to react with pyridine to generate pyridyl sulfonyl chloride with higher activity, the pyridyl sulfonyl chloride and the carboxyl hydroxyl of (E) -3- (3, 4-difluorophenyl) acrylic acid carry out substitution reaction to generate (E) -3- (3, 4-difluorophenyl) acryloyl chloride, and the pyridine nitrogen atom is converted into pyridine again by electrons.

In the reaction, pyridine activates thionyl chloride to generate pyridyl sulfonyl chloride with higher activity, so that the reaction speed is accelerated, and the pyridine also serves as an acid-binding agent in the process of accelerating the acyl chlorination reaction process, so that the generation of alkyl chloride is prevented, side reactions are reduced, and the reaction yield is improved. In the existing acyl chlorination reaction, thionyl chloride is usually used as a solvent to directly react with carboxylic acid, the thionyl chloride has strong irritation and can be decomposed to generate hydrogen chloride gas when meeting water, although the thionyl chloride can be recovered through distillation after the reaction is finished, air pollution is inevitably caused when the thionyl chloride is distilled, only thionyl chloride with the equivalent weight close to that of (E) -3- (3, 4-difluorophenyl) acrylic acid is added in the reaction, almost no thionyl chloride is left after the reaction is finished, and the air pollution caused by using a large amount of thionyl chloride is avoided.

And thirdly, taking toluene as a solvent, and carrying out esterification reaction on (E) -3- (3, 4-difluorophenyl) acryloyl chloride and L-menthol in the presence of pyridine to generate (E) -3- (3, 4-difluorophenyl) menthyl acrylate, wherein the reaction formula is as follows:

in the reaction, pyridine is used as organic weak base to provide an alkaline environment for a reaction system and promote the esterification reaction, and the pyridine has a stable structure and is also used as an acid-binding agent in the process of accelerating the reaction process, so that the generation of alkyl chloride is prevented, side reactions are reduced, and the reaction yield is improved.

Fourthly, reacting (E) -3- (3, 4-difluorophenyl) menthyl acrylate with a thioylide reagent in a solvent in the presence of chiral auxiliary groups and alkali to generate 2- (3, 4-difluorophenyl) -cyclopropane menthyl formate, wherein the reaction formula is as follows:

the possible reaction mechanisms are: the sulfur ylide reagent has a sulfur positive ion and an adjacent carbon negative ion, the carbon negative ion has strong nucleophilicity and can attack double bonds, when a carbonyl is arranged at the ortho position of the double bonds, oxygen on the carbonyl can absorb electrons to form oxygen negative ions, the double bonds are opened, one end of the double bonds is connected with the carbon negative ion of the sulfur ylide reagent, one end of the double bonds and unpaired electrons on the carbon of the carbonyl form a double bond intermediate, the newly formed double bonds are opened under the action of the oxygen negative ion and the sulfur positive ion, one carbon is connected with the carbon of the original carbon negative ion to form a three-membered ring, and the mechanism is as follows:

the method is a very effective cycloaddition synthesis method by introducing a cyclopropane structure into (E) -3- (3, 4-difluorophenyl) menthyl acrylate through a sulfur ylide reagent, can efficiently and quickly synthesize products with different configurations by changing the substituent of the sulfur ylide reagent, introduces L-menthol into molecules, can also form certain steric hindrance in the molecules through the chiral configuration of the L-menthol, and guides the reverse arrangement of the molecular configuration during double bond addition to obtain a final target product.

Further, in the first step, the molar ratio of the 3, 4-difluorobenzaldehyde, malonic acid, pyridine and piperidine is 1: 1-3: 2-8: 0.01 to 0.5, the reaction temperature is 50 to 110 ℃, and the reaction time is 1 to 5 hours.

Further, the first specific step is as follows: adding 3, 4-difluorobenzaldehyde and malonic acid into a dry reaction bottle under the protection of nitrogen, adding piperidine and pyridine, heating to 50-110 ℃ under stirring for reacting for 1-5 h, then adding 2mol/L hydrochloric acid solution, separating out solids, filtering, recrystallizing a filter cake with ethanol to obtain (E) -3- (3, 4-difluorophenyl) acrylic acid, and carrying out reduced pressure distillation on the filtrate to separate the piperidine and the pyridine.

Further, in the second step, the molar ratio of the (E) -3- (3, 4-difluorophenyl) acrylic acid, the thionyl chloride, the pyridine and the toluene is 1: 1-3: 0.01-0.5: 2-8 ℃, the reaction temperature is 40-90 ℃, and the reaction time is 1-5 h.

Further, the second step comprises the following specific steps: adding (E) -3- (3, 4-difluorophenyl) acrylic acid into toluene, adding pyridine, dropwise adding thionyl chloride into the reaction liquid within 1h, heating to 40-90 ℃ after dropwise adding, reacting for 1-5 h, then distilling under reduced pressure to remove toluene and pyridine, adding distilled water, extracting the reaction liquid for 3 times with ethyl acetate, combining ethyl acetate solutions, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain (E) -3- (3, 4-difluorophenyl) acryloyl chloride.

Further, in the third step, the molar ratio of (E) -3- (3, 4-difluorophenyl) acryloyl chloride, L-menthol, pyridine and toluene was 1: 1-3: 0.01-0.2: 2-8 ℃, the reaction temperature is 40-100 ℃, and the reaction time is 2-10 h.

Further, the third step is specifically as follows: under the protection of nitrogen, dissolving (E) -3- (3, 4-difluorophenyl) acryloyl chloride in toluene, adding pyridine and L-menthol, heating to 40-100 ℃ for reacting for 2-10 h, then carrying out reduced pressure concentration on the reaction liquid to remove the toluene and the pyridine, and carrying out recrystallization by using ethanol to obtain the (E) -3- (3, 4-difluorophenyl) menthyl acrylate.

Further, in the fourth step, the solvent is one of toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran, the base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the molar ratio of the (E) -3- (3, 4-difluorophenyl) menthyl acrylate, the sulfoxonium reagent, the base, the chiral auxiliary and the solvent is 1: 1-2: 1-3: 0.01-0.5: 2 to 8, and the reaction temperature is-10 to 50 ℃.

Furthermore, in the fourth step, the chiral auxiliary group is R-binaphthol or S-binaphthol, the molecule of the binaphthol has two hydroxyl groups, a double hydrogen bond can be provided in the reaction, the reaction rate is improved, and the framework of the chiral binaphthol has larger steric hindrance and can improve the selectivity of the reaction.

Further, in the fourth step, the sulfur ylide reagent is selected from one of the compounds having the following structures, preferably compound A is used as the sulfur ylide reagent,

further, the synthesis method of the compound A comprises the following steps:

dissolving a chiral sulfur compound of a D-camphor derivative in acetone, cooling to-10 ℃, dripping bromomethane into a reaction solution within 1-2 h, heating to 10-40 ℃, stirring and reacting for 8-24 h, filtering the reaction solution, washing a filter cake twice with acetone, washing with petroleum ether once to obtain a crude product of a thioylide reagent, recrystallizing the crude product with methanol to obtain the thioylide reagent, wherein the molar ratio of the chiral sulfur compound of the D-camphor derivative to the bromomethane is 1: 1-2, and the reaction equation is as follows:

the chiral sulfur ylide reagent has a spatial conformation, and can induce the corresponding spatial structure of a product to generate through the spatial structure when reacting with (E) -3- (3, 4-difluorophenyl) menthyl acrylate, so that the product spatial selectivity can be improved, the generation of a spatial isomer can be reduced, the reaction yield can be improved, the reaction condition is mild, the raw materials are easy to obtain, and toxic and harmful substances are not generated in the reaction process.

The invention has the beneficial effects that:

a new route for synthesizing a ticagrelor intermediate is designed, firstly, 3, 4-difluorobenzaldehyde is used as a raw material and reacts with malonic acid under the catalysis of piperidine to prepare (E) -3- (3, 4-difluorophenyl) acrylic acid, in the reaction process, the piperidine and solvent pyridine can perform a concerted catalytic reaction, the reaction speed is high, side reactions are few, the product yield is high, and the piperidine and the pyridine can be recycled through rectification, so that the resource waste and the environmental pollution are reduced; then pyridine is used for catalyzing (E) -3- (3, 4-difluorophenyl) acrylic acid and thionyl chloride to carry out acyl chlorination reaction, so that the using amount of the thionyl chloride is reduced, and the pollution to the environment caused by using a large amount of the thionyl chloride is avoided; then, L-menthol reacts with (E) -3- (3, 4-difluorophenyl) acryloyl chloride, and pyridine is added as an acid binding agent, so that side reactions are reduced, and the reaction yield is improved; the reaction route has high reaction yield, and the reaction reagent can be recycled, so that the method is a green and environment-friendly synthesis process route;

in the synthesis process of 2- (3, 4-difluorophenyl) -cyclopropane menthyl formate, cycloaddition reaction is carried out by a sulfur ylide reagent, molecules have chiral configuration by L-menthol introduced into the molecules, certain steric hindrance can be formed in the molecules, the selectivity of the reaction can be improved during double bond addition, meanwhile, binaphthol is selected as a chiral auxiliary group, two hydroxyl groups in the molecules of the binaphthol are utilized, a double hydrogen bond can be provided in the reaction, the reaction rate is improved, the selectivity of the reaction can be improved by utilizing the larger steric hindrance of the skeletons of the chiral binaphthol, in addition, the sulfur ylide reagent with chirality can be used for inducing the corresponding spatial structure of a product to generate during the reaction with (E) -3- (3, 4-difluorophenyl) menthyl acrylate, the product space selectivity can be improved, the generation of a space isomer is reduced, the reaction yield is improved, the reaction conditions are mild, the raw materials are easy to obtain, and toxic and harmful substances are not generated in the reaction process; therefore, the stereoselectivity of the target product is improved by the cycloaddition reaction of sulfur ylide.

Detailed Description

The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.