CN112778152A - Synthesis method of bilastine intermediate - Google Patents
Synthesis method of bilastine intermediate Download PDFInfo
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- CN112778152A CN112778152A CN202011629464.0A CN202011629464A CN112778152A CN 112778152 A CN112778152 A CN 112778152A CN 202011629464 A CN202011629464 A CN 202011629464A CN 112778152 A CN112778152 A CN 112778152A
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- hexafluoroisopropanol
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention discloses a synthesis method of a bilastine intermediate, belonging to the technical field of organic synthesis. The method comprises the following steps: (1) performing Friedel-crafts reaction on benzene and alpha-methyl methacrylate in the fluoroalcohol A at the temperature of between 15 ℃ below zero and 25 ℃ to obtain a compound A; (2) performing amine transesterification on the compound A and diisopropylamine at the temperature of 20-50 ℃ to obtain a compound B; (3) the compound B and ethylene oxide in the fluoroalcohol B are subjected to Friedel-crafts reaction at a temperature of between 15 ℃ below zero and 25 ℃ to obtain a bilastine intermediate. The method takes cheap benzene as a raw material, and obtains an intermediate alpha, alpha-dimethyl-4- (2-hydroxyethyl) phenylacetyl diisopropylamine through Friedel-crafts alkylation, amine ester exchange and one-step Friedel-crafts alkylation. In the step (2), because the diisopropyl group is larger, the localization effect is changed, and the problem of excessive isomers in the Friedel-crafts alkylation process is avoided. The proportion of Friedel-crafts alkylated para-meta products in the present invention may be above 95%.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of a bilastine intermediate.
Background
Bilastine (blst), chemical name 2- [ 4- (2- { 4- [ 1- (2-ethoxy-ethyl) -1H-benzimidazol-2-yl } ethyl) -phenyl ] 2-methyl-propionic acid, cas number 202189-78-4. Bilastine is an oral generation 2 histamine H1 receptor antagonist developed by Spain FAES pharmaceuticals. Registration of new drugs was carried out in the european union in 2009, which was first approved for marketing in the uk and irish in 2011 and subsequently marketed in italy, japan and canada, etc., in succession, for the treatment of seasonal allergic rhinitis and perennial allergic rhinitis, at a dosage specification of 20 mg/tablet. Other approved indications also include cutaneous pruritus, eczema and urticaria. The product has good safety, and has no sedative effect and cardiotoxicity of conventional antihistamine.
The structural formula of bilastine is as follows:
methyl α, α -dimethyl-4- (2-hydroxyethyl) phenylacetate or its analogous derivatives can be used as key intermediates of bilastine, and the structural formulas are respectively:
methyl α, α -dimethyl-4- (2-hydroxyethyl) phenylacetate can be synthesized in the following manner:
patent WO2009102155 reports its synthesis method, which is as follows:
the method has the advantages of strict anhydrous and anaerobic operating conditions, difficult purification, expensive raw materials and the like, and is difficult to realize industrially.
Patent CN104276952B reports a process utilizing friedel-crafts reaction, reduction of ketone carbonyl, epoxidation, ring opening of epoxy:
the method produces a large amount of meta-isomers in the Friedel-crafts reaction, and reports that the para-meta ratio is about 7:3, so that the method cannot meet the pharmaceutical requirements.
The oxazole alcohol, an alpha, alpha-dimethyl-4- (2-hydroxyethyl) phenylacetic acid derivative, can be synthesized in the following manner:
in the synthetic process, methyl iodide, sodium cyanide and ethylene oxide are used to react with bromobenzene under the action of Grignard reagent or n-butyl lithium, and the whole synthetic process is long and is not easy to be industrialized.
The alpha, alpha-dimethyl phenylacetic acid methyl ester is generally prepared by a similar methyl-adding method, benzyl cyanide is subjected to two methyl groups on sodium amide or sodium hydride under the action of methylating agents such as methyl iodide or dimethyl sulfate and the like, and then is hydrolyzed into carboxylic acid and esterified, so that the synthesis process has the defects of high pollution, flammability and explosiveness and difficulty in industrialization.
Disclosure of Invention
In order to solve the problems, the invention develops a novel intermediate for synthesizing bilastine, which is similar in mother ring structure and has the following structural formula:
the synthesis process of the intermediate comprises the following steps:
(1) performing Friedel-crafts reaction on benzene and alpha-methyl methacrylate in the fluoroalcohol A at the temperature of between 15 ℃ below zero and 25 ℃ to obtain a compound A; wherein the mass ratio of benzene to the fluoroalcohol A to the alpha-methyl methacrylate is 2-8: 1: 0.5-2.
(2) Performing amine ester exchange reaction on the compound A and diisopropylamine (simultaneously used as a solvent) at the temperature of between 20 and 50 ℃ to obtain a compound B; wherein the mass ratio of the compound A to the diisopropylamine is 1: 2-10.
(3) Performing a Friedel-crafts reaction on a compound B and ethylene oxide in a fluoroalcohol B at a temperature of between 15 ℃ below zero and 25 ℃ to obtain a bilastine intermediate, wherein the mass ratio of the compound B to the fluoroalcohol B to the ethylene oxide is 1: 2-10: 0.5-4.0.
The synthetic route is as follows:
in the present invention, the fluoroalcohol a is hexafluoroisopropanol, trifluoroethanol, or the like.
Preferably, the fluoroalcohol a in the present invention is hexafluoroisopropanol.
In the present invention, the fluoroalcohol B is hexafluoroisopropanol, trifluoroethanol, or the like.
Preferably, the fluoroalcohol B in the present invention is hexafluoroisopropanol.
Wherein, the fluoroalcohol A and the fluoroalcohol B are used as a reaction solvent and a catalyst; compared with the conventional solvent, the method has the advantages of high yield, less impurities and the like, and is convenient to recycle.
Wherein, the step (1) of the invention specifically comprises the following steps: mixing benzene and fluoroalcohol A, dripping alpha-methyl methacrylate, reacting at-15-25 deg.c, decompression distilling to recover benzene and fluoroalcohol A, water washing and regulating pH value of water phase to 7-9 to eliminate acid impurity, separating liquid, drying organic phase and distilling to obtain compound A.
Wherein, the step (2) of the invention specifically comprises the following steps: and (3) carrying out amine transesterification on the compound A and diisopropylamine at the temperature of 20-50 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the diisopropylamine, washing with water, and drying to obtain a compound B.
Wherein, the step (3) of the invention specifically comprises the following steps: adding ethylene oxide into the compound B, dropwise adding the fluoroalcohol B, reacting at-15 to 25 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the fluoroalcohol B, washing with water, and drying to obtain a bilastine intermediate.
Preferably, the synthesis method of the bilastine intermediate comprises the following steps:
(1) mixing benzene and hexafluoroisopropanol, dropwise adding alpha-methyl methacrylate, reacting at-15 to 25 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the benzene and the hexafluoroisopropanol, washing with water, adjusting the pH value of a water phase to 7-9, separating liquid, drying an organic phase, and distilling to obtain a compound A. Wherein the mass ratio of benzene, hexafluoroisopropanol to alpha-methyl methacrylate is 2-8: 1: 0.5-2.
Wherein the temperature of the reduced pressure distillation in the step (1) is 30 to 40 ℃, and the recovered benzene and hexafluoroisopropanol are returned to the step (1) to be reused (with or without supplementing benzene as required). And (3) similarly.
(2) And (3) carrying out amine transesterification on the compound A and diisopropylamine at the temperature of 20-50 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the diisopropylamine, washing with water, and drying to obtain a compound B. Wherein the mass ratio of the compound A to the diisopropylamine is 1: 2-10.
(3) Adding ethylene oxide into the compound B (firstly cooling to about 0 ℃), dripping hexafluoroisopropanol, reacting at-15 to 25 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover hexafluoroisopropanol, washing with water, and drying to obtain a bilastine intermediate. Wherein the mass ratio of the compound B to the hexafluoroisopropanol to the ethylene oxide is 1: 2-10: 0.5-4.0.
The invention discloses a novel intermediate for synthesizing bilastine and a preparation method thereof, wherein the method takes cheap benzene as a raw material, and obtains an intermediate alpha, alpha-dimethyl-4- (2-hydroxyethyl) phenylacetyl diisopropylamine through Friedel-crafts alkylation, amine ester exchange and one-step Friedel-crafts alkylation. In the step (2), because the diisopropyl group is larger, the localization effect is changed, and the problem of excessive isomers in the Friedel-crafts alkylation process is avoided. In step (3), the proportion of Friedel-crafts alkylated para-product in the present invention may be more than 95%. In addition, the method has the advantages of convenient and safe operation (normal temperature and no high pressure), low cost and little environmental pollution (less solvent and reutilization), and is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
EXAMPLE 1 preparation of methyl alpha, alpha-Dimethylphenylacetate
200g of benzene and 40g of hexafluoroisopropanol are added, stirring is carried out at normal temperature, 100g of alpha-methyl methacrylate is dropwise added, stirring is carried out at normal temperature, the reaction is completely carried out for 10-15 hours, excess benzene is recovered under reduced pressure at 30-40 ℃, hexafluoroisopropanol is recovered, water washing is carried out, the pH of an aqueous phase is adjusted to be =7-9, liquid separation is carried out, an organic phase is dried and distilled, and an intermediate compound A125g is obtained, the purity is 98%, and the yield is 70%.
EXAMPLE 2 preparation of alpha, alpha-Dimethylphenylacetyldiisopropylamine
100g of the compound A and 200g of diisopropylamine are mixed, stirred and mixed at normal temperature, the reaction is completed, the diisopropylamine is recovered by reduced pressure distillation, and the intermediate compound B160g can be obtained after washing and drying, with the yield of 92%.
EXAMPLE 3 preparation of α, α -dimethyl-4- (2-hydroxyethyl) phenylacetyldiisopropyl amine
The compound B100g is cooled to 0 ℃, 50g of ethylene oxide is added, 200g of hexafluoroisopropanol is added dropwise, the mixture is stirred at 0-5 ℃ and reacts completely, after the reaction is finished, the hexafluoroisopropanol is recovered under reduced pressure at 30-40 ℃, and the mixture is washed and dried to obtain 106g of alpha, alpha-dimethyl-4- (2-hydroxyethyl) phenylacetyl diisopropylamine with the purity of 99 percent and the yield of 90 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A method for synthesizing a bilastine intermediate, comprising:
(1) performing a Friedel-crafts reaction on benzene and alpha-methyl methacrylate in a fluoroalcohol A at a temperature of between 15 ℃ below zero and 25 ℃ to obtain a compound A, wherein the mass ratio of the benzene to the fluoroalcohol A to the alpha-methyl methacrylate is 2-8: 1: 0.5 to 2;
(2) performing amine transesterification on the compound A and diisopropylamine at the temperature of 20-50 ℃ to obtain a compound B, wherein the mass ratio of the compound A to the diisopropylamine is 1: 2-10;
(3) performing Friedel-crafts reaction on a compound B and ethylene oxide in a fluoroalcohol B at-15 to 25 ℃ to obtain a bilastine intermediate, wherein the mass ratio of the compound B to the fluoroalcohol B to the ethylene oxide is 1: 2-10: 0.5-4.0;
the synthetic route is as follows:
2. the method for synthesizing the bilastine intermediate as claimed in claim 1, wherein the fluoroalcohol A is hexafluoroisopropanol or trifluoroethanol.
3. The method for synthesizing a bilastine intermediate as claimed in claim 1, wherein the fluoroalcohol a is hexafluoroisopropanol.
4. The method for synthesizing the bilastine intermediate as claimed in claim 1, wherein the fluoroalcohol B is hexafluoroisopropanol or trifluoroethanol.
5. The method for synthesizing a bilastine intermediate as claimed in claim 1, wherein the fluoroalcohol B is hexafluoroisopropanol.
6. The method for synthesizing a bilastine intermediate as claimed in claim 1, wherein the step (1) specifically comprises: mixing benzene and fluoroalcohol A, dropwise adding alpha-methyl methacrylate, reacting at-15 to 25 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the benzene and the fluoroalcohol A, washing with water, adjusting the pH value of a water phase to 7-9, carrying out liquid separation, drying an organic phase, and distilling to obtain the compound A.
7. The method for synthesizing a bilastine intermediate as claimed in claim 1, wherein the step (2) specifically comprises: and (3) carrying out amine transesterification on the compound A and diisopropylamine at the temperature of 20-50 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the diisopropylamine, washing with water, and drying to obtain a compound B.
8. The method for synthesizing a bilastine intermediate as claimed in claim 1, wherein the step (3) specifically comprises: adding ethylene oxide into the compound B, dropwise adding the fluoroalcohol B, reacting at-15 to 25 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover the fluoroalcohol B, washing with water, and drying to obtain a bilastine intermediate.
9. The method of synthesizing a bilastine intermediate as claimed in claim 1, wherein the method comprises:
(1) mixing benzene and hexafluoroisopropanol, dropwise adding alpha-methyl methacrylate, reacting at-15 to 25 ℃, after the reaction is finished, performing reduced pressure distillation to recover the benzene and the hexafluoroisopropanol, washing with water, adjusting the pH value of a water phase to 7-9, separating liquid, drying an organic phase, and distilling to obtain a compound A, wherein the mass ratio of the benzene to the hexafluoroisopropanol to the alpha-methyl methacrylate is 2-8: 1: 0.5 to 2;
(2) performing amine transesterification on the compound A and diisopropylamine at the temperature of 20-50 ℃, after the reaction is finished, performing reduced pressure distillation to recover the diisopropylamine, washing with water, and drying to obtain a compound B, wherein the mass ratio of the compound A to the diisopropylamine is 1: 2-10;
(3) adding ethylene oxide into a compound B, dropwise adding hexafluoroisopropanol, reacting at-15 to 25 ℃, after the reaction is finished, carrying out reduced pressure distillation to recover hexafluoroisopropanol, washing with water, and drying to obtain a bilastine intermediate, wherein the mass ratio of the compound B to the hexafluoroisopropanol to the ethylene oxide is 1: 2-10: 0.5-4.0.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104276952A (en) * | 2013-07-11 | 2015-01-14 | 南京华威医药科技开发有限公司 | Preparation method of bilastine key intermediate |
| CN106565467A (en) * | 2016-11-04 | 2017-04-19 | 杭州励德生物科技有限公司 | Preparation method of new anti-allergic medicine Bilastine intermediate |
| CN112110811A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of bilastine intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104276952A (en) * | 2013-07-11 | 2015-01-14 | 南京华威医药科技开发有限公司 | Preparation method of bilastine key intermediate |
| CN106565467A (en) * | 2016-11-04 | 2017-04-19 | 杭州励德生物科技有限公司 | Preparation method of new anti-allergic medicine Bilastine intermediate |
| CN112110811A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of bilastine intermediate |
Non-Patent Citations (3)
| Title |
|---|
| IGNACIO COLOMER: "Hydroarylation of alkenes using anilines in hexafluoroisopropanol", 《ACS CATAL.》 * |
| M.K.MAMEDOV: "Synthesis of aromatic alcohols and their alkanoic acid esters", 《RUSSIAN JOURNAL OF APPLIED CHEMISTRY》 * |
| 彭卡等: "抗组胺新药索菲那定的合成", 《华东师范大学学报（自然科学版）》 * |
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