阅读说明：本技术 一种匹伐他汀叔丁酯的合成方法 (Synthetic method of pitavastatin tert-butyl ester ) 是由 黄欢 李凯 黄庆云 詹福明 黄庆国 于 2020-08-06 设计创作，主要内容包括：本发明公开了一种匹伐他汀叔丁酯的合成方法,包括如下步骤：(4R-Cis)-6-氯甲基-2,2-二甲基-1,3-二氧戊环-4-乙酸叔丁酯与物质A在第一碱催化剂作用下反应得到物质B；然后经氧化剂氧化得到物质C；再与2-环丙基-4-(4-氟苯基)-喹啉-3-甲醛在第二碱催化剂作用下反应得到物质D；最后经酸脱保护得到匹伐他汀叔丁酯。本发明反应条件温和可控,茱利亚烯烃合成的反应条件不需要超低温反应,操作方便简单,立体选择性好,收率高,合成得到的匹伐他汀叔丁酯是完全无顺式异构体,纯度高。(The invention discloses a synthetic method of pitavastatin tert-butyl ester, which comprises the following steps: reacting (4R-Cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing with oxidant to obtain matter C; then reacting with 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; finally, acid deprotection is carried out to obtain pitavastatin tert-butyl ester. The method has mild and controllable reaction conditions, the reaction conditions for synthesizing the corneliylidene olefin do not need ultralow temperature reaction, the operation is convenient and simple, the stereoselectivity is good, the yield is high, and the synthesized pitavastatin tert-butyl ester is completely free of cis-isomer and has high purity.)

1. A synthetic method of pitavastatin tert-butyl ester comprises the following steps: reacting (4R-Cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing with oxidant to obtain matter C; then reacting with 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; finally obtaining pitavastatin tert-butyl ester through acid deprotection; the structural formulas of the substance A, the substance B, the substance C, the substance D and the pitavastatin tert-butyl ester are as follows:

r is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, preferably hydrogen or alkyl.

2. The method of claim 1, wherein the first base catalyst is at least one of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; preferably, the first base catalyst is sodium carbonate.

3. The process according to claim 1 or 2, characterized in that the oxidizing agent is a system or m-chloroperoxybenzoic acid, preferably the oxidizing agent is a hydrogen peroxide system; wherein the hydrogen peroxide system is a mixture of hydrogen peroxide and a catalyst, the catalyst is ammonium molybdate tetrahydrate or sodium tungstate or a mixture thereof, and preferably, the catalyst is ammonium molybdate tetrahydrate.

4. The method according to any one of claims 1 to 3, wherein the second base catalyst is at least one of sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide; preferably, the second base catalyst is sodium hydride.

5. The method according to any one of claims 1 to 4, wherein the reaction solvent for the synthesis of substance B is at least one of N, N-dimethylformamide, N-dimethylacetamide, toluene, xylene, N-methylpyrrolidone, and 1, 4-dioxane; preferably, the reaction solvent for the synthesis of substance B is 1, 4-dioxane.

6. The method according to any one of claims 1 to 5, wherein the oxidation reaction solvent is at least one of methanol, ethanol, and isopropanol; preferably, the oxidation reaction solvent is isopropanol.

7. The process according to any one of claims 1 to 6, wherein the molar ratio of the substance A to the first base catalyst is 1: 0.5-5, preferably, the molar ratio of the substance A to the first base catalyst is 1:1 to 2.

8. The process according to any one of claims 1 to 7, wherein the molar ratio of the substance B to the catalyst is 1: 0.01-0.5, preferably, the molar ratio of the substance B to the catalyst is 1:0.03 to 0.1; the molar ratio of the substance B to the hydrogen peroxide is 1: 1-20, preferably, the molar ratio of the substance B to the hydrogen peroxide is 1:4 to 10.

9. The process according to any one of claims 1 to 8, wherein the molar ratio of the substance C to the second base catalyst is 1: 0.5-10, preferably, the molar ratio of the substance C to the second base catalyst is 1:1 to 6.

10. The method according to any one of claims 1 to 9, wherein the reaction temperature of the synthetic material B is 10 to 100 ℃, preferably, the reaction temperature of the synthetic material B is 30 to 80 ℃; the temperature of the oxidation reaction is 0-100 ℃, and preferably, the temperature of the oxidation reaction is 20-50 ℃; the temperature of the synthetic substance D is-40-30 ℃, and preferably-10 ℃.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of pitavastatin tert-butyl ester.

Background

Pitavastatin calcium was the first fully synthetic HMG-CoA reductase inhibitor developed by japan chemical and two companies, of the company xinghe, ltd, and belongs to the statin class of drugs. It reduces the ability of the liver to make cholesterol, primarily by inhibition of the liver enzyme, an HMG-CoA reductase, thereby improving elevated blood cholesterol levels. 6- [ [ (1E) -2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -ethenyl ] -2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate abbreviated as pitavastatin tert-butyl ester is a key intermediate of pitavastatin calcium. In the existing pitavastatin calcium synthesis routes, most of them require the synthesis of the intermediate.

The existing synthetic route of pitavastatin tert-butyl ester mainly comprises the following steps:

the first synthetic route is a method for preparing pitavastatin and salts thereof reported in patent WO2007/132482, wherein 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline reacts with triphenylphosphine to generate triphenylphosphine bromide, the triphenylphosphine bromide reacts with side chain aldehyde through Wittig, and pitavastatin tert-butyl ester is obtained through hydrolysis by hydrochloric acid. In the method, 20% of cis-isomer is generated due to the Wittig reaction, so that the yield is not high, and a large amount of triphenyl phosphorus is generated, so that the three wastes are generated, and the method is not environment-friendly. The synthetic route is shown as follows:

the second synthetic route is a preparation method of pivastatin tert-butyl ester reported in Chinese patent CN102174039A, which comprises the steps of taking (4R,6S) -6-hydroxymethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate as a starting material, carrying out Mitsunobu reaction with 1, 1' - (1, 4-phenylene) bis (1H-tetrazole-5-thiol) and diisopropyl azodicarboxylate, carrying out oxidation reaction to obtain a sulfone compound, and finally obtaining pitavastatin tert-butyl ester with 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-formaldehyde under alkaline conditions. The method has harsh reaction conditions, needs ultralow temperature reaction, and has the defects that a small amount of sulfoxide stays in the oxidation process due to large steric hindrance, so that the conversion selectivity is influenced, and the yield and the purity of the next reaction are influenced. And the yield is low because column chromatography is needed for many times. The second synthetic route is as follows:

in summary, the existing synthetic method of pivalatin tert-butyl ester mainly has the problems of poor stereoselectivity, harsh reaction conditions, incomplete oxidation of an intermediate, need of column chromatography for multiple times, low yield and unsuitability for industrial production.

Disclosure of Invention

In order to solve the problems, the invention provides a novel synthetic method of pitavastatin tert-butyl ester. The method has the advantages of mild reaction conditions, good stereoselectivity, high yield, high purity and easy industrial production.

The present invention solves the above problems by the following means.

The invention provides a synthetic method of pitavastatin tert-butyl ester, which comprises the following steps:

reacting (4R-Cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing with oxidant to obtain matter C; then reacting with 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; finally, acid deprotection is carried out to obtain pitavastatin tert-butyl ester. The synthetic route is as follows:

wherein R is selected from hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, preferably hydrogen or alkyl.

The first base catalyst is at least one of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate. Preferably, the first base catalyst is sodium carbonate.

The oxidant is a hydrogen peroxide system or m-chloroperoxybenzoic acid, and preferably, the oxidant is a hydrogen peroxide system. Wherein the hydrogen peroxide system is a mixture of hydrogen peroxide and a catalyst, the catalyst is ammonium molybdate tetrahydrate or sodium tungstate or a mixture thereof, and preferably, the catalyst is ammonium molybdate tetrahydrate.

The second base catalyst is at least one of sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Preferably, the second base catalyst is sodium hydride.

The molar ratio of the substance A to the first base catalyst is 1: 0.5-5. Preferably, the molar ratio of the substance A to the first base catalyst is 1: 1-2.

The molar ratio of the (4R-Cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to the substance A is 1: 1.1-1.5, and preferably 1: 1.1-1.3.

The reaction solvent of the synthetic substance B is at least one of N, N-dimethylformamide, N-dimethylacetamide, toluene, xylene, N-methylpyrrolidone and 1, 4-dioxane. Preferably, the reaction solvent for the synthesis of substance B is 1, 4-dioxane.

Further, the weight ratio of the reaction solvent of the synthetic substance B to (4R-Cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate is 1-20: 1. preferably, the weight ratio of the reaction solvent for synthesizing the substance B to the (4R-Cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate is 5-10: 1.

the reaction temperature of the synthetic substance B is 10-100 ℃. Preferably, the reaction temperature of the synthetic substance B is 30-80 ℃.

In the oxidation reaction, when the oxidant is a mixture of hydrogen peroxide and a catalyst, the molar ratio of the substance B to the catalyst is 1: 0.01-0.5, preferably, the molar ratio of the substance B to the catalyst is 1: 0.03-0.1; the molar ratio of the substance B to the hydrogen peroxide is 1: 1-20. Preferably, the molar ratio of the substance B to the hydrogen peroxide is 1: 4-10.

In the oxidation reaction, when the oxidizing agent is m-chloroperoxybenzoic acid, the molar ratio of the substance B to the m-chloroperoxybenzoic acid is 1: 2-10, preferably, the molar ratio of the substance B to the m-chloroperoxybenzoic acid is 1: 2-4.

The temperature of the oxidation reaction is 0-100 ℃, and preferably, the temperature of the oxidation reaction is 20-40 ℃.

The oxidation reaction solvent is an alcoholic solvent, such as methanol, ethanol, isopropanol, or a combination thereof. Preferably, the oxidation reaction solvent is isopropanol.

The weight ratio of the reaction solvent of the synthetic substance C to the substance B is 1-20: 1. Preferably, the weight ratio of the reaction solvent for synthesizing the substance C to the substance B is 5-10: 1.

The molar ratio of the substance C to the second base catalyst is 1:0.5 to 10. Preferably, the molar ratio of the substance C to the second base catalyst is 1: 1-6.

The molar ratio of the substance C to the 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-formaldehyde is 1:1: 01-1.3, and preferably 1: 1.01-1.1.

The temperature of the synthetic substance D is-40 ℃ to 20 ℃. Preferably, the temperature of the synthesis substance D is between-10 ℃ and 10 ℃.

The reaction solvent of the synthetic substance D is any one or the combination of tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, toluene, dichloromethane and 1, 2-dichloroethane. Preferably, the solvent for the synthesis of substance D is tetrahydrofuran.

When the substance D is synthesized, the substance C and the 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-formaldehyde are added into the solvent, stirred and dissolved at room temperature, cooled to about 0 ℃, added with the second base catalyst in batches slowly, and then the temperature is controlled to continue the reaction after the addition.

Further, the synthetic substance D also comprises the steps of concentration, recrystallization and the like.

The solvent in the last step of reaction is any one of acetonitrile, toluene and xylene or the combination of the acetonitrile, the toluene and the xylene. Preferably, the solvent of hydrolysis is acetonitrile.

The acid in the last step is an acid capable of removing ether protecting groups, such as hydrochloric acid, sulfuric acid and the like, and the preferred acid is hydrochloric acid. Further preferably, a hydrochloric acid aqueous solution is adopted in the deprotection process, and the concentration of the hydrochloric acid aqueous solution is 0.01-1 mol/L. Preferably, the concentration of the hydrochloric acid aqueous solution is 0.02-0.2 mol/L.

The alkyl group as referred to herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, and the like.

The cycloalkyl group as referred to herein means a saturated monocyclic cyclic hydrocarbon substituent having 3 to 6 carbon atoms, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The substituted phenyl refers to single substitution at any position or more than two substitutions at any position on a benzene ring. The substituent is selected from hydrogen, halogen, nitro, cyano, C1-C4 alkyl.

The alkyl group of C1-C4 refers to a straight or branched chain alkyl group containing 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like.

The reagents with the sources not indicated in the invention are all conventional reagents purchased in the market.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention adopts Julia olefine to carry out conversion without ultralow temperature reaction, and the constructed double bond almost has no cis-isomer, good stereoselectivity and high purity; and the pitavastatin tert-butyl ester obtained after acidolysis in the last step of reaction is completely free of cis-isomer;

(2) because thiazole rings are adopted in the reaction of the synthetic substance B, oxidation is easy to occur, the conversion is complete, and the yield of the reaction in the first 2 steps can reach more than 81.6 percent; in addition, in the reaction of the synthetic substance D, the thiazole ring is easy to leave due to small steric hindrance, the product purity is good, and the yield is high;

(3) compared with the traditional Wittig reaction, because the substance D almost does not generate cis-isomer, the conversion rate is improved, the difficulty of separating the isomer and the problem of three wastes caused by post-treatment are reduced;

(4) the method for synthesizing the pitavastatin tert-butyl ester has mild and controllable reaction conditions in each step, is convenient and simple to operate and is suitable for technological production.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of substance B in example 1

FIG. 2 is a nuclear magnetic hydrogen spectrum of substance C in example 1

FIG. 3 is a nuclear magnetic hydrogen spectrum of substance D in example 1

FIG. 4 is a nuclear magnetic hydrogen spectrum of pitavastatin tert-butyl ester

Detailed Description

The technical solution of the present invention will be described in detail below with reference to specific examples.