阅读说明：本技术 一种瑞舒伐他汀钙中间体的高选择性合成方法 (High-selectivity synthesis method of rosuvastatin calcium intermediate ) 是由 陈挺 刘成 钱坚锋 余依玲 王正豪 黄亮亮 于 2021-08-06 设计创作，主要内容包括：本发明涉及一种瑞舒伐他汀钙中间体的高选择性合成方法,包括以下步骤：以(4R-cis)-6-氯甲基-2,2-二甲基-1,3-二氧戊环-4-乙酸叔丁酯为起始原料与苯环取代的巯基苯并噻唑通过缩合反应得到化合物2；化合物2通过氧化反应得到化合物3；化合物3与嘧啶醛通过Julia-KocienskiOlefination缩合反应得到瑞舒伐他汀中间体。本发明的合成方法反应路线简单、反应条件温和,以苯环取代的巯基苯并噻唑代替现有的巯基苯并噻唑为原料,提高了反应的立体选择性,大大降低了产物顺式异构体的比例,将异构体的比例由1～2％降低至0.1％以内,可以避免原料药瑞舒伐他汀钙中顺式异构体杂质的产生,提高了药物纯度,对于改善药品的质量具有显著的意义。(The invention relates to a high-selectivity synthesis method of a rosuvastatin calcium intermediate, which comprises the following steps: taking (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate as a starting material to perform condensation reaction with benzene ring substituted mercaptobenzothiazole to obtain a compound 2; the compound 2 is subjected to oxidation reaction to obtain a compound 3; the compound 3 and pyrimidine aldehyde are subjected to Julia-Kocienskiolefination condensation reaction to obtain a rosuvastatin intermediate. The synthetic method disclosed by the invention is simple in reaction route and mild in reaction conditions, and the benzene ring-substituted mercaptobenzothiazole is used as a raw material to replace the existing mercaptobenzothiazole, so that the stereoselectivity of the reaction is improved, the proportion of cis-isomer of the product is greatly reduced, the proportion of the isomer is reduced to be within 0.1% from 1-2%, the generation of cis-isomer impurities in the rosuvastatin calcium serving as a raw material can be avoided, the medicine purity is improved, and the synthetic method has a remarkable significance for improving the quality of medicines.)

1. A high-selectivity synthesis method of a rosuvastatin calcium intermediate is characterized by comprising the following steps:

s1, (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and the compound 1 are subjected to condensation reaction to obtain a compound 2;

s2, carrying out oxidation reaction on the compound 2 to obtain a compound 3;

s3, carrying out Julia-Kocienski Olefination condensation reaction on the compound 3 and the compound 4 to obtain a rosuvastatin intermediate;

the reaction route is as follows:

wherein R is C₁～C₃Alkyl or C₁～C₃An alkoxy group.

2. A highly selective synthesis method of rosuvastatin calcium intermediate according to claim 1, wherein the compound 1 is at least one of 4-methyl-2-mercaptobenzothiazole, 5-methyl-2-mercaptobenzothiazole, 6-methyl-2-mercaptobenzothiazole, 5-methoxy-2-mercaptobenzothiazole, and 6-methoxy-2-mercaptobenzothiazole.

3. The high-selectivity synthesis method of the rosuvastatin calcium intermediate according to claim 1, wherein the steps are specifically:

carrying out condensation reaction on (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and the compound 1 in the presence of inorganic base, a phase transfer catalyst and a solvent A to obtain a compound 2;

carrying out oxidation reaction on the compound 2 in the presence of a catalyst, an oxidant and a solvent B to obtain a compound 3;

and synthesizing a compound 5 from the compound 3 and the compound 4 in the presence of an organic base and a solvent C at low temperature.

4. A highly selective synthesis method of rosuvastatin calcium intermediate according to claim 3, wherein the inorganic base is Na₂CO₃、K₂CO₃、KHCO₃、NaHCO₃At least one of NaOH and KOH; the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst; the solvent A is at least one of acetonitrile, DMF, DMAc, NMP and DMSO.

5. The high-selectivity synthesis method of the rosuvastatin calcium intermediate according to claim 3, wherein the molar ratio of the (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to the compound 1 is 1: 1.02-1.10; the mass ratio of the (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to the inorganic base to the phase transfer catalyst is 1: (0.2-0.5): (0.05-0.1).

6. A highly selective synthesis method of rosuvastatin calcium intermediate according to claim 3, wherein the catalyst is at least one of phosphomolybdic acid, tungsten trioxide, ammonium molybdate; the oxidant is hydrogen peroxide or peroxy acid; the solvent B is at least one of acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane and carbon tetrachloride.

7. A highly selective synthesis method of rosuvastatin calcium intermediate according to claim 3, wherein the molar ratio of the compound 2 to the catalyst and the oxidant is 1: (0.01-0.5): (3-6).

8. A highly selective synthesis method of rosuvastatin calcium intermediate according to claim 3, wherein the organic base is one of sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, butyllithium, LDA; the solvent C is at least one of toluene, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, chloroform, 1, 2-dichloroethane and carbon tetrachloride.

9. A highly selective synthesis method of rosuvastatin calcium intermediate according to claim 3, wherein the molar ratio of compound 3 to compound 4 is 1: (1.05-1.10); the mass ratio of the compound 3 to the organic base is 1: (0.1-0.3).

10. The high-selectivity synthesis method of the rosuvastatin calcium intermediate according to claim 3, wherein the condensation reaction temperature is 60 to 150 ℃, and the condensation reaction time is 12 to 24 hours; the temperature of the oxidation reaction is 10-50 ℃, and the time of the oxidation reaction is 10-20 h; the temperature of the compound synthesized at the low temperature is-50-0 ℃, and the time is 8-16 h.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a high-selectivity synthesis method of a rosuvastatin calcium intermediate.

Background

Rosuvastatin calcium, chemically known as bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2:1), is a selective HMG-CoA reductase inhibitor, developed by the company asikang, and marketed in various countries and regions such as the united states, japan, europe, china, etc.

The preparation process of rosuvastatin calcium has been reported in numerous patents and literatures. The compound 5(6- [ (1E) -2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -5-pyrimidine ] ethenyl ] -2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate) is an important intermediate for the preparation of rosuvastatin calcium. The prior art reports that (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and mercaptobenzothiazole are used as raw materials, and a compound 5 is prepared through condensation, oxidation and condensation steps. The method has few byproducts, but the proportion of cis-isomer in the product is high (about 1-2%), and the purity of the medicine still needs to be improved.

Disclosure of Invention

In view of this, a high-selectivity synthesis method of rosuvastatin calcium intermediate is needed to be provided, so as to solve the technical problem of high ratio of cis-isomer of rosuvastatin calcium intermediate in the prior art.

The invention provides a high-selectivity synthesis method of a rosuvastatin calcium intermediate, which comprises the following steps:

carrying out condensation reaction on (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and the compound 1 to obtain a compound 2;

the compound 2 is subjected to oxidation reaction to obtain a compound 3;

the rosuvastatin intermediate (compound 5) is obtained by Julia-Kocienski Olefination condensation reaction of compound 3 and compound 4.

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

the synthetic method disclosed by the invention is simple in reaction route and mild in reaction conditions, and the benzene ring-substituted mercaptobenzothiazole is used as a raw material to replace the existing mercaptobenzothiazole, so that the stereoselectivity of the reaction is improved, the proportion of cis-isomer of the product is greatly reduced, the proportion of the isomer is reduced to be within 0.1% from 1-2%, the generation of cis-isomer impurities in the rosuvastatin calcium serving as a raw material can be avoided, the medicine purity is improved, and the synthetic method has a remarkable significance for improving the quality of medicines.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The invention provides a high-selectivity synthesis method of a rosuvastatin calcium intermediate, which comprises the following steps:

s1, (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and the compound 1 are subjected to condensation reaction to obtain a compound 2;

s2, carrying out oxidation reaction on the compound 2 to obtain a compound 3;

s3, compound 3 and compound 4 are subjected to Julia-Kocienski Olefination condensation reaction to obtain rosuvastatin intermediate (compound 5).

The reaction route is as follows:

wherein R is C₁～C₃Alkyl or C₁～C₃An alkoxy group.

In some embodiments of the invention, R is methyl or methoxy. Further, the compound 1 is at least one of 4-methyl-2-mercaptobenzothiazole (1a), 5-methyl-2-mercaptobenzothiazole (1b), 6-methyl-2-mercaptobenzothiazole (1c), 5-methoxy-2-mercaptobenzothiazole (1d), and 6-methoxy-2-mercaptobenzothiazole (1e), preferably 5-methylbenzothiazole (1 b). The specific structural formula of compound 1 is as follows:

in the present invention, step S1 is specifically: carrying out condensation reaction on (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and the compound 1 in the presence of inorganic base, a phase transfer catalyst and a solvent A to obtain a compound 2.

Further, the molar ratio of the (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to the compound 1 is 1: 1.02-1.10.

Further, the inorganic base is Na₂CO₃、K₂CO₃、KHCO₃、NaHCO₃At least one of NaOH and KOH, preferably NaHCO₃Or KHCO₃. The mass ratio of the (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to the inorganic base is 1: (0.2 to 0.5), preferably 1: 0.32.

Further, the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst. Further, the phase transfer catalyst is at least one of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate (TBAB), trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride, and is preferably tetrabutylammonium bromide; the mass ratio of (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to the phase transfer catalyst is 1: (0.05-0.1), preferably 1: 0.084.

Further, the solvent A is at least one of acetonitrile, DMF, DMAc, NMP and DMSO; the dosage ratio of (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to solvent A is 1 g: (1-5) ml, preferably 1 g: 2 ml.

Further, the temperature of the condensation reaction is 60-150 ℃, preferably 105-150 ℃; the condensation reaction time is 12-24 h, preferably 14-18 h.

In the present invention, step S2 is specifically: the compound 2 is subjected to oxidation reaction in the presence of a catalyst, an oxidant and a solvent B to obtain a compound 3.

Further, the catalyst is at least one of phosphomolybdic acid, tungsten trioxide, and ammonium molybdate is preferable.

Further, the oxidizing agent is hydrogen peroxide or peroxy acid, preferably hydrogen peroxide.

In some embodiments of the present invention, the oxidant is hydrogen peroxide with a concentration of 30-50%.

Further, the molar ratio of the compound 2 to the catalyst and the oxidant is 1: (0.01-0.5): (3-6).

Further, the solvent B is at least one of acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, and carbon tetrachloride, and preferably dichloromethane or chloroform. The mass ratio of the compound 2 to the solvent B is 1 (3-6).

Further, the temperature of the oxidation reaction is 10-50 ℃, preferably 30-50 ℃; the time of the oxidation reaction is 10-20 h, preferably 12-20 h.

In the present invention, step S3 is specifically: compound 3 and compound 4 are synthesized into compound 5 in the presence of organic base and solvent C at low temperature.

The organic base is one of sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, butyllithium, and LDA, and preferably sodium tert-butoxide or potassium tert-butoxide.

Further, the temperature of the compound synthesized at the low temperature is-50 to 0 ℃, preferably-40 to-20 ℃, and more preferably-40 to-30 ℃; the time is 8-16 h, preferably 8-10 h.

Further, the solvent C is at least one of toluene, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, chloroform, 1, 2-dichloroethane, and carbon tetrachloride, preferably dichloromethane or tetrahydrofuran.

Further, the molar ratio of the compound 3 to the compound 4 is 1: (1.05-1.10); the mass ratio of the compound 3 to the organic base is 1: (0.1-0.3), wherein the dosage ratio of the compound 3 to the solvent C is 1 g: (8-12) ml.

In the invention, the high-selectivity synthesis method of the rosuvastatin calcium intermediate comprises the following steps:

s1, mixing (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate, the compound 1, a solvent A, inorganic base and a phase transfer catalyst, reacting for 12-24 h at 60-150 ℃, cooling to room temperature, extracting and concentrating to obtain a compound 2; wherein, the extractant selected for extraction is dichloromethane. The dosage ratio of (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate to extractant is 1: (3-10).

S2, dissolving the compound 2 in a solvent B, adding a catalyst, slowly adding an oxidant at 10-50 ℃, keeping the temperature, stirring, reacting for 10-20 hours, dropwise adding a sodium sulfite solution after the reaction is finished, quenching, layering, recovering the solvent B at normal pressure from an organic layer, and recrystallizing to obtain a compound 3; wherein the solvent selected for recrystallization is methanol, and the mass ratio of the compound 2 to the methanol is 1: (3-6).

S3, dissolving the compound 3 and the compound 4 in a solvent C, cooling to-50-0 ℃, slowly adding an organic base, controlling the temperature to-50-0 ℃, carrying out heat preservation reaction for 8-16 h after the addition is finished, adding a sodium carbonate solution to quench the reaction after the reaction is finished, and then carrying out layering, organic phase decompression concentration and recrystallization to obtain a compound 5; wherein the solvent selected for recrystallization is methanol, and the dosage ratio of the compound 3 to the methanol is 1 g: (15-25) ml. In the process, the lower dropping temperature of the organic base and the heat preservation reaction temperature are more beneficial to reducing the cis-isomer content.

Example 1

(1) To a reaction flask, 100ml of DMF, 50 g of (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-acetic acid tert-butyl ester and 34 g of 5-methyl-2-mercapto-benzothiazole (1b) were added, followed by 4.2 g of tetrabutylammonium bromide and 16 g of sodium bicarbonate, and the mixture was heated to 105 ℃ to react for about 16 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding 300ml of dichloromethane into the reaction liquid to extract products after the temperature is reduced, concentrating at normal pressure to recover dichloromethane, and cooling to room temperature after the concentration is finished to obtain a solid product 2b, wherein the yield is 97% compared with the pure weight of 73.7 g;

(2) adding 300 g of dichloromethane into 73.7g of the compound 2b concentrated solution for dissolving, adding 12 g of ammonium molybdate, dropwise adding 100 g of 30% hydrogen peroxide into a reaction bottle, controlling the temperature to be 40-50 ℃ in the dropwise adding process, and preserving heat and stirring for 20 hours after dropwise adding until the reaction is complete. After the reaction is finished, dropwise adding a 10% sodium sulfite aqueous solution into the reaction liquid to quench hydrogen peroxide, after the hydrogen peroxide is completely neutralized, layering, recovering dichloromethane from an organic layer at normal pressure, adding 300 g methanol into the concentrated solid to recrystallize, heating to dissolve, slowly cooling to 0-10 ℃ to crystallize, filtering out the solid, and drying at 60 ℃ to obtain 68g of a compound 3b, wherein the yield is 86%;

(3) adding 47.8 g of compound 3b and 36.8 g of compound 4 into a reaction bottle, adding 500 g of dichloromethane into the reaction bottle, stirring for dissolving, cooling to-40 ℃, slowly adding 10 g of sodium tert-butoxide, controlling the temperature to be-40 to-30 ℃, finishing adding after about 1 hour, keeping the temperature at-40 to-20 ℃ for 8 hours after finishing adding, finishing the reaction, pouring the reaction solution into 400 g of 10% sodium carbonate aqueous solution for quenching after the reaction is finished, layering, concentrating the organic phase under reduced pressure after layering, adding 1000ml of methanol after concentrating, heating to reflux for dissolving, cooling to room temperature for crystallization, performing suction filtration, leaching a filter cake with methanol, and drying in vacuum at 60 ℃ to obtain 50 g of white solid product 5, wherein the yield is 87%, the purity is 99.8%, and the isomer is not detected.

Example 2

(1) 100ml of DMAc, 50 g of (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-acetic acid tert-butyl ester and 38.9 g of 6-methoxy-2-mercapto-benzothiazole (1e) were charged into a reaction flask, and 4.2 g of benzyltriethylammonium chloride and 16 g of sodium carbonate were further added, and the reaction was heated to 150 ℃ for about 16 hours. After the reaction is finished, cooling the reaction liquid to room temperature, adding 300ml of dichloromethane into the reaction liquid after cooling to extract products, concentrating at normal pressure to recover dichloromethane, and cooling to room temperature after concentration to obtain a solid product 2e with the pure weight of 75g and the yield of 94.8%;

(2) and adding 300 g of dichloromethane into 75g of the compound 2e concentrated solution for dissolving, adding 20 g of phosphomolybdic acid, dropwise adding 80 g of 30% hydrogen peroxide into the reaction bottle, controlling the temperature to be 30-40 ℃ in the dropwise adding process, and preserving heat and stirring for 12 hours after the dropwise adding is finished until the reaction is complete. After the reaction is finished, dropwise adding a 10% sodium sulfite aqueous solution into the reaction liquid to quench hydrogen peroxide, after the hydrogen peroxide is completely neutralized, layering, recovering dichloromethane from an organic layer at normal pressure, adding 300 g methanol into the concentrated solid to recrystallize, heating to dissolve, slowly cooling to 0-10 ℃ to crystallize, filtering out the solid, and drying at 60 ℃ to obtain 69g of a compound 3e, wherein the yield is 84.2%;

(3) adding 49.5 g of compound 3e and 40.5 g of compound 4 into a reaction bottle, adding 500 g of dichloromethane into the reaction bottle, stirring for dissolving, cooling to-40 ℃, slowly adding 10 g of sodium ethoxide, controlling the temperature to be-30 to-20 ℃, finishing the adding within about 1 hour, keeping the temperature at-30 to-20 ℃ for 8 hours after the adding is finished, finishing the reaction, pouring the reaction liquid into 400 g of 10% sodium carbonate aqueous solution for quenching after the reaction is finished, layering after the quenching is finished, concentrating the organic phase under pressure, adding 1000ml of methanol after the concentrating is finished, heating to reflux for dissolving, cooling to room temperature for crystallization, carrying out suction filtration, leaching a filter cake with methanol, and carrying out vacuum drying at 60 ℃ to obtain 47 g of white solid product 5, wherein the yield is 81.8%, the purity is 99.2%, and the isomer is 0.08%.

Comparative example 1

(1) To a reaction flask, 100ml of DMF, 50 g of (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-acetic acid tert-butyl ester and 31.4 g of 2-mercapto-benzothiazole (1f) were added, followed by 4.2 g of tetrabutylammonium bromide and 16 g of sodium bicarbonate, and the mixture was heated to 105 ℃ to react for about 16 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding 300ml of dichloromethane into the reaction liquid after cooling to extract products, concentrating at normal pressure to recover dichloromethane, cooling to room temperature after concentrating to obtain a solid product 2f, wherein the weight of the solid product is 70.7g compared with the pure weight, and the yield is 96.1%;

(2) and adding 300 g of dichloromethane into 70.7g of the compound 2f concentrated solution for dissolving, adding 12 g of ammonium molybdate, dropwise adding 100 g of 30% hydrogen peroxide into the reaction bottle, controlling the temperature to be 40-50 ℃ in the dropwise adding process, and preserving heat and stirring for 20 hours after dropwise adding until the reaction is complete. After the reaction is finished, dropwise adding a 10% sodium sulfite aqueous solution into the reaction liquid to quench hydrogen peroxide, after the hydrogen peroxide is completely neutralized, layering, recovering dichloromethane from an organic layer at normal pressure, adding 300 g methanol into the concentrated solid to recrystallize, heating to dissolve, slowly cooling to 0-10 ℃ to crystallize, filtering out the solid, and drying at 60 ℃ to obtain 65.6g of a compound 3f, wherein the yield is 85.6%;

(3) adding 46.3 g of compound 3f and 36.8 g of compound 4 into a reaction bottle, adding 500 g of dichloromethane into the reaction bottle, stirring and dissolving, cooling to-40 ℃, slowly adding 10 g of sodium tert-butoxide, controlling the temperature to be-40 to-30 ℃, finishing adding after about 1 hour, keeping the temperature at-40 to-20 ℃ for 8 hours after finishing adding, finishing the reaction, pouring the reaction solution into 400 g of 10% sodium carbonate aqueous solution for quenching after the reaction is finished, layering, concentrating the organic phase under reduced pressure after layering, adding 1000ml of methanol after concentrating, heating to reflux and dissolving, cooling to room temperature for crystallization, carrying out suction filtration, leaching a filter cake with methanol, and carrying out vacuum drying at 60 ℃ to obtain 51 g of white solid product 5, wherein the yield is 88.7%, the purity is 99.5%, and the isomer is 1.5%.

In comparative example 1, the structural formula of 2-mercapto-benzothiazole (1f) is as follows:

the above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.