阅读说明：本技术 一种瑞舒伐他汀叔丁胺盐及其制备方法 (Rosuvastatin tert-butylamine salt and preparation method thereof ) 是由 孙学喜 杨会来 毛杰 于 2020-06-18 设计创作，主要内容包括：本发明公开了一种瑞舒伐他汀叔丁胺盐及其制备方法,先将3-羟基戊二酸二乙酯的醇羟基进行保护,再在碱性条件下进行水解,进而制得中间体1,将中间体1与1-苯乙胺反应制得手性试剂,经2-碘-2-甲基丙烷酯化,进一步还原制得中间体2,中间体2与氯甲酸甲酯进行取代反应后,与三苯基甲基碘化磷反应制得中间体3,中间体3进一步反应,制得中间体4,中间体4在碱性条件下水解并与叔丁胺反应,制得瑞舒伐他汀叔丁胺盐,本发明制备瑞舒伐他汀叔丁胺盐的制备方法制得的瑞舒伐他汀叔丁胺盐的产率高,且与现有制备方法相比,使用的原料多为价格较低的原料,工艺相对简单,大大降低了瑞舒伐他汀叔丁胺盐的生产成本。(The invention discloses rosuvastatin tert-butylamine salt and a preparation method thereof, alcoholic hydroxyl of diethyl 3-hydroxyglutarate is protected, hydrolysis is carried out under alkaline conditions, an intermediate 1 is further prepared, the intermediate 1 and 1-phenylethylamine react to prepare a chiral reagent, 2-iodine-2-methylpropane esterification is carried out, further reduction is carried out to prepare an intermediate 2, the intermediate 2 and methyl chloroformate are subjected to substitution reaction and then react with triphenyl methyl iodide to prepare an intermediate 3, the intermediate 3 further reacts to prepare an intermediate 4, the intermediate 4 is hydrolyzed under alkaline conditions and reacts with tert-butylamine to prepare the rosuvastatin tert-butylamine salt, the yield of the rosuvastatin tert-butylamine salt prepared by the preparation method of rosuvastatin tert-butylamine salt is high, and compared with the existing preparation method, most of used raw materials are low-price raw materials, the process is relatively simple, and the production cost of the rosuvastatin tert-butylamine salt is greatly reduced.)

1. Rosuvastatin tert-butylamine salt, characterized by: the method comprises the following steps:

step S1: adding 3-hydroxy diethyl glutarate and dimethylformamide into a reaction kettle, stirring until the 3-hydroxy diethyl glutarate is completely dissolved, adding imidazole under the conditions of the rotation speed of 200-300 r/min and the temperature of 30-35 ℃, adding tert-butyldimethylsilyl chloride, stirring for 30-40min, adding sodium hydroxide and methanol, reacting for 20-30 min under the condition of the temperature of 0-5 ℃, adding acetic anhydride, and reacting for 1-1.5h under the condition of the temperature of 80-85 ℃ to obtain an intermediate 1;

step S2: adding the intermediate 1 and 1-phenylethylamine prepared in the step S1 into a reaction kettle, stirring and adding triethylamine and toluene at the rotation speed of 200-300 r/min and the temperature of 0-3 ℃, stirring for 10-15 min, heating to the temperature of 25-30 ℃, reacting for 8-10 h, adding 2-iodine-2-methylpropane, continuing to react for 20-30 min, adding sodium acetate and introducing dinitrogen tetroxide until the dinitrogen tetroxide is filled in the reaction kettle, reacting for 1-1.5h, adding 1-amantadine and palladium hydroxide, introducing hydrogen, reacting for 2-3 h after the reaction kettle is filled with hydrogen, and preparing an intermediate 2;

step S3: reacting the intermediate 2, methyl chloroformate and triethylamine prepared in the step S3 for 2-3 h at the rotation speed of 100-200r/min and the temperature of-40 to-30 ℃, adding triphenyl methyl phosphorus iodide and n-butyl lithium, and reacting for 5-8h at the temperature of-60 to-50 ℃ to prepare an intermediate 3;

step S4: adding 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-formaldehyde, the intermediate 3 prepared in the step S3 and acetonitrile into a reaction kettle, reacting for 20-25h at the rotation speed of 100-200r/min and the temperature of 80-85 ℃, adding hydrofluoric acid, and continuously stirring at the temperature of 0-5 ℃ to prepare rosuvastatin tert-butylamine salt;

step S5: and (4) adding the intermediate 4 prepared in the step (S4) and a sodium hydroxide solution into a reaction kettle, reacting for 30-40min at the temperature of 60-70 ℃, adding tert-butylamine, and continuing to react for 1-1.5h to prepare the rosuvastatin tert-butylamine salt.

2. Rosuvastatin tert-butylamine salt according to claim 1, characterized by: the mass ratio of the 3-hydroxyglutaric acid diethyl ester, the dimethylformamide, the imidazole, the tert-butyldimethylsilyl chloride, the sodium hydroxide, the methanol and the acetic anhydride in the step S1 is 1: 3: 1.1: 1.1: 2: 1.5: 3.

3. rosuvastatin tert-butylamine salt according to claim 1, characterized by: the intermediate 1, 1-phenylethylamine, triethylamine, toluene, 2-iodo-2-methylpropane, sodium acetate, 1-amantadine and palladium hydroxide in the step S2 are used in an amount of 3: 5: 0.5: 10: 3: 3: 1: 1.5.

4. rosuvastatin tert-butylamine salt according to claim 1, characterized by: the mass ratio of the intermediate 2, methyl chloroformate, triethylamine, triphenylmethyl phosphorus iodide and n-butyllithium in the step S3 is 2: 4: 0.5: 3: 1.

5. rosuvastatin tert-butylamine salt according to claim 1, characterized by: the dosage mass ratio of the 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-formaldehyde, the intermediate 3, the acetonitrile and the hydrofluoric acid in the step S4 is 3: 5: 5: 1.

6. rosuvastatin tert-butylamine salt according to claim 1, characterized by: the mass ratio of the intermediate 4, the sodium hydroxide solution and the tert-butylamine in the step S5 is 1: 2: 3.

7. the process for the preparation of rosuvastatin tert-butylamine salt according to claim 1, characterized by: the method specifically comprises the following steps:

step S1: adding 3-hydroxy diethyl glutarate and dimethylformamide into a reaction kettle, stirring until the 3-hydroxy diethyl glutarate is completely dissolved, adding imidazole under the conditions of the rotation speed of 200-300 r/min and the temperature of 30-35 ℃, adding tert-butyldimethylsilyl chloride, stirring for 30-40min, adding sodium hydroxide and methanol, reacting for 20-30 min under the condition of the temperature of 0-5 ℃, adding acetic anhydride, and reacting for 1-1.5h under the condition of the temperature of 80-85 ℃ to obtain an intermediate 1;

step S2: adding the intermediate 1 and 1-phenylethylamine prepared in the step S1 into a reaction kettle, stirring and adding triethylamine and toluene at the rotation speed of 200-300 r/min and the temperature of 0-3 ℃, stirring for 10-15 min, heating to the temperature of 25-30 ℃, reacting for 8-10 h, adding 2-iodine-2-methylpropane, continuing to react for 20-30 min, adding sodium acetate and introducing dinitrogen tetroxide until the dinitrogen tetroxide is filled in the reaction kettle, reacting for 1-1.5h, adding 1-amantadine and palladium hydroxide, introducing hydrogen, reacting for 2-3 h after the reaction kettle is filled with hydrogen, and preparing an intermediate 2;

step S3: reacting the intermediate 2, methyl chloroformate and triethylamine prepared in the step S3 for 2-3 h at the rotation speed of 100-200r/min and the temperature of-40 to-30 ℃, adding triphenyl methyl phosphorus iodide and n-butyl lithium, and reacting for 5-8h at the temperature of-60 to-50 ℃ to prepare an intermediate 3;

step S4: adding 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-formaldehyde, the intermediate 3 prepared in the step S3 and acetonitrile into a reaction kettle, reacting for 20-25h at the rotation speed of 100-200r/min and the temperature of 80-85 ℃, adding hydrofluoric acid, and continuously stirring at the temperature of 0-5 ℃ to prepare rosuvastatin tert-butylamine salt;

step S5: and (4) adding the intermediate 4 prepared in the step (S4) and a sodium hydroxide solution into a reaction kettle, reacting for 30-40min at the temperature of 60-70 ℃, adding tert-butylamine, and continuing to react for 1-1.5h to prepare the rosuvastatin tert-butylamine salt.

Technical Field

The invention belongs to the technical field of chemical medicine preparation, and particularly relates to rosuvastatin tert-butylamine salt and a preparation method thereof.

Background

Rosuvastatin is a selective HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors are rate-limiting enzymes that convert 3-hydroxy-3-methylglutaryl coenzyme a to mevalonate, the precursor of cholesterol, the main site of action of rosuvastatin is the liver, a cholesterol-lowering target organ, rosuvastatin increases the number of hepatic LDL cell surface receptors, promotes the absorption and catabolism of LDL, inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

The rosuvastatin tert-butylamine salt prepared by the existing rosuvastatin tert-butylamine salt preparation process has low yield, and the price of raw materials used for preparing the rosuvastatin tert-butylamine salt is high, so that the preparation cost of the rosuvastatin tert-butylamine salt is greatly improved, and further the market popularization is not facilitated.

Disclosure of Invention

The invention aims to provide rosuvastatin tert-butylamine salt and a preparation method thereof.

The technical problems to be solved by the invention are as follows:

the rosuvastatin tert-butylamine salt prepared by the existing rosuvastatin tert-butylamine salt preparation process has low yield, and the price of raw materials used for preparing the rosuvastatin tert-butylamine salt is high, so that the preparation cost of the rosuvastatin tert-butylamine salt is greatly improved, and further the market popularization is not facilitated.

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

rosuvastatin tert-butylamine salt is prepared by the following steps:

step S1: adding 3-hydroxy diethyl glutarate and dimethylformamide into a reaction kettle, stirring until the 3-hydroxy diethyl glutarate is completely dissolved, adding imidazole under the conditions of the rotation speed of 200-300 r/min and the temperature of 30-35 ℃, adding tert-butyldimethylsilyl chloride, stirring for 30-40min, adding sodium hydroxide and methanol, reacting for 20-30 min under the condition of the temperature of 0-5 ℃, adding acetic anhydride, and reacting for 1-1.5h under the condition of the temperature of 80-85 ℃ to obtain an intermediate 1;

the reaction process is as follows:

step S2: adding the intermediate 1 and 1-phenylethylamine prepared in the step S1 into a reaction kettle, stirring and adding triethylamine and toluene under the conditions that the rotation speed is 200-300 r/min and the temperature is 0-3 ℃, stirring for 10-15 min, heating to the temperature of 25-30 ℃, reacting for 8-10 h, adding 2-iodine-2-chloromethylpropane, continuing to react for 20-30 min, adding sodium acetate and introducing dinitrogen tetroxide until the dinitrogen tetroxide is filled in the reaction kettle, reacting for 1-1.5h, adding 1-amantadine and palladium hydroxide, introducing hydrogen, reacting for 2-3 h after the hydrogen is filled in the reaction kettle, and preparing an intermediate 2;

the reaction process is as follows:

step S3: reacting the intermediate 2, methyl chloroformate and triethylamine prepared in the step S3 for 2-3 h at the rotation speed of 100-200r/min and the temperature of-40 to-30 ℃, adding triphenyl methyl phosphorus iodide and n-butyl lithium, and reacting for 5-8h at the temperature of-60 to-50 ℃ to prepare an intermediate 3;

the reaction process is as follows:

step S4: adding 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-formaldehyde, the intermediate 3 prepared in the step S3 and acetonitrile into a reaction kettle, reacting for 20-25h at the rotation speed of 100-200r/min and the temperature of 80-85 ℃, adding hydrofluoric acid, and continuously stirring at the temperature of 0-5 ℃ to prepare an intermediate 4;

the reaction process is as follows:

step S5: and (4) adding the intermediate 4 prepared in the step (S4) and a sodium hydroxide solution into a reaction kettle, reacting for 30-40min at the temperature of 60-70 ℃, adding tert-butylamine, and continuing to react for 1-1.5h to prepare the rosuvastatin tert-butylamine salt.

The reaction process is as follows:

further, in step S1, the usage amount by mass ratio of 3-hydroxyglutaric acid diethyl ester, dimethylformamide, imidazole, tert-butyldimethylsilyl chloride, sodium hydroxide, methanol, and acetic anhydride is 1: 3: 1.1: 1.1: 2: 1.5: 3.

further, the intermediate 1, 1-phenylethylamine, triethylamine, toluene, 2-iodo-2-methylpropane, sodium acetate, 1-amantadine, and palladium hydroxide described in step S2 are used in an amount by mass ratio of 3: 5: 0.5: 10: 3: 3: 1: 1.5.

further, in step S3, the use amount mass ratio of the intermediate 2, methyl chloroformate, triethylamine, triphenylmethyl phosphonium iodide, and n-butyllithium is 2: 4: 0.5: 3: 1.

further, in step S4, the dosage mass ratio of 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-carbaldehyde to intermediate 3 to acetonitrile to hydrofluoric acid is 3: 5: 5: 1.

further, the mass ratio of the intermediate 4, the sodium hydroxide solution and the tert-butylamine in the step S5 is 1: 2: 3.

further, the preparation method of rosuvastatin tert-butylamine salt specifically comprises the following steps:

step S1: adding 3-hydroxy diethyl glutarate and dimethylformamide into a reaction kettle, stirring until the 3-hydroxy diethyl glutarate is completely dissolved, adding imidazole under the conditions of the rotation speed of 200-300 r/min and the temperature of 30-35 ℃, adding tert-butyldimethylsilyl chloride, stirring for 30-40min, adding sodium hydroxide and methanol, reacting for 20-30 min under the condition of the temperature of 0-5 ℃, adding acetic anhydride, and reacting for 1-1.5h under the condition of the temperature of 80-85 ℃ to obtain an intermediate 1;

step S2: adding the intermediate 1 and 1-phenylethylamine prepared in the step S1 into a reaction kettle, stirring and adding triethylamine and toluene at the rotation speed of 200-300 r/min and the temperature of 0-3 ℃, stirring for 10-15 min, heating to the temperature of 25-30 ℃, reacting for 8-10 h, adding 2-iodine-2-methylpropane, continuing to react for 20-30 min, adding sodium acetate and introducing dinitrogen tetroxide until the dinitrogen tetroxide is filled in the reaction kettle, reacting for 1-1.5h, adding 1-amantadine and palladium hydroxide, introducing hydrogen, reacting for 2-3 h after the reaction kettle is filled with hydrogen, and preparing an intermediate 2;

step S3: reacting the intermediate 2, methyl chloroformate and triethylamine prepared in the step S3 for 2-3 h at the rotation speed of 100-200r/min and the temperature of-40 to-30 ℃, adding triphenyl methyl phosphorus iodide and n-butyl lithium, and reacting for 5-8h at the temperature of-60 to-50 ℃ to prepare an intermediate 3;

step S4: adding 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-formaldehyde, the intermediate 3 prepared in the step S3 and acetonitrile into a reaction kettle, reacting for 20-25h at the rotation speed of 100-200r/min and the temperature of 80-85 ℃, adding hydrofluoric acid, and continuously stirring at the temperature of 0-5 ℃ to prepare rosuvastatin tert-butylamine salt;

step S5: and (4) adding the intermediate 4 prepared in the step (S4) and a sodium hydroxide solution into a reaction kettle, reacting for 30-40min at the temperature of 60-70 ℃, adding tert-butylamine, and continuing to react for 1-1.5h to prepare the rosuvastatin tert-butylamine salt.

The invention has the beneficial effects that: the invention prepares rosuvastatin tert-butylamine salt, reacting 3-hydroxy diethyl glutarate with tert-butyldimethyl chlorosilane, protecting alcoholic hydroxyl of 3-hydroxy diethyl glutarate, hydrolyzing under alkaline condition, further preparing an intermediate 1 with acetic anhydride and a ring, reacting the intermediate 1 with 1-phenylethylamine to prepare a chiral reagent, esterifying with 2-iodine-2-methyl propane, introducing nitrite through dinitrogen tetroxide, reducing under the action of 1-amantadine and palladium hydroxide to prepare an intermediate 2, carrying out substitution reaction on the intermediate 2 and methyl chloroformate, reacting with triphenyl methyl iodide to prepare an intermediate 3, reacting the intermediate 3 and 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonylamino) pyrimidine-5-formaldehyde under the condition of acetonitrile as a solvent, the rosuvastatin tert-butylamine salt prepared by the preparation method has high yield, compared with the existing preparation method, the used raw materials are mostly low-price raw materials, the process is relatively simple, and the production cost of the rosuvastatin tert-butylamine salt is greatly reduced.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious 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.