CN110563680A - Preparation method of medicine for treating hyperlipemia - Google Patents
Preparation method of medicine for treating hyperlipemia Download PDFInfo
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- CN110563680A CN110563680A CN201910853110.5A CN201910853110A CN110563680A CN 110563680 A CN110563680 A CN 110563680A CN 201910853110 A CN201910853110 A CN 201910853110A CN 110563680 A CN110563680 A CN 110563680A
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- A61P3/06—Antihyperlipidemics
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- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the field of medicines, and particularly relates to a preparation method of a medicine for treating hyperlipidemia. The invention utilizes a compound II to prepare a compound III through hydrolysis, prepares a compound IV with acetone under an acidic condition, and prepares the final product simvastatin (I) through acylation, acidic hydrolysis and lactonization. The product prepared by the reaction of the invention has high total yield and purity, low impurity content and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, relates to a preparation method of a drug for treating hyperlipidemia, and particularly relates to a preparation method of a simvastatin compound.
background
Simvastatin is a partially-synthesized HMG-CoA reductase inhibitor which is developed by American merck company and takes lovastatin as a raw material, the product is marketed in 1988, and is approved by the FDA in U.S. 12 months in 1991, and is mainly used for clinically treating hypercholesterolemia, hypertriglyceridemia and other dyslipidemia which originally occur. The activity in vivo is four times of that of pravastatin, can effectively prevent the development of atherosclerosis and the recurrence of heart disease, and reduce the risk of non-lethal myocardial infarction and myocardial angiogenesis in operation.
The methods for preparing simvastatin in the prior art mainly comprise the following steps:
(1) The route reported in US4444784 is to hydrolyze with the addition of an excess of strong base to remove the 2-methyl acyl side chain and simultaneously open the lactone ring, selectively silanize with TBDS to protect the hydroxyl group on the lactone ring, then acylate the hydroxyl group at C-8 of the hexahydronaphthalene ring with 2, 2-dimethylbutanoic acid in the presence of dicyclohexylcarbodiimide or 2, 2-dimethylchloride, and deprotect with tetrabutylammonium fluoride to obtain the final product.
However, the method requires high temperature and reaction time as long as 56 hours in the hydrolysis and acylation steps, and meanwhile, the lactone ring hydroxyl is not sufficiently protected by silicon-based selectivity, so that a competitive reaction exists, the yield and purity of the product are reduced, the content of byproducts is increased, and certain difficulty is brought to the post-treatment; and the expensive silicon-based protecting group has high cost and the economical efficiency of the process route is relatively poor.
(2) The American Merk company applies for the process patents (USP4820850, EP0299656B1 and CN1019395B) of the route, and the synthetic route is to carry out amination ring opening on lovastatin, carry out dihydroxy silicon-based protection on ring-opened products, and then carry out methylamine reaction, dihydroxy deprotection, hydrolysis-ammoniation and lactone formation to obtain the final product simvastatin.
However, the yield and purity of the product in the amination ring-opening step in the reaction are not high, and the number of byproducts is large, which is not favorable for industrial production.
In order to solve a series of problems in the prior art, the invention improves the prior art, can solve or avoid the problems and is suitable for industrial mass production.
Disclosure of Invention
The invention aims to provide a preparation method of a medicine for treating hyperlipemia aiming at the defects of the prior art, the used reaction raw materials are cheap and easy to obtain, the reaction process is controllable, the total yield and purity of the product are higher, the by-products are less, and the preparation method is suitable for industrial production.
The reaction route of the invention is as follows:
The preparation method of the medicine for treating hyperlipemia provided by the invention comprises the following steps:
a. Placing the compound II in methanol and potassium hydroxide for refluxing, cooling to room temperature after the reaction is finished, adjusting the pH value to 2 by hydrochloric acid, and carrying out post-treatment to obtain a compound III;
b. Reacting the compound III with acetone under an acidic condition to prepare a compound IV;
c. Reacting the compound IV with 2, 2-dimethylbutyric acid in a concentrated sulfuric acid environment to prepare a compound V;
d. The compound V is subjected to depropylidene under the acidic condition to prepare a compound VI;
e. And carrying out lactonization on the compound VI under the condition of phosphorus pentoxide to prepare a final product simvastatin (I).
Preferably, the molar ratio of the compound II to the potassium hydroxide in the step a is 1: 2-2.2.
Preferably, the acid in step b is concentrated sulfuric acid, and the molar ratio of the compound III to the acid is 1: 1.5-3.
Preferably, the reaction operation step in the step c is to slowly dropwise add the compound IV into a reaction bottle containing 2, 2-dimethylbutyric acid for reaction; the molar ratio of the 2, 2-dimethylbutyric acid to the compound IV is 1:0.9-1, and the molar amount of the concentrated sulfuric acid is 0.5 times of that of the 2, 2-dimethylbutyric acid.
Preferably, the acid in step d is trifluoroacetic acid; the molar amount of the acid is 1.5-2 times of that of the compound V.
Preferably, the molar ratio of the compound VI to the phosphorus pentoxide in step e is 1: 1.2-1.5.
Compared with the prior art, the invention has the beneficial effects that: the preparation method has the advantages of simple whole route, simple operation and low production cost, improves the total yield and purity of the product, reduces the generation of byproducts, and is suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Example 1
preparation of Compound III
Adding 48.54g (0.120mol) of compound II into a reaction bottle, adding 180ml of potassium hydroxide solution (0.240mol) and methanol, heating to reflux, reacting for 4-5h, cooling to room temperature, adjusting the pH value to 2 with hydrochloric acid, removing the methanol under reduced pressure to obtain a solid, and drying in vacuum to obtain 37.77g of compound III, wherein the yield is 93%, and the purity is 99.2%.
Example 2
Preparation of Compound III
Adding a compound II (0.120mol) into a reaction bottle, adding a potassium hydroxide solution (0.260mol) and 180ml of methanol, heating to reflux, reacting for 4-5h, cooling to room temperature, adjusting the pH to 2 by using hydrochloric acid, removing the methanol under reduced pressure to obtain a solid, and drying in vacuum to obtain 39.80g of a compound III, wherein the yield is 98%, and the purity is 99.5%.
Example 3
Preparation of Compound III
Adding a compound II (0.120mol) into a reaction bottle, adding a potassium hydroxide solution (0.120mol) and 180ml of methanol, heating to reflux, reacting for 4-5h, cooling to room temperature, adjusting the pH value to 2 by using hydrochloric acid, removing the methanol under reduced pressure to obtain a solid, and drying in vacuum to obtain 32.49g of a compound III, wherein the yield is 80%, and the purity is 99.0%.
Example 4
Preparation of Compound IV
200ml of acetone is added into a reaction bottle, and the temperature of ice water is reduced to 0-5 ℃. Dropwise adding concentrated sulfuric acid (0.167mol) under the protection of nitrogen, adding the concentrated sulfuric acid after 25min, then adding 37.77g of the compound III, controlling the temperature at room temperature, stirring and reacting for 2-2.5h, cooling to below 10 ℃ after the reaction is finished, separating out solids, washing with acetone, combining filtrates, and concentrating under reduced pressure to obtain 38.44g of the compound IV, wherein the yield is 91%, the purity is 99.5%, the maximum single impurity is 0.035%, and the total impurity is 0.51%.
example 5
Preparation of Compound IV
200ml of acetone is added into a reaction bottle, and the temperature of ice water is reduced to 0-5 ℃. Dropwise adding concentrated sulfuric acid (0.353mol) under the protection of nitrogen, adding 39.80g of the compound after 25min, controlling the temperature at room temperature, stirring and reacting for 2-2.5h, cooling to below 10 ℃ after the reaction is finished, separating out solids, washing with acetone, combining filtrates, and concentrating under reduced pressure to obtain 42.29g of the compound IV, wherein the yield is 95%, the purity is 99.7%, the maximum single impurity is 0.032%, and the total impurity is 0.30%.
example 6
Preparation of Compound IV
200ml of acetone is added into a reaction bottle, and the temperature of ice water is reduced to 0-5 ℃. Dropwise adding concentrated sulfuric acid (0.115mol) under the protection of nitrogen, adding 32.49g of the compound III after 25min, controlling the temperature at room temperature, stirring and reacting for 2-2.5h, cooling to below 10 ℃ after the reaction is finished, separating out solids, washing with acetone, combining filtrates, and concentrating under reduced pressure to obtain 29.80g of the compound IV, wherein the yield is 82%, the purity is 98.9%, the maximum single impurity is 0.056%, and the total impurity is 1.02%.
example 7
Preparation of Compound V
2, 2-dimethylbutyric acid (0.113mol), benzene (300 ml) and concentrated sulfuric acid (0.057mol) are added into a reaction bottle, and then compound IV 38.58g is slowly added to react for 3 hours under heating and refluxing. After the reaction, the reaction mixture was cooled, washed with water, filtered, and then subjected to distillation under reduced pressure to remove the solvent, thereby obtaining 44.73g of the compound v, 92% in yield, 99.4% in purity, 0.025% of the maximum single impurity, and 0.58% of the total impurities.
Example 8
preparation of Compound V
2, 2-dimethylbutyric acid (0.112mol), benzene (300 ml) and concentrated sulfuric acid (0.056mol) are added into a reaction bottle, and then compound IV 42.29g is slowly added to react for 3 hours under heating and refluxing. After the reaction, the reaction mixture was cooled, washed with water, filtered, and then subjected to distillation under reduced pressure to remove the solvent, thereby obtaining 50.72g of the compound v, with a yield of 95%, a purity of 99.3%, a maximum of 0.028% as a single impurity, and 0.69% as a total impurity.
Example 9
Preparation of Compound V
2, 2-dimethylbutyric acid (0.072mol), benzene (300 ml) and concentrated sulfuric acid (0.036mol) are added into a reaction bottle, 30.13g of compound IV is slowly added, and the mixture is heated and refluxed for reaction for 3 hours. After the reaction, the reaction mixture was cooled, washed with water, filtered, and then subjected to vacuum distillation to remove the solvent, thereby obtaining 32.95g of the compound v, with a yield of 96%, a purity of 97.8%, a maximum of 0.046% of a single impurity, and a total of 2.1% of impurities.
Example 10
preparation of Compound VI
110ml of methylene chloride and 44.73g of compound V were put into a reaction flask, trifluoroacetic acid (0.141mol) was added dropwise with magnetic stirring, the reaction was controlled at room temperature, and the reaction was monitored by TLC until the starting material was completely reacted. Concentrating, and performing column chromatography (eluent: V)Petroleum ether：Vethyl acetateSeparation under 5:1) gave 35.22g of compound vi in 86% yield and 99.6% purity.
Example 11
Preparation of Compound VI
110ml of methylene chloride and 50.72g of Compound V were charged into a reaction flask, trifluoroacetic acid (0.212mol) was added dropwise with magnetic stirring, the reaction was controlled at room temperature, and the reaction was monitored by TLC until completion of the reaction of the starting materials. Concentrating, and performing column chromatography (eluent: V)Petroleum ether：VEthyl acetateSeparation under 5:1) gave 40.88g of compound vi in 88% yield and 99.8% purity.
example 12
Preparation of Compound VI
110ml of methylene chloride and 32.95g of compound V were charged into a reaction flask, trifluoroacetic acid (0.069mol) was added dropwise with magnetic stirring, the reaction was controlled at room temperature, and the reaction was monitored by TLC until completion of the reaction of the starting materials. Concentrating, and performing column chromatography (eluent: V)Petroleum ether：VEthyl acetateSeparation under 5:1) gave 23.84g of compound vi in 79% yield and 99.4% purity.
Example 13
Preparation of simvastatin (I)
35.22g of compound VI is dissolved in 300ml of tetrahydrofuran, phosphorus pentoxide (0.097mol) is added, and the reaction is stirred at room temperature for 4.5h, thus the reaction is finished. The filtrate was evaporated under reduced pressure, dissolved in 150ml of dichloromethane, and washed with saturated sodium bicarbonate solution, water, and saturated brine (150 ml each). The organic solvent was evaporated to dryness under reduced pressure and dried under vacuum to obtain 31.74g of simvastatin (I) with a yield of 94%, a purity of 99.6%, a maximum of 0.029% of a single impurity and 0.42% of total impurities.
Example 14
Preparation of simvastatin (I)
40.88g of compound VI is dissolved in 300ml of tetrahydrofuran, phosphorus pentoxide (0.140mol) is added, and the reaction is stirred at room temperature for 4.5h, thus the reaction is finished. The filtrate was evaporated under reduced pressure, dissolved in 150ml of dichloromethane, and washed with saturated sodium bicarbonate solution, water, and saturated brine (150 ml each). The organic solvent was evaporated to dryness under reduced pressure and dried under vacuum to obtain 38.00g of simvastatin (I) with a yield of 97%, a purity of 99.7%, a maximum of 0.027% of a single impurity, and 0.31% of total impurities.
Example 15
Preparation of simvastatin (I)
23.84g of the compound VI is dissolved in 300ml of tetrahydrofuran, phosphorus pentoxide (0.055mol) is added, and the reaction is stirred at room temperature for 4.5h, and the reaction is finished. The filtrate was evaporated under reduced pressure, dissolved in 150ml of dichloromethane, and washed with saturated sodium bicarbonate solution, water, and saturated brine (150 ml each). The organic solvent was evaporated to dryness under reduced pressure and dried under vacuum to obtain 19.42g of simvastatin (I) with a yield of 85%, a purity of 99.4%, a maximum of 0.038% of a single impurity and 0.58% of total impurities.
Claims (8)
1. The preparation method of the medicine for treating hyperlipemia is characterized by comprising the following steps:
a. Placing the compound II in methanol and potassium hydroxide for refluxing, cooling to room temperature after the reaction is finished, adjusting the pH value to 2 by hydrochloric acid, and carrying out post-treatment to obtain a compound III;
b. Reacting the compound III with acetone under an acidic condition to prepare a compound IV;
c. Reacting the compound IV with 2, 2-dimethylbutyric acid in a concentrated sulfuric acid environment to prepare a compound V;
d. The compound V is subjected to depropylidene under the acidic condition to prepare a compound VI;
e. carrying out lactonization on the compound VI under the condition of phosphorus pentoxide to prepare a final product simvastatin (I);
The reaction route is as follows:
2. The process according to claim 1, wherein the molar ratio of compound II to potassium hydroxide in step a is 1:2 to 2.2.
3. The method according to claim 1, wherein the acid in step b is concentrated sulfuric acid, and the molar ratio of compound III to acid is 1: 1.5-3.
4. The preparation method according to claim 1, wherein the reaction operation in step c comprises slowly dropping the compound IV into a reaction flask containing 2, 2-dimethylbutyric acid to effect the reaction.
5. the method according to claim 1, wherein the molar ratio of 2, 2-dimethylbutyric acid to compound iv in step c is 1:0.9-1, and the molar amount of concentrated sulfuric acid is 0.5 times that of 2, 2-dimethylbutyric acid.
6. The method according to claim 1, wherein the acid in step d is trifluoroacetic acid.
7. The method according to claim 1, wherein the molar amount of the acid used in step d is 1.5 to 2 times that of compound V.
8. The process according to claim 1, wherein the molar ratio of compound VI to phosphorus pentoxide in step e is 1: 1.2-1.5.
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| CN201910853110.5A CN110563680A (en) | 2019-09-10 | 2019-09-10 | Preparation method of medicine for treating hyperlipemia |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1290261A (en) * | 1998-12-10 | 2001-04-04 | 钟渊化学工业株式会社 | process for producing simvastatin |
| US6294680B1 (en) * | 1997-01-28 | 2001-09-25 | Plus Chemicals, B.V. | Process for the production of semi synthetic statins via novel intermediates |
| CN101613341A (en) * | 2009-03-09 | 2009-12-30 | 鲁南制药集团股份有限公司 | A kind of synthetic method of rosuvastatin calcium side chain key intermediate |
| CN105153110A (en) * | 2015-09-23 | 2015-12-16 | 河南师范大学 | Synthesis method for chiral intermediate of atorvastatin calcium |
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- 2019-09-10 CN CN201910853110.5A patent/CN110563680A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294680B1 (en) * | 1997-01-28 | 2001-09-25 | Plus Chemicals, B.V. | Process for the production of semi synthetic statins via novel intermediates |
| CN1290261A (en) * | 1998-12-10 | 2001-04-04 | 钟渊化学工业株式会社 | process for producing simvastatin |
| CN101613341A (en) * | 2009-03-09 | 2009-12-30 | 鲁南制药集团股份有限公司 | A kind of synthetic method of rosuvastatin calcium side chain key intermediate |
| CN105153110A (en) * | 2015-09-23 | 2015-12-16 | 河南师范大学 | Synthesis method for chiral intermediate of atorvastatin calcium |
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Application publication date: 20191213 |