CN108101891B - Preparation method of atorvastatin intermediate - Google Patents
Preparation method of atorvastatin intermediate Download PDFInfo
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- CN108101891B CN108101891B CN201711276755.4A CN201711276755A CN108101891B CN 108101891 B CN108101891 B CN 108101891B CN 201711276755 A CN201711276755 A CN 201711276755A CN 108101891 B CN108101891 B CN 108101891B
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a preparation method of an atorvastatin intermediate. Adding ATS-9 and M4 into a high-pressure kettle by taking 2-methyltetrahydrofuran as a solvent, slowly adding pivalic anhydride under stirring, replacing air in the reaction kettle with nitrogen for 2-3 times, heating to 150-200 ℃, reacting for 2-4 hours, concentrating under reduced pressure after the reaction is finished, recovering the solvent to obtain viscous oily matter, adding water and isopropanol into the oily substance, heating to 40-60 ℃, slowly cooling to 20-30 ℃, precipitating a solid, and performing post-treatment to obtain an atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrole-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxane-4-yl-tert-butyl acetate. The method has the advantages of low operation cost, high selectivity and no environmental pollution, and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis process of a compound, and particularly relates to a preparation method of an atorvastatin intermediate.
Background
(4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrol-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxane-4-yl-acetic acid tert-butyl ester is a key intermediate for the synthesis of atorvastatin calcium. EP1659110a1, IE20060197, US5280126, US5298627, US6476235, US6545153, WO2007/096751a1 and the like disclose processes for the synthesis of atorvastatin calcium and intermediates thereof. In WO2007/096751a1, 100 g of M4 and 261.9 g of ATS-9 were added to 2L of cyclohexane and 100mL of tetrahydrofuran, 11.0 g of pivalic acid was used as a catalyst, the mixture was refluxed at 70 to 85 ℃ for 18 hours, cooled to 25 to 35 ℃, 500mL of water was added, liquid ammonia was added to adjust the pH to 8.5 to 9.5, the mixture was extracted with 1000mL of dichloromethane, the organic phase was concentrated, the residue was dissolved in isopropanol, and water was added to precipitate a solid, thereby obtaining (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrol-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxan-4-yl-acetic acid tert-butyl ester. The reaction solvent consumption is large, and the post-treatment is complex.
CN101429195 discloses that the acid catalyst for the reaction of M4 with ATS-9 is a carboxylic acid, inorganic acid or acidic resin with 1-8 carbon atoms; wherein the carboxylic acid having 1-8 carbon atoms is formic acid, acetic acid, n-butyric acid, n-valeric acid, n-caproic acid, etc., and the inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, etc.; the acidic resin is 732 strongly acidic styrene cation exchange resin, 122 macroporous phenolic weak acid resin, etc. However, the structure of ketal is hydrolyzed under strong acidity (inorganic acid, strong organic acid) to remove protection, and is also easy to form salt with amino, and the disubstituted compound (I) is easy to generate under weak acid condition, and pyrrole ring can not be formed.
Thus, pivalic acid is the optimal catalyst. In order to take 2 moles of water generated by the reaction out of the reaction system, researchers have adopted various methods. Li Happy silk (a study on the synthesis process of atorvastatin calcium, Master's academic thesis of university of Henan, university) studied toluene, n-heptane, tetrahydrofuran, n-hexane and a mixture thereof as a reaction solvent. Reacting tetrahydrofuran: the best dehydration effect is achieved by heating and refluxing the n-hexane (1: 4). The synthesis process of atorvastatin calcium is optimized by an orthogonal experimental method in the application chemical industry, namely, the application chemical industry, 2013, 42 (11): 1972-1974), and a ternary solvent of n-heptane, tetrahydrofuran and toluene is adopted. CN106938996A adopts n-heptane and tetrahydrofuran as solvents, and CN102766136A adopts tetrahydrofuran and n-butyl ether as solvents. The purpose of solvent change is to quickly bring water generated by reaction out of a reaction system through constant boiling water, so that the reaction rate is increased, and the conversion rate of raw materials is improved. CN 102127060A adopts a mixed solvent which is not mutually soluble with water and has a proper boiling point and a constant-temperature reflux water separation mode, so that the reaction time is greatly shortened, and the yield is higher.
The method is verified to have slower reaction rate and longer reaction time, and the reaction can be completed in at least 24 hours.
Disclosure of Invention
The invention aims to overcome the defects that water generated by reaction is not easy to be brought out of a reaction system and the reaction time is long in the prior art, and provides a preparation method of an atorvastatin intermediate.
The technical scheme of the invention is as follows:
using 2-methyltetrahydrofuran as a solvent, tert-butyl [ (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxan-4-yl-acetate and tert-butyl [ 5-methyl-4-isopropyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -1, 4-hexanedione ], [ (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxan-4-yl-acetate and [ 5-methyl-4-isopropyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -were added to an autoclave The molar ratio of 1, 4-hexanedione ] is 1: 1-1.1. Slowly adding pivalic anhydride under stirring, wherein the molar ratio of [ (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxane-4-yl-tert-butyl acetate to pivalic anhydride is 1: 2.5-3, replacing air in a reaction kettle with nitrogen for 2-3 times, heating to 150-200 ℃, reacting for 2-4 hours, after the reaction is finished, carrying out reduced pressure concentration to recover a solvent to obtain a viscous oily substance, adding water and isopropanol into the oily substance, wherein the volume ratio of the water to the isopropanol is 1: 1-3, heating to 40-60 ℃, slowly cooling to 20-30 ℃, precipitating a yellow solid, carrying out suction filtration and drying to obtain an atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrol-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxane-4-yl-acetic acid tert-butyl ester.
The invention uses single solvent 2-methyltetrahydrofuran, which is convenient and simplifies the post-treatment process of mixed solvent separation. The invention still adopts pivalic acid as the catalyst, ensures the selectivity of the reaction, adopts pivalic anhydride to react with the water generated by the reaction synchronously to generate pivalic acid, catalyzes the reaction, and achieves the effects of high speed, high selectivity and high yield. After the reaction, a complex post-treatment process is not needed, and the (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrol-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxane-4-yl-tert-butyl acetate can be obtained by simple operations such as solvent removal, recrystallization, suction filtration, drying and the like.
Detailed Description
The reaction equation of the invention is as follows:
example 1
A1000 mL autoclave was charged with 500mL of 2-methyltetrahydrofuran, and [ (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3]]-dioxan-4-yl-acetic acid tert-butyl ester 27.3 g, [ 5-methyl-4-isopropyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -1, 4-hexanedione]41.7 g, slowly adding 46.5 g of pivalic anhydride under stirring, closing the cover of the reaction kettle, replacing air in the reaction kettle with nitrogen for 2 times, heating to 150 ℃, reacting for 4 hours, and after the reaction is finished, decompressing, concentrating and recovering 480mL of solvent 2-methyltetrahydrofuran and 50.1 g of pivalic acid to obtain viscous oilAnd (4) forming a substance. Adding 100mL of water and 100mL of isopropanol into the oily substance, heating to 40 ℃, slowly cooling to 20 ℃, precipitating yellow solid, filtering, and drying to obtain the atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrole-1-yl-ethyl } -2, 2-dimethyl- [1,3]-dioxane-4-yl-tert-butyl acetate 65.0 g. mp:145 to 148 ℃, [ α ℃]＝4.6°(c＝1,CHCl3)，1H NMR(400MHz,CDCl3):＝1.18(s,3H),1.30(s,3H),1.35(s,6H),1.40(s,9H),1.50-1.64(m,2H),2.30-2.33(m,1H),2.50(s,4H),3.20-3.25(m,1H),3.35(s,1H),3.75-3.80(m,1H),3.90-3.95(m,1H),4.10-4.12(m,1H),6.96-7.02(m,2H),7.07-7.08(m,4H),7.18-7.28(m,5H),7.52(d,J＝8.0Hz,2H),9.80(s,1H)。
Example 2
To a 1000mL autoclave were charged 500mL of 2-methyltetrahydrofuran, 27.3 g of [ (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxan-4-yl-acetic acid tert-butyl ester, [ 5-methyl-4-isopropyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -1, 4-hexanedione ] and 45.9 g, 55.8 g of pivalic anhydride was slowly added with stirring, the reaction vessel lid was closed, the air in the reaction vessel was replaced with nitrogen 3 times, the temperature was raised to 200 ℃ and the reaction was carried out for 2 hours, after the reaction was completed, 457mL of the solvent 2-methyltetrahydrofuran and 56.7 g of pivalic acid were recovered by concentration under reduced pressure to obtain a viscous oil. To the oil was added 100mL of water and 300mL of isopropanol, the temperature was raised to 60 ℃, the mixture was slowly cooled to 30 ℃, and a yellow solid precipitated, which was filtered and dried to obtain 58.7 g of atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrol-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxane-4-yl-acetic acid tert-butyl ester.
Example 3
A1000 mL autoclave was charged with 500mL of recovered 2-methyltetrahydrofuran, 27.0 g of [ (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxan-4-yl-acetic acid tert-butyl ester, [ 5-methyl-4-isopropyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -1, 4-hexanedione ] and 45.0 g, followed by slowly adding 55.0 g of pivalic anhydride while stirring, closing the reaction vessel lid, replacing the air in the reaction vessel with nitrogen gas 3 times, raising the temperature to 180 ℃ and reacting for 2 hours, after the reaction was completed, 450mL of 2-methyltetrahydrofuran and 56.0 g of pivalic acid as a solvent were recovered by concentration under reduced pressure to obtain a viscous oil. To the oil was added 100mL of water and 300mL of isopropanol, the temperature was raised to 50 ℃, the mixture was slowly cooled to 25 ℃, a yellow solid precipitated, and the yellow solid was filtered off with suction and dried to give 61.2 g of atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorophenyl) -4- (phenylcarbamoyl) -pyrrol-1-yl-ethyl } -2, 2-dimethyl- [1,3] -dioxan-4-yl-acetic acid tert-butyl ester.
Claims (1)
1. A preparation method of an atorvastatin intermediate is characterized by comprising the following steps:
using 2-methyltetrahydrofuran as a solvent, (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxan-4-yl-acetic acid tert-butyl ester and 5-methyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -1, 4-hexanedione, (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxan-4-yl-acetic acid tert-butyl ester with 5-methyl-2-phenyl-1- (4-fluorophenyl) -3- (phenylcarbamoyl) -1, the method comprises the following steps of (1: 1) - (1.1) molar ratio of 4-hexanedione, slowly adding pivalic anhydride, (4R,6R) -2, 2-dimethyl-6- (2-aminoethyl) - [1,3] -dioxane-4-yl-tert-butyl acetate and pivalic anhydride with stirring, replacing air in a reaction kettle with nitrogen for 2-3 times, heating to 150-200 ℃, reacting for 2-4 hours, decompressing, concentrating and recovering a solvent after the reaction is finished to obtain a viscous oily substance, adding water and isopropanol into the oily substance, wherein the volume ratio of the water to the isopropanol is 1: 1-3, heating to 40-60 ℃, slowly cooling to 20-30 ℃, precipitating a yellow solid, performing suction filtration and drying to obtain an atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorobenzene), and drying to obtain an atorvastatin intermediate (4R,6R) -6- {2- [ 5-isopropyl-3-phenyl-2- (4-fluorobenzene) -4- (phenylcarbamoyl) -pyrrol-1-yl ] ethyl } -2, 2-dimethyl- [1,3] -dioxane-4-yl-acetic acid tert-butyl ester.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110998A1 (en) * | 2003-05-16 | 2004-12-23 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| CN102127060A (en) * | 2010-12-17 | 2011-07-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN102344401A (en) * | 2011-09-15 | 2012-02-08 | 景德镇市富祥药业有限公司 | Method for preparing amorphous atorvastatin calcium |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110998A1 (en) * | 2003-05-16 | 2004-12-23 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| CN102127060A (en) * | 2010-12-17 | 2011-07-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN102344401A (en) * | 2011-09-15 | 2012-02-08 | 景德镇市富祥药业有限公司 | Method for preparing amorphous atorvastatin calcium |
Non-Patent Citations (1)
| Title |
|---|
| 阿托伐他汀钙的合成工艺改进;周汨等，;《精细化工中间体》;20151031;第45卷(第5期);第19-21,29页 * |
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