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Preparation method of atorvastatin calcium intermediate

A technology for atorvastatin calcium and intermediates, applied in the field of preparation of atorvastatin calcium intermediates, can solve the problem that the yield of N-phenylisobutyrylacetamide is only 76%, and the yield of multi-component reaction is not high. High, serious wastewater pollution and other problems, to achieve the effect of environmental friendliness, high product purity and low cost

Pending Publication Date: 2021-12-14
江苏阿尔法集团盛基药业(宿迁)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Chinese patent CN101307009A discloses a synthesis process of N-phenylisobutyrylacetamide, using toluene as the reaction solvent, adding methyl isopropyl ketone dropwise to dimethyl carbonate, and reacting for 4 hours under the action of sodium hydride , the obtained intermediate is reacted with aniline for 2 hours, the operation steps are simple, but the yield of N-phenylisobutyrylacetamide is only 76%
The raw materials of this process are cheap and easy to obtain, but the yield of the multi-component reaction in the first step is not high; secondly, the highly toxic reagent NaCN is used in the process, which has a high safety risk and serious wastewater pollution

Method used

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  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] A kind of preparation method of atorvastatin calcium intermediate, concrete steps are:

[0041] (1) Preparation of N-acetylacetanilide (compound 2)

[0042]

[0043] Add ethanol (325g) into the reaction kettle, set the temperature at 30°C, add diketene (84g, 1mol) and aniline (93g, 1mol) dropwise while stirring, keep stirring after the dropwise addition, and acylation reaction begins at 30°C 3h; after the completion of the reaction, cool to 0°C, filter, and dry to obtain a white powder (177g, yield 100%);

[0044] (2) Preparation of N-phenylisobutyrylacetamide (compound 1)

[0045]

[0046] Add compound 2 (177g, 1mol), 4-dimethylaminopyridine (0.24g, 0.002mol), toluene (921g, 10mol) in the reaction kettle, stir and make it mix uniformly, obtain clear light yellow solution; Control temperature 20 ~25°C, then add calcium hydroxide (111g, 1.5mol) and calcium oxide (5.6g, 0.1mol); drop the temperature to 5~8°C and add isobutyryl chloride (128g, 1.2mol) dropwise, hea...

Embodiment 2～11

[0056] According to the method disclosed in Example 1, only the feed ratio or other conditions in the first step reaction were changed, see Table 1 for details.

[0057] Note: the blank part in the table represents that the condition is the same as that in Example 1.

[0058] Different conditions and results of the first step reaction in table 1

[0059]

[0060]

Embodiment 12～21

[0062] According to the method disclosed in Example 1, only the feed ratio or other conditions in the second step reaction were changed, see Table 2 for details.

[0063] Note: the blank part in the table represents that the condition is the same as that in Example 1.

[0064] Different conditions and results of the second step reaction in table 2

[0065]

[0066] Here, DMAP represents 4-dimethylaminopyridine.

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Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of an atorvastatin calcium intermediate, which comprises the following steps of: carrying out an acylation reaction on aniline and diketene as starting materials in an organic solvent to obtain N-acetoacetanilide; reacting N-acetoacetanilide with isobutyryl chloride to obtain 2-acetyl-4-methyl-3-oxo-N-phenyl pentanamide; reacting 2-acetyl-4-methyl-3-oxo-N-phenyl pentanamide with an ammonium chloride aqueous solution to synthesize N-phenyl isobutyryl acetamide; and reacting N-phenyl isobutyryl acetamide with 2-halo-1-(4-fluorophenyl)-2-acetophenone to synthesize the atorvastatin calcium intermediate. According to the method, post-treatment is carried out through simple liquid separation, washing and recrystallization, petroleum ether and sodium cyanide which are high in toxicity are prevented from being used, the operation method is simple, the operation safety is high, the product purity is high, the yield is high, and the method is environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing an atorvastatin calcium intermediate. Background technique [0002] Atorvastatin calcium, the chemical name is [R-(R',R')]-2-(4-fluorophenyl)-β,α-dihydroxy-5-(1-methylethyl)-3 -Phenyl-4-[(anilino)carbonyl]-1-hydro-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate, CAS number is 134523-03-8, HMG-CoA reductase is a selective, competitive inhibitor for the treatment of elevated total cholesterol, elevated LDL cholesterol, elevated apolipoprotein B, and elevated triglycerides. Its structural formula is as follows: [0003] [0004] The synthesis of atorvastatin calcium involves two important intermediates, namely N-phenylisobutyrylacetamide (hereinafter referred to as "compound 1") and 4-(4-fluorophenyl)-2-(2-methyl propionyl)-3-phenyl-4-oxo-N-phenylbutyramide (hereinafter referred to as "M4"). [0005] N-phenylisobutyrylacetamide, CAS num...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C235/80
CPCC07C231/04C07C231/12C07C235/80Y02P20/55
Inventor 石利平陈本顺孙伟振尹强江涛仲召亮黄忠邱磊于娜娜施莉莉
Owner 江苏阿尔法集团盛基药业(宿迁)有限公司