CN102702014B - Method for preparing atorvastatin calcium intermediate - Google Patents
Method for preparing atorvastatin calcium intermediate Download PDFInfo
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- CN102702014B CN102702014B CN201210168067.7A CN201210168067A CN102702014B CN 102702014 B CN102702014 B CN 102702014B CN 201210168067 A CN201210168067 A CN 201210168067A CN 102702014 B CN102702014 B CN 102702014B
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Abstract
The invention provides a method for preparing atorvastatin calcium intermediate. The method comprises the steps of dissolving compound A and compound B into a solvent with a molar ratio of A to B of 1:(1.0-1.5), heating to 30-60 DEG C, stirring to dissolve, slowly dripping concentrated acid with a mole number of 2-8 times of that of compound A for a reaction for 16-36 hours at 80-110 DEG C, removing water formed during the reaction by using a water separator after the reaction, removing the solvent through rotary dying, dissolving with ethyl acetate, adding petroleum ether dropwise for recrystallization and treating for several times to obtain the final product. The two raw materials A and B used in the method are cheap and available, the catalyst of the reaction is common acid, and the product of the side reaction is only water. The obtained product has a purity of over 98% and a yield of about 80% and accords with the requirements of friendly environment and green chemistry.
Description
Technical field
The present invention relates to a kind of preparation method of atorvastatincalcuim intermediate, belong to medical production technical field.
Background technology
(Lipitor, is Lipitor) the maximum anticholesteremic agent of current global recipe quantity to atorvastatin, becomes the whole world prescription drugs that is in great demand most from 2002, and annual sales amount reaches 10,000,000,000 dollars.Five patents about Lipitor all will expire in the recent period successively.Wherein the related Lipitor calcium salt patent (US 5273995) of this problem will expire in June, 2011.At present, to the end of the year 2010, the Lipitor of Rui Hui company occupies Chinese market annual turnover 69.18%, and annual sales amount reaches several hundred million yuans.In addition, on market, domestic preparation mainly contains the atorvastatin that the good woods medicine company in Beijing rushes to register (trade(brand)name: A Le) and the atorvastatin calcium capsule (trade(brand)name: You Jia) of Henan old name for the Arabian countries in the Middle East medicine company.
The main method of at present synthetic atorvastatincalcuim is the linked reaction (as follows) of two fragments, and wherein AT-9 mainly contains following two kinds of synthetic routes:
Article one, be 1992 by people such as Butler, take Stetter reaction as committed step, make aldehyde carry out Isosorbide-5-Nitrae addition with alpha, beta-unsaturated ketone under catalyst action, generate Isosorbide-5-Nitrae-diketone.The advantage of this route is that step is fairly simple, is suitable for industrialized production, and main drawback is: 1) price comparison of key intermediate p-Fluorobenzenecarboxaldehyde is expensive; 2) selection of Stetter catalysts has a lot, finally finds that effective catalyzer is a class thiazoles carbone catalyst, and this class catalyzer is not easy to obtain, and cost is high again, but also foul smelling taste, environment is unfriendly.
Equations of The Second Kind route, is to take phenyllacetyl chloride as raw material, by Friedel-Crafts reaction and the synthetic bromo-1-of 2-(4-the fluorophenyl)-methyl phenyl ketone of bromo-reaction, subsequently bromine is carried out to substitution reaction and obtains Segment A.Compare with article one route, its advantage is: 1) respectively walk reagent and be cheaply easy to get, be beneficial to and reduce costs; 2) reaction conditions is also gentleer, and by product is less; 3) overall yield is higher.But still there are some shortcomings, mainly contain: 1) reactions steps is longer; 2) reaction first will be on carbonyl alpha-position bromine, final step removes bromine while replacing again, Atom economy is poor; 3) although reaction has avoided using expensive catalyzer, the bromine of using still has pungency and corrodibility, aspect waste pollution processing and environment protection, is still needing to improve.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art part, a kind of preparation method of atorvastatincalcuim intermediate is provided.
The preparation method of atorvastatincalcuim intermediate of the present invention, comprise the steps: compd A and compd B to be dissolved in solvent, wherein the molar ratio of A and B is 1:(1.0-1.5), be heated to temperature 30-60 ℃, stirring and dissolving, slowly drip concentrated acid, the 2-8 that the mole number of concentrated acid is compd A doubly; At 80-110 ℃, react 16-36 hour, reaction finishes the rear water trap that utilizes and removes the water that dereaction generates, and is spin-dried for solvent, with acetic acid ethyl dissolution, drips sherwood oil recrystallization, repeatedly process repeatedly,
Concrete reaction formula is as follows:
Described solvent is DMSO, ethyl acetate or toluene;
Described concentrated acid is the vitriol oil, phosphoric acid or polyphosphoric acid;
Described A and the molar ratio of B are 1:(1.1-1.3);
Described temperature of reaction is 90-100 ℃;
The described reaction times is 24-28 hour.
The present invention's two raw material A used and B is relatively inexpensive is easy to get, this reaction used catalyst is customary acid, side reaction is only water.Products therefrom purity is greater than 98%, and yield 80% left and right, meets the requirement of environmental friendliness and Green Chemistry.
Embodiment
Now in conjunction with the embodiments, the present invention is further elaborated.
embodiment 1
Compd A (2.3g) and compd B (2.7g) are dissolved in the toluene solvant dry with 50ml, be heated to 45 ℃, stir 30min, slowly drip the 3.5g vitriol oil, dropwise, continue to stir 30min, be warming up to 90 ℃, fraction water device water-dividing.React 24 hours. after finishing, reaction is washed with water to neutrality, saturated solution of sodium bicarbonate washing organic phase.Anhydrous sodium sulfate drying. remove under reduced pressure after solvent, use 50ml acetic acid ethyl dissolution, mechanical stirring.Be heated to 30 ℃, slowly drip sherwood oil 150ml, obtain product. repeat above-mentioned re-crystallization step 2 times, obtain product 3.2g.
embodiment 2
Compd A (30g) and compd B (35g) are dissolved in 300ml dry toluene solvent, are heated to 45 ℃, stir 30min, slowly drip 50g strong phosphoric acid, dropwise, continue to stir 30min, be warming up to 90 ℃, fraction water device water-dividing.React 26 hours. after finishing, reaction is washed with water to neutrality, saturated solution of sodium bicarbonate washing organic phase.Anhydrous sodium sulfate drying. remove under reduced pressure after solvent, use 200ml acetic acid ethyl dissolution, mechanical stirring. be heated to 30 ℃, slowly drip sherwood oil 600ml, obtain product. repeat above-mentioned re-crystallization step 2 times, obtain product 44.8g.
embodiment 3
Compd A (100g) and compd B (115g) are dissolved in 1000ml dry toluene solvent, are heated to 45 ℃, stir 30min, slowly drip 160g strong phosphoric acid, dropwise, continue to stir 30min, be warming up to 90 ℃, fraction water device water-dividing. react 26 hours.After finishing, reaction is washed with water to neutrality, saturated solution of sodium bicarbonate washing organic phase.Anhydrous sodium sulfate drying.Remove under reduced pressure after solvent, use 1000ml acetic acid ethyl dissolution, mechanical stirring.Be heated to 30 ℃, slowly drip sherwood oil 3000ml, obtain product. repeat above-mentioned re-crystallization step 2 times, obtain product 151.0g.
Claims (6)
1. the preparation method of an atorvastatincalcuim intermediate, it is characterized in that, comprise the steps: compd A and compd B to be dissolved in solvent, wherein the molar ratio of A and B is 1:(1.0-1.5), be heated to temperature 30-60 ℃, stirring and dissolving, slowly drips concentrated acid, and the 2-8 that the mole number of concentrated acid is compd A doubly; At 80-110 ℃, react 16-36 hour, reaction finishes the rear water trap that utilizes and removes the water that dereaction generates, and is spin-dried for solvent, with acetic acid ethyl dissolution, drips sherwood oil recrystallization, repeatedly process repeatedly,
Concrete reaction formula is as follows:
2. the preparation method of atorvastatincalcuim intermediate according to claim 1, is characterized in that, described solvent is toluene.
3. the preparation method of atorvastatincalcuim intermediate according to claim 1, is characterized in that, described concentrated acid is the vitriol oil, phosphoric acid or polyphosphoric acid.
4. the preparation method of atorvastatincalcuim intermediate according to claim 1, is characterized in that, described A and the molar ratio of B are 1:(1.1-1.3).
5. the preparation method of atorvastatincalcuim intermediate according to claim 1, is characterized in that, described temperature of reaction is 90-100 ℃.
6. the preparation method of atorvastatincalcuim intermediate according to claim 1, is characterized in that, the described reaction times is 24-28 hour.
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| CN201210168067.7A CN102702014B (en) | 2012-05-28 | 2012-05-28 | Method for preparing atorvastatin calcium intermediate |
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| CN201210168067.7A CN102702014B (en) | 2012-05-28 | 2012-05-28 | Method for preparing atorvastatin calcium intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
| CN114195670B (en) * | 2021-12-31 | 2024-03-15 | 河南豫辰药业股份有限公司 | Refining method of atorvastatin mother nucleus M4 |
| CN115260051A (en) * | 2022-08-26 | 2022-11-01 | 江苏阿尔法药业股份有限公司 | Preparation process of atorvastatin calcium intermediate |
| CN115466196B (en) * | 2022-08-30 | 2024-03-26 | 宿迁阿尔法科技有限公司 | Preparation method of atorvastatin calcium intermediate |
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| CN101307009A (en) * | 2007-05-15 | 2008-11-19 | 浙江京新药业股份有限公司 | New synthetic method for (earth)4-fluor-alpha-(2-methyl-1-oxypropyl )-gamma-oxo-N, beta-diphenyl benzene butanamide |
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| KR20090070233A (en) * | 2007-12-27 | 2009-07-01 | 동아제약주식회사 | Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom |
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| CN101307009A (en) * | 2007-05-15 | 2008-11-19 | 浙江京新药业股份有限公司 | New synthetic method for (earth)4-fluor-alpha-(2-methyl-1-oxypropyl )-gamma-oxo-N, beta-diphenyl benzene butanamide |
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