CN102702014A - Method for preparing atorvastatin calcium intermediate - Google Patents
Method for preparing atorvastatin calcium intermediate Download PDFInfo
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- CN102702014A CN102702014A CN2012101680677A CN201210168067A CN102702014A CN 102702014 A CN102702014 A CN 102702014A CN 2012101680677 A CN2012101680677 A CN 2012101680677A CN 201210168067 A CN201210168067 A CN 201210168067A CN 102702014 A CN102702014 A CN 102702014A
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- 0 CC(C)C(C)C(*)C(CC1(C)C=CC(*)CC1)[C@]1C#C*C1 Chemical compound CC(C)C(C)C(*)C(CC1(C)C=CC(*)CC1)[C@]1C#C*C1 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Oc1ccccc1 Chemical compound Oc1ccccc1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
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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 atorvastatincalcuim intermediates preparation, belong to medical production technical field.
Background technology
(Lipitor was the maximum anticholesteremic agent of present global recipe quantity Lipitor) to atorvastatin, became 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 auspicious brightness company occupies Chinese market annual turnover 69.18%, and annual sales amount reaches several hundred million yuans.In addition, domestic preparation mainly contains the atorvastatin calcium tablet (trade(brand)name: A Le) cut down his spit of fland calcium capsule (trade(brand)name: You Jia) with the holder of Henan old name for the Arabian countries in the Middle East medicine company that the good woods medicine company in Beijing is rushed to register on the market.
The main method of at present synthetic atorvastatincalcuim is two segmental linked reactions (as follows), and wherein AT-9 mainly contains following two kinds of synthetic routes:
Article one, be 1992 by people such as Butler, be committed step with the Stetter reaction, make aldehyde under catalyst action, carry out 1,4 addition with alpha, beta-unsaturated ketone, generate 1, the 4-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, finds that finally effective catalyzer is one type of thiazoles carbone catalyst, and this type catalyzer is not easy to obtain, and cost is high again, but also the foul smelling flavor, environment is unfriendly.
Second type of route then is to be raw material with the phenyllacetyl chloride, through Friedel-Crafts reaction and bromo-reaction Synthetic 2-bromo-1-(4-fluorophenyl)-methyl phenyl ketone, subsequently bromine carried out substitution reaction and obtains Segment A.Compare with article one route, its advantage is: 1) respectively go on foot reagent and cheaply be easy to get, be beneficial to and reduce cost; 2) reaction conditions is also relatively gentleer, and by product is less; 3) overall yield is higher.But still have some shortcomings, mainly contain: 1) reactions step is longer; 2) reaction earlier will be on the carbonyl alpha-position bromine, final step removes bromine when replacing again, Atom economy is relatively poor; 3) though the use expensive catalysts has been avoided in reaction, the liquid bromine that uses still has pungency and corrodibility, still need improve aspect waste pollution processing and the environment protection.
Summary of the invention
The objective of the invention is to overcome the weak point of prior art, a kind of atorvastatincalcuim intermediates preparation is provided.
Atorvastatincalcuim intermediates preparation of the present invention; Comprise the steps: compd A and compd B are dissolved in the 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 mole number of concentrated acid is 2-8 a times of compd A; 80-110 ℃ of down reaction 16-36 hour, utilize water trap to remove the water that dereaction generates after reaction finishes, revolve dried solvent, use acetic acid ethyl dissolution, dropping sherwood oil recrystallization, repeated treatments repeatedly,
Concrete reaction formula is following:
Described solvent is DMSO, ETHYLE ACETATE or toluene;
Described concentrated acid is the vitriol oil, phosphoric acid or polyphosphoric acid;
The molar ratio of described A and B is 1: (1.1-1.3);
Described temperature of reaction is 90-100 ℃;
The described reaction times is 24-28 hour.
Used two raw material A of the present invention and B is relatively inexpensive is easy to get, this reaction catalyst system therefor is a customary acid, side reaction is merely water.Products therefrom purity is greater than 98%, and yield about 80% meets the requirement of environmental friendliness and Green Chemistry.
Embodiment
Combine embodiment at present, the present invention is done further elaboration.
Embodiment 1
In compd A (2.3g) and compd B (2.7g) dissolving and 50ml exsiccant toluene solvant, be heated to 45 ℃, stir 30min, slowly drip the 3.5g vitriol oil, dropwise, continue stirring 30min, be warming up to 90 ℃, fraction water device water-dividing.To react 24 hours. reaction is washed with water to neutrality after finishing, saturated solution of sodium bicarbonate washing organic phase.Anhydrous sodium sulfate drying. after removing solvent under reduced pressure, use the 50ml acetic acid ethyl dissolution, mechanical stirring.Be heated to 30 ℃, slowly drip sherwood oil 150ml, get product. repeat above-mentioned re-crystallization step 2 times, get product 3.2g.
Embodiment 2
Compd A (30g) and compd B (35g) are dissolved in the 300ml dry toluene solvent, are heated to 45 ℃, stir 30min, slowly Dropwise 5 0g SPA dropwises, and continues to stir 30min, is warming up to 90 ℃, fraction water device water-dividing.To react 26 hours. reaction is washed with water to neutrality after finishing, saturated solution of sodium bicarbonate washing organic phase.Anhydrous sodium sulfate drying. after removing solvent under reduced pressure, use the 200ml acetic acid ethyl dissolution, mechanical stirring. be heated to 30 ℃, slowly drip sherwood oil 600ml, get product. repeat above-mentioned re-crystallization step 2 times, get product 44.8g.
Embodiment 3
Compd A (100g) and compd B (115g) are dissolved in the 1000ml dry toluene solvent, are heated to 45 ℃, stir 30min, slowly drip the 160g SPA, dropwise, continue to stir 30min, be warming up to 90 ℃, fraction water device water-dividing. reacted 26 hours.Reaction is washed with water to neutrality after finishing, saturated solution of sodium bicarbonate washing organic phase.Anhydrous sodium sulfate drying.After removing solvent under reduced pressure, use the 1000ml acetic acid ethyl dissolution, mechanical stirring.Be heated to 30 ℃, slowly drip sherwood oil 3000ml, get product. repeat above-mentioned re-crystallization step 2 times, get product 151.0g.
Claims (6)
1. atorvastatincalcuim intermediates preparation; It is characterized in that comprise the steps: compd A and compd B are dissolved in the 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 mole number of concentrated acid is 2-8 a times of compd A; 80-110 ℃ of down reaction 16-36 hour, utilize water trap to remove the water that dereaction generates after reaction finishes, revolve dried solvent, use acetic acid ethyl dissolution, dropping sherwood oil recrystallization, repeated treatments repeatedly,
Concrete reaction formula is following:
2. atorvastatincalcuim intermediates preparation according to claim 1 is characterized in that, described solvent is DMSO, ETHYLE ACETATE or toluene.
3. atorvastatincalcuim intermediates preparation according to claim 1 is characterized in that, described concentrated acid is the vitriol oil, phosphoric acid or polyphosphoric acid.
4. atorvastatincalcuim intermediates preparation according to claim 1 is characterized in that, the molar ratio of described A and B is 1: (1.1-1.3).
5. atorvastatincalcuim intermediates preparation according to claim 1 is characterized in that, described temperature of reaction is 90-100 ℃.
6. atorvastatincalcuim intermediates preparation according to claim 1 is characterized in that, the described reaction times is 24-28 hour.
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| Application Number | Priority Date | Filing Date | Title |
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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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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
| CN114195670A (en) * | 2021-12-31 | 2022-03-18 | 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 |
| CN115466196A (en) * | 2022-08-30 | 2022-12-13 | 宿迁阿尔法科技有限公司 | Preparation method of atorvastatin calcium intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2009084827A2 (en) * | 2007-12-27 | 2009-07-09 | Dong-A Pharm.Co., Ltd. | Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom |
-
2012
- 2012-05-28 CN CN201210168067.7A patent/CN102702014B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2009084827A2 (en) * | 2007-12-27 | 2009-07-09 | Dong-A Pharm.Co., Ltd. | Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
| CN114195670A (en) * | 2021-12-31 | 2022-03-18 | 河南豫辰药业股份有限公司 | Refining method of atorvastatin mother nucleus M4 |
| 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 |
| CN115466196A (en) * | 2022-08-30 | 2022-12-13 | 宿迁阿尔法科技有限公司 | Preparation method 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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| CN102702014B (en) | 2014-03-19 |
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