CN101429195B - Process for producing important synthesis midbody of high purity atorvastatin - Google Patents
Process for producing important synthesis midbody of high purity atorvastatin Download PDFInfo
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- CN101429195B CN101429195B CN2008102021276A CN200810202127A CN101429195B CN 101429195 B CN101429195 B CN 101429195B CN 2008102021276 A CN2008102021276 A CN 2008102021276A CN 200810202127 A CN200810202127 A CN 200810202127A CN 101429195 B CN101429195 B CN 101429195B
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Abstract
The invention relates to a method for preparing high-purity (4R, 6R)-6-{2-[5-isopropyl-3-phenyl-2(4-fluorophenyl)-4-(phenylcarbamoyl)-yrrol-1-yl]- ethyl}-2, 2-dimethyl-[1, 3]-dioxane-4-yl-tert-butyl acetate, which comprises the following steps: step one, [5-methyl-4-isopropyl-2-phenyl-1(4-fluorophenyl)-3-(phenylcarbamoy1)-1,4-hexanedione](II) and [(4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxane-4-yl-tert-butyl acetate](III) with a mol ratio of between 0.71 and 1.12 to 1 are weighed, an acid catalyst which is 1.05 to 1.15 times of mol number of the formula (II) is weighed, the mixture is dissolved in a non-hydroxy solvent which is 3.0 to 4.2 times of the weight of the formula (II) under the protection of nitrogen and the stirring, and heating reflux and azeotropic water entrainment areperformed until an HPLC shows that the reaction is finished; and second two, the solvent is removed under vacuum, then a water-isopropanol mixed solvent with a volume ratio of 2 to 5 is used to recrystallize the mixture, and a key intermediate of synthetic atorvastatin calcium which has an HPLC purity not less than 99.0 percent and is expressed by the formula (I) is obtained after the pump filtration and drying. The method has the advantages of simple process, low equipment requirement, low cost, convenient and quick recovery of the solvent, less environmental pollution, and high product purity.
Description
Technical field
The present invention relates to a kind of preparation high purity (4R; 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl }-2; 2-dimethyl-[1; 3] method of-dioxs-4-base-tert.-butyl acetate, this compound are the key intermediates of preparation atorvastatincalcuim.Belong to pharmacy synthesis technology field.
Background technology
(the 4R of following formula (I) expression; 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl }-2; 2-dimethyl-[1; 3]-dioxs-4-base-tert.-butyl acetate; be synthetic atorvastatincalcuim (Lipitor, key intermediate Atorvatatin).The chemistry of atorvastatincalcuim is called (3R; 5R)-and 7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl 4-(carbaniloyl,phenylcarbamoyl) pyrroles-1-yl]-3; 5-dihydroxy heptyl acid calcium salt trihydrate; be by Bai Ke-Davis Co., Ltd (Warner-Lambert branch office) development, and with the Statins blood lipid regulation medicine of Pfizer's joint sales.Atorvastatin calcium belongs to a kind of competitiveness, selectivity HMG-CoA reductase inhibitor, and can block HMG-CoA and be reduced into hydroxyl first valeric acid, thus the content of reducing total cholesterol and low-density lipoprotein greatly.
Because the activity of atorvastatin is better than all statinses before it, and toxic side effect is little, therefore just show outstanding ascendant trend once listing.Suddenly become the highest medicine of global marketing volume after 2000, the occupation rate on lipid lowering agent market, the world is 55%; 2002 annual sales amounts record high, and have also created the new record of global marketing, have reached 7,900,000,000 dollars; Global marketing E Gaoda to 92.31 was hundred million dollars in 2003, took the leading position of global drug market at one stroke; Global marketing in 2004 income becomes the medicine of broken 10,000,000,000 dollars of global first sales volume up to 12,000,000,000 dollars; Reached 121.87 hundred million dollars in 2005.Huge economic benefit is stimulating people to pay close attention to the research of its synthetic method for a long time, and relevant its synthetic research constantly is in the news.
As: EP1,659,110, A1; IE2006/0197; US5,280,126; US5,298,627; US6,476,235; US6, patents such as 545,153 disclose the synthesis technique of the key intermediate of atorvastatincalcuim and formula (I) expression thereof.At EP1,659,110, the preparation technology who has comprised the key intermediate of formula (I) expression among the A1 in 7 of the disclosed atorvastatincalcuim step synthetic routes, the preparation technology of this key intermediate uses normal heptane, tetrahydrofuran (THF), toluene is as reaction solvent, use the more expensive PIVALIC ACID CRUDE (25) of price as catalyzer, reflux, aftertreatment has then comprised alkali cleaning-pickling-salt and has washed-complicated processes such as activated carbon treatment, complicated operation, loss is serious, the process refuse is more, this method productive rate is on the low side, and 2 recrystallizations just obtain 〉=99% HPLC purity, and the recovery of solvent difficulty.IE2006/0197 discloses the key intermediate technology with organic acid salt catalysis synthesis type (I) expression, mild condition, but have long, shortcoming such as catalyzer is expensive and be difficult to remove of reaction times.US5,298,627 disclosed preparation methods' post-processing step is comparatively loaded down with trivial details, and has used the disagreeableness toluene of environment.Generally speaking, the subject matter that existing technology exists is: the key intermediate of formula (I) expression that the preparation atorvastatincalcuim is used exists speed of response slow excessively, and transformation efficiency is low, and energy consumption is big; And need drop into the [(4R of formula (III) expression of excessive costliness, 6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxs-4-base-tert.-butyl acetate] raw material, thereby increased cost greatly, excessive raw material (III) residual influenced the purifying of the intermediate of formula (I) expression, causes preparing the very loaded down with trivial details postprocessing working procedures of key intermediate needs of highly purified formula (I) expression.
Because existing processes route production cost is higher, makes the scale preparation of atorvastatincalcuim still face difficulty, is difficult to become popular universal medicine.
Summary of the invention
The object of the present invention is to provide the method for the key intermediate of a kind of technology highly purified formula of simple, lower-cost preparation (I) expression.
For reaching above-mentioned purpose; we are through discovering: by [5-methyl-4-sec.-propyl-2-phenyl-1-(4-fluorophenyl)-3-(phenyl amino formyl radical)-1; the 4-hexanedione] (II) and [(4R; 6R)-2; 2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxs-4-base-tert.-butyl acetate] (III) reaction of the key intermediate of preparation formula (I) expression be following Paal-Knorr pyrroles's building-up reactions.
The characteristics of this reaction are: need acid catalyzed condition, and produce 2 normal water.Owing to the ketal structure of formula (III) is easily separated and generated by product issuing unboiled water than strong acidic condition, therefore the acid catalyst acidity of using can not be strong excessively, is a kind of more weak organic acid as PIVALIC ACID CRUDE (25) of the prior art; Like this, the selection of acid catalyst and expansion just have been subjected to great limitation.On the other hand, existing processes all fails to take the water that reaction produces out of reaction system, this be cause reacting slow, major cause that feed stock conversion is low, also be that the ketal structure that causes formula (III) is easily separated and ruined root issuing unboiled water than strong acidic condition; If take the measure of solvent azeotropic band water to address this problem, can not implement with water is miscible because of the solvent in the existing technology again.The present invention improves around these problems and clue, uses non-hydroxyl solvent, cooperates azeotropic band water, effectively reduces production cost, facilitates and simplifies postprocessing working procedures, and the solvent recuperation utilization is more convenient.
The present invention prepares the key intermediate (4R of highly purified formula (I) expression; 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl }-2; the method of 2-dimethyl-[1,3]-dioxs-4-base-tert.-butyl acetate comprises 2 steps:
The first step takes by weighing formula (II) earlier: (III)=0.71～1.12: 1 mol ratio.The amount that takes by weighing acid catalyst then is 1.05～1.15 times a mole number of formula (II).Then, under the nitrogen protection, (II), (III) and acid catalyst under agitation are dissolved in weight in 3.0～4.2 times the non-hydroxyl solvent of (II).Reheat to 70 ℃～110 ℃; reflux and azeotropic band water; finish until HPLC demonstration reaction; promptly obtain (the 4R of formula (I) expression; 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl }-2; the crude product of 2-dimethyl-[1,3]-dioxs-4-base-tert.-butyl acetate.
Above-mentioned acid catalyst is selected from the carboxylic acid of 1-8 carbon atom, mineral acid or acidic resins.Wherein, the carboxylic acid of 1-8 carbon atom is a formic acid, acetate, butanic acid, positive valeric acid, n-caproic acid, phenylformic acid, toluylic acid, tartrate or citric acid.Mineral acid is a hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid.Acidic resins are that 732 strongly acidic styrene's Zeo-karbs, 122 macropore phenolic aldehyde weak acid resins, D113 macropore acidulous acrylic acid are that daughter ion exchange resin, D151 macropore weakly acidic cation-exchange resin, D152 macropore weakly acidic cation-exchange resin or D155 macropore weak acid sun are from exchange resin.
Non-hydroxyl solvent is the alkane of 5-7 carbon atom, or the ether of 4-8 carbon atom, or alkane: ether is the mixture of 1:0.85 volume ratio.According to preferable methods, the alkane of 5-7 carbon atom can be selected Skellysolve A for use, or normal hexane, or normal heptane; The ether of 4-8 carbon atom is ether, or n-butyl ether, or methyl tertiary butyl ether, or isopropyl ether, or the 2-methyltetrahydrofuran.
Second step, elder generation's vacuum removes solvent, measure water again: the Virahol volume ratio is 2: 5, mix, make water-isopropyl alcohol mixed solvent, water-isopropyl alcohol mixed solvent to the first step obtain (4R, 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl-2, the crude product recrystallization of 2-dimethyl-[1,3]-dioxs-4-base-tert.-butyl acetate (I); Suction filtration, drying, what obtain formula (I) expression detects a kind of important intermediate that purity is not less than 99.0% synthetic atorvastatin through HPLC.
Advantage of the present invention is:
1. because the present invention has used non-hydroxyl solvent, cooperate azeotropic band water, therefore, reaction times significantly shortens, and feed stock conversion increases, thereby has reduced the consumption of expensive intermediate formula (III), effectively reduce production cost, also facilitate and simplify postprocessing working procedures; The solvent recuperation utilization is more convenient.
2. the acid catalyst decapacitation of the present invention's selection keeps outside its catalytic effect, also have characteristics cheap, that remove easily, simultaneously, because the solvent azeotropic band water measure of taking, can effectively reduce the water content in the reaction system, thereby stop the acid-catalyzed hydrolysis reaction of formula (III) compound ketal structure, can have large quantities of acid catalysts to be used, reduced dependency and the limitation of industrial production, the effect that reached fast, selectivity is high, yield is high to single catalyst.
3. the conversion of raw material height of the present invention's use, convenient catalyst are removed, need not loaded down with trivial details postprocessing working procedures, only need remove solvent, recrystallization, suction filtration, simple formality such as drying, can obtain the key intermediate of highly purified formula (I) expression, with existingly comprised alkali cleaning-pickling-salt and washed-postprocessing working procedures of complicated processes such as activated carbon treatment compares, aftertreatment formality provided by the invention has simple to operate, loses for a short time, and the process refuse is less, low for equipment requirements, plurality of advantages such as environmental friendliness.
4. the present invention has widened the range of choice of cheap acid catalyst, when keeping good catalytic effect, reducing cost, helping removing of catalyzer utilizes non-hydroxyl solvent as reaction medium simultaneously, and azeotropic band water technology, reached simplification technology, reduced cost, made things convenient for postprocessing working procedures, the recycling of solvent requirement easily.
5. the present invention can be with 〉=70% yield, and the key intermediate of formula (I) expression of preparation purity 〉=99.0% is with comparing of prior art, the same 1Kg atorvastatin calcium of producing, the unit consumption of the raw material of formula (II) expression reduces 0.089Kg, and formula (III) raw material reduces 0.494Kg, and cost greatly reduces.
Description of drawings
Fig. 1 detects figure for the purity HPLC of the key intermediate retention time 10.61min of formula (I) expression of the present invention's preparation
Fig. 2 detects figure for the purity HPLC of the key intermediate retention time 11.63min of formula (I) expression of the present invention's preparation
Fig. 3 reacted 5～6 hours for the present invention, and the HPLC of feed stock conversion detects figure
When Fig. 4 reacted end for the present invention, the HPLC of feed stock conversion detected figure
As shown in Figure 1; (the 4R of (I) expression of the present invention's preparation; 6R)-6-{2-[5-isopropyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formoxyl)-pyrroles-1-yl]-ethyl }-2; 2-dimethyl-[1; 3]-dioxane-4-yls-tert-butyl acetate; retention time 10.61min, the content of peak mark mark 5 corresponding components is 99.4846%, illustrates with method of the present invention to prepare the purity of the key intermediate of highly purified formula (I) expression 〉=99%.
As shown in Figure 2, the key intermediate of formula (I) expression of the present invention's preparation, retention time 11.63min, the content of peak mark mark 3 corresponding components is 99.3657%, illustrates with method of the present invention to prepare the purity of the key intermediate of highly purified formula (I) expression 〉=99%.
As shown in Figure 3, heated 5～6 hours, when HPLC tracked to sampling, the feed stock conversion of formula (II) expression was 78.7018%. Illustrate that method reaction rate provided by the present invention is very fast, when being reacted to 5～6 hours, feed stock conversion can reach more than 60～70%.
As shown in Figure 4, when HPLC tracked to the reaction end, the raw material of formula (II) expression only remained 0.6221%, illustrated in the method provided by the present invention, and when reaction finished, the feed stock conversion of formula (II) expression was up to 94.6736%.
Embodiment
By the following examples technology of the present invention is advanced an elaboration, but be not limited to the described method of embodiment.
Under the nitrogen protection; raw material (12.51g with formula (II) expression; 0.03mol), the raw material of formula (III) expression (10.65g, 0.039mol) and butanic acid (3.02g 0.03425mol) evenly is being dissolved in Skellysolve A (27.5ml) and the isopropyl ether (32.5ml) under the stirring.Heat 80 ℃ of backflows, azeotropic band water.Finish until HPLC demonstration reaction.Vacuum removes solvent, water (100ml)-Virahol (250ml) mixed solvent recrystallization; Suction filtration, 30 ℃ of vacuum-dryings; Obtain the key intermediate 14.8g of formula (I) expression, HPLC purity 〉=99.0%.
Under the nitrogen protection, with formula (II) (12.51g, 0.03mol), formula (III) (9.83g, 0.036mol) and polyphosphoric acid (3.26g) under evenly stirring, be dissolved in Skellysolve A (27.5ml) and the methyl tertiary butyl ether (32.5ml).Heat 70 ℃ of backflows, azeotropic band water.Finish until HPLC demonstration reaction.Vacuum removes solvent, water (100ml)-Virahol (250ml) mixed solvent recrystallization; Suction filtration, 30 ℃ of vacuum-dryings; Obtain the key intermediate 14.4g of formula (I) expression, HPLC purity 〉=99.0%.
Under the nitrogen protection, formula (II) (12.51g, 0.03mol), formula (III) (10.65g, 0.039mol) and acetate (2.05g 0.03425mol) is being dissolved in normal hexane (27.5ml) and the 2-methyltetrahydrofuran (32.5ml) under evenly stirring.Heat 90 ℃ of backflows, azeotropic band water.Finish until HPLC demonstration reaction.Vacuum removes solvent, water (100ml)-Virahol (250ml) mixed solvent recrystallization; Suction filtration, 30 ℃ of vacuum-dryings; Obtain the key intermediate 14.6g of formula (I) expression, HPLC purity 〉=99.0%.
Embodiment 4
Under the nitrogen protection, formula (II) (12.51g, 0.03mol), formula (III) (9.83g, 0.036mol) and 732 strongly acidic styrene's Zeo-karbs (5.2g) under evenly stirring, be dissolved in normal heptane (27.5ml) and the n-butyl ether (32.5ml).Heat 110 ℃ of backflows, azeotropic band water.Finish until HPLC demonstration reaction.Vacuum removes solvent, water (100ml)-Virahol (250ml) mixed solvent recrystallization; Suction filtration, 30 ℃ of vacuum-dryings; Obtain the key intermediate 14.3g of formula (I) expression, HPLC purity 〉=99.0%.
Under the nitrogen protection, formula (II) (12.51g, 0.03mol), formula (III) (8.19g, 0.03mol) and positive valeric acid (3.2g 0.0315mol) is being dissolved in normal heptane (27.5ml) and the n-butyl ether (32.5ml) under evenly stirring.Heat 110 ℃ of backflows, azeotropic band water.Finish until HPLC demonstration reaction.Vacuum removes solvent, water (100ml)-Virahol (250ml) mixed solvent recrystallization; Suction filtration, 30 ℃ of vacuum-dryings; Obtain the key intermediate 14.0g of formula (I) expression, HPLC purity 〉=99.0%.
Under the nitrogen protection, formula (II) (12.51g, 0.03mol), formula (III) (7.37g, 0.027mol) and formic acid (1.587g 0.0345mol) is being dissolved in normal heptane (27.5ml) and the n-butyl ether (32.5ml) under evenly stirring.Heat 110 ℃ of backflows, azeotropic band water.Finish until HPLC demonstration reaction.Vacuum removes solvent, water (100ml)-Virahol (250ml) mixed solvent recrystallization; Suction filtration, 30 ℃ of vacuum-dryings; Obtain the key intermediate 13.8g of formula (I) expression, HPLC purity 〉=99.0%.
Claims (1)
- One kind prepare high purity (4R, 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl-2, the method for 2-dimethyl-[1,3]-diox-4-base-tert.-butyl acetate is characterized in that:The first step, take by weighing [5-methyl-4-sec.-propyl-2-phenyl-1-(4-fluorophenyl)-3-(phenyl amino formyl radical)-1, the 4-hexanedione] (II): [(4R, 6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxs-4-base-tert.-butyl acetate] mol ratio=0.71～1.12 of (III): 1, the amount of measuring acid catalyst again is 1.05～1.15 times a mole number of formula II; Then, under the nitrogen protection, (II), (III) and acid catalyst under agitation are dissolved in weight in 3.0～4.2 times the non-hydroxyl solvent of (II); Azeotropic band water is refluxed in reheat to 70～110 ℃; Finish until HPLC demonstration reaction, promptly prepare (the 4R that formula I is represented, 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl }-2, the crude product of 2-dimethyl-[1,3]-dioxs-4-base-tert.-butyl acetate;Above-mentioned acid catalyst is carboxylic acid, mineral acid or the acidic resins of 1-8 carbon atom; Wherein, the carboxylic acid of 1-8 carbon atom is formic acid, acetate, butanic acid, positive valeric acid, n-caproic acid, phenylformic acid, toluylic acid, tartrate or citric acid; Mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid; Acidic resins are that 732 strongly acidic styrene's Zeo-karbs, 122 macropore phenolic aldehyde weak acid resins, D113 macropore acidulous acrylic acid are ion exchange resin, D151 macropore weakly acidic cation-exchange resin, D152 macropore weakly acidic cation-exchange resin or D155 macroporous ion exchange resin;Non-hydroxyl solvent is the alkane of 5-7 carbon atom, or the ether of 4-8 carbon atom, or alkane: ether is the mixture of 1: 0.85 volume ratio; Wherein, the alkane of 5-7 carbon atom is Skellysolve A, normal hexane or normal heptane; The ether of 4-8 carbon atom is ether, n-butyl ether, methyl tertiary butyl ether, isopropyl ether or 2-methyltetrahydrofuran;Second step, elder generation's vacuum removes solvent, measure water again: the Virahol volume ratio is that mix 2: 5 backs, make water-isopropyl alcohol mixed solvent, (the 4R that water-isopropyl alcohol mixed solvent is represented the formula I of the first step, 6R)-6-{2-[5-sec.-propyl-3-phenyl-2-(4-fluorophenyl)-4-(phenyl amino formyl radical)-pyrroles-1-yl]-ethyl }-2,2-dimethyl-[1,3]-dioxs-4-base-tert.-butyl acetate crude product carries out recrystallization, suction filtration, drying obtains HPLC that formula I represents and detects the intermediate that purity is not less than 99.0% synthetic atorvastatincalcuim;The structural formula of above-mentioned formula I, (II), (III) is as follows:
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| CN102101855B (en) * | 2009-12-16 | 2013-06-05 | 武汉启瑞药业有限公司 | Preparation method of atorvastatin calcium isomer mixture and its intermediate |
| CN102127060B (en) * | 2010-12-17 | 2013-12-04 | 蚌埠丰原医药科技发展有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN110372677B (en) * | 2019-07-25 | 2021-01-05 | 浙江海森药业股份有限公司 | Method for preparing atorvastatin key intermediate L1 by solvent-free method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5298627A (en) * | 1993-03-03 | 1994-03-29 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| US6476235B2 (en) * | 2001-01-09 | 2002-11-05 | Warner-Lambert Company | Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide |
| EP1659110A1 (en) * | 2004-03-17 | 2006-05-24 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium un amorphous form |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5298627A (en) * | 1993-03-03 | 1994-03-29 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| US6476235B2 (en) * | 2001-01-09 | 2002-11-05 | Warner-Lambert Company | Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide |
| EP1659110A1 (en) * | 2004-03-17 | 2006-05-24 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium un amorphous form |
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