CN102627580B - Preparation process of atorvastatin intermediate ethyl-4-cyan -3-hydroxybutyate - Google Patents
Preparation process of atorvastatin intermediate ethyl-4-cyan -3-hydroxybutyate Download PDFInfo
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- CN102627580B CN102627580B CN 201210073893 CN201210073893A CN102627580B CN 102627580 B CN102627580 B CN 102627580B CN 201210073893 CN201210073893 CN 201210073893 CN 201210073893 A CN201210073893 A CN 201210073893A CN 102627580 B CN102627580 B CN 102627580B
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Abstract
A new technology for obtaining a high yield atorvastatin intermediate is provided. According to the invention, chloropropylene oxide and hydrocyanic acid are used to synthesize 4-chloro-3-hydroxybutyronityile (ATS-3 for short) which is used to synthesize ethyl-4-chloro -3-hydroxybutyate (ATS-4 for short), and the ATS-4 is reacted with solid sodium cyanide to synthesize the final product ethyl-4-cyan -3-hydroxybutyate (ATS-5 for short). The synthetic technology which has the advantages of no generation of cyanogen-containing wastewater, high yield, and full resource utilization is an ideal synthetic technology.
Description
Technical field
The invention belongs to medicine and chemical technology field, relate to a kind of novel process of atorvastatin intermediate 4-cyano-3-hydroxy ethyl butyrate.
Background technology
Zarator is that Pifzer company produces medicine, and it is approved for and merges sitotherapy reduction elevated cholesterol.Share on the sitotherapy basis, Zarator can reduce total cholesterol level 29～45% in it gets permission dosage range.Reduce density lipoprotein cholesterol levels 39～60%.Zarator has been used widely and has been become the maximum medicine of recipe quantity in the Statins anticholesteremic agent.Zarator has many clinical characters and potential ability, and everything all will guarantee its future market still can continue the rapid growth.And 4-cyano group-3 3-hydroxyethyl butyrate is as an important intermediate of Zarator, the technique of new preparation 4-cyano-3-hydroxy ethyl butyrate must be the better condition of synthetic creation of Zarator.
CN1675200 be take non-chiral compound and is synthesized as raw material, and the cost of its catalyzer is higher, and product purity is lower.
Northeast Agricultural University biochemical industry system to the literary composition victory take (L)-oxysuccinic acid as raw material through the synthetic final product of four steps, total recovery 56.7%, this processing step complexity, and used more raw material, as boride, Hydrogen bromide etc., the wastewater treatment difficulty is larger.
Scientific and Technological Institutes Of Zhejiang is biological becomes monarch to adopt (S)-(-)-epoxy chloropropane to obtain (S)-4-chloro-3-hydroxyl butyronitrile through the sodium cyanide open loop with Jiang of chemical engineering institute; obtain (S)-4-chloro-3-hydroxyl ethyl butyrate with the ethanol alcoholysis; again through three silyl protections, sodium cyanide cyaniding, deprotection base; obtain Zarator key intermediate (R)-(-)-4-cyano-3-hydroxy ethyl butyrate; total recovery approximately 57%; three silyl protections have been used; need again to slough protection; route is long and complicated, and cost is high.
It is raw material that CN200910061164 is used epoxy chloropropane, first pass through the sodium cyanide open loop, then use the ethanol solution of hydrogen chloride alcoholysis, and then with the liquid sodium cyanide effect, synthetic intermediate (R)-(-)-4-cyano-3-hydroxy ethyl butyrate, whole yield is 42% left and right, produces a large amount of cyanide wastewater, and cost for wastewater treatment is high.
Summary of the invention
1. the problem that the objective of the invention is to exist for prior art provides a kind of new preparation process of 4-cyano-3-hydroxy ethyl butyrate, it is characterized in that being comprised of following steps:
(1) preparation of 4-chloro-3-hydroxyl butyronitrile
By in the disposable input reactor of epoxy chloropropane, the catalyst A that adds epoxy chloropropane weight 0.1～3%, control temperature at 30～90 ℃, slowly add prussic acid, then insulation reaction 3～8h, distillation obtains 4-chloro-3-hydroxyl butyronitrile, and molar ratio is: epoxy chloropropane: prussic acid=1: 1.0～1.2, and reaction formula is as follows:
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate
The 4-chloro-3-hydroxyl butyronitrile generated is dropped in reactor, the ethanol that adds 1～6 times of epoxy chloropropane molar weight, be warmed up to 10～100 ℃, slowly add the catalyst B of epoxy chloropropane weight 1～10%, react 2～10h, then the strong acid that adds epoxy chloropropane weight 1～10%, as sulfuric acid, hydrochloric acid etc., separatory, distillation, obtain 4-chloro-3-hydroxyl ethyl butyrate, reaction formula is as follows:
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate
The anhydrous organic solvent of 1～5 times of the solid sodium cyanide of 0.9～1.5 times of epoxy chloropropane molar weight and epoxy chloropropane weight is dropped in ultrasound reactor, control temperature at 30～100 ℃, drip 4-chloro-3-hydroxyl butyronitrile, insulation reaction 10-30 minute then, the frequency of ultrasound reactor is 20000～30000Hz, after reaction finishes, be cooled to room temperature, filter, distillation obtains the 4-cyano-3-hydroxy ethyl butyrate of content more than 98%, yield reaches more than 90%, and reaction formula is as follows:
Above-mentioned reaction molar ratio is preferably: epoxy chloropropane: prussic acid: ethanol: solid sodium cyanide=1: 1.0～1.1: 2～4: 0.95～1.1;
The aqueous solution of any concentration that above-mentioned prussic acid is liquid hydrogen cyanic acid, gaseous hydrogen cyanic acid, prussic acid etc., preferably 50～90% hydrocyanic acid aqueous solution;
Above-mentioned catalyst A is Padil-hydrochloric acid, Potassium Hydrogen Phthalate-hydrochloric acid, buffered soln;
Its preparation method is:
Padil-hydrochloric acid buffer solution: dissolve the 150g Padil in 500ml water, add the 480ml concentrated hydrochloric acid, be diluted with water to 1000ml;
Potassium Hydrogen Phthalate-hydrochloric acid buffer solution: the Potassium Hydrogen Phthalate of 25ml 0.2mol/L and 6ml 0.1mol/L mixed in hydrochloric acid are diluted with water to 100ml.
Above-mentioned catalyst B is ZnCl
2or AlCl
3;
Above-mentioned solid sodium cyanide used is blocks of solid sodium cyanide, granular solids sodium cyanide or powdery solid sodium cyanide, preferably the powdery solid sodium cyanide;
In above-mentioned steps (3), anhydrous organic solvent used is methyl alcohol, ethanol, tetrahydrofuran (THF), acetone, benzene,toluene,xylene etc., preferred alcohol;
Above-mentioned needed temperature of reaction: step (1) is 30-50 ℃ preferably, and step (2) is 80-100 ℃ preferably, and step (3) is 70-90 ℃ preferably;
The above-mentioned needed reaction times: step (1) is 3-5h preferably, and step (2) is 5-10h preferably, and step (3) is 20-30min preferably.
Beneficial effect:
1. operational path of the present invention has adopted catalyst A and HCN in step (1), and this technique does not produce cyanide wastewater, and productive rate is higher.
2. in step (2), first use ZnCl
2or AlCl
3make itrile group hydrolysis, and then " one kettle way " carry out esterification, the shortcoming that the productive rate of having avoided using strong acid hydrolysis itrile group to cause in the prior art is low, product thickness, by product are difficult for removing, be conducive to suitability for industrialized production.
3. adopt microwave reactor in step (3), greatly accelerated speed of response, make product purity and productive rate greatly improve simultaneously.Therefore, this operational path does not only produce cyanide wastewater, easy handling, and the good product quality obtained, and yield is high, and cost is low; Very high economic worth and social value are arranged.
The accompanying drawing explanation
Fig. 1 is process flow sheet of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1
(1) preparation of 4-chloro-3-hydroxyl butyronitrile:
By the 92g epoxy chloropropane is disposable add after, add catalyzer Padil-hydrochloric acid buffer solution 0.5g, control temperature and slowly pass into 22g prussic acid gas at 40-50 ℃, ventilate complete, insulation 4h, distillation obtains the 4-chloro-3-hydroxyl butyronitrile of 91g content 98%, yield 95.1%;
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate:
120g 4-chloro-3-hydroxyl butyronitrile, with after 55g ethanol mixes, is warming up to 30 ℃, adds ZnCl
24g then continues insulation 10h at this temperature, is incubated completely, and hydrolysis, passing into hydrogenchloride 9g, reaction 10h, and phase-splitting, then distillation obtains 156g 4-chloro-3-hydroxyl ethyl butyrate.Content 97%, yield 96%.
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate:
By 166.6g 4-chloro-3-hydroxyl ethyl butyrate with join in microwave reactor after 200g ethanol mixes, add the 39g solid sodium cyanide, then start to be warming up to 80 ℃, insulation 20min, microwave frequency is 20000Hz, insulation reaction is complete, remove by filter sodium-chlor wherein, then distillation obtains 115g product, product content: 98%, and yield: 91.2%.
Embodiment 2
(1) preparation of 4-chloro-3-hydroxyl butyronitrile:
By the 92g epoxy chloropropane is disposable add after, add Potassium Hydrogen Phthalate-hydrochloric acid buffer solution 0.6g, control temperature and pass into 24.3g prussic acid gas at 30 ℃.Ventilate complete, insulation 3h, distillation obtains 92g4-chloro-3-hydroxyl butyronitrile.Content: 98%, yield 96%.
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate:
120g 4-chloro-3-hydroxyl butyronitrile, with after 55g ethanol mixes, is warming up to 30 ℃, adds AlCl
33g then continues insulation 8h at this temperature, is incubated completely, and hydrolysis, passing into hydrogenchloride 5g, reaction 10h, and phase-splitting, then distillation obtains 150g 4-chloro-3-hydroxyl ethyl butyrate.Content 97%, yield 90%.
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate:
By 166.6g 4-chloro-3-hydroxyl ethyl butyrate with join in microwave reactor after the 200g tetrahydrofuran (THF) mixes, add 39 solid sodium cyanides, then start to be warming up to 90 ℃, insulation 25min, microwave frequency is 30000Hz, insulation reaction is complete, remove by filter sodium-chlor wherein, then distillation obtains 113.5g product, product content: 98%, and yield: 90%.
(1) preparation of 4-chloro-3-hydroxyl butyronitrile:
By the 92g epoxy chloropropane is disposable add after, add Padil-hydrochloric acid buffer solution 0.45g, control temperature and add the 22g liquid hydrogen cyanide at 40 ℃.Ventilate complete, insulation 3h, distillation obtains 4-chloro-3-hydroxyl butyronitrile 89.5g.Content: 98%, yield 93.4%.
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate:
120g 4-chloro-3-hydroxyl butyronitrile, with after 55g ethanol mixes, is warming up to 30 ℃, adds AlCl
35g then continues insulation 5h at this temperature, is incubated completely, and hydrolysis, passing into hydrogenchloride 7g, reaction 8h, and phase-splitting, then distillation obtains 151g 4-chloro-3-hydroxyl ethyl butyrate.Content 97%, yield 90.6%.
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate:
By 166.6g 4-chloro-3-hydroxyl ethyl butyrate with join in microwave reactor after 200g toluene mixes, add the 39g solid sodium cyanide, then start to be warming up to 70 ℃, insulation 20min, microwave frequency is 25000Hz, insulation reaction is complete, remove by filter sodium-chlor wherein, then distillation obtains product 113g, product content: 98%, and yield: 90.3%.
Embodiment 4
(1) preparation of 4-chloro-3-hydroxyl butyronitrile:
By the 92g epoxy chloropropane is disposable add after, add Potassium Hydrogen Phthalate-hydrochloric acid 0.55g, control temperature and add the 22g liquid hydrogen cyanide at 30 ℃.Ventilate complete, insulation 5h, distillation obtains 4-chloro-3-hydroxyl butyronitrile 89g.Content: 98%, yield 92.9%.
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate:
120g 4-chloro-3-hydroxyl butyronitrile, with after 55g ethanol mixes, is warming up to 30 ℃, adds ZnCl
27g then continues insulation 5h at this temperature, is incubated completely, and hydrolysis, passing into hydrogenchloride 8g, reaction 8h, and phase-splitting,, then distillation obtains 4-chloro-3-hydroxyl ethyl butyrate 150g.Content 97%, yield 90%.
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate:
To after 166.8g 4-chloro-3-hydroxyl ethyl butyrate and 200g methanol mixed, join in microwave reactor, add the 39g solid sodium cyanide, then start to be warming up to 70 ℃, insulation 30min, microwave frequency is 20000Hz, insulation reaction is complete, remove by filter sodium-chlor wherein, then distillation obtains product 119.2g, product content: 98%, and yield: 95%.
Embodiment 5
(1) preparation of 4-chloro-3-hydroxyl butyronitrile:
By the 92g epoxy chloropropane is disposable add after, add Padil-hydrochloric acid buffer solution 0.65g, control temperature and add the 22g liquid hydrogen cyanide at 40 ℃.Ventilate complete, insulation 3h, distillation obtains 4-chloro-3-hydroxyl butyronitrile 91.5g.Content: 98%, yield 95.5%.
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate:
120g 4-chloro-3-hydroxyl butyronitrile, with after 55g ethanol mixes, is warming up to 30 ℃, adds AlCl
32g then continues insulation 7h at this temperature, is incubated completely, and hydrolysis, passing into hydrogenchloride 6g, reaction 8h, and phase-splitting,, then distillation obtains 150.3g 4-chloro-3-hydroxyl ethyl butyrate.Content 97%, yield 90.2%.
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate:
By 166.7g 4-chloro-3-hydroxyl ethyl butyrate with join in microwave reactor after 200g acetone mixes, add the 39g solid sodium cyanide, then start to be warming up to 70 ℃, insulation 20min, microwave frequency is 30000Hz, insulation reaction is complete, remove by filter sodium-chlor wherein, then distillation obtains product 100.5g, product content: 98%, and yield: 80.2%.
Embodiment 6
(1) preparation of 4-chloro-3-hydroxyl butyronitrile:
By the 92g epoxy chloropropane is disposable add after, add Potassium Hydrogen Phthalate-hydrochloric acid buffer solution 0.5g, control temperature and add the 22g liquid hydrogen cyanide at 40 ℃.Ventilate complete, insulation 4h, distillation obtains 4-chloro-3-hydroxyl butyronitrile 90g.Content: 98%, yield 93.9%.
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate:
120g 4-chloro-3-hydroxyl butyronitrile, with after 55g ethanol mixes, is warming up to 30 ℃, adds ZnCl
23g then continues insulation 5h at this temperature, is incubated completely, and hydrolysis, passing into hydrogenchloride 4g, reaction 9h, and phase-splitting,, then distillation obtains 150g 4-chloro-3-hydroxyl ethyl butyrate.Content 97%, yield 90%.
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate:
By 166.7g 4-chloro-3-hydroxyl ethyl butyrate with join in microwave reactor after 200g dimethylbenzene mixes, add the 39g solid sodium cyanide, then start to be warming up to 90 ℃, microwave frequency is 30000Hz, and insulation 10min, be incubated complete, remove by filter sodium-chlor wherein, then distillation obtains product 118.7g, product content: 98%, and yield: 93.8%.
Above-described embodiment is only explanation technical conceive of the present invention and characteristics, and its purpose is to allow the person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (4)
1. the technique of a synthetic atorvastatin intermediate 4-cyano-3-hydroxy ethyl butyrate is characterized in that being comprised of following steps:
(1) preparation of 4-chloro-3-hydroxyl butyronitrile
By in the disposable input reactor of epoxy chloropropane, the catalyst A that adds epoxy chloropropane weight 0.1～3%, control temperature at 30～90 ℃, slowly add prussic acid, then insulation reaction 3～8h, distillation obtains 4-chloro-3-hydroxyl butyronitrile, and molar ratio is: epoxy chloropropane: prussic acid=1: 1.0～1.2;
(2) preparation of 4-chloro-3-hydroxyl ethyl butyrate
The 4-chloro-3-hydroxyl butyronitrile generated is dropped in reactor, the ethanol that adds 1～6 times of epoxy chloropropane molar weight, be warmed up to 10～100 ℃, slowly add the catalyst B of epoxy chloropropane weight 1～10%, react 2～10h, then add sulfuric acid or the hydrochloric acid of epoxy chloropropane weight 1～10%, react again 2-10h, separatory, distillation, obtain 4-chloro-3-hydroxyl ethyl butyrate;
(3) preparation of 4-cyano-3-hydroxy ethyl butyrate
The anhydrous organic solvent of 1～5 times of the solid sodium cyanide of 0.9～1.5 times of epoxy chloropropane molar weight and epoxy chloropropane weight is dropped in ultrasound reactor, control temperature at 30～100 ℃, drip 4-chloro-3-hydroxyl butyronitrile, insulation reaction 3～10h then, reaction is cooled to room temperature after finishing, and filters, distillation obtains the 4-cyano-3-hydroxy ethyl butyrate of content more than 98%, and yield reaches more than 90%;
The buffered soln that described catalyst A is Padil-hydrochloric acid or Potassium Hydrogen Phthalate-hydrochloric acid;
Described catalyst B is ZnCl
2or A1Cl
3.
2. the technique of a kind of atorvastatin intermediate 4-cyano-3-hydroxy ethyl butyrate according to claim 1, is characterized in that described reaction molar ratio is preferably: epoxy chloropropane: prussic acid: ethanol: solid sodium cyanide=1: 1.0～1.1: 2～4: 0.95～1.1.
3. the technique of a kind of atorvastatin intermediate 4-cyano-3-hydroxy ethyl butyrate according to claim 1, is characterized in that solid sodium cyanide used is blocks of solid sodium cyanide, granular solids sodium cyanide or powdery solid sodium cyanide.
4. the technique of a kind of atorvastatin intermediate 4-cyano-3-hydroxy ethyl butyrate according to claim 1, is characterized in that anhydrous organic solvent used is methyl alcohol, ethanol, tetrahydrofuran (THF), acetone, benzene, toluene or dimethylbenzene.
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| CN103467291A (en) * | 2013-09-26 | 2013-12-25 | 南京年吉冷冻食品有限公司 | New chemical synthetic method for ethyl 3-hydroxybutyrate |
| CN109628511A (en) * | 2019-01-16 | 2019-04-16 | 抚顺顺能化工有限公司 | The environmentally protective preparation method of one kind (R)-(-) -4- cyano-3-hydroxy ethyl butyrate |
| CN110218162A (en) * | 2019-04-04 | 2019-09-10 | 江苏万年长药业有限公司 | The continuous preparation method of one kind (R) -4- cyano-3-hydroxy ethyl butyrate |
| CN111138316A (en) * | 2020-01-14 | 2020-05-12 | 营口德瑞化工有限公司 | Synthesis method of phenylacetonitrile |
| CN111875520A (en) * | 2020-08-03 | 2020-11-03 | 连云港宏业化工有限公司 | Novel synthesis method of (S) -4-chloro-3-hydroxybutyronitrile |
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| CN1764636A (en) * | 2003-04-16 | 2006-04-26 | 株式会社Lg生命科学 | Process for preparing 4-chloro-3-hydroxybutanoic acid ester |
| CN101838221A (en) * | 2009-03-16 | 2010-09-22 | 罗田县华阳生化有限公司 | Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate |
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| WO2007139238A1 (en) * | 2006-05-26 | 2007-12-06 | Enzytech, Ltd. | Process for l-carnitine and acetyl l-carnitine hydrochloride |
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| US5302263A (en) * | 1993-04-29 | 1994-04-12 | Ethyl Corporation | Ultrasonic cyano-de-halogenation |
| CN1764636A (en) * | 2003-04-16 | 2006-04-26 | 株式会社Lg生命科学 | Process for preparing 4-chloro-3-hydroxybutanoic acid ester |
| CN101838221A (en) * | 2009-03-16 | 2010-09-22 | 罗田县华阳生化有限公司 | Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate |
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