CN115894290A - Preparation method of atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate - Google Patents
Preparation method of atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate Download PDFInfo
- Publication number
- CN115894290A CN115894290A CN202211292889.6A CN202211292889A CN115894290A CN 115894290 A CN115894290 A CN 115894290A CN 202211292889 A CN202211292889 A CN 202211292889A CN 115894290 A CN115894290 A CN 115894290A
- Authority
- CN
- China
- Prior art keywords
- cyano
- formula
- atorvastatin calcium
- reaction
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 30
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 7
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- LOQFROBMBSKWQY-ZCFIWIBFSA-N ethyl (3r)-4-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CC#N LOQFROBMBSKWQY-ZCFIWIBFSA-N 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000276 potassium ferrocyanide Substances 0.000 claims description 7
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 claims description 7
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 4
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 3
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 238000004821 distillation Methods 0.000 description 7
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 6
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 6
- 239000002351 wastewater Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- -1 ethyl epoxybutyrate Chemical compound 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 102000011965 Lipoprotein Receptors Human genes 0.000 description 1
- 108010061306 Lipoprotein Receptors Proteins 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- WHUSTVAXKRFVPD-YFKPBYRVSA-N ethyl 2-[(2s)-oxiran-2-yl]acetate Chemical compound CCOC(=O)C[C@H]1CO1 WHUSTVAXKRFVPD-YFKPBYRVSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 108010013164 halohydrin dehalogenase Proteins 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate, belonging to the technical field of drug synthesis. In order to solve the problem of reducing the post-treatment difficulty, the method for preparing the atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate comprises the steps of adding a compound solution in a formula 3 into a catalyst and alkali to perform cyclization reaction, filtering and removing an organic solvent after the reaction is finished to obtain a compound in a formula 2, adding a cyaniding reagent and acid into the compound in the formula 2 to perform ring-opening reaction, and performing reduced pressure rectification after the solvent is removed to obtain a compound in the formula 1; the method has the advantages of no need of using a highly toxic cyaniding reagent in the production process, less by-products, lower post-treatment difficulty and lower treatment cost on the whole.
Description
The invention relates to a preparation method of an atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate, belonging to the field of preparation of pharmaceutical intermediates.
Background
Atorvastatin calcium (Atorvastatin calcium) is a statin blood lipid regulating drug, is a drug produced and developed by the Hurrill company, is approved to be used for reducing high cholesterol level by combining diet therapy, has a main action part in the liver, reduces the synthesis of free cholesterol in cells and the synthesis of a density lipoprotein receptor by inhibiting the activity of HMG-CoA reductase of a human body, and reduces the blood cholesterol level and the low density lipoprotein cholesterol level.
The compound of formula 1, ethyl (R) -4-cyano-3-hydroxybutyrate, is an important intermediate for HMG-CoA reductase inhibitor and also an important intermediate for preparing atorvastatin calcium, and has the following chemical structural formula:
in CN101838221A, epichlorohydrin is used as a raw material, and is subjected to ring opening by sodium cyanide, alcoholysis by a hydrogen chloride ethanol solution and then reaction with liquid sodium cyanide to synthesize an intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate, wherein the overall yield is about 42%, a large amount of cyanide-containing wastewater is generated, the wastewater treatment cost is high, and the synthetic route is as follows:
patent CN103014082A discloses the production of ethyl (R) -4-cyano-3-hydroxybutyrate from ethyl (R) -4-3-hydroxybutyrate as a raw material by reaction with sodium cyanide under the catalysis of recombinant halohydrin dehalogenase. However, the activity maintaining conditions of the biological enzyme are extremely harsh, the requirements on reaction temperature and pH are high, a large amount of hydrocyanic acid is inevitably generated in the production process, great hidden danger is brought to production safety, a large amount of cyanide and high-salt wastewater is generated in the enzyme process, and the post-treatment cost is high.
It can be seen from the above documents that the disadvantages of the common occurrence are that a large amount of harmful by-products are easily produced during the production process, and the post-treatment cost is high.
Therefore, there is a need to find a synthetic method that produces fewer harmful by-products.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of an atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate, which solves the problems of reducing the generation of harmful byproducts and reducing the post-treatment cost.
The invention aims to realize the technical scheme that the preparation method of the atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate comprises the following steps:
s1: dissolving the compound shown in the formula 3 in an organic solvent, adding a catalyst and alkali, controlling the temperature to perform cyclization reaction, and filtering to remove the organic solvent after the reaction is finished to obtain a compound shown in the formula 2;
s2: adding a cyaniding reagent and acid into the compound shown in the formula 2, and controlling the temperature to perform a ring-opening reaction to generate a compound solution shown in the formula 1;
s3: and (3) extracting and recovering an organic layer by using an organic solvent, and performing reduced pressure rectification after solvent removal to obtain the compound shown in the formula 1.
The total synthetic route is as follows:
the structural formula of the compound (R) - (-) -4-cyano-3-hydroxy butyric acid ethyl ester in the formula 1 is as follows:
the structural formula of the compound (S) -3, 4-epoxybutyric acid ethyl ester of the formula 2 is as follows:
the structural formula of the compound S (-) -4-chloro-3-hydroxy ethyl butyrate of the formula 3 is as follows:
dissolving a reaction raw material S (-) -4-chloro-3-hydroxy ethyl butyrate in an organic solvent in an alkaline environment, reacting under the catalysis of a catalyst to obtain an intermediate product (S) -3, 4-epoxy ethyl butyrate after desolventizing, adding a cyaniding reagent into the intermediate product (S) -3, 4-epoxy ethyl butyrate to perform a ring-opening reaction with acid to obtain an organic solution of (R) -4-cyano-3-hydroxy ethyl butyrate, taking back and recycling several layers of the organic solution, and performing reduced pressure rectification after removing the organic solvent to obtain an atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate; in the reaction process, no dehalogenase is needed, and due to the active property of epoxy ethyl, the reaction with hydrocyanic acid can be carried out quickly, so that the hydrocyanic acid is prevented from remaining in the reaction liquid for a long time, and the potential safety hazard in the production process is reduced. Meanwhile, in the production process, highly toxic cyaniding reagents such as sodium cyanide and potassium cyanide are not used, so that the generation of cyanide-containing wastewater can be reduced.
In the above method for synthesizing an intermediate of atorvastatin calcium, preferably, the organic solvent in step S1 is one of dichloromethane, tetrahydrofuran, acetone, or the like. Most preferably, tetrahydrofuran enhances the stability of the reaction.
In the synthesis method of the atorvastatin calcium intermediate, preferably, the catalyst in the step S1 is one of tetrabutylammonium iodide, tetrabutylammonium chloride, potassium iodide, silver sulfate and the like. Most preferably, tetrabutylammonium iodide is selected with minimal impact on the reaction environment, which can reduce additional side reactions during the reaction.
In the above method for synthesizing an intermediate of atorvastatin calcium, preferably, the cyaniding reagent in the step S2 is one of potassium ferrocyanide and TMSCN. Most preferably, potassium ferrocyanide is selected at a lower cost, with less by-products being produced and easier to handle.
In the synthesis method of the atorvastatin calcium intermediate, the mass concentration of the cyanidation reagent solution is preferably 15-25%. Most preferably, the cyanating reagent is selected to have a reaction rate of 25% by mass.
In the above method for synthesizing an intermediate of atorvastatin calcium, preferably, the organic solvent in the step S3 is one of ethyl acetate and dichloromethane.
In the synthesis method of the atorvastatin calcium intermediate, preferably, the base added in the step S1 is one of potassium carbonate and potassium hydroxide. Most preferably, potassium carbonate is selected to adjust the pH to be alkaline, so that the production cost is reduced.
In the above method for synthesizing an intermediate of atorvastatin calcium, preferably, the acid added in the step S2 is one of acetic acid and citric acid. Most preferably, acetic acid is selected to adjust the pH value to be acidic, so that the production cost is reduced.
In the above method for synthesizing an atorvastatin calcium intermediate, preferably, the reaction temperature required for the ring-opening reaction in the step S2 is 5 to 28 ℃. Most preferably, the reaction is carried out at a temperature of 25 ℃.
In the synthetic method of the atorvastatin calcium intermediate, the S3 step is preferably rectified under the pressure of-735 to-745 mmHg.
In summary, compared with the prior art, the invention has the following advantages:
1. the cyaniding reagent used in the invention is low-toxicity potassium ferrocyanide and TMSCN, so that the safety of workers in the operation process is improved, the generation of cyanide-containing wastewater is reduced, the generation of other toxic and harmful byproducts is also greatly reduced, and the post-treatment difficulty and the treatment cost are reduced.
2. In the invention, dehalogenase is not used for reaction in the reaction process, so that the production difficulty is not increased due to the generation of a large amount of hydrocyanic acid, and meanwhile, an enzyme method process can generate a large amount of cyanide-containing and high-salt wastewater, so that the post-treatment difficulty is high, and the treatment cost is increased.
Drawings
FIG. 1 is a synthetic scheme of the present invention;
FIG. 2 shows the structural formula of the compound of formula 1;
FIG. 3 is a structural formula of a compound of formula 2 according to the present invention;
FIG. 4 shows the structural formula of the compound of formula 3 according to the present invention.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 73.87g (0.2 mol) of tetrabutylammonium iodide and 400ml of tetrahydrofuran were put into a reaction flask, the reaction temperature was 25 ℃, stirring was continued, the reaction was completed after about 24 hours of exhaustion of the reaction raw materials, heating was stopped, filtration was carried out, and tetrahydrofuran was removed by atmospheric distillation to obtain 119.9g of the compound of formula 2, the yield was 92.1%, and the purity was 98.5%.
200ml of tetrahydrofuran and 130.14g (1 mol) of the compound of the formula 2 are added into a flask, after the temperature is reduced to 0 ℃, 206.27g (0.56 mol) of potassium ferrocyanide solution (25 percent of mass fraction) is added, 60.05g of acetic acid is simultaneously dripped, the pH value is controlled to be 8-9, the temperature is controlled to be about 10 ℃ in the dripping process, the dripping is finished, and the temperature is controlled to be 20 ℃ for heat preservation reaction for 10 hours. After the reaction is finished, filtering, collecting organic phases by layers from the filtrate, washing the organic phases with 100ml of ethyl acetate, extracting a water layer with ethyl acetate for three times, combining the organic phases, obtaining a crude product of the compound of the formula 1 after desolventizing, and rectifying under reduced pressure to obtain 146.64g of a refined product of the compound of the formula 1, wherein the yield is 93.3 percent and the purity is 99.1 percent.
Example 2
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 73.87g (0.2 mol) of tetrabutylammonium iodide and 400ml of dichloromethane were put into a reaction flask, the reaction temperature was 25 ℃, stirring was continued, the reaction was completed after about 24 hours of exhaustion of the reaction raw materials, heating was stopped, filtration was carried out, and tetrahydrofuran was removed by atmospheric distillation to obtain 112.87g of the compound of formula 2, with a yield of 86.7% and a purity of 96%.
Example 3
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 73.87g (0.2 mol) of tetrabutylammonium iodide and 400ml of acetone were put into a reaction flask, the reaction temperature was 25 ℃, stirring was continued, the reaction was completed after about 24 hours of exhaustion of the reaction raw materials, heating was stopped, filtration was carried out, and tetrahydrofuran was removed by atmospheric distillation to obtain 113.91g of the compound of formula 2, the yield was 87.5%, and the purity was 96.8%.
Example 4
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 59.18g (0.2 mol) of tetrabutylammonium chloride and 400ml of tetrahydrofuran are put into a reaction bottle, the reaction temperature is 25 ℃, stirring is carried out continuously, after about 24 hours of reaction raw materials are exhausted, the reaction is finished, heating is stopped, filtering is carried out, and the tetrahydrofuran is removed by atmospheric distillation, so that 111.05g of the compound of formula 2 is prepared, the yield is 85.3%, and the purity is 97.3%.
Example 5
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 33.2g (0.2 mol) of potassium iodide and 400ml of tetrahydrofuran were put into a reaction flask, the reaction temperature was 25 ℃, stirring was continued, the reaction was completed after about 24 hours of exhaustion of the reaction raw materials, heating was stopped, filtration was carried out, and tetrahydrofuran was distilled off under normal pressure to obtain 109.36g of the compound of formula 2, with a yield of 84% and a purity of 95.8%.
Example 6
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 62.35g (0.2 mol) of silver sulfate and 400ml of tetrahydrofuran are put into a reaction flask, the reaction temperature is 25 ℃, the stirring is continued, the reaction is finished after about 24 hours of reaction raw materials are exhausted, the heating is stopped, the tetrahydrofuran is removed by filtering and normal pressure distillation, and 110.1g of the compound of formula 2 is prepared, the yield is 84.6%, and the purity is 96.4%.
Example 7
200ml of tetrahydrofuran and 130.14g (1 mol) of the compound of the formula 2 are added into a flask, after the temperature is reduced to 0 ℃, 198.4g (2 mol) of TMSCN solution (25 percent of mass fraction) is added, 60.05g of acetic acid is simultaneously dripped, the pH value is controlled to be 8-9, the temperature is controlled to be about 10 ℃ in the dripping process, the dripping is finished, and the temperature is controlled to be 20 ℃ for heat preservation reaction for 10 hours. After the reaction is finished, filtering, collecting organic phases by layers from the filtrate, washing the organic phases with 100ml of ethyl acetate, extracting a water layer with ethyl acetate for three times, combining the organic phases, obtaining a crude product of the compound of the formula 1 after desolventizing, and rectifying under reduced pressure to obtain 140.82g of a refined product of the compound of the formula 1, wherein the yield is 89.6 percent and the purity is 98 percent.
Example 8
166.6g (1 mol) of the compound of formula 3, 44.88g (0.8 mol) of potassium hydroxide, 73.87g (0.2 mol) of tetrabutylammonium iodide and 400ml of tetrahydrofuran were put into a reaction flask, the reaction temperature was 25 ℃, stirring was continued, the reaction was completed after about 24 hours of exhaustion of the reaction raw materials, heating was stopped, filtration was carried out, and the tetrahydrofuran was removed by atmospheric distillation to obtain 116.26g of the compound of formula 2, the yield was 89.3%, and the purity was 98.5%.
200ml of tetrahydrofuran and 130.14g (1 mol) of the compound of the formula 2 are added into a flask, after the temperature is reduced to 0 ℃, 206.27g (0.56 mol) of potassium ferrocyanide solution (25 percent of mass fraction) is added, 100.5g of citric acid is dripped at the same time, the pH value is controlled to be 8-9, the temperature is controlled to be about 10 ℃ in the dripping process, the dripping is finished, and the temperature is controlled to be 20 ℃ for heat preservation and reaction for 10 hours. After the reaction is finished, filtering, collecting organic phases by layers from the filtrate, washing the organic phases with 100ml of dichloromethane, extracting a water layer with dichloromethane for three times, combining the organic phases, obtaining a crude product of the compound of the formula 1 after desolventizing, and rectifying under reduced pressure to obtain 139.1g of a refined product of the compound of the formula 1, wherein the yield is 88.5 percent and the purity is 95.2 percent.
Example 9
200ml of tetrahydrofuran and 130.14g (1 mol) of the compound of the formula 2 are added into a flask, after the temperature is reduced to 0 ℃, 206.27g (0.56 mol) of potassium ferrocyanide solution (15 percent of mass fraction) is added, 60.05g of acetic acid is simultaneously dripped, the pH value is controlled to be 8-9, the temperature is controlled to be about 10 ℃ in the dripping process, the dripping is finished, and the temperature is controlled to be 20 ℃ for heat preservation reaction for 10 hours. After the reaction is finished, filtering, collecting organic phases by separating the filtrate, washing the organic phases with 100ml of ethyl acetate, extracting a water layer for three times with ethyl acetate, combining the organic phases, obtaining a crude product of the compound of the formula 1 after desolventizing, and carrying out reduced pressure rectification to obtain 137.05g of a refined product of the compound of the formula 1, wherein the yield is 87.2 percent and the purity is 97.3 percent.
Example 10
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 73.87g (0.2 mol) of tetrabutylammonium iodide and 400ml of tetrahydrofuran were put into a reaction flask, the reaction temperature was 5 ℃, stirring was continued, the reaction was completed after about 24 hours of exhaustion of the reaction raw materials, heating was stopped, filtration was carried out, and the tetrahydrofuran was removed by atmospheric distillation to obtain 112.35g of the compound of formula 2, the yield was 86.3%, and the purity was 95.7%.
Example 11
166.6g (1 mol) of the compound of formula 3, 110.56g (0.8 mol) of potassium carbonate, 73.87g (0.2 mol) of tetrabutylammonium iodide and 400ml of tetrahydrofuran were put into a reaction flask, the reaction temperature was 28 ℃, stirring was continued, after about 24 hours of exhaustion of the reaction raw materials, the reaction was terminated, heating was stopped, filtration was carried out, and tetrahydrofuran was distilled off under normal pressure to obtain 117.68g of the compound of formula 2, with a yield of 90.4% and a purity of 98.2%.
Example 12
The embodiment is the embodiment of the published patent CN 102295579B;
1) Adding 130.0g of ethyl epoxybutyrate into a 1L three-necked flask, then adding 500ml of tetrahydrofuran, cooling to 0 ℃, then adding 0.4g of (S, S) -N, N' -bis (3, 5-di-tert-butylsalicylidene) -1, 2-cyclohexanediaminato cobalt SnCl2, stirring to dissolve, dropwise adding 9.0g of water at 0 ℃, reacting for 12 hours, adding 0.088g of L-ascorbic acid, reacting for 1 hour, filtering, concentrating the filtrate to obtain 129.5g of a mixture of ethyl (S) -epoxybutyrate and ethyl (R) -ethyl-3, 4-dihydroxybutyrate, controlling the kettle temperature to be less than 80 ℃, distilling under reduced pressure to obtain 53.0g of ethyl (S) -epoxybutyrate, and determining the ee value of gas chromatography to be 99.8%;
2) In a 1L three-necked flask, 53.0g of (S) -epoxybutyric acid ethyl ester is added, the mixture is cooled to the temperature of 0 ℃,5 percent sodium cyanide solution 400ml is added dropwise, the mixture reacts for 5 hours at the temperature of 0 ℃, 400ml of ethyl acetate is added for extraction once, 400ml of ethyl acetate is added into a water phase for extraction once, the ethyl acetate is combined, and the ethyl acetate is concentrated to obtain 59.7g of (R) -4-cyano-3-hydroxybutyric acid ethyl ester with the purity of 99.6 percent.
Compared with the preparation method of the invention, the yield in the embodiment is lower, and the highly toxic compound sodium cyanide is used in the production process, so that a large amount of cyanide-containing wastewater and hydrocyanic acid are easily generated in the production process, which is not beneficial to post-treatment.
The embodiments of the invention are not limited to the above-described examples, and various changes and modifications in form and detail may be made by one skilled in the art without departing from the spirit and scope of the invention, which is considered to fall within the scope of the invention.
Claims (10)
1. A method for preparing an atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxybutyric acid ethyl ester, the method comprising the steps of:
s1: dissolving the compound shown in the formula 3 in an organic solvent, adding a catalyst and alkali, controlling the temperature to perform cyclization reaction, and filtering to remove the organic solvent after the reaction is finished to obtain a compound shown in the formula 2;
s2: adding a cyaniding reagent and acid into the compound of the formula 2, and controlling the temperature to perform a ring-opening reaction to generate a compound solution of the formula 1;
s3: and (3) extracting and recovering an organic layer by using an organic solvent, and performing reduced pressure rectification after solvent removal to obtain the compound shown in the formula 1.
2. The process for preparing the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate of claim 1 wherein: the organic solvent in the step S1 is one of dichloromethane, tetrahydrofuran or acetone.
3. The process for preparing the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate of claim 1 wherein: in the step S1, the catalyst is one of tetrabutylammonium iodide, tetrabutylammonium chloride, potassium iodide, silver sulfate and the like.
4. The process for preparing the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate of claim 1 wherein: and in the step S2, a cyaniding reagent is one of potassium ferrocyanide or TMSCN.
5. The process of claim 4 for the preparation of the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate, wherein: the mass concentration of the cyanidation reagent solution is 15-25%.
6. The process for preparing the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate of claim 1 wherein: and the organic solvent in the step S3 is one of ethyl acetate and dichloromethane.
7. The process for preparing the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate of claim 1 wherein: and adding alkali in the step S1, wherein the alkali is one of potassium carbonate or potassium hydroxide.
8. The process of claim 1 for the preparation of the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate, wherein: and in the step S2, acid is added and is selected from acetic acid or citric acid.
9. The process of claim 1 for the preparation of the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate, wherein: the reaction temperature required by the ring-opening reaction in the step S2 is 5-28 ℃.
10. The process for preparing the atorvastatin calcium intermediate ethyl (R) - (-) -4-cyano-3-hydroxybutyrate of claim 1 wherein: and in the step S3, the rectification is carried out under the pressure environment of-735 to-745 mmHg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211292889.6A CN115894290A (en) | 2022-10-21 | 2022-10-21 | Preparation method of atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211292889.6A CN115894290A (en) | 2022-10-21 | 2022-10-21 | Preparation method of atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115894290A true CN115894290A (en) | 2023-04-04 |
Family
ID=86490584
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211292889.6A Pending CN115894290A (en) | 2022-10-21 | 2022-10-21 | Preparation method of atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115894290A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102442927A (en) * | 2011-10-17 | 2012-05-09 | 黄冈华阳药业有限公司 | Preparation method of atorvastatin intermediate (R)-(-)-4-(cyano)-3-butyl hydroxyacetate |
| CN105316369A (en) * | 2015-12-10 | 2016-02-10 | 江苏理工学院 | Process for enzymatic synthesis of (R)-4-cyano-3-hydroxybutyrate from sodium alginate immobilized halogenohydrin dehalogenase |
| CN105368886A (en) * | 2015-12-11 | 2016-03-02 | 江苏万年长药业有限公司 | Process of using resin-immobilized halohydrin dehalogenase to catalytically synthesize (R)-4-cyan-3-hydroxy ethyl butyrate |
| CN106244642A (en) * | 2016-08-22 | 2016-12-21 | 江苏理工学院 | A kind of halide alcohol dehalogenase catalyzes and synthesizes the preparation method of (R) 4 cyano group 3 3-hydroxyethyl butyrate |
-
2022
- 2022-10-21 CN CN202211292889.6A patent/CN115894290A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102442927A (en) * | 2011-10-17 | 2012-05-09 | 黄冈华阳药业有限公司 | Preparation method of atorvastatin intermediate (R)-(-)-4-(cyano)-3-butyl hydroxyacetate |
| CN105316369A (en) * | 2015-12-10 | 2016-02-10 | 江苏理工学院 | Process for enzymatic synthesis of (R)-4-cyano-3-hydroxybutyrate from sodium alginate immobilized halogenohydrin dehalogenase |
| CN105368886A (en) * | 2015-12-11 | 2016-03-02 | 江苏万年长药业有限公司 | Process of using resin-immobilized halohydrin dehalogenase to catalytically synthesize (R)-4-cyan-3-hydroxy ethyl butyrate |
| CN106244642A (en) * | 2016-08-22 | 2016-12-21 | 江苏理工学院 | A kind of halide alcohol dehalogenase catalyzes and synthesizes the preparation method of (R) 4 cyano group 3 3-hydroxyethyl butyrate |
Non-Patent Citations (1)
| Title |
|---|
| 谢如刚主编: "现代有机合成化学", 31 January 2007, pages: 12 - 13 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1106396A (en) | Intermediates useful in the production of aromatic amino-alcohol derivatives having anti-diabetic an21443/o1besity properties | |
| WO1998004543A1 (en) | Improved process for the synthesis of protected esters of (s)-3,4-dihydroxybutyric acid | |
| CN1113053C (en) | Preparation of cyclohexene carboxylate derivatives | |
| CN115160158B (en) | Preparation method of chiral tertiary leucinol | |
| CN112479878B (en) | Method for preparing 6, 8-dichloro ethyl caprylate | |
| CN112812091B (en) | Synthetic method of cyclic carbonate | |
| US20140200355A1 (en) | Method for Preparing Optically Pure (-)-Clausenamide Compound | |
| JPH0441449A (en) | Production of cyclohexane-1,2-diol | |
| CN115894290A (en) | Preparation method of atorvastatin calcium intermediate (R) - (-) -4-cyano-3-hydroxy ethyl butyrate | |
| CN109942514B (en) | Method for preparing azalazavir sulfate intermediate | |
| CN112225666A (en) | Preparation method of (R) -3-amino-4- (2,4, 5-trifluorophenyl) methyl butyrate | |
| US4228084A (en) | Process for the production of glycidyl methacrylate | |
| CN110668958B (en) | Method for preparing (R) -3-aminobutanol | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| EP3130586B1 (en) | Process for treating homoserine-based compound | |
| JPH0557248B2 (en) | ||
| CA2574625A1 (en) | Process for the preparation of (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionamide and (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionic acid alkyl ester | |
| JP4651178B2 (en) | Method for producing 2-glycidyloxyethyl (meth) acrylate | |
| CN107827811B (en) | Method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine | |
| CN114561440B (en) | Preparation method of high-purity (R) - (+) -1- (4-methoxyphenylethyl amine monomer | |
| JPH1160529A (en) | Production of ether | |
| WO2005051910A1 (en) | Method for preparing (s)-indoline-2-carboxylic acid and (s)-indoline-2-carboxylic acid methyl ester using hydrolytic enzyme | |
| JPH11302268A (en) | Purification and production for glycidyl (meth)acrylate | |
| CN116904530A (en) | Biological preparation method of atorvastatin calcium intermediate | |
| Jin et al. | A facile synthesis of optically active four stereoisomers of 1-aminobenz [f] indan-2-ol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |