CN112028881B - Synthesis method of rosuvastatin calcium higher intermediate R-1 - Google Patents
Synthesis method of rosuvastatin calcium higher intermediate R-1 Download PDFInfo
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
A synthesis method of a high-grade intermediate R-1 of rosuvastatin calcium comprises the steps of condensing a compound 1 serving as a starting material with 2-mercapto-5-methyl-1, 3, 4-thiadiazole to generate a compound 2, oxidizing the compound 2 by hydrogen peroxide to obtain a compound 3, and condensing the compound 3 and the compound 4 by Julia-Kocienski Olefination to obtain R-1; the compound 1 is (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate, and the compound 4 is pyrimidine aldehyde; the synthesis method has the advantages of simple reaction route, mild reaction condition, low price of raw materials, high reaction selectivity and almost no cis isomer, and avoids using phosphine salt in the route, thereby avoiding generating triphenylphosphine oxide as a byproduct with large polarity in the product, greatly reducing the cost of synthesizing the raw material medicine of rosuvastatin calcium, avoiding the subsequent reaction to form cis-rosuvastatin calcium impurity, avoiding the influence of the impurity on the drug effect of the medicine, and having great significance in reducing the drug burden of residents.
Description
Technical Field
The invention relates to a synthesis method of a high-grade intermediate R-1 of rosuvastatin calcium, wherein the chemical name of R-1 is 6- [ (1E) -2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -5-pyrimidine ] vinyl ] -2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, and the method belongs to the technical field of fine chemical synthesis.
Background
Rosuvastatin calcium.
Chemical name: (+) - (3R, 5S) -bis {7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) pyrimidin-5-yl ] -3, 5-dihydroxy-6- (E) -heptenoic acid } hemicalcium salt
Trade name: can decides (Crestor)
The developer: the japanese salt field pharmaceutical corporation was developed and screened at the end of the last 80 th century, and later, the company AstraZeneca in england was developed again worldwide except for eastern countries such as japan. Time to market: month 2 2003 and 2006 in China.
Country and region of marketing: sixty countries and regions in the united kingdom, the united states, canada, china, etc.
The indications are as follows:
1. hyperlipidemia and hypercholesterolemia.
2. For patients without clinical manifestations of heart disease but at risk of potential cardiovascular disease to reduce the risk of myocardial infarction, stroke and coronary revascularization.
3. It is also suitable for patients with homozygous familial hypercholesterolemia as an adjunct to diet control and other lipid lowering measures (e.g., LDL removal therapy), or when these methods are not applicable.
Mechanism of action: is a selective HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors are rate-limiting enzymes for converting 3-hydroxy-3-methylglutaryl CoA to the first precursor of mevalonate-cholesterol. The main site of action of rosuvastatin is the liver, the cholesterol lowering target organ. Rosuvastatin increases the number of hepatic LDL cell surface receptors, promotes LDL uptake and catabolism, inhibits liver synthesis of VLDL, and thereby reduces the total number of VLDL and LDL particles. Rosuvastatin reduces total cholesterol, LDL-C, apoB, non-HDL-C levels in homozygous and heterozygous familial hypercholesterolemia patients, non-familial hypercholesterolemia patients, mixed dyslipidemia patients. Rosuvastatin also lowers TG and increases HDL-C levels. Rosuvastatin has reduced total cholesterol, LDL-C, VLDL-C, apoB, non-HDL-C, TG levels, and elevated HDL-C levels in patients with hypertriglyceridemia alone. In therapy, rosuvastatin is administered as its calcium salt and is a single enantiomer having the following chemical structural formula.
The prior art reports a number of processes for the preparation of rosuvastatin: among these, the earliest was "developed successfully by japanese salt field company", which later assigned this drug technology to asteranneca (Astrazeneca) in the united kingdom. In 1992, japanese patent JP-B-2648897, which was the earliest and most basic compound for this product, disclosed the compound and its preparation. The preparation method is characterized in that the pyrimidine mother nucleus is subjected to polysubstituted formaldehyde, in addition, chiral side chains are synthesized into phosphine salts, and then the phosphine salts are subjected to condensation through Weixi (Witting) reaction to obtain the rosuvastatin skeleton. The key synthesis steps are as follows:
in 10 months 2002, the Ranbaxy company in India adopts the mode of the basic patent [5], and converts methyl ester side chains in the basic patent into nitrile groups, so that the target product is obtained by deprotection, chiral reduction, hydrolysis of the nitrile groups into sodium salts and conversion into calcium salts after condensation of the side chains and parent nuclei. The synthetic route is as follows:
after 2 months 2000, the company of aslick in the uk has undertaken the study. Firstly, providing a parent nucleus to prepare phosphine salt, preparing tertiary J ester side chains to prepare aldehyde, thus completing Weixi (Wittig) reaction condensation to obtain a rosuvastatin skeleton, then deprotecting, alkaline hydrolysis and converting calcium salt to obtain a target product. The key synthesis steps are as follows: among them, tert-butyl side chain aldehyde was as early as 1988, and there is a patent to obtain dicarbonyl ester containing chiral hydroxyl group by condensation using (R) -4-bromo-3-hydroxybutyric acid ethyl ester. Then sodium borohydride and borane are used for chiral reduction, then acetone fork protection is carried out,
then acetyl halogen group (chlorine or bromine), hydrolyzing acetyl to obtain side chain alcohol, and oxidizing DMS0 by oxalyl chloride to obtain tert-butyl J ester side chain aldehyde, wherein the key synthesis steps are as follows:
the three routes are relatively good in the way of the aspartame, the Wittig condensation reaction is carried out without a deep cooling condition, but due to the fact that the Wittig reaction has the cis-trans isomer ratio, even though the E-configuration compound is subjected to recrystallization and other operations, the Z-configuration compound still remains, so that the cis-rosuvastatin calcium impurity is formed by unavoidable subsequent reactions, and the impurity has influence on the drug effect and the like of the drug.
Disclosure of Invention
The invention aims to provide a synthesis method of a high-grade intermediate R-1 of rosuvastatin calcium, aiming at the defects of the prior art, wherein the synthesis method can obtain rosuvastatin calcium only through simple deprotection, hydrolysis and calcification, and is a route with the lowest cost for synthesizing rosuvastatin calcium raw material medicines.
The invention realizes the aim through the following technical scheme:
a synthesis method of a high-grade intermediate R-1 of rosuvastatin calcium is characterized in that a compound 1 is taken as a starting material to be condensed with 2-mercapto-5-methyl-1, 3, 4-thiadiazole to generate a compound 2, the compound 2 is oxidized by hydrogen peroxide to obtain a compound 3, and the compound 3 and the compound 4 are subjected to a Julia-Kocienski Olefination condensation reaction to obtain the high-grade intermediate R-1 of rosuvastatin calcium; the compound 1 is (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate, and the compound 4 is pyrimidine aldehyde;
the specific synthesis method comprises the following steps:
step 1), reacting the compound 1 and 2-mercapto-5-methyl-1, 3, 4-thiadiazole in an inorganic base and a phase transfer catalyst to obtain a compound 2;
step 2), the compound 2 reacts with hydrogen peroxide under the action of a catalyst to obtain a compound 3;
step 3), synthesizing the compound 3 and the compound 4 at low temperature under the condition of organic alkali to obtain a compound 5;
the reaction route is as follows:
the phase transfer catalyst in the step 1) is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, benzyl triethyl ammonium chloride, 18 crown 6 ether, 15 crown 5 and polyethylene glycol, preferably tetrabutylammonium bromide or benzyl triethyl ammonium chloride; the inorganic base in the step 1) is Na 2 CO 3 、K 2 CO 3 、KHCO 3 、NaHCO 3 One of NaOH and KOH, preferably Na 2 CO 3 Or K 2 CO 3 。
The solvent selected for the reaction in step 1) is one of NMP, DMSO, DMF, DMAc, preferably NMP or DMSO; the extraction solvent is one of n-heptane, toluene and ethyl acetate, preferably ethyl acetate; the reaction temperature in step 1) is 80-140℃and preferably 100-120 ℃.
The catalyst in the step 2) is one of phosphomolybdic acid, tungsten trioxide and ammonium molybdate, and phosphomolybdic acid is preferred.
The reaction solvent selected in the step 2) is selected from one of acetonitrile and DMSO, DMF, DMAc, preferably acetonitrile or DMSO; the reaction temperature in step 2) is 20-60℃and preferably 30-40 ℃.
The extraction solvent selected in the step 2) is one of methyl acetate, ethyl acetate and isopropyl acetate, preferably ethyl acetate; the crystallization solvent selected in the step 2) is one of n-heptane, toluene, xylene and chlorobenzene, preferably toluene.
The organic base in the step 3) is one of sodium hydride, naHMDS, liHMDS, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, butyllithium and LDA, preferably sodium hydride or LDA.
The reaction temperature for the low temperature synthesis described in step 3) is between 0 and 20 ℃, preferably between 5 and 10 ℃.
The reaction solvent selected in the step 3) is one of toluene, tetrahydrofuran, dioxane, ethyl acetate, methyl tertiary butyl ether, methyl isopropyl ketone and acetone, and toluene or tetrahydrofuran is preferred; the crystallization solvent selected in the step 3) is one of methanol, isopropanol and acetonitrile, preferably methanol.
The step 1) and the step 3) react in an inert gas atmosphere, wherein the inert gas is selected from one of nitrogen, argon and helium, and nitrogen is preferred.
1 part of compound 1, 0.65-0.75 part of 2-mercapto-5-methyl-1, 3, 4-thiadiazole, 0.5-0.7 part of inorganic base and 0.05-0.15 part of phase transfer catalyst in the step 1);
1 part of compound 2, 0.1-0.2 part of catalyst and 4-8 parts of 30% hydrogen peroxide in the step 2);
in the step 3), 1 part of compound 3, 1-1.3 parts of compound 4 and 0.1-0.2 part of organic base.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, julia-Kocienski Olefination is adopted to synthesize the rosuvastatin higher intermediate R-1, and rosuvastatin calcium can be obtained only through simple deprotection, hydrolysis and calcification, so that the method is a route for synthesizing rosuvastatin calcium with the lowest cost of raw materials. The method has the advantages of simple reaction route, mild reaction conditions, low price of raw materials, high reaction selectivity and almost no cis isomer, and avoids the use of phosphine salt in the route, so that the generation of a by-product triphenylphosphine oxide with large polarity in the product is avoided, the cost of synthesizing the rosuvastatin calcium bulk drug is greatly reduced, and the method has great significance in reducing the drug burden of residents. Solves the problems that the cis-trans isomer ratio exists in the Wittig reaction, and even though the operations such as recrystallization and the like are carried out, the compound with Z configuration still exists in the compound with E configuration, so that the cis-rosuvastatin calcium impurity is formed in the unavoidable subsequent reaction, and the effect on the drug effect of the drug is influenced.
Detailed Description
Example 1
To a 500ml three-port reaction flask, 70 g of NMP, 35 g of Compound 1 and 23.8 g of 2-mercapto-5-methyl-1, 3, 4-thiadiazole were added, 3.5 g of benzyl triethyl ammonium chloride and 21.2 g of sodium carbonate were further added, and after three times of nitrogen substitution under vacuum, the temperature was raised in an oil bath under nitrogen protection, the temperature was controlled at 115.+ -. 5 ℃ and the reaction was completed for about 20 hours (HPLC analysis+spot plate analysis). Cooling the reaction liquid to room temperature after sampling and confirming the completion of the reaction, adding 140 g of water and 140 g of ethyl acetate into the reaction liquid after cooling, adding 140 g of ethyl acetate into the water phase after layering to extract the water phase once again, combining the organic phases and adding 140 g of water to wash once, concentrating at normal pressure to recover ethyl acetate, and weighing 61.2 g of a purity product with 73% of content 44.5g after concentrating, thereby obtaining the yield; 95%.
Example 2
To a 5000ml three-port reaction flask, 700g DMSO, 350 g Compound 1 and 238 g 2-mercapto-5-methyl-1, 3, 4-thiadiazole were added, 35 g tetrabutylammonium bromide and 212 g sodium carbonate were further added, and after three times of nitrogen substitution under vacuum, the temperature was raised in an oil bath under nitrogen protection, and the temperature was controlled at 115.+ -. 5 ℃ for about 20 hours, and the reaction was completed (HPLC analysis+spot plate analysis). Cooling the reaction liquid to room temperature after sampling and confirming the completion of the reaction, adding 1400 g of water and 1400 g of ethyl acetate into the reaction liquid after cooling, adding 1400 g of ethyl acetate into the water phase after layering to extract the water phase once again, combining the organic phases and adding 1400 g of water to wash once, concentrating at normal pressure to recover the ethyl acetate, and weighing 587 g of total 422 g of a folded product with the content of 72% after concentrating, wherein the yield is obtained; 90%.
Example 3
To 61.2 g of the concentrated solution of Compound 2 was added 300g of acetonitrile for dissolution, and after dissolution, the solution was transferred to a 1000ml three-necked flask, and 10g of phosphomolybdic acid was added to the solution to react300g of 30% hydrogen peroxide is added dropwise into the bottle, the temperature is controlled at 30-40 ℃ in the process of adding dropwise, the mixture is stirred at room temperature until the reaction is complete (raw materials and intermediates are all converted into products), and HPLC analysis is completed for about 20 hours. After the reaction is finished, 300g of 10% sodium bisulphite aqueous solution is added dropwise to the reaction solution to quench hydrogen peroxide, after the completion of dropwise adding and stirring, the normal pressure recovery of acetonitrile is started after the absence of hydrogen peroxide is detected, the heating is stopped when the internal temperature reaches 100 ℃, 600 g of ethyl acetate is added after the internal temperature is reduced to the room temperature for extraction, and 600 g of 5% NaHCO is added to the organic phase after layering 3 Washing the aqueous solution once, concentrating under reduced pressure to obtain ethyl acetate to obtain solid, adding 700g of toluene into the concentrated solid for recrystallization, heating to a solution clear (T-85-90 ℃), slowly cooling to room temperature for crystallization, filtering out the solid, leaching the solid with a small amount of toluene, and drying at 60 ℃ to obtain 41.4g of compound 3 with the content of 98%, thereby obtaining the yield; 85%.
Example 4
To 62 g of the concentrated solution of Compound 2, 300g of DMSO was added for dissolution, the solution was transferred to a 1000ml three-necked flask after dissolution, 10g of phosphomolybdic acid was added, 300g of 30% hydrogen peroxide was added dropwise to the flask, the temperature was controlled at 30-40℃during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at room temperature until the reaction was completed (raw material+intermediate was all converted into product), and HPLC analysis was completed for about 20 hours. After the reaction is finished, 300g of 10% sodium bisulphite aqueous solution is added dropwise to the reaction solution to quench hydrogen peroxide, 600 g of ethyl acetate is added for extraction after the completion of the dropwise addition and stirring to detect that no hydrogen peroxide exists, and 600 g of 5% NaHCO is added to the organic phase after layering 3 Washing the aqueous solution once, concentrating under reduced pressure to obtain ethyl acetate to obtain solid, adding 700g of toluene into the concentrated solid for recrystallization, heating to a solution clear (T-85-90 ℃), slowly cooling to room temperature for crystallization, filtering out the solid, leaching the solid with a small amount of toluene, and drying at 60 ℃ to obtain 44g of compound 3 with the content of 98.1%, thereby obtaining the yield; 90%.
Example 5
Adding 41 g of compound 3 and 35 g of compound 4 into a 1000ml three-port bottle, adding 400 g of toluene into a reaction bottle, cooling under the protection of nitrogen, adding 4.8 g of sodium hydride and 200 g of tetrahydrofuran to prepare a tetrahydrofuran solution of sodium hydride into another 500ml reaction bottle, cooling the raw material reaction liquid to 5 ℃, starting to dropwise add the sodium hydride solution, dropwise adding the raw material reaction liquid for 2 hours at the temperature of not more than 10 ℃, carrying out heat preservation reaction at 5-10 ℃ after dropwise adding, carrying out reaction for 8-10 hours, pouring the reaction liquid into 400 g of 30% aqueous solution of potassium carbonate for quenching after the reaction is finished, layering after the quenching is finished, washing an organic phase once by 400 g of 5% aqueous solution of sodium bicarbonate, concentrating the organic phase under reduced pressure, adding 800 g of methanol for recrystallization after the concentration is finished, heating to reflux for dissolving to room temperature, stirring the mixture for 2 hours, carrying out suction filtration, and carrying out vacuum drying at 60 ℃ to obtain 51.8 g of a filter cake with the purity of 99.6% and the content of 99.1% by HPLC, wherein the yield is obtained; 90%.
The above description is merely a preferred embodiment of the present invention, and the above illustration is not to be construed as limiting the spirit of the present invention in any way, and any simple modification or variation of the above embodiments according to the technical spirit of the present invention, and equivalent embodiments that may be changed or modified to equivalent variations using the above disclosed technical spirit of the present invention, will still fall within the scope of the technical solutions of the present invention, without departing from the spirit and scope of the present invention.
Claims (3)
1. A synthesis method of a higher intermediate R-1 of rosuvastatin calcium is characterized by comprising the following steps of:
the method comprises the steps of condensing a compound 1 serving as an initial raw material with 2-mercapto-5-methyl-1, 3, 4-thiadiazole to generate a compound 2, oxidizing the compound 2 by hydrogen peroxide to obtain a compound 3, performing a condensation reaction on the compound 3 and the compound 4 by Julia-Kocienski Olefination to obtain R-1, wherein the compound 1 is (4R-cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxolane-4-butyl acetate, and the compound 4 is pyrimidine aldehyde;
the specific synthesis method comprises the following steps:
step 1), reacting the compound 1 and 2-mercapto-5-methyl-1, 3, 4-thiadiazole in an inorganic base and a phase transfer catalyst to obtain a compound 2;
the phase transfer catalyst in the step 1) is tetrabutylammonium bromide or benzyl triethyl ammonium chloride; the inorganic alkali is Na2CO3 or K2CO3;
the solvent selected for the reaction in the step 1) is NMP or DMSO; the extraction solvent is ethyl acetate;
the reaction temperature in the step 1) is 100-120 ℃;
step 2), reacting the compound 2 with 30% hydrogen peroxide under the action of a catalyst to obtain a compound 3;
the catalyst in the step 2) is phosphomolybdic acid;
the reaction solvent selected in the step 2) is acetonitrile or DMSO, and the reaction temperature is 30-40 ℃;
the extraction solvent selected in the step 2) is ethyl acetate; the crystallization solvent is toluene;
step 3), synthesizing the compound 3 and the compound 4 at low temperature under sodium hydride to obtain a compound 5;
the reaction temperature for synthesis at low temperature in the step 3) is 5-10 ℃;
the reaction solvent selected in the step 3) is toluene or tetrahydrofuran; the crystallization solvent is one of methanol, isopropanol and acetonitrile;
the reaction route is as follows:
2. the method for synthesizing the higher intermediate R-1 of rosuvastatin calcium according to claim 1, wherein the method comprises the steps of: the step 1) and the step 3) react in an inert gas atmosphere, wherein the inert gas is selected from one of nitrogen, argon and helium.
3. The method for synthesizing the higher intermediate R-1 of rosuvastatin calcium according to claim 1, wherein the method comprises the steps of: 1 part of compound 1, 0.65-0.75 part of 2-mercapto-5-methyl-1, 3, 4-thiadiazole, 0.5-0.7 part of inorganic base and 0.05-0.15 part of phase transfer catalyst in the step 1);
1 part of compound 2, 0.1-0.2 part of catalyst and 4-8 parts of 30% hydrogen peroxide in the step 2);
in the step 3), 1 part of compound 3, 1-1.3 parts of compound 4 and 0.1-0.2 part of sodium hydride.
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| CN112679490A (en) * | 2021-01-28 | 2021-04-20 | 安徽美诺华药物化学有限公司 | Chiral side chain of rosuvastatin calcium containing sulfone structure and preparation method and application thereof |
| CN112592336A (en) * | 2021-01-28 | 2021-04-02 | 安徽美诺华药物化学有限公司 | High-grade intermediate of rosuvastatin calcium and preparation method thereof |
| CN113387944B (en) * | 2021-07-09 | 2021-12-28 | 浙江宏元药业股份有限公司 | Synthetic method of rosuvastatin calcium intermediate |
| CN113754650B (en) * | 2021-08-06 | 2023-10-20 | 湖北宇阳药业有限公司 | High-selectivity synthesis method of rosuvastatin calcium intermediate |
| CN114805164A (en) * | 2022-03-30 | 2022-07-29 | 法姆瑞斯医药科技(北京)有限公司 | Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011104725A2 (en) * | 2010-02-23 | 2011-09-01 | Cadila Healthcare Limited | Hmg-coa reductase inhibitors and process for the preparation thereof |
| CN103313983A (en) * | 2011-01-18 | 2013-09-18 | 中化帝斯曼制药有限公司荷兰公司 | Process for the preparation of statins in the presence of base |
| CN103313984A (en) * | 2011-01-18 | 2013-09-18 | 中化帝斯曼制药有限公司荷兰公司 | Methyltetrazole sulfides and sulfones |
| CN103328470A (en) * | 2011-01-18 | 2013-09-25 | 中化帝斯曼制药有限公司荷兰公司 | Process for the preparation of diol sulfones |
| WO2014108795A2 (en) * | 2013-01-10 | 2014-07-17 | Aurobindo Pharma Limited | An improved process for the preparation of chiral diol sulfones and statins |
| CN104513232A (en) * | 2015-01-08 | 2015-04-15 | 苏州莱克施德药业有限公司 | Preparation process for rosuvastatin ethyl ester |
| CN110627736A (en) * | 2019-09-26 | 2019-12-31 | 江苏阿尔法药业有限公司 | Method for recycling 1-phenyl-5-hydroxy tetrazole |
| CN110642790A (en) * | 2019-10-21 | 2020-01-03 | 山东理工职业学院 | Preparation method of rosuvastatin calcium and intermediate thereof |
| CN111875538A (en) * | 2020-08-06 | 2020-11-03 | 安徽省庆云医药股份有限公司 | Synthetic method of pitavastatin tert-butyl ester |
| CN114805164A (en) * | 2022-03-30 | 2022-07-29 | 法姆瑞斯医药科技(北京)有限公司 | Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2560970A1 (en) * | 2010-04-23 | 2013-02-27 | Ranbaxy Laboratories Limited | NOVEL INTERMEDIATES FOR THE PREPARATION OF HMG-CoA REDUCTASE INHIBITORS |
-
2020
- 2020-09-02 CN CN202010909539.4A patent/CN112028881B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011104725A2 (en) * | 2010-02-23 | 2011-09-01 | Cadila Healthcare Limited | Hmg-coa reductase inhibitors and process for the preparation thereof |
| CN103313983A (en) * | 2011-01-18 | 2013-09-18 | 中化帝斯曼制药有限公司荷兰公司 | Process for the preparation of statins in the presence of base |
| CN103313984A (en) * | 2011-01-18 | 2013-09-18 | 中化帝斯曼制药有限公司荷兰公司 | Methyltetrazole sulfides and sulfones |
| CN103328470A (en) * | 2011-01-18 | 2013-09-25 | 中化帝斯曼制药有限公司荷兰公司 | Process for the preparation of diol sulfones |
| WO2014108795A2 (en) * | 2013-01-10 | 2014-07-17 | Aurobindo Pharma Limited | An improved process for the preparation of chiral diol sulfones and statins |
| CN104513232A (en) * | 2015-01-08 | 2015-04-15 | 苏州莱克施德药业有限公司 | Preparation process for rosuvastatin ethyl ester |
| CN110627736A (en) * | 2019-09-26 | 2019-12-31 | 江苏阿尔法药业有限公司 | Method for recycling 1-phenyl-5-hydroxy tetrazole |
| CN110642790A (en) * | 2019-10-21 | 2020-01-03 | 山东理工职业学院 | Preparation method of rosuvastatin calcium and intermediate thereof |
| CN111875538A (en) * | 2020-08-06 | 2020-11-03 | 安徽省庆云医药股份有限公司 | Synthetic method of pitavastatin tert-butyl ester |
| CN114805164A (en) * | 2022-03-30 | 2022-07-29 | 法姆瑞斯医药科技(北京)有限公司 | Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole |
Non-Patent Citations (1)
| Title |
|---|
| Anonmously."Novel intermediates for the preparation of statins".《 IP.com Journal》.2011,第11卷第1-19页. * |
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