CN1872841A - Method for preparing Rosuvastatin Calcium and key intermediate - Google Patents
Method for preparing Rosuvastatin Calcium and key intermediate Download PDFInfo
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- CN1872841A CN1872841A CN 200510026350 CN200510026350A CN1872841A CN 1872841 A CN1872841 A CN 1872841A CN 200510026350 CN200510026350 CN 200510026350 CN 200510026350 A CN200510026350 A CN 200510026350A CN 1872841 A CN1872841 A CN 1872841A
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Abstract
This invention provides a method for preparing rosuvastatin intermediate compound I-XI. The method can ensure a high purity of I-XI, thus ensuring the completeness of the stereoselectivity in subsequent reactions. Although the yield of I-XII from I-X in this invention is a little lower than that in the invention EP 0,521,471 A1, the purification of I-XII only needs a low-efficiency chromatographic column. The method thus has such advantages as low cost and high efficiency.
Description
Technical field
The present invention relates to the preparation of rosuvastain calcium (Rosuvastatin), especially wherein the preparation method of a key intermediate.
Background technology
The structure I compound that shows below is a kind of HMG-CoA reductase inhibitor, is used to treat that atherosclerosis, blood fat are too high, in familial hypercholesterolemia and the similar disease.
Wherein, R
1Be C
1-6Alkyl, aryl or aralkyl (C1-C6); R
2And R
3Be hydrogen, C
1-6Alkyl or aralkyl (C1-C6); R
4Be hydrogen, C
1-6Alkyl (C1-C6) or connect the salt that does not have toxicity and do not influence pharmacological action; X is sulphur, oxygen or alkylsulfonyl or substituent imino-is arranged.
The structure I compound comprises that lovastatin (mevinolin) is (by United States Patent (USP) 4,231,938 disclose), Pravastatin (pravatatin) is (by United States Patent (USP) 4,346,227 disclose), Simvastatin (simvastatin) is (by United States Patent (USP) 4,444,784 disclose), fluvastatin (fluvastatin) (by world patent 2,202,846 disclose).
Structure I I compound is a rosuvastain calcium:
Rosuvastain calcium is a single enantiomorph (3R, 5S) the calcium salt of carboxylic acid through alkalizing and, dihydric heptene acid in the molecule partly is the general character drug effect base of Statins, rest part is different from other Statins, and the existence of its Semi-polarity methanesulfonamido makes it present relatively low lipotropy character.The wetting ability of rosuvastain calcium means that its passive diffusibility is lower, so be difficult to enter non-liver cell.But it can be the liver cell absorption by selectivity organic anion fortune process of assembling, has the advantages that selectivity distributes and acts on HMG-CoA reductase enzyme in the liver.The relative water-soluble nature of rosuvastain calcium also makes it promptly needing can avoid cytochrome P before elimination
450Extensive metabolic defective is so its drug interaction potentiality also reduce greatly.
It is stronger than existing listing statins that rosuvastain calcium suppresses the effect of HMG-CoA reductase enzyme, and have the liver cell selectivity, and market outlook are fairly good.But because it has the chemical structure of two chiral carbon, in preparation suitable difficulty is arranged, the control of its content of isomer is very strict, needs the technology that more can guarantee its optical texture and prepares.
The preparation method of rosuvastain calcium such as European patent EP 0,521,471 A1 are described, can be illustrated as follows:
Wherein, the preparation method of intermediate compound I-XI is: Compound I-X is dissolved in acetonitrile, gets solution 1; Dropwise 48% (v/w) HF aqueous solution is added acetonitrile, get solution 2; Under condition of ice bath, solution 2 is dropwise joined in the solution 1; Dropwise post-heating to room temperature, stir 1.5hr; Neutralize with sodium carbonate solution; Use extracted with diethyl ether; Organic layer washs with sodium chloride solution, and drying removes solvent under reduced pressure, promptly gets Compound I-XI.
Then, gained Compound I-XI and the reaction of diethyl methoxyl group borine make Compound I-XII.The two-step reaction total yield is about 85.2%.
Compound I-XI promptly directly carries out next step reaction without making with extra care in the above method.Then single step reaction is to introduce the gene that contains second chiral carbon on Compound I-XI, promptly carries out the stereoselectivity reaction, and this is the committed step that guarantees the rosuvastain calcium optical texture.Experiment shows, without purified Compound I-XI (developping agent sherwood oil: on the TLC plate ethyl acetate=2: 1) except that having the principal spot at the Rf=0.48 place, at Rf=0.64 and Rf=0.40 place the impurity spot is arranged, these impurity enter the reaction of back one step generation Compound I-XII, then produce plurality of impurities, and measure manyly, can influence the thoroughness of stereoselective reaction, cause that 3 of unwanted dihydric heptene acid groups go up the enantiomer foreign matter contents and raise.And in case after the reaction that generates Compound I-XII finished, because by product and purpose product I-XII structural similitude, Rf was close, and dopant species is many, content is big, it is also very difficult with their removal promptly to use silica gel column chromatography to cross the post method.Like this, in order to reach the purifying purpose, for example reach 90% above purity, must adopt post to imitate (being the ratio of chromatography column length and diameter of section) very high chromatography column, this has not only prolonged the production cycle, and has improved running cost, has reduced production efficiency on the whole.
Summary of the invention:
In order to overcome the above problems, the invention provides a kind of method for preparing midbody compound I-XI, guaranteed the pure of Compound I-XI, guaranteed that thus the subsequent reactions neutral body is optionally complete.In industrialization, though make the yield of Compound I-XII two-step reaction a little less than EP 0,521 by Compound I-X, 471A1, but in the purifying of Compound I-XII, only need post to imitate lower chromatography column and get final product, reduce production cost thus, and shortened the production cycle, improved overall efficiency.
Specifically, the invention provides a kind of preparation rosuvastain calcium midbody compound I-XI method, its step comprises:
Provide Compound I-X, reacting generating compound I-XI as follows:
Use the extracted with diethyl ether reaction mixture;
Isolate organic phase, steaming desolventizes, and makes the concentrated solution that contains Compound I-XI;
In the gained concentrated solution, add toluene/ether mixture, be stirred to dissolving under the room temperature;
Be cooled to then and crystallize under the 0-4 ℃ of condition fully;
Filter, get filter cake vacuum-drying, get the purified compound I-XI of yellow crystals shape;
Wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1～1: 1.5 was good with 1: 1.5; Toluene: ether (v/v)=3: 1～1: 1 was good with 2: 1.
The present invention also provides a kind of method for preparing rosuvastain calcium, comprising:
Prepare midbody compound I-XI with the inventive method, and make rosuvastain calcium by gained Compound I-XI.
Embodiment
Embodiment 1:
According to EP 0,521, the described preparation Compound I-X of 471 A1.Take by weighing 16g Compound I-X, it is dissolved in the 100ml acetonitrile, get solution 1.Under condition of ice bath, 20ml 48% (w/v) the HF aqueous solution is added the 380ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath.Dropwise post-heating to room temperature, stir 1.5hr.Use Na then
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 14.6ml concentrated solution with sodium-chlor washing, drying.3: 2 (v/v) mixture 14.6ml that add toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.Be stirred to dissolving under the room temperature.Be cooled to 0-4 ℃ of crystallization.Get the reacting liquid filtering after the crystallization, get filtrate point TLC plate, if immaculate on the corresponding Rf value of the Compound I-XI position can assert that crystallization is complete.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 12.8g.The purity that records with HPLC (with dissolve with methanol, moving phase is ammonium acetate-acetonitrile solution) is 98.7%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 2:
30g Compound I-X is dissolved in the 800ml acetonitrile, adds 20ml 48% (w/v) HF solution, under room temperature, react 10hr.The molten cooling of cryosel adds NaHCO down
3, pH is transferred to 7, use extracted with diethyl ether.Separate and the results organic layer,, use anhydrous Na with the saturated common salt washing
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets 26.8g oily concentrated solution.2: 1 (v/v) mixture 40.2ml that add toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 2: 3, is stirred to dissolving under the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 22.5g.As previously mentioned with HPLC mensuration, purity is 98.8%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 3:
20g Compound I-X is dissolved in the 125ml acetonitrile, gets solution 1.Under condition of ice bath, 25ml48% (w/v) the HF aqueous solution is added the 475ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath, dropwise post-heating, stir 1.5hr to room temperature.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 18.3g concentrated solution with sodium-chlor washing, drying.Add toluene in concentrated solution: 3: 1 (v/v) mixtures of ether 27.5ml, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.5, dissolves in the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising then.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 16.1g.As previously mentioned with HPLC mensuration, purity 98.9%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 4:
40g Compound I-X is dissolved in the 250ml acetonitrile, gets solution 1.Under condition of ice bath, 50m148% (w/v) the HF aqueous solution is added the 950ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath, dropwise post-heating, stir 1.5hr to room temperature.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 37.3g concentrated solution with sodium-chlor washing, drying.1: 1 (v/v) mixture 56.0ml that adds toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.5, dissolves in the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 32.5g.As previously mentioned with HPLC mensuration, purity is 99.0%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Embodiment 5:
50g Compound I-X is dissolved in the 312.5ml acetonitrile, gets solution 1.Under condition of ice bath, 62.5ml48% (w/v) the HF aqueous solution is added the 1187.5ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath.Dropwise post-heating to room temperature, stir 1.5hr.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get the 46.1g concentrated solution with sodium-chlor washing, drying.2: 1 (v/v) mixture 69.2ml that add toluene/ether in concentrated solution, concentrated solution: the ratio (w/v) of mixed solution is 1: 1.5, dissolves in the room temperature.Be cooled to 0-4 ℃ of sufficient crystallising.Filter, get filter cake vacuum-drying, get the Compound I-XI of yellow crystals shape, 41.6g.As previously mentioned with HPLC mensuration, purity 99.1%.
HNMR(CDCl
3)δ：1.28(d，6H)，2.52(m，2H)，2.73(m，2H)，3.36(hept，1H)，3.51(s，3H)，3.59(s，3H)，3.72(s，3H)，4.48(m，1H)，6.16(d，1H)，7.13(t，2H)，7.59(m，2H)，7.63(d，1H)。
Comparing embodiment
Contrast:
10g Compound I-X is dissolved in the 62.5ml acetonitrile, gets solution 1.Under condition of ice bath, 12.5ml48% (w/v) the HF aqueous solution is added the 237.5ml acetonitrile, get solution 2.Solution 1 is dropwise added in the solution 2 under condition of ice bath.Dropwise post-heating to room temperature, stir 1.5hr.Use Na
2CO
3Extracted with diethyl ether is used in neutralization.Separate and the results organic layer,, remove solvent under reduced pressure, get 9.2g Compound I-XI concentrated solution with sodium-chlor washing, drying.As previously mentioned with HPLC mensuration, purity is 92%.
1M diethyl methoxyl group borine reaction with gained concentrated solution 9.2g and 18.4ml obtains 6.95g Compound I-XII.The two-step reaction total yield is about 85.2%.
HNMR(CDCl
3)δ：1.27(d，J＝7，6H)，1.52(m，2H)，2.47(d，J＝6，2H)，3.36(hept，J＝2，1H)，3.52(s，3H)，3.57(s，3H)，3.73(s，3H)，4.2(m，1H)，4.43(m，1H)，5.45(dd，J＝5，16，1H)，6.64(dd，J＝2，16，1H)，7.09(m，2H)，7.64(m，2H)。
With purification by silica gel column chromatography gained Compound I-above purity of XII to 90% (the HPLC method is measured, and with dissolve with methanol, moving phase is ammonium acetate-acetonitrile solution).Then, as EP 0,521,471 A1 are described, carry out subsequent reactions, until making rosuvastain calcium.
The present invention:
With 10g embodiment 5 gained Compound I-XI and the reaction of 8.3g diethyl methoxyl group borine, make 6.67g Compound I-XII.The two-step reaction total yield is about 81.8%.
HNMR(CDCl
3)δ：1.27(d，J＝7，6H)，1.52(m，2H)，2.47(d，J＝6，2H)，3.36(hept，J＝2，1H)，3.52(s，3H)，3.57(s，3H)，3.73(s，3H)，4.2(m，1H)，4.43(m，1H)，5.45(dd，J＝5，16，1H)，6.64(dd，J＝2，16，1H)，7.09(m，2H)，7.64(m，2H)。
With purification by silica gel column chromatography gained Compound I-above purity of XII to 90% (the HPLC method is measured, and with dissolve with methanol, moving phase is ammonium acetate-acetonitrile solution).Then, as EP 0,521,471 A1 are described, carry out subsequent reactions, until making rosuvastain calcium.
Table 1
| The present invention | Contrast | |
| Compound I-XI purity (%) | 99.1 | 92 |
| Compound I-X is to the total yield (%) of Compound I-XII | 81.8 | 85.2 |
| The required post of purifying compounds I-XII () purity＞90% is imitated (in chromatography column Φ=10cm, the length of chromatography column) | Low (15cm) | High (40-45cm) |
| The amount of every purifying 10g Compound I-XII used silica gel (300 order) is (in chromatography column Φ=10cm) (g) | 450 | 1200 |
| Purifying compounds I-XII required time (hr) | 8 | 20 |
| Impurity (%) (measuring) in the reaction gained rosuvastain calcium except that isomer with the HPLC method | 1 | 1.5 |
| Rosuvastain calcium isomer impurities content (%) (measuring) with HPLC method chiral column | 0.5 | 1 |
Claims (6)
1. one kind prepares rosuvastain calcium midbody compound I-XI method,
Its step comprises:
Provide Compound I-X, reacting generating compound I-XI as follows:
Use the extracted with diethyl ether reaction mixture;
Isolate organic phase, steaming desolventizes, and makes the concentrated solution that contains Compound I-XI;
In the gained concentrated solution, add toluene/ether mixture, be stirred to dissolving under the room temperature;
Be cooled to and crystallize under the 0-4 ℃ of condition fully;
Filter, get filter cake vacuum-drying, get the purified compound I-XI of yellow crystals shape;
Wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1～1: 1.5, toluene: ether (v/v)=3: 1～1: 1.
2. the method for claim 1, wherein concentrated solution: toluene/ether mixture (w/v)=1: 1.5.
3. the method for claim 1, wherein toluene: ether (v/v)=2: 1.
4. method for preparing rosuvastain calcium comprises:
Provide Compound I-X, reacting generating compound I-XI as follows:
Use the extracted with diethyl ether reaction mixture;
Isolate organic phase, steaming desolventizes and makes the concentrated solution that contains Compound I-XI;
In the gained concentrated solution, add toluene/ether mixture, be stirred to dissolving under the room temperature;
Be cooled to then and crystallize under the 0-4 ℃ of condition fully;
Filter, get filter cake vacuum-drying, get the purified compound I-XI of yellow crystals shape;
Compound I-XI makes rosuvastain calcium by gained;
Wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1～1: 1.5, toluene: ether (v/v)=3: 1～1: 1.
5. method as claimed in claim 4, wherein, concentrated solution: toluene/ether mixture (w/v)=1: 1.5.
6. method as claimed in claim 4, wherein, toluene: ether (v/v)=2: 1.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7582759B2 (en) | 2005-02-22 | 2009-09-01 | Teva Pharmaceutical Industries Ltd. | Diastereomeric purification of rosuvastatin |
| WO2009128091A2 (en) * | 2008-02-20 | 2009-10-22 | Matrix Laboratories Limited | Crystalline form of(7-[4-(4-fluorophenyl)-6-isopropyl-2-(n- methyl-n-methylsulfonylamino)pyrimidin-5-yl]-(3r,5s)- dihydroxy-(e)-6-heptenoic acid intermediate, process for preparing the same and use thereof |
| WO2009143776A1 (en) | 2008-05-27 | 2009-12-03 | 常州制药厂有限公司 | Preparation method of rosuvastatin calcium and its intermediates |
| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| US7868169B2 (en) | 2005-08-16 | 2011-01-11 | Teva Pharmaceutical Industries, Ltd. | Crystalline rosuvastatin intermediate |
| CN101955463A (en) * | 2010-08-04 | 2011-01-26 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN101591302B (en) * | 2008-05-27 | 2011-08-31 | 常州制药厂有限公司 | Preparation technique of heptenoic acid ester derivative |
| CN103298793A (en) * | 2010-11-29 | 2013-09-11 | 埃吉斯药物股份公开有限公司 | Method for the preparation of high-purity pharmaceutical intermediates |
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2005
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| US8063211B2 (en) | 2005-02-22 | 2011-11-22 | Teva Pharmaceutical Industries, Ltd. | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| US7612203B2 (en) | 2005-02-22 | 2009-11-03 | Teva Pharmaceutical Industries Ltd. | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| US7582759B2 (en) | 2005-02-22 | 2009-09-01 | Teva Pharmaceutical Industries Ltd. | Diastereomeric purification of rosuvastatin |
| US7868169B2 (en) | 2005-08-16 | 2011-01-11 | Teva Pharmaceutical Industries, Ltd. | Crystalline rosuvastatin intermediate |
| WO2009128091A2 (en) * | 2008-02-20 | 2009-10-22 | Matrix Laboratories Limited | Crystalline form of(7-[4-(4-fluorophenyl)-6-isopropyl-2-(n- methyl-n-methylsulfonylamino)pyrimidin-5-yl]-(3r,5s)- dihydroxy-(e)-6-heptenoic acid intermediate, process for preparing the same and use thereof |
| WO2009128091A3 (en) * | 2008-02-20 | 2010-11-04 | Matrix Laboratories Limited | Crystalline form of(7-[4-(4-fluorophenyl)-6-isopropyl-2-(n- methyl-n-methylsulfonylamino)pyrimidin-5-yl]-(3r,5s)- dihydroxy-(e)-6-heptenoic acid intermediate, process for preparing the same and use thereof |
| WO2009143776A1 (en) | 2008-05-27 | 2009-12-03 | 常州制药厂有限公司 | Preparation method of rosuvastatin calcium and its intermediates |
| CN101591302B (en) * | 2008-05-27 | 2011-08-31 | 常州制药厂有限公司 | Preparation technique of heptenoic acid ester derivative |
| US8653265B2 (en) | 2008-05-27 | 2014-02-18 | Changzhou Pharmaceutical Factory | Preparation method of rosuvastatin calcium and its intermediates |
| US8765947B2 (en) | 2008-05-27 | 2014-07-01 | Changzhou Pharmaceutical Factory | Preparation method of Rosuvastatin calcium and its intermediates |
| CN101955463A (en) * | 2010-08-04 | 2011-01-26 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN103298793A (en) * | 2010-11-29 | 2013-09-11 | 埃吉斯药物股份公开有限公司 | Method for the preparation of high-purity pharmaceutical intermediates |
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