KR101304640B1 - Novel n-methylbenzylamine salt of rosuvastatin and process for the preparation thereof - Google Patents
Novel n-methylbenzylamine salt of rosuvastatin and process for the preparation thereof Download PDFInfo
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- KR101304640B1 KR101304640B1 KR1020100086009A KR20100086009A KR101304640B1 KR 101304640 B1 KR101304640 B1 KR 101304640B1 KR 1020100086009 A KR1020100086009 A KR 1020100086009A KR 20100086009 A KR20100086009 A KR 20100086009A KR 101304640 B1 KR101304640 B1 KR 101304640B1
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- BPRHUIZQVSMCRT-VEUZHWNKSA-M CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1/C=C/[C@H](C[C@H](CC([O-])=O)O)O Chemical compound CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1/C=C/[C@H](C[C@H](CC([O-])=O)O)O BPRHUIZQVSMCRT-VEUZHWNKSA-M 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N CNCc1ccccc1 Chemical compound CNCc1ccccc1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
The present invention relates to a novel crystalline salt of rosuvastatin, and more particularly to (E) -7- [4- (4-fluorophenyl) of formula (I) which is an intermediate useful for preparing optically pure rosuvastatin calcium salts. ) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydroxyhept-6-enoic acid (hereafter rosuvastatin) N-methylbenzylamine salt and a method for preparing the same.
Formula I
Rosuvastatin calcium (Formula II) is a HMG-CoA reduction inhibitor developed by Shionogi and is a hyperlipidemic drug sold under the brand name CRESTOR. Rosuvastatin calcium has the best LDL cholesterol reduction effect among statin preparations, is pharmacologically water soluble and has good selectivity for liver and has good effects and stability.
(II)
(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-Dihydroxy-6-heptene-carboxylic acid is known by the international generic name (INN) rosuvastatin.
(III)
Since rosuvastatin calcium (Formula II) is an optically pure chemical having two chiral centers, it is very important to obtain pure rosuvastatin calcium by removing other isomeric impurities as much as possible.
The known rosuvastatin calcium salt was first introduced by European Patent No. 521471, which discloses an amorphous form of a pharmaceutically acceptable calcium salt and includes a method for synthesizing calcium salt from rosuvastatin sodium salt in aqueous solution. . However, there is no mention of a purification method for removing the resulting isomeric impurities.
International patent publication WO 01/60804 mentions rosuvastatin crystalline salts, and instead of calcium salts, ammonium salts, methylammonium salts, ethylammonium salts, tris (hydroxymethyl) methylammonium salts, benzylammonium salts or 4-methoxybenzylammonium salts. Crystalline salts and methods for preparing the same are described. However, only references to other salts instead of calcium salts are not described for the purity improvement effects of the salts.
International Patent Publication No. WO 2010/035284 discloses Rosuva with improved optical purity by using amines (S) -2-amino-3,3-dimethylbutane and (S)-(-)-α-methylbenzylamine. Statin amine salts are prepared separately, and a method for producing rosuvastatin calcium salts from these salts is presented. However, this method is difficult to obtain both commercially available amines as optical isomers, and because it is very expensive, it is not economical and is not suitable for industrial mass production. Furthermore, in the case of (S) -2-amino-3,3-dimethylbutane salt, there is no mention of yield and purity and the effect of removing isomeric impurities is not described.
And (S)-(-)-α-methylbenzylamine, it is described that the isomeric impurities are removed by 0.15% or less. However, isomeric impurities may have very high toxicity in some cases, or may exhibit completely different pharmacological effects, so these impurities should be kept as low as possible. In addition, considering that the international standards such as the ICH guideline recommend that the impurity content be 0.1% or less, the existing technology that removes isomeric impurities only 0.15% has little industrial value as a pharmaceutical manufacturing technology. For this reason, there is a need for a method of synthesizing optically pure rosuvastatin calcium.
To obtain optically pure rosuvastatin calcium, it is essential to remove isomeric impurities. Accordingly, an object of the present invention is to find a novel rosuvastatin amine salt which has an excellent purification function as an intermediate of rosuvastatin calcium salt, which is easy to remove isomeric impurities, and which is economically and industrially easy to mass-produce. It is to provide a method for producing an optically high purity amorphous rosuvastatin calcium salt.
In order to achieve the above object, the present invention overcomes the problems of the prior art, such as using an expensive reagent, inferior effect of removing isomeric impurities, or having a low yield, while industrially producing high purity rosuva, which is easily mass-produced. Various studies have been conducted to find ways to prepare statin amine salts. However, phenethylamine and (R)-(+)-methylbenzylamine were used to make rosuvastatin amine salts. However, most of the amine salts did not form or absorb the solvent during crystal formation. Even if the obtained amine was very expensive and the purification effect was also low.
So, while continuing research, the new rosuvastatin N-methylbenzylamine salt can be easily obtained in high yield by reacting rosuvastatin with N-methylbenzylamine in a specific organic solvent (methylene chloride, acetonitrile, acetone). It has been found that, surprisingly, the isomeric impurities that are generally difficult to remove are very well removed to prepare high purity rosuvastatin N-methylbenzylamine salts. In addition, high purity amorphous rosuvastatin calcium salts could be easily prepared from high purity rosuvastatin amine salts.
That is, although the inventors used N-methylbenzylamine, which is a non-optical amine, the optical purity is higher than that of the prior art, such as using an optical isomer amine such as (S)-(-)-α-methylbenzylamine. Found a surprising fact that is further improved.
In general, when using a non-optical amine such as N-methylbenzylamine used in the present invention, it is easy to remove the structurally different general impurities, but the improvement of optical purity is unknown, the furnace which has an effect of improving optical purity The discovery of the subvastatin N-methylbenzylamine salt and its preparation is a distinctive and original invention.
The rosuvastatin N-methylbenzylamine salt of the present invention is a novel amine salt, which has not been mentioned in the prior art, which can surprisingly remove most of the isomeric impurities such as diastereomers and enantiomers.
In addition, in the prior art in which the improvement of the optical purity is mentioned, the expensive optical isomer amine which is difficult to use commercially is used, whereas the N-methylbenzylamine used in the present invention is commercially available as a non-optical amine, and the price is very low.
In addition, the rosuvastatin N-methylbenzylamine salt can be economically and industrially mass-produced because the manufacturing process is convenient and can be obtained with high yield, and the prepared rosuvastatin N-methylbenzylamine salt is stable without being absorbed or decomposed. There is an advantage of easy storage.
Figure 1 shows the X-ray powder diffraction spectrum of the rosuvastatin N-methylbenzylamine salt prepared from Example 1.
The rosuvastatin N-methylbenzylamine salt of the present invention comprises a crystalline form characterized by a peak at a diffraction angle of at least 13.63, 14.32, 18.50, 19.52 and 20.05 ± 0.2 ° in X-ray powder diffraction analysis.
X-ray powder diffraction (referred to herein as XRD) spectra were obtained using a measuring instrument PANanlytical, X'pert-Pro X-ray Diffractometer (XRD). Radiation used CuK α (40 kv, 30 mA). At room temperature (25 ° C.), 2Θ was 2 to 50 degrees, step size was 0.0200 degrees, and data were collected with a step count time of 0.5000 seconds. Samples were prepared in a thin layer of solvent-free powder material on a glass specimen container.
High purity new rosuvastatin N-methylbenzylamine salt and high purity amorphous rosuvastatin calcium salt are prepared as in Scheme 1 below.
Reaction 1.
(1) reacting rosuvastatin (Formula III) with N-methylbenzylamine in an organic solvent to obtain a high purity rosuvastatin N-methylbenzylamine salt.
(2) C 1 -C 3 alcohol in dissolved rosuvastatin N- methyl-benzyl amine salt (Formula I) with a solvent, and then stirring was added an aqueous sodium hydroxide solution here, C 1 -C 3 alcohol to remove the solvent under reduced pressure And adding water to the residue, washing with an organic solvent, and then adding a calcium source to the aqueous solution to prepare rosuvastatin calcium salt (Formula II).
As the organic solvent used in the step (1) may be used acetonitrile, methylene chloride, acetone, or a mixed solvent thereof. Also optionally, the obtained rosuvastatin N-methylbenzylamine salt can be recrystallized with the solvent, in which case a higher purity rosuvastatin N-methylbenzylamine salt can be produced.
The alcohols that dissolve rosuvastatin N-methylbenzylamiline salt in step (2) are methanol, ethanol and isopropanol, preferably methanol.
The organic solvent for washing the aqueous solution in step (2) may be ethyl acetate, isopropyl acetate, methyl acetate and toluene, preferably ethyl acetate.
In step (3), calcium chloride and calcium acetate can be used as the calcium source, and preferably calcium chloride.
According to step (1), the new rosuvastatin N-methylbenzylamine salt has a chemical purity of at least 99.8% (diastereomer 0.06% or less), an optical purity of 99.8% or more (enantiomer) 0.005% or less ) Can also be prepared in high purity of the amorphous rosuvastatin calcium salt according to step (2) above 99.8% of chemical purity (0.07% or less of diastereomer), 99.8% or more of optical purity (enantiomer) (enantiomer) 0.005% or less).
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
Example
Example 1 Preparation of Rosuvastatin N-Methylbenzylamine Salt
35 g of (E) -7- [4- (4-fluorophenyl) -2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-dihydrate Roxyhept-6-enoic acid was dissolved in 140 mL of methylene chloride, followed by addition of 9.4 mL of N-methylbenzylamine. The reaction mixture was stirred at reflux for 1 hour, and the reaction mixture was cooled to room temperature and then stirred overnight. Subsequently, the mixture was cooled at 0 ° C. for 1 hour, filtered, and dried at 40 ° C. for 4 hours to obtain 40.7 g of rosuvastatin N-methylbenzylamine salt. The resulting rosuvastatin N-methylbenzylamine salt was stirred at reflux with 206 mL of methylene chloride for 1 hour, then cooled to room temperature and stirred at room temperature overnight. Next day, the mixture was cooled at 0 ° C. for 1 hour, filtered, and dried at 40 ° C. for 4 hours to obtain 38.3 g of high purity rosuvastatin N-methylbenzylamine salt.
1 H NMR (400 MHz, CD 3 OD) δ ppm: 1.27 (d, 6H) 1.6 (m, 2H) 2.27 (m, 2H) 2.65 (S, 3H) 3.51 (m, 7H) 3.95 (m, 1H) 4.11 ( s, 2H) 4.35 (m, 1H) 5.56 (dd, 1H) 6.61 (d, 1H) 7.16 (m, 2H) 7.42 (m, 5H) 7.72 (m, 2H)
99.8% chemical purity (0.06% or less diastereomer)
99.8% optical purity (0.005% or less enantiomer)
Example 2 Preparation of Rosuvastatin N-Methylbenzylamine Salt
18.27 g of (E) -7- [4- (4-fluorophenyl) -2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S) -3,5-di Hydroxyhept-6-enoic acid was dissolved in 54.9 ml of acetonitrile, 18.3 mL of methylene chloride and 18.3 mL of acetone, followed by addition of 5.88 mL of N-methylbenzylamine. The reaction mixture was stirred at reflux for 1 hour, and the reaction mixture was cooled to room temperature and then stirred overnight. Subsequently, the mixture was cooled at 0 ° C. for 1 hour, filtered, and dried at 40 ° C. for 4 hours to obtain 21.8 g of rosuvastatin N-methylbenzylamine salt. The resulting rosuvastatin N-methylbenzylamine salt was stirred under reflux with 43 mL of methylene chloride, 64.5 mL of acetonitrile, and 43 mL of acetone mixed solvent for 1 hour, then cooled to room temperature and stirred at room temperature overnight. Next day, the mixture was cooled at 0 ° C. for 1 hour, filtered, and dried at 40 ° C. for 4 hours to obtain 20.5 g of high purity rosuvastatin N-methylbenzylamine salt.
99.8% chemical purity (0.07% or less diastereomer)
99.8% optical purity (0.005% or less enantiomer)
Example 3 Preparation of Amorphous (Amorphous) Rosuvastatin Calcium Salt
10.7 g of rosuvastatin N-methylbenzylamine salt was dissolved in 75 mL of methyl alcohol and 21 mL of 1.0 M sodium hydroxide solution was added for 20 minutes under 0 ° C. conditions. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was distilled off under reduced pressure to remove methyl alcohol. 107 mL of water is added to the residue, stirred until complete dissolution, and the aqueous solution is washed three times with 86 mL of ethyl acetate. The aqueous solution was distilled off under reduced pressure, concentrated to about 54 mL, and 21 mL of 1.0 M aqueous calcium chloride solution was added dropwise at room temperature for 20 minutes. The reaction was stirred for 2 hours, filtered and dried under reduced pressure at 40 ° C. to obtain 8.0 g of high purity amorphous rosuvastatin calcium salt.
99.8% chemical purity (0.07% or less diastereomer)
99.8% optical purity (0.005% or less enantiomer)
Claims (5)
Formula I
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