WO2010035284A2 - An improved process for the preparation of rosuvastatin calcium - Google Patents

An improved process for the preparation of rosuvastatin calcium Download PDF

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Publication number
WO2010035284A2
WO2010035284A2 PCT/IN2009/000527 IN2009000527W WO2010035284A2 WO 2010035284 A2 WO2010035284 A2 WO 2010035284A2 IN 2009000527 W IN2009000527 W IN 2009000527W WO 2010035284 A2 WO2010035284 A2 WO 2010035284A2
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Prior art keywords
rosuvastatin
amine
crystalline form
salt
calcium
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PCT/IN2009/000527
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French (fr)
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WO2010035284A3 (en
Inventor
Madhuresh Kumar Sethi
Sanjay Mahajan
Bhairaiah Mara
Laxmi Karthikeyan Ayyaran
Debashish Datta
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Matrix Laboratories Ltd
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Publication of WO2010035284A3 publication Critical patent/WO2010035284A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the present invention relates to an improved process for the preparation of Rosuvastatin calcium.
  • Rosuvastatin calcium is well known as CRESTOR. It is a lipid lowering agent. It appears as white amorphous powder that is sparingly soluble in water and methanol and slightly soluble in ethanol.
  • the chemical name of rosuvastatin calcium is bis[(E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)ammo]pyrimidin-5-yl](3R,5S)-3 ! ,5- dihydroxyhept-6-enoic acid]calcium salt with the following structural formula:
  • US patent No. USRE 37,314 discloses pharmaceutically acceptable salt of Rosuvastatin and process for the preparation of Rosuvastatin Calcium by dissolving the corresponding sodium salt in water, adding calcium chloride and collecting the resultant precipitate by filtration.
  • US 6,841,554 discloses the preparation of amine salts of rosuvastatin and further conversion to rosuvastatin calcium.
  • This patent specifically claims the ammonium, methylammonium, ethylammonium, diethanolammonium, tris(hydroxymethyl)methyl- ammonium, benzylammonium, 4-methoxybenzylammoniurn, lithium and magnesium salt of rosuvastatin.
  • US 20050131066 discloses the isopropylammonium and cyclohexylammonium salt of rosuvastatin and further conversion to rosuvastatin calcium.
  • WO 2005077916 discloses the diisopropylammonium, dicyclohexylammonium and (S) (+)-D-methylbenzylammonium salt of rosuvastatin and further conversion to rosuvastatin calcium.
  • WO 2008097440 discloses the dehydroabietylarnine salt of rosuvastatin and further conversion to rosuvastatin calcium.
  • ammonium salts of rosuvastatin are not likely to be used for administration to a patient, they provide a method for purifying rosuvastatin through crystallization. There is need in the art to provide a method. of preparing the pure rosuvastatin calcium by controlling the isomeric impurity at minimal level.
  • the main object of the present invention is to provide an improved process for the preparation of amorphous rosuvastatin calcium.
  • Yet another object of the present invention is to provide the novel amine salts of rosuvastatin wherein amine is selected from (S)-2-amino-3, 3 -dimethyl butane and (S)-(-)- ⁇ -methyl benzyl amine.
  • Yet another object of the present invention is to provide crystalline (S)-2-amino-3,3- dimethyl butane salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure- 1 with peaks at 11.42, 12.67, 15.28, 17.19, 17.71, 18,27, 19.38, 21.12, 23.13, 24.02 and 26.00 degrees ⁇ 0.2 2 ⁇ values.
  • Yet another object of the present invention is to provide crystalline (S)-(-)- ⁇ -methyl benzyl amine salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure-3 with peaks at 5.98, 11.57, 12.02, 15.28, 16.40, 18.08, 19.02, 20.22, 22.15, 22.85, 24.19, 25.59 and 26.73 degrees ⁇ 0.2 20 values.
  • the main aspect of the present invention is to provide an improved process for the preparation of amorphous rosuvastatin calcium, wherein the amorphous calcium salt is prepared from the novel amine salts of rosuvastatin.
  • Another object of the present invention is to provide process for the preparation of novel amine salts of rosuvastatin from ester of rosuvastatin.
  • Fig. 1 is an X-ray powder diffraction (XRD) pattern of 2-Amino-3, 3 -dimethyl butane salt of Rosuvastatin.
  • Fig. 2 is the Thermo Gravimetric Analysis (TGA) thermogram of 2- Amino-3, 3 -dimethyl butane salt of Rosuvastatin.
  • Fig. 3 is an X-ray powder diffraction (XRD) pattern of (S)-(-)- ⁇ -methyl benzyl amine salt of Rosuvastatin.
  • the present invention relates to an improved process for preparation of rosuvastatin calcium from novel Rosuvastatin amine salts.
  • the present invention also provides a process for the preparation of Rosuvastatin amine salts.
  • amine salts wherein the amine salt is (S)-2 -Amino-3 ,3 -dimethyl butane or (S)-(-)- ⁇ -methyl benzyl amine.
  • the present invention provides a crystalline amine salt of Rosuvastatin.
  • the present invention provides a crystalline 2-amino-3,3- dimethyl butane salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure-1 with peaks at 11.42, 12.67, 15.28, 17.19, 17.71, 18,27, 19.38, 21.12, 23.13, 24.02 and 26.00 degrees ⁇ 0.2 2 ⁇ values.
  • the present invention provides a crystalline 2-amino- 3,3-dimethyl butane salt of rosuvastatin further characterized by TGA as depicted in figure- 2.
  • the present invention provides crystalline (S)-(-)- ⁇ - methyl benzyl amine salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure-3 with peaks at 5.98, 11.57, 12.02, 15.28, 16.40, 18.08, 19.02, 20.22, 22.15, 22.85, 24.19, 25.59 and 26.73 degrees ⁇ 0.2 20 values.
  • Another aspect of the present invention provides a process for preparing organic amine salt of rosuvastatin comprising the steps of: a) reducing methyl-7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methyl- sulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate with reducing agent, b) hydrolyzing rosuvastatin ester into rosuvastatin, c) reacting rosuvastatin with organic amine to get organic amine salt of rosuvastatin, and d) optionally purifying the organic amine salt of rosuvastatin in presence of alcohol.
  • reducing agent in reduction of Methyl-7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-rnethylsulfonyl amino)-pyrimidin-5-yl]-(3R)-3-hydiOxy-5-oxo-(E)-6-heptenate is selected from alkali metal hydrides or alkali borohydrides preferably sodium borohydride.
  • Methyl-7-[4- (4-fiourophenyl)-6-isopiOpyl-2-(N-methyl-N-methyls ⁇ lfonylamino)-pyrimidin-5-yl]-(3R) -3-hydroxy-5-oxo-(E)-6-heptenate is carried out in presence of diethylmethoxyborane in ether solvent preferably tetrahydrofuran.
  • hydrolysis of rosuvastatin ester is carried out in presence of mineral acid or base, wherein mineral acid is selected from hydrochloric acid, hydrofluoric acid or sulfuric acid preferably hydrochloric acid and base is selected from sodium hydroxide or potassium hydroxide preferably sodium hydroxide.
  • hydrolysis of rosuvastatin ester is carried out in presence of solvent selected from methanol, ethanol and butanol preferably ethanol.
  • organic amine used in the preparation of organic amine salt of rosuvastatin is (S)-2-Amino-3,3-dimethyl butane or (S)-(-)- ⁇ -methylbenzylamine.
  • the solvents used in the preparation of rosuvastatin organic amine salt from rosuvastatin is selected from acetonitrile, methyl ether, ethyl ether and diisopropyl ether preferably acetonitrile and diisopropyl ether.
  • purification of rosuvastatin organic amine salt is carried out in solvent selected from methanol, ethanol and isopropanol or their mixtures thereof, preferably methanol and isopropanol.
  • reduction, hydrolysis and organic amine salt formation are carried out as a one pot synthesis.
  • the present invention provides further conversion of organic amine salt of rosuvastatin to rosuvastatin calcium comprising the steps of: a) treating rosuvastatin organic amine salt with mineral acid, b) reacting with alkali metal / alkaline earth metal hydroxide to get alkali metal / alkaline earth metal salt of rosuvastatin, and c) treating alkali metal / alkaline earth metal salt of rosuvastatin with calcium source to get rosuvastatin calcium.
  • mineral acid which is treated with rosuvastatin organic amine salt is selected from hydrochloric acid, hydrofluoric acid or sulfuric acid preferably hydrochloric acid.
  • preparation of rosuvastatin alkali metal / alkaline earth metal salt from rosuvastatin is carried out in presence of alkali metal / alkaline earth metal hydroxide is selected from sodium hydroxide, potassium hydroxide or magnesium hydroxide preferably sodium hydroxide.
  • preparation of rosuvastatin calcium in presence of calcium source is selected from calcium chloride or calcium acetate preferably calcium acetate.
  • preparation of rosuvastatin calcium is carried out in presence of solvent selected from water, methanol and ethanol and their mixtures thereof preferably water.
  • keto compound of formula I is reduced with reducing agent such as sodium borohydride in an aprotic solvent like tetrahydrofuran at -100 to -7O 0 C.
  • reducing agent such as sodium borohydride in an aprotic solvent like tetrahydrofuran at -100 to -7O 0 C.
  • the obtained reaction mass is hydrolyzed in a base such as sodium hydroxide in presence of alcohol preferably ethanol.
  • the obtained product is reacted with organic amine selected from (S)-2-amino-3 ,3 -dimethyl-butane or (S)-(-)- ⁇ -methyl benzyl amine in aprotic solvent such as acetonitrile at a temperature selected from 20-40°C.
  • the obtained amine salt of compound of formula (III) (wherein R 1 , R 2 represents hydrogen and R 3 is 3,3-dimethyl butyl or methyl benzyl group) is purified using alcohol solvents such as isopropanol, methanol or their mixtures thereof.
  • rosuvastatin as per the prior art procedure involves the formation of isomeric impurity, according to our present invention, formation of isomeric impurities are controlled.
  • rosuvastatin calcium is prepared with high yield and high purity without the need for tedious, complicated purification steps.
  • the said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l e and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.
  • Tetrahydrofuran THF
  • 1Og sodium borohydride was added followed by 230ml diethylmethoxyborane (1 M solution in THF) in 90-120mins.
  • reaction mass was concentrated up to thick residue at 40-45°C.
  • 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 3.5- 4.0 with 1:4 aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.
  • the compound of example 1 was suspended in 1000 ml ethyl acetate followed by 500 ml DM water and then cooled to 5°C and pH was adjusted to 3.0 to 4.0 by using aqueous hydrochloric acid. The reaction mass was stirred for 15 min at 5-10°C. Both the layers were separated and the organic layer was washed with brine solution. The organic layer was dried over sodium sulphate and concentrated at 25 -35 0 C under vacuum. To the above concentrated mass, 1000 ml methyl tert-butyl ether was added & stirred for 20-30 min and then 1000 ml DM water was added and the reaction mass was cooled to 15 0 C.
  • the pH was adjusted to 9.0-11.5 by using ⁇ 87 ml 4 % sodium hydroxide solution and then stirred for 30 min at 15-2O 0 C. Both the layers were separated and the aqueous layer was washed with methyl tert-butyl ether.10 gm activated carbon was added in aqueous layer, stirred for 20 min at 25-30 0 C.
  • the solid was filtered through celite bed and washed with DM water.
  • the filtrate was filtered through 0.45 micron filter paper.
  • the filtrate was cooled to 20 0 C and then filtered calcium acetate solution (16.2 g calcium acetate in 500 ml DM water and filter through 0.45 micron filter paper) was slowly added at 20-25 0 C.
  • the reaction mass was stirred for 2 hrs and then solid was filtered and washed with DM water.
  • the solid was dried for 20-30 hrs at 40-45 0 C under vacuum to yield 95 gms of rosuvastatin calcium
  • Tetrahydrofuran THF
  • 1Og sodium borohydride was added followed by 46 gm of diethylmethoxyborane ( ⁇ 50 % solution in THF) in 90-120mins.
  • reaction mass was diluted with 1500ml ethyl acetate and washed with brine solution.
  • 500 ml DM water was added and pH was adjusted to 7-8 by adding ⁇ 1000 ml of sodium bicarbonate solution. Both the layers were separated & the organic layer was dried over sodium sulphate.
  • the organic layer was concentrated at 40-45°C and diluted with 900ml ethyl alcohol followed by cooling to 0°C.
  • Sodium hydroxide solution was added in 60-90 min. The reaction mass was stirred for 30 min at room temperature and the pH was adjusted 12-13 by using sodium hydroxide solution, hi this reaction mass, 1Og activated carbon was added and stirred for 20 min.
  • reaction mass was filtered and washed with ethanol/DM water mixture.
  • the reaction mass was concentrated up to thick residue at 40-45°C.
  • 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 2-4 with aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.
  • the compound of example 3 was suspended in 1000 ml ethyl acetate followed by 500 ml DM water and then cooled to 5°C and pH was adjusted by using aqueous hydrochloric acid. The reaction mass was stirred for 15 min at 5-10°C. Both the layers were separated and the organic layer was washed with brine solution. The organic layer was dried over sodium sulphate and concentrated at 25-35 0 C under vacuum. To the above concentrated mass, 1000 ml tert-butyl methyl ether was added & stirred for 20-30 min and then 1000 ml DM water was added and the reaction mass was cooled to 15°C.
  • the pH was adjusted by using ⁇ 170 ml of sodium hydroxide solution and then stirred for 20 min at 15-20°C. Both the layers were separated and the aqueous layer was washed with methyl tert-butyl ether.10 gm activated carbon was added in aqueous layer, stirred for 20 min at 25-30°C. The solid was filtered through celite bed and washed with DM water. The filtrate was filtered through 0.45 micron filter paper. The filtrate was cooled to 20°C and then filtered calcium acetate solution (16.2 g calcium acetate in 500 ml DM water and filter through 0.45 micron filter paper) was slowly added at 20-25°C.
  • reaction mass was stirred for 2 hrs and then solid was filtered and washed with DM water.
  • the solid was dried for 20- 30 hrs at 40-45°C under vacuum to yield rosuvastatin calcium with chemical purity 99.5 % and chiral purity 99.7 % (other isomer less than 0.15%).

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Abstract

The present invention provides an improved process for the preparation of amorphous Rosuvastatin Calcium through novel amine salts of Rosuvastatin.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF ROSUVASTATIN
CALCIUM
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Rosuvastatin calcium.
BACKGROUND OF THE INVENTION
Rosuvastatin calcium is well known as CRESTOR. It is a lipid lowering agent. It appears as white amorphous powder that is sparingly soluble in water and methanol and slightly soluble in ethanol. The chemical name of rosuvastatin calcium is bis[(E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)ammo]pyrimidin-5-yl](3R,5S)-3!,5- dihydroxyhept-6-enoic acid]calcium salt with the following structural formula:
Figure imgf000002_0001
US patent No. USRE 37,314 discloses pharmaceutically acceptable salt of Rosuvastatin and process for the preparation of Rosuvastatin Calcium by dissolving the corresponding sodium salt in water, adding calcium chloride and collecting the resultant precipitate by filtration.
US 6,841,554 discloses the preparation of amine salts of rosuvastatin and further conversion to rosuvastatin calcium. This patent specifically claims the ammonium, methylammonium, ethylammonium, diethanolammonium, tris(hydroxymethyl)methyl- ammonium, benzylammonium, 4-methoxybenzylammoniurn, lithium and magnesium salt of rosuvastatin. US 20050131066 discloses the isopropylammonium and cyclohexylammonium salt of rosuvastatin and further conversion to rosuvastatin calcium.
WO 2005077916 discloses the diisopropylammonium, dicyclohexylammonium and (S) (+)-D-methylbenzylammonium salt of rosuvastatin and further conversion to rosuvastatin calcium.
WO 2008097440 discloses the dehydroabietylarnine salt of rosuvastatin and further conversion to rosuvastatin calcium.
Though ammonium salts of rosuvastatin are not likely to be used for administration to a patient, they provide a method for purifying rosuvastatin through crystallization. There is need in the art to provide a method. of preparing the pure rosuvastatin calcium by controlling the isomeric impurity at minimal level.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of amorphous rosuvastatin calcium.
Yet another object of the present invention is to provide the novel amine salts of rosuvastatin wherein amine is selected from (S)-2-amino-3, 3 -dimethyl butane and (S)-(-)- α-methyl benzyl amine.
Yet another object of the present invention is to provide crystalline (S)-2-amino-3,3- dimethyl butane salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure- 1 with peaks at 11.42, 12.67, 15.28, 17.19, 17.71, 18,27, 19.38, 21.12, 23.13, 24.02 and 26.00 degrees ± 0.2 2Θ values.
Yet another object of the present invention is to provide crystalline (S)-(-)-α-methyl benzyl amine salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure-3 with peaks at 5.98, 11.57, 12.02, 15.28, 16.40, 18.08, 19.02, 20.22, 22.15, 22.85, 24.19, 25.59 and 26.73 degrees ± 0.2 20 values. SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of amorphous rosuvastatin calcium, wherein the amorphous calcium salt is prepared from the novel amine salts of rosuvastatin.
Another object of the present invention is to provide process for the preparation of novel amine salts of rosuvastatin from ester of rosuvastatin.
BRIEF DESCRIPTION OF THE DRAWINGS
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :
Fig. 1 is an X-ray powder diffraction (XRD) pattern of 2-Amino-3, 3 -dimethyl butane salt of Rosuvastatin.
Fig. 2 is the Thermo Gravimetric Analysis (TGA) thermogram of 2- Amino-3, 3 -dimethyl butane salt of Rosuvastatin.
Fig. 3 is an X-ray powder diffraction (XRD) pattern of (S)-(-)-α-methyl benzyl amine salt of Rosuvastatin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparation of rosuvastatin calcium from novel Rosuvastatin amine salts. The present invention also provides a process for the preparation of Rosuvastatin amine salts.
In one aspect of the present invention provides novel Rosuvastatin amine salts, wherein the amine salt is (S)-2 -Amino-3 ,3 -dimethyl butane or (S)-(-)-α-methyl benzyl amine.
In one embodiment, the present invention provides a crystalline amine salt of Rosuvastatin. In another embodiment, the present invention provides a crystalline 2-amino-3,3- dimethyl butane salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure-1 with peaks at 11.42, 12.67, 15.28, 17.19, 17.71, 18,27, 19.38, 21.12, 23.13, 24.02 and 26.00 degrees ± 0.2 2Θ values.
In one more embodiment, the present invention provides a crystalline 2-amino- 3,3-dimethyl butane salt of rosuvastatin further characterized by TGA as depicted in figure- 2.
In another embodiment, the present invention provides crystalline (S)-(-)-α- methyl benzyl amine salt of rosuvastatin characterized by powder X-ray diffraction pattern as shown in Figure-3 with peaks at 5.98, 11.57, 12.02, 15.28, 16.40, 18.08, 19.02, 20.22, 22.15, 22.85, 24.19, 25.59 and 26.73 degrees ± 0.2 20 values.
Another aspect of the present invention provides a process for preparing organic amine salt of rosuvastatin comprising the steps of: a) reducing methyl-7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methyl- sulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate with reducing agent, b) hydrolyzing rosuvastatin ester into rosuvastatin, c) reacting rosuvastatin with organic amine to get organic amine salt of rosuvastatin, and d) optionally purifying the organic amine salt of rosuvastatin in presence of alcohol.
According to one embodiment of the present invention, reducing agent in reduction of Methyl-7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-rnethylsulfonyl amino)-pyrimidin-5-yl]-(3R)-3-hydiOxy-5-oxo-(E)-6-heptenate is selected from alkali metal hydrides or alkali borohydrides preferably sodium borohydride.
According to one embodiment of the present invention, reduction of Methyl-7-[4- (4-fiourophenyl)-6-isopiOpyl-2-(N-methyl-N-methylsιιlfonylamino)-pyrimidin-5-yl]-(3R) -3-hydroxy-5-oxo-(E)-6-heptenate is carried out in presence of diethylmethoxyborane in ether solvent preferably tetrahydrofuran.
According to one more embodiment of the present invention, hydrolysis of rosuvastatin ester is carried out in presence of mineral acid or base, wherein mineral acid is selected from hydrochloric acid, hydrofluoric acid or sulfuric acid preferably hydrochloric acid and base is selected from sodium hydroxide or potassium hydroxide preferably sodium hydroxide.
According to one more embodiment of the present invention, hydrolysis of rosuvastatin ester is carried out in presence of solvent selected from methanol, ethanol and butanol preferably ethanol.
According to one more embodiment of the present invention, organic amine used in the preparation of organic amine salt of rosuvastatin is (S)-2-Amino-3,3-dimethyl butane or (S)-(-)-α-methylbenzylamine.
According to one more embodiment of the present invention, the solvents used in the preparation of rosuvastatin organic amine salt from rosuvastatin is selected from acetonitrile, methyl ether, ethyl ether and diisopropyl ether preferably acetonitrile and diisopropyl ether.
According to another embodiment of the present invention, purification of rosuvastatin organic amine salt is carried out in solvent selected from methanol, ethanol and isopropanol or their mixtures thereof, preferably methanol and isopropanol.
According to another embodiment of the present invention, reduction, hydrolysis and organic amine salt formation are carried out as a one pot synthesis.
In another aspect, the present invention provides further conversion of organic amine salt of rosuvastatin to rosuvastatin calcium comprising the steps of: a) treating rosuvastatin organic amine salt with mineral acid, b) reacting with alkali metal / alkaline earth metal hydroxide to get alkali metal / alkaline earth metal salt of rosuvastatin, and c) treating alkali metal / alkaline earth metal salt of rosuvastatin with calcium source to get rosuvastatin calcium.
According to one embodiment of the present invention, mineral acid which is treated with rosuvastatin organic amine salt, is selected from hydrochloric acid, hydrofluoric acid or sulfuric acid preferably hydrochloric acid.
According to another embodiment of the present invention, preparation of rosuvastatin alkali metal / alkaline earth metal salt from rosuvastatin is carried out in presence of alkali metal / alkaline earth metal hydroxide is selected from sodium hydroxide, potassium hydroxide or magnesium hydroxide preferably sodium hydroxide.
According to another embodiment of the present invention, preparation of rosuvastatin calcium in presence of calcium source is selected from calcium chloride or calcium acetate preferably calcium acetate.
According to another embodiment of the present invention, preparation of rosuvastatin calcium is carried out in presence of solvent selected from water, methanol and ethanol and their mixtures thereof preferably water.
The synthetic scheme of Rosuvastatin calcium is depicted in the following synthetic scheme.
Figure imgf000008_0001
IV III
As per the present invention, keto compound of formula I is reduced with reducing agent such as sodium borohydride in an aprotic solvent like tetrahydrofuran at -100 to -7O0C. The obtained reaction mass is hydrolyzed in a base such as sodium hydroxide in presence of alcohol preferably ethanol. The obtained product is reacted with organic amine selected from (S)-2-amino-3 ,3 -dimethyl-butane or (S)-(-)-α-methyl benzyl amine in aprotic solvent such as acetonitrile at a temperature selected from 20-40°C. The obtained amine salt of compound of formula (III) (wherein R1, R2 represents hydrogen and R3 is 3,3-dimethyl butyl or methyl benzyl group) is purified using alcohol solvents such as isopropanol, methanol or their mixtures thereof.
Compound of formula (III) wherein R1, R2 represents hydrogen and R3 is 3,3- dimethyl butyl or methyl benzyl group is treated with mineral acid preferably hydrochloric acid in presence of solvent such as ethyl acetate, which is further reacted with alkali/ alkali earth metal hydroxides preferably sodium hydroxide in presence of ether solvent such as methyl tert butyl ether and water to get alkali/alkali earth metal salt of rosuvastatin. It is further reacted with a calcium source preferably calcium acetate in presence of water to get the compound of formula (IV). Preparation of the rosuvastatin as per the prior art procedure involves the formation of isomeric impurity, according to our present invention, formation of isomeric impurities are controlled. Thus rosuvastatin calcium is prepared with high yield and high purity without the need for tedious, complicated purification steps.
Powder X-rav Diffraction (PXRD)
The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Thermo gravimetric Analysis (TGA)
TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 le and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.
The following examples are provided to illustrate specific embodiment of the present invention. They are however not intended to limiting the scope of the present invention in any way.
Example 1 Preparation of (S) 2-Amino-3,3-dimethyl butane salt of rosuvastatin
In a round bottom flask 2000 ml Tetrahydrofuran (THF) was added under the nitrogen atmosphere and cooled to -90°C then 1Og sodium borohydride was added followed by 230ml diethylmethoxyborane (1 M solution in THF) in 90-120mins. In this reaction mass, mixture of lOOg of Methyl -7-[4-(4-fiourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylaniino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate5 700 ml THF and 700 ml methanol was added for a duration of 90-120min then stirred for 2 hrs at -90 to -80°C. After the completion of reaction, 124 ml acetic acid was added and stirred for 30-60 min at same temperature. Above reaction mass was diluted with 1500ml ethyl acetate and washed with brine solution. To the organic layer, 500 ml DM water was added and pH was adjusted to neutral by ~ 500 ml 6 % sodium bicarbonate solution. Both the layers were separated Sc the organic layer was dried over sodium sulphate. The organic layer was concentrated at 40-450C. Above concentrated mass was diluted with 900ml ethyl alcohol and then cooled to 0°C. Sodium hydroxide solution was added in 60- 90 min. The reaction mass was stirred for 30 min at room temperature and the pH was adjusted to 11.5-12.0 by using ~ 4 % sodium hydroxide solution. In this reaction mass, 1Og activated carbon was added and stirred for 20 min. The reaction mass was filtered and washed with ethanol/DM water mixture. The reaction mass was concentrated up to thick residue at 40-45°C. To this concentrated mass, 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 3.5- 4.0 with 1:4 aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.
The organic layer was dried over sodium sulphate and concentrated till dryness at 40-45°C. To the above concentrated mass, 1000 ml acetonitrile was added & stirred at room temperature for half an hour. Slowly 20.5 g (S)-2-amino-3, 3 -dimethyl butane was added and stirred for almost 2 hrs. The solid was filtered and washed with acetonitrile and diisopropyl ether. Finally the solid was dried for 6-9 hrs at 40-45°C.
Above obtained (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was suspended in 1000 ml isopropanol followed by 100 ml methanol. This reaction mass was heated for half an hour at 60-80°C then stirred for 3-4 hrs at 5-1O0C. The solid was filtered & washed with isopropanol and diisopropyl ether. 95 gms of (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was obtained. Example 2 Preparation of amorphous rosuvastatin calcium
The compound of example 1 was suspended in 1000 ml ethyl acetate followed by 500 ml DM water and then cooled to 5°C and pH was adjusted to 3.0 to 4.0 by using aqueous hydrochloric acid. The reaction mass was stirred for 15 min at 5-10°C. Both the layers were separated and the organic layer was washed with brine solution. The organic layer was dried over sodium sulphate and concentrated at 25 -350C under vacuum. To the above concentrated mass, 1000 ml methyl tert-butyl ether was added & stirred for 20-30 min and then 1000 ml DM water was added and the reaction mass was cooled to 150C. The pH was adjusted to 9.0-11.5 by using ~ 87 ml 4 % sodium hydroxide solution and then stirred for 30 min at 15-2O0C. Both the layers were separated and the aqueous layer was washed with methyl tert-butyl ether.10 gm activated carbon was added in aqueous layer, stirred for 20 min at 25-300C. The solid was filtered through celite bed and washed with DM water. The filtrate was filtered through 0.45 micron filter paper. The filtrate was cooled to 200C and then filtered calcium acetate solution (16.2 g calcium acetate in 500 ml DM water and filter through 0.45 micron filter paper) was slowly added at 20-250C. The reaction mass was stirred for 2 hrs and then solid was filtered and washed with DM water. The solid was dried for 20-30 hrs at 40-450C under vacuum to yield 95 gms of rosuvastatin calcium.
Example 3 Preparation of (SV(-)-α-methyΙ benzyl amine salt of Rosuvastatin
In a round bottom flask 2000 ml Tetrahydrofuran (THF) was added under the nitrogen atmosphere and cooled to -900C then 1Og sodium borohydride was added followed by 46 gm of diethylmethoxyborane (~ 50 % solution in THF) in 90-120mins. In this reaction mass, mixture of lOOg of Methyl -7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- metliylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate, 700 ml THF and 700 ml methanol mixture was added for a duration of 90-120 min then stirred for 2-3 hrs at -90 to -800C. After the completion of reaction, 124 ml acetic acid was added and stirred for 30-60 min at same temperature. Above reaction mass was diluted with 1500ml ethyl acetate and washed with brine solution. To the organic layer, 500 ml DM water was added and pH was adjusted to 7-8 by adding ~ 1000 ml of sodium bicarbonate solution. Both the layers were separated & the organic layer was dried over sodium sulphate. The organic layer was concentrated at 40-45°C and diluted with 900ml ethyl alcohol followed by cooling to 0°C. To this Sodium hydroxide solution was added in 60-90 min. The reaction mass was stirred for 30 min at room temperature and the pH was adjusted 12-13 by using sodium hydroxide solution, hi this reaction mass, 1Og activated carbon was added and stirred for 20 min. The reaction mass was filtered and washed with ethanol/DM water mixture. The reaction mass was concentrated up to thick residue at 40-45°C. To this concentrated mass, 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 2-4 with aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.
The organic layer was dried over sodium sulphate and concentrated till dryness at 35-40°C. To the above concentrated mass, 900 ml acetonitrile was added & stirred at same temperature for half an hour. To this (S)-(-)-α-methyl benzyl amine solution which was prepared by dissolving 24.6 gm of (S)-(-)-α-methyl benzyl amine in 100 ml acetonitrile was added and stirred for almost 2 hrs. The solid was filtered and washed with acetonitrile and diisopropyl ether and dried for 6-9 hrs at 40-45°C.
Above obtained (S)-(-)-α-methyl benzyl amine salt of rosuvastatin was suspended in 1000 ml isopropanol followed by 100 ml methanol. This reaction mass was heated for half an hour at 75-8O0C then stirred for 2-3 hrs at 8-12°C. The solid was filtered & washed with isopropanol and diisopropyl ether to yield pure (S)-(-)-α-methyl benzyl amine salt of rosuvastatin (95 g) with chemical purity 99.5 % and chiral purity 99.7 % (other isomer less than 0.15%).
Example-4 Preparation of amorphous rosuvastatin calcium
The compound of example 3 was suspended in 1000 ml ethyl acetate followed by 500 ml DM water and then cooled to 5°C and pH was adjusted by using aqueous hydrochloric acid. The reaction mass was stirred for 15 min at 5-10°C. Both the layers were separated and the organic layer was washed with brine solution. The organic layer was dried over sodium sulphate and concentrated at 25-350C under vacuum. To the above concentrated mass, 1000 ml tert-butyl methyl ether was added & stirred for 20-30 min and then 1000 ml DM water was added and the reaction mass was cooled to 15°C. The pH was adjusted by using ~ 170 ml of sodium hydroxide solution and then stirred for 20 min at 15-20°C. Both the layers were separated and the aqueous layer was washed with methyl tert-butyl ether.10 gm activated carbon was added in aqueous layer, stirred for 20 min at 25-30°C. The solid was filtered through celite bed and washed with DM water. The filtrate was filtered through 0.45 micron filter paper. The filtrate was cooled to 20°C and then filtered calcium acetate solution (16.2 g calcium acetate in 500 ml DM water and filter through 0.45 micron filter paper) was slowly added at 20-25°C. The reaction mass was stirred for 2 hrs and then solid was filtered and washed with DM water. The solid was dried for 20- 30 hrs at 40-45°C under vacuum to yield rosuvastatin calcium with chemical purity 99.5 % and chiral purity 99.7 % (other isomer less than 0.15%).

Claims

We Claim:
1. An amine salt of Rosuvastatin, wherein the amine is (S)-2-Amino-3 ,3 -dimethyl butane or (S)-(-)-α-methyl benzyl.amine.
2. A crystalline Form of Rosuvastatin (S)-2-Amino-3, 3 -dimethyl butane.
3. The crystalline Form according to claim 2, wherein the crystalline Form has an X- ray powder diffraction pattern with peaks at 11.42, 12.67, 15.28, 17.19, 17.71, 18,27, 19.38, 21.12, 23.13, 24.02 and 26.00 ± 0.2 deg. 2Θ.
4. The crystalline Form according to claim 2, wherein the crystalline Form has an X- ray powder diffraction pattern substantially as depicted in Figure 1.
5. A crystalline Form of Rosuvastatin (S)-(-)-α-methylbenzylamine.
6. The crystalline Form according to claim 5, wherein the crystalline Form has an X- ray powder diffraction pattern with peaks at 5.98, 11.57, 12.02, 15.28, 16.40, 18.08, 19.02, 20.22, 22.15, 22.85, 24.19, 25.59 and 26.73 degrees ± 0.2 2Θ values.
7. The crystalline Form according to claim 5, wherein the crystalline Form has an X- ray powder diffraction pattern substantially as depicted in Figure 3.
8. A process for the preparation of Rosuvastatin amine salt of claim 1 comprising the steps of: a) reducing methyl-7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methyl-sulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6- heptenate with reducing agent, b) hydrolyzing rosuvastatin ester into rosuvastatin, c) reacting rosuvastatin with organic amine to get organic amine salt of rosuvastatin, and d) optionally purifying the organic amine salt of rosuvastatin in presence of alcohol.
9. A process for the preparation of Rosuvastatin Calcium from the amine salt of Rosuvastatin wherein amine is selected from (S)-2-Amino-3, 3 -dimethyl butane or (S)-(-)-α-methyl benzyl amine, comprising the steps of: a) treating rosuvastatin organic amine salt with mineral acid, b) reacting with alkali metal / alkaline earth metal hydroxide to get alkali metal / alkaline earth metal salt of rosuvastatin, and c) treating alkali metal / alkaline earth metal salt of rosuvastatin with calcium source to get rosuvastatin calcium.
10. A process for the preparation of Rosuvastatin Calcium from the amine salt of Rosuvastatin wherein amine is selected from (S)-2-Amino-3,3-dimethyl butane or (S)-(-)-α-methyl benzyl amine having (3S,5R)-isomer & (3R,5R)-isomer less than 0.15%
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KR101304640B1 (en) 2010-09-02 2013-09-05 일동제약주식회사 Novel n-methylbenzylamine salt of rosuvastatin and process for the preparation thereof
WO2012063115A2 (en) 2010-11-11 2012-05-18 Jubilant Life Sciences Ltd. Process for the preparation of rosuvastatin calcium via novel amine intermediate
WO2012063115A3 (en) * 2010-11-11 2012-10-26 Jubilant Life Sciences Ltd. Process for the preparation of rosuvastatin calcium via novel amine intermediate
CN102358747A (en) * 2011-08-30 2012-02-22 浙江宏元药业有限公司 Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium
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CN108586358A (en) * 2018-07-06 2018-09-28 苏州中联化学制药有限公司 The preparation process of Rosuvastatin calcium preparation

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