WO2008038132A1

WO2008038132A1 - Crystalline diamine salts of rosuvastatin

Info

Publication number: WO2008038132A1
Application number: PCT/IB2007/002880
Authority: WO
Inventors: Ramesh Dandala; Sambhu Prasad Sarma Mallela; Sukumar Nandi; Gangadhar Bhima Shankar Nangi; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2006-09-28
Filing date: 2007-09-24
Publication date: 2008-04-03

Abstract

The present invention relates to crystalline rosuvastatin amine salts represented by Formula (I) wherein R1, R2, R3, R4 independently represent hydrogen, straight or branched chain C1-15 alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocycloalkyl, a heterocyclic residue containing one or more hetero atoms.

Description

CRYSTALLINE DIAMINE SALTS OF ROSUVASTATIN

FIELD OF THE INVENTION

The present invention relates to salts of HMG CoA reductase inhibitors and in particular, crystalline rosuvastatin amine salts represented by Formula I

Formula I

wherein Ri, R₂, R₃, R₄ independently represent hydrogen, straight or branched chain Ci_-I5 alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocycloalkyl, a heterocyclic residue containing one or more hetero atoms.

The present invention also relates to conversion of salt of Formula I to Rosuvastatin calcium of Formula II

Formula II

BACKGROUND OF THE INVENTION

Rosuvastatin is chemically known as (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-(l- methylethyl)-2-[methyl(methylsulfonyl)amino-5-pyrimidinyl]-3,5-dihydroxy-6- heptenoic acid, is a synthetic lipid-lowering agent, which is an inhibitor of 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

US RE 37,314 discloses an amorphous form of the calcium salt of rosuvastatin and the sodium salt is obtained therein as powdery crystals. The calcium salt of rosuvastatin is presently available in the market as CRESTOR. Further, this patent describes the preparation of calcium salt of rosuvastatin by dissolving the corresponding sodium salt in water and adding calcium chloride and collecting the resultant precipitate by filtration.

WO 01/60804 describes the preparation of crystalline rosuvastatin salts, namely, ammonium, methylammonium, ethylammonium, diethanolammonium, tri(hydroxyrnethyl)-methylammonium, benzylammonium, 4- methoxybenzylammonium, lithium and magnesium salts . respectively. This patent publication also describes a process for the preparation of all these salts.

WO 2005/077916 Al discloses various amine salts of rosuvastatin comprising cyclohexyl ammonium salt, diisopropyl ammonium salt, isopropyl ammonium salt, dicyclohexyl ammonium salt and (S) (+)-methylbenzyl ammonium salts.

US 6,838,566 also describes novel salts of HMG-CoA reductase inhibitors with organic amines which include (±)-l,2-dimethylpropylamine, 3-(2-aminoethylamino)- propylamine, n-butylamine, secondary butylamine, tertiary butylamine (TBA), dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine (DCHA), N-methylcyclohexylamine, N₅N'- diisopropylethylenediamine (DIPEDA), N,N'-diethylenediamine, N-methyl-1,3- propanediamine, N-methylethylenediamine, N,N,N',N'-tetramethyl-l,2- diaminoethane, N,N,N',N'-tetramethyl- 1 ,4-diaminobutane, N,N,N',N'-tetramethyl- 1 ,6- diaminohexane, 1,2-dipiperidinethane, dipiperidinemethane, 2-amino-3, 3- dimethylbutane, N^-dimethylcyclohexylamine, neopentylarhine, adamantylamine, NjN-diethylcyclohexylamine, N-isopropylcyclohexylamine, N- methylcyclohexylamine, cyclobutylamine and norborylamine. However, this patent also mentions that amines having larger organic groups and especially those having bulky groups generally show a more easy crystallization and to lower extent form salts with unwanted side products when compared with amines having small organic groups.

A number of organic and inorganic salts are described in literature that are mainly used for purifying rosuvastatin. There is a need in the art for additional salts of rosuvastatin that would allow purification of rosuvastatin. The present invention describes new amine salts that are hitherto unreported and having larger organic group.

OBJECTIVE

The main objective of the present invention is to provide novel crystalline diamine salts of rosuvastatin.

Another objective of the present invention is to develop a simple, improved purification process for the preparation of pure rosuvastatin and their pharmaceutically acceptable salts through crystalline diamine salts. Yet another objective of the present invention is to isolate and recover rosuvastatin from mother liquors in pure form.

SUMMARY OF THE INVENTION

The present invention provides rosuvastatin amine salts of Formula I

Formula I

wherein R|, R₂, R₃, R₄ independently represents hydrogen, straight or branched chain Ci_i₅ alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocyclylalkyl, a heterocyclic residue containing one or more hetero atoms.

These novel amine salts of Formula I could be further in the form of solvates, hydrates, crystalline or amorphous forms thereof or a mixture of crystalline and amorphous forms.

The present invention also provides a crystalline rosuvastatin N,N'- dibenzylethylenediamine salt having an X-ray powder diffraction pattern with peaks at 5.6, 10.1, 11.3, 13.0, 14.7, 15.1, 16.0, 16.3, 17.0, 17.3, 17.8, 18.6, 19.0, 21.3, 21.9,

22.5, 23.5, 25.4, 30.9, 32.7 ± 0.2 °2Θ.

The present invention also provides a process for the preparation of rosuvastatin amine salts of Formula I Formula I

wherein Ri, R₂, R₃, R₄ are same as defined above; which comprises: a) treating a solution of rosuvastatin of Formula IV

Formula IV

wherein X represents hydrogen or sodium; in water or in a mixture of water miscible organic solvent with an amine of Formula III or a salt thereof

Formula III

and b) isolating rosuvastatin amine salts of Formula I.

The present invention also provides a process for preparation of rosuvastatin calcium of Formula II

Formula II

from amine salts of Formula I

Formula I

wherein Ri, R₂, R₃, R₄ independently represent hydrogen, straight or branched chain Ci-15 alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocyclylalkyl, a heterocyclic residue containing one or more hetero atoms; wherein the process comprises: i) treating a solution of rosuvastatin of Formula IV

Formula IV

wherein X represents hydrogen or sodium with a compound of Formula III or a salt thereof Formula III

ii) to obtain the amine salt of Formula I and converting the amine salt of Formula I to rosuvastatin calcium of Formula II, wherein most of the process related impurities get eliminated.

The present invention also relates to a process for the preparation of amorphous rosuvastatin calcium of Formula II, wherein the process comprises: i) treating the amine salt of Formula I with an acid in presence of an organic solvent; ii) optionally isolating rosuvastatin acid; iii) treating the rosuvastatin acid with calcium ions or optionally converting acid to sodium salt of rosuvastatin; iv) conversion of above sodium salt to its calcium salt; and v) isolating rosuvastatin calcium.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a X-Ray Powder Diffraction of Rosuvastatin N,N'- dibenzylethylenediamine salt.

DETAILED DESCRIPTION OF THE INVENTION

In an aspect of the invention, amine salts of rosuvastatin of Formula I or solvates, hydrates, crystalline forms thereof are provided, wherein amine salts are represented by Formula HNRi R₂CH₂CH₂NHR₃R₄ wherein R|, R₂, R₃, R₄ independently represent hydrogen, straight or branched chain C|.|₅ alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocyclylalkyl, a heterocyclic residue containing one or more hetero atoms. The amine used is preferably N,N'-dibenzylethylenediamine salt.

Another aspect of the present invention, a process for the preparation of N,N'- dibenzylethylenediamine salt of rosuvastatin of Formula I is carried out by dissolving rosuvastatin of Formula IV in water or in a mixture of water miscible organic solvent.

The resulting solution is treated with an amine of Formula III or its salt. The precipitated product is isolated by filtration, which is optionally washed with another solvent. The resulting product is dried and purified if required by recrystallization. The water miscible organic solvents are selected from ethyl acetate, ethanol, methanol, tetrahydrofuran or acetonitrile, more preferably in methanol or ethanol.

The compound of Formula I is recrystallized with polar organic solvents like ethyl acetate, acetone, methanol, acetonitrile, tetrahydrofuran, ether or mixture thereof.

Alternatively the rosuvastatin N,N'-dibenzylethylenediamine salt is purified by dissolving the salt in methanol and then precipitated by the addition of ethyl acetate.

Finally the compound of Formula I is treated with aqueous acid in presence of organic solvent to produce rosuvastatin acid. The organic solvent used in the neutralization process is selected from ethyl acetate, butyl acetate, methylene chloride, toluene, methyl tert-butyl ether (MTBE) and the like, more preferably ethyl acetate. The aqueous acids used are hydrochloric acid, sulphuric, acid, phosphoric acid or organic acids like acetic acid, formic acid, more preferably hydrochloric acid. The organic layer is separated, washed with water or brine solution. The organic layer containing rosuvastatin acid is concentrated and further treated with calcium chloride in water. The reaction mixture is stirred for 2 hrs at 25-30⁰C wherein the product precipitates out. The precipitated product is filtered and washed with DM water, which was subsequently dried under reduced pressure to obtain rosuvastatin calcium salt as a white amorphous powder.

Alternatively the organic layer containing rosuvastatin acid is treated with aqueous sodium hydroxide solution to convert rosuvastatin acid to its sodium salt. This organic layer is again treated with another less polar organic solvent like toluene so that all the rosuvastatin sodium goes into the aqueous layer. Also the addition of toluene removes the hydrophobic impurities. This aqueous sodium salt solution of rosuvastatin is subsequently treated with calcium ions to give rosuvastatin calcium.

The N,N'-dibenzylethylenediamine salt can also be treated with an inorganic base followed by extraction of base into a solvent such as toluene or ether etc. Thereafter the aqueous layer containing rosuvastatin salt (like sodium) is treated with calcium ions to yield rosuvastatin calcium.

Rosuvastatin methyl ester was prepared following the method described in US patent No RE 37,314.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

REFERENCE EXAMPLE

PREPARATION OF ROSUVASTATIN CALCIUM FOLLOWING THE PROCEDURE REPORTED IN THE US PATENT No RE 37,314

Ethanolic solution of rosuvastatin methyl ester (5.53 g in ethanol (78 ml) was treated with aqueous solution of sodium hydroxide (0.1N, 100 ml) at cold temperature and the resulting solution was warmed to 25-30 ⁰C and stirred at this temperature for lhr. Ethanol was evaporated under vacuum at 40-45 ⁰C and the resulting aqueous layer was washed twice with a mixture of 30% v/v ethyl acetate/toluene (50 ml). The resulting rosuvastatin sodium solution was concentrated and treated with aqueous solution of calcium chloride (1 N, 10 ml). The resulting mass was stirred for 2 hrs, filtered, washed with DM water and dried under vacuum at 35-40 ⁰C. Dry Wt. 3.2 g, Chromatographic purity (HPLC): 97.05 %

EXAMPLE 1

PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE ROSUVASTATIN SALT

Rosuvastatin methyl ester (1 g) was dissolved in acetonitrile (15 ml) at 25-30⁰C, and cooled to 0-5⁰C. To this cooled solution, aqueous sodium hydroxide (0. IN, 20 ml) was added at 0-5⁰C for 15 min and the temperature of the resulting solution was raised to 25-30⁰C in 1 hr. After completion of the reaction, acetonitrile was evaporated under reduced pressure at 40-45⁰C. The resulting reaction mass was diluted with DM water (15 ml) and washed with 30% v/v ethyl actetate/toluene (50 ml) at 25-30⁰C. The aqueous layer was treated with an aqueous hydrochloric acid (0.1N, 20 ml) at 0-5⁰C. The resulting solution containing rosuvastatin acid was treated with an aqueous solution of N,N'-dibenzylethylenediamine diacetate (0.9 g in 5 ml DM water) at 24-3O⁰C and stirred for 2 h for complete precipitation of N₅N¹- dibenzylethylenediamine rosuvastatin salt. The off-white N₅N¹- dibenzylethylenediamine rosuvastatin salt was filtered and washed with DM water. This wet salt was slurry washed with ethyl acetate (5 ml) at 25-30⁰C and dried under vacuum at 40-45⁰C. Dry Wt. 0.3 g, Chromatographic purity (HPLC): 99.79, Anti isomer: 0.21%.

¹HNMR (DMSO-d6): 1.2 (d, 6H₅ J=6.6 Hz, (CHjS)₂CH)), 1.39-1.52(m, 2H, CH₂CHOH)₅ 2.19-2.27(m, 2H₅ CH₂COOH)₅ 2.6(s, 2H₅ CH₂NH₂ ⁺CH₂Ar)₅ 3.46(s, 3H, NCH₃), 3.55(s, 3H, CH₃SO₂N), 3.45(m, IH₅ (CH₃)₂CH), 3.72(s, 2H₅ CH₂Ar)₅ 3.82(m, IH, CHOH), 4.2(m,lH, CHOH), 5.50-5.57( dd, IH, J=16.2 Hz, 5.7Hz, =CHCHOH), 6.5(d, IH, J= 16.2Hz, CH=CHCHOH), 7.25(m, 7H, ArH), 7.72(m, 2H, ArH).

EXAMPLE 2

PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE

ROSUVASTATIN SALT

Rosuvastatin methyl ester was (1 g) was dissolved in ethanol (15 ml) at 25-30⁰C and cooled to 0-5⁰C and treated with aqueous sodium hydroxide (0.1 N, 20 ml) at 0-5⁰C. The temperature of the reaction mass was raised to 25-30⁰C and stirred for 1 hr. Ethanol was evaporated from the reaction mass under reduced pressure at 40-45⁰C and the resulting aqueous layer was diluted further with 15 ml of DM water. This aqueous layer containing rosuvastatin was washed with 30% v/v ethyl acetate/toluene (50 ml) at 25-30⁰C and treated with aqueous solution of N,N'- dibenzylethylenediamine diacetate (0.9 g in 5 ml). The resulting suspension was stirred for 1 hr for complete precipitation and the precipitated product was filtered, slurry washed with ethyl acetate (20 ml) and dried under vacuum at 40-45⁰C. Dry wt. 0.68 g; Chromatographic purity (HPLC): 99.28%, Anti isomer: 0.59%.

EXAMPLE 3

PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE

ROSUVASTATIN

A solution of rosuvastatin methyl ester (5 g) in ethanol (70 ml) was treated with aqueous sodium hydroxide (0.1N, 88 ml) at 0-5⁰C and the temperature of the reaction was raised to 30⁰C and stirred for 1 h. Ethanol from the reaction mass was evaporated at 40-45⁰C. This aqueous layer was washed with 30 v/v ethyl acetate/toluene (3 x 25 ml) and treated with an aqueous solution of N,N'-dibenzylethylenediamine diacetate

(1.8 g in 10 ml water). The resulting mass was further stirred for a period of 2 h, filtered, slurry washed with ethyl acetate (30 ml) and dried under vacuum at 40-45⁰C. Dry Wt. 3.3 g, Chromatographic purity: 99.48 %, Anti isomer: 0.47%.

EXAMPLE 4

PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE

ROSUVASTATIN

Rosuvastatin ethyl ester (0.8 g, 0.0001 mol) was dissolved in ethanol (16 ml) at 25°C and 1 N sodium hydroxide (1.57 ml) was added to it slowly over a period of 10 min. The above reaction mass was stirred at 25-30⁰C for 1 h and the solvent was distilled at 35-40⁰C under reduced pressure. The obtained residue was dissolved in water (25 ml) and extracted with a mixture of toluene-ethyl acetate (6:4, 25 ml x 2). Aqueous solution of N,N'-dibenzylethylenediamine diacetate (0.28 g dissolved in 2 ml of water) was added to the above aqueous layer at 15-20⁰C and stirred for 1 h. The precipitated product was filtered, washed with water and dried at 40-45⁰C under vacuum.

Dry Wt. 0.6 g

EXAMPLE 5

PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE

ROSUVASTATIN

Rosuvastatin t-butyl ester (1 g) was dissolved in ethanol (15 ml). The resulting solution was treated with 1 N aqueous sodium hydroxide (1.96 ml) at 25-30⁰C. The mixture was stirred for 1 h at 25-30⁰C for completion of hydrolysis. Ethanol was rotoevaporated and the residue is diluted with DM water (25 ml) and extracted with a mixture of ethyl acetate - toluene (4:6, 2 x 20 ml). To the above aqueous layer, a solution of N.N'-dibenzylethylenediamine diacetate (0.34 g dissolved in 2 ml of water) was added and stirred for 2 h. The precipitated product was filtered, washed with water and dried under vacuum at 40-45⁰C. Dry Wt. 0.75 g

EXAMPLE 6

PURIFICATION OF N,N'-DIBENZYLETHYLENEDIAMINE

ROSUVASTATIN N,N'-dibenzylethylenediamine rosuvastatin (0.5 g) was dissolved in methanol (1 ml) and treated with ethyl acetate (5 ml) at 25-30⁰C. The resulting mixture was cooled to 0-5⁰C and stirred for 1 h. The precipitated product was filtered and dried under vacuum. Dry. Wt. 0.2 g, Chromatographic purity: 99.91%, Anti isomer: 0.19%. Input Chromatographic purity: 99.33, Anti isomer: 0.66%.

PXRD (°2Θ) 5.6, 10.1, 1 1.3, 13.0, 14.7, 15.1, 16.0, 16.3, 17.0, 17.3, 17.8, 18.6, 19.0, 21.3, 21.9, 22.5, 23.5, 25.4, 30.9, 32.7 ± 0.2

EXAMPLE 7

PREPARATION OF ROSUVASTATIN CALCIUM

N,N'-dibenzylethylenediamine rosuvastatin salt (2 g) was dissolved in a mixture of ethyl acetate (30 ml) and DM water (30 ml) and cooled to 0-5⁰C. The above cold mixture was treated with aqueous hydrochloric acid (3 ml) at 0-5⁰C. The resulting clear solution was stirred for 10 min. The organic layer was separated, washed with water and cooled to 0-5⁰C. Aqueous sodium hydroxide (1 N, 30 ml) was added to the above organic layer and stirred at room temperature for 30 min for conversion of rosuvasatin acid to it sodium salt. Toluene (70 ml) was added to the above mixture and stirred for 10 min. The aqueous layer was separated and traces of solvent were removed at 40-45°C under vacuum. The resulting clear aqueous layer was treated with an aqueous solution of calcium chloride (IN, 3 ml) and resulting rosuvastatin calcium was filtered and dried.

Dry Wt. 0.6 g; Chromatographic purity: 99.3%.

EXAMPLE 8

PREPARATION OF ROSUVASTATIN CALCIUM

N,N'-dibenzylethylenediamine rosuvastatin salt (1 g) was suspended in DM water(20ml) and treated with aqueous sodium hydroxide solution (0.1N, 16.63 ml) at 25-30° C. The resulting suspension was stirred for 30 min and the undissolved matter was filtered off. The clear aqueous layer was washed twice with 30%v/v ethyl acetate/toluene (5 ml). Traces of organic solvent from aqueous layer was removed under vacuum at 40-45°C. The clear aqueous layer containing Rosuvastatin sodium was treated with aqueous solution of calcium chloride (1 N, 1.66 ml), precipitated rosuvastatin calcium was filtered, washed with water and dried. Dry Wt. 0.35; Chromatographic purity: 99.24%; Anti isomer: 0.71%

Claims

WE CLAIM

1) A rosuvastatin amine salts of Formula I

Formula I

wherein Ri, R₂, R₃, R₄ independently represents hydrogen, straight or branched chain C_{M 5} alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocyclylalkyl, a heterocyclic residue containing one or more hetero atoms.

2) The rosuvastatin amine salts, according to claim 1, is in the form of solvates, hydrates, crystalline or amorphous forms thereof or a mixture of crystalline and amorphous forms.

3) The rosuvastatin amine salts, according to claim 1, is rosuvastatin N,N'- dibenzylethylenediamine salt

4) A crystalline rosuvastatin N,N'-dibenzylethylenediamine salt having an X-ray powder diffraction pattern with peaks at 5.6, 10.1, 1 1.3, 13.0, 14.7, 15.1, 16.0,

16.3, 17.0, 17.3, 17.8, 18.6, 19.0, 21.3, 21.9, 22.5, 23.5, 25.4, 30.9, 32.7 ± 0.2 °2θ.

5) A process for the preparation of rosuvastatin amine salts of Formula I Formula I

Formula IV

Formula III

and c) isolating rosuvastatin amine salts of Formula I.

6) A process for the preparation of rosuvastatin N,N'-dibenzylethylenediamine salt, which comprises: a) treating a solution of rosuvastatin of Formula IV Formula IV

wherein X represents hydrogen or sodium; in water or in a mixture of water miscible organic solvent with N,N'-dibenzylethylenediamine salt; and b) isolating rosuvastatin N,N'-dibenzylethylenediamine salt.

7) The process according to claim 5 and 6, the water-miscible organic solvent is selected form ethylacetate, methanol, ethanol, tetrahydrofuran, acetonitrile.

8) A process for preparation of rosuvastatin calcium of Formula II

Formula II

from amine salts of Formula I

Formula I

wherein Ri, R₂, R₃, R₄ independently represent hydrogen, straight or branched chain C_{M 5} alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocyclylalkyl, a heterocyclic residue containing one or more hetero atoms; wherein the process comprises: i) treating rosuvastatin of Formula IV

Formula IV

wherein X represents hydrogen or sodium with a compound of Formula III or a salt thereof

Formula III

ii) to obtain the amine salt of Formula I and converting the amine salt of Formula I to rosuvastatin calcium of Formula H, wherein most of the process related impurities get eliminated.

9) A process for the preparation of amorphous rosuvastatin calcium of Formula II

Formula II

wherein the process comprises: i) treating the amine salt of Formula I with an acid in the presence of an organic solvent; ii) optionally isolating rosuvastatin acid; iii) treating the rosuvastatin acid with calcium ions or optionally converting acid to sodium salt of rosuvastatin; iv) conversion of above sodium salt to its calcium salt; and v) isolating rosuvastatin calcium.

10) The process according to claim 9, wherein the acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, formic acid.

1 1) The process according to claim 9, wherein the organic solvent is selected from ethyl acetate, butyl acetate, methylene chloride, toluene, methyl tert-butyl ether.