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WO2008038132A1 - Forme cristalline de sels de diamine de rosuvastatine - Google Patents

Forme cristalline de sels de diamine de rosuvastatine Download PDF

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Publication number
WO2008038132A1
WO2008038132A1 PCT/IB2007/002880 IB2007002880W WO2008038132A1 WO 2008038132 A1 WO2008038132 A1 WO 2008038132A1 IB 2007002880 W IB2007002880 W IB 2007002880W WO 2008038132 A1 WO2008038132 A1 WO 2008038132A1
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WO
WIPO (PCT)
Prior art keywords
rosuvastatin
formula
salt
acid
calcium
Prior art date
Application number
PCT/IB2007/002880
Other languages
English (en)
Inventor
Ramesh Dandala
Sambhu Prasad Sarma Mallela
Sukumar Nandi
Gangadhar Bhima Shankar Nangi
Sivakumaran Meenakshisunderam
Original Assignee
Aurobindo Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aurobindo Pharma Limited filed Critical Aurobindo Pharma Limited
Publication of WO2008038132A1 publication Critical patent/WO2008038132A1/fr

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Classifications

    • 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 salts of HMG CoA reductase inhibitors and in particular, crystalline rosuvastatin amine salts represented by Formula I
  • Ri, R 2 , R 3 , R 4 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
  • 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.
  • HMG-CoA 3- hydroxy-3-methylglutaryl-coenzyme A
  • 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, N 5 N'- 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 ,
  • the main objective of the present invention is to provide novel crystalline diamine salts of rosuvastatin.
  • the present invention provides rosuvastatin amine salts of Formula I
  • , R 2 , R 3 , R 4 independently represents hydrogen, straight or branched chain Ci_i 5 alkyl, cycloalkyl, optionally substituted aryl, aralkyl, heterocyclylalkyl, a heterocyclic residue containing one or more hetero atoms.
  • 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,
  • the present invention also provides a process for the preparation of rosuvastatin amine salts of Formula I Formula I
  • Ri, R 2 , R 3 , R 4 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
  • the present invention also provides a process for preparation of rosuvastatin calcium of Formula II
  • Ri, R 2 , R 3 , R 4 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.
  • Figure 1 is a X-Ray Powder Diffraction of Rosuvastatin N,N'- dibenzylethylenediamine salt.
  • amine salts of rosuvastatin of Formula I or solvates, hydrates, crystalline forms thereof are provided, wherein amine salts are represented by Formula HNRi R 2 CH 2 CH 2 NHR 3 R 4 wherein R
  • the amine used is preferably N,N'-dibenzylethylenediamine salt.
  • 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.
  • polar organic solvents like ethyl acetate, acetone, methanol, acetonitrile, tetrahydrofuran, ether or mixture thereof.
  • the rosuvastatin N,N'-dibenzylethylenediamine salt is purified by dissolving the salt in methanol and then precipitated by the addition of ethyl acetate.
  • 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 25-30 0 C 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.
  • 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.
  • a solvent such as toluene or ether etc.
  • Rosuvastatin methyl ester was prepared following the method described in US patent No RE 37,314.
  • Rosuvastatin methyl ester (1 g) was dissolved in acetonitrile (15 ml) at 25-30 0 C, and cooled to 0-5 0 C. To this cooled solution, aqueous sodium hydroxide (0. IN, 20 ml) was added at 0-5 0 C for 15 min and the temperature of the resulting solution was raised to 25-30 0 C in 1 hr. After completion of the reaction, acetonitrile was evaporated under reduced pressure at 40-45 0 C. The resulting reaction mass was diluted with DM water (15 ml) and washed with 30% v/v ethyl actetate/toluene (50 ml) at 25-30 0 C.
  • the aqueous layer was treated with an aqueous hydrochloric acid (0.1N, 20 ml) at 0-5 0 C.
  • 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 24-3O 0 C and stirred for 2 h for complete precipitation of N 5 N 1 - dibenzylethylenediamine rosuvastatin salt.
  • the off-white N 5 N 1 - dibenzylethylenediamine rosuvastatin salt was filtered and washed with DM water.
  • This wet salt was slurry washed with ethyl acetate (5 ml) at 25-30 0 C and dried under vacuum at 40-45 0 C. Dry Wt. 0.3 g, Chromatographic purity (HPLC): 99.79, Anti isomer: 0.21%.
  • Rosuvastatin methyl ester (1 g) was dissolved in ethanol (15 ml) at 25-30 0 C and cooled to 0-5 0 C and treated with aqueous sodium hydroxide (0.1 N, 20 ml) at 0-5 0 C. The temperature of the reaction mass was raised to 25-30 0 C and stirred for 1 hr. Ethanol was evaporated from the reaction mass under reduced pressure at 40-45 0 C 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 25-30 0 C 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 40-45 0 C. Dry wt. 0.68 g; Chromatographic purity (HPLC): 99.28%, Anti isomer: 0.59%.
  • 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 25-30 0 C for 1 h and the solvent was distilled at 35-40 0 C 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 15-20 0 C and stirred for 1 h.
  • the precipitated product was filtered, washed with water and dried at 40-45 0 C under vacuum.
  • 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 25-30 0 C. The mixture was stirred for 1 h at 25-30 0 C 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).
  • ROSUVASTATIN N,N'-dibenzylethylenediamine rosuvastatin 0.5 g was dissolved in methanol (1 ml) and treated with ethyl acetate (5 ml) at 25-30 0 C. The resulting mixture was cooled to 0-5 0 C 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%.
  • 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 0-5 0 C.
  • the above cold mixture was treated with aqueous hydrochloric acid (3 ml) at 0-5 0 C.
  • the resulting clear solution was stirred for 10 min.
  • the organic layer was separated, washed with water and cooled to 0-5 0 C.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la forme cristalline de sels d'amine de rosuvastatine représentés par la formule (I) dans laquelle R1, R2, R3 et R4 sont indépendamment hydrogène, chaîne C1-C15 alkyle droite ou ramifiée, cycloalkyle, aryle éventuellement ramifié, aralkyle, hétérocycloalkyle, résidu hétérocyclique contenant un ou plusieurs hétéroatomes.
PCT/IB2007/002880 2006-09-28 2007-09-24 Forme cristalline de sels de diamine de rosuvastatine WO2008038132A1 (fr)

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IN1807/CHE/2006 2006-09-28
IN1807CH2006 2006-09-28

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010128346A2 (fr) 2009-05-07 2010-11-11 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Sels de rosuvastatine et leur procédé de préparation
US7994178B2 (en) 2006-09-18 2011-08-09 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia
WO2012063115A2 (fr) 2010-11-11 2012-05-18 Jubilant Life Sciences Ltd. Procédé de préparation de rosuvastatine calcique via un nouvel intermédiaire amine
WO2012066365A2 (fr) 2010-11-16 2012-05-24 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Ingrédients cristallins actifs au plan pharmaceutique
WO2012073256A1 (fr) 2010-11-29 2012-06-07 Cadila Healthcare Limited Sels de rosuvastatine
WO2012073055A1 (fr) 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'intermédiaires pharmaceutiques de haute pureté
CN103232398A (zh) * 2012-04-28 2013-08-07 天津滨江药物研发有限公司 一种瑞舒伐他汀氨基酸盐及其制备方法和应用
WO2014154856A1 (fr) * 2013-03-29 2014-10-02 Dsm Sinochem Pharmaceuticals Netherlands B.V. Sels d'amine de la pravastatine et de la rosuvastatine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060804A1 (fr) * 2000-02-15 2001-08-23 Astrazeneca Ab Sels cristallises d'acide 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-enoique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060804A1 (fr) * 2000-02-15 2001-08-23 Astrazeneca Ab Sels cristallises d'acide 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-enoique

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994178B2 (en) 2006-09-18 2011-08-09 Teva Pharmaceutical Industries, Ltd. Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia
WO2010128346A2 (fr) 2009-05-07 2010-11-11 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Sels de rosuvastatine et leur procédé de préparation
WO2012063115A3 (fr) * 2010-11-11 2012-10-26 Jubilant Life Sciences Ltd. Procédé de préparation de rosuvastatine calcique via un nouvel intermédiaire amine
WO2012063115A2 (fr) 2010-11-11 2012-05-18 Jubilant Life Sciences Ltd. Procédé de préparation de rosuvastatine calcique via un nouvel intermédiaire amine
WO2012066365A2 (fr) 2010-11-16 2012-05-24 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Ingrédients cristallins actifs au plan pharmaceutique
WO2012073055A1 (fr) 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'intermédiaires pharmaceutiques de haute pureté
WO2012073256A1 (fr) 2010-11-29 2012-06-07 Cadila Healthcare Limited Sels de rosuvastatine
CN103298793A (zh) * 2010-11-29 2013-09-11 埃吉斯药物股份公开有限公司 高纯度药物中间体的制备方法
US9133132B2 (en) 2010-11-29 2015-09-15 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Method for the preparation of high-purity pharmaceutical intermediates
EA029079B1 (ru) * 2010-11-29 2018-02-28 Эгиш Дьёдьсердьяр Ньильваношан Мюкёдё Ресвеньтаршашаг Способ получения фармацевтических промежуточных соединений высокой чистоты
CN103232398A (zh) * 2012-04-28 2013-08-07 天津滨江药物研发有限公司 一种瑞舒伐他汀氨基酸盐及其制备方法和应用
CN103232398B (zh) * 2012-04-28 2016-04-06 上海科州药物研发有限公司 一种瑞舒伐他汀氨基酸盐及其制备方法和应用
WO2014154856A1 (fr) * 2013-03-29 2014-10-02 Dsm Sinochem Pharmaceuticals Netherlands B.V. Sels d'amine de la pravastatine et de la rosuvastatine
CN105189458A (zh) * 2013-03-29 2015-12-23 中化帝斯曼制药有限公司荷兰公司 匹伐他汀和罗素伐他汀的胺盐
US9630906B2 (en) 2013-03-29 2017-04-25 Dsm Sinochem Pharmaceuticals Netherlands B.V. Amine salts of pitavastatin and rosuvastatin

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