WO2006011155A1 - Procede en enceinte unique pour calcium d'atorvastatine amorphe - Google Patents
Procede en enceinte unique pour calcium d'atorvastatine amorphe Download PDFInfo
- Publication number
- WO2006011155A1 WO2006011155A1 PCT/IN2004/000331 IN2004000331W WO2006011155A1 WO 2006011155 A1 WO2006011155 A1 WO 2006011155A1 IN 2004000331 W IN2004000331 W IN 2004000331W WO 2006011155 A1 WO2006011155 A1 WO 2006011155A1
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- WIPO (PCT)
- Prior art keywords
- aqueous
- amorphous
- calcium
- solution
- atorvastatin calcium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to a one pot process for the preparation of amorphous atorvastatin calcium salt of formula (2) from compound (4R-Cis)-1-1- dimethylyl 6-[2[2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4[(phenylamino carbonyl] -lH-pyrral-l-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetate of formula (1).
- the invention also relates to an improved process for obtaining amorphous atorvastatin hemi calcium salt (herein further referred as atorvastatin calcium) having enhanced yield.
- Atorvastatin is a member of the class of drugs called statins.
- Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL), particle concentration in the blood stream of patients at risks for cardiovascular disease.
- LDL low density lipoprotein
- a high level of LDL in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis.
- statin drugs The mechanism of action of statin drugs has been elucidated in some detail. They interfere with the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutary-coenzyme.
- a reductase enzyme (“HMG-CoA reductase”). HMG-CoA reductase catalzes, the conversion HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol, and so, its inhibition leads to a reduction in the concentration of cholesterol in the liver.
- Very low density lipoprotein (VLDL) is the biological vehicle for transporting cholesterol and triglycerides from the liver to peripheral cells.
- VLDL is catabolized in the peripheral cells which release fatty acids which may be stored in adopcytes or oxidized by music.
- the VLDL is converted to intermediate density lipoprotein (IDL), which is either removed by an LDL, receptor, or is converted to LDL.
- IDL intermediate density lipoprotein
- US 6,750,353 (US 2004072895 and 2003109569) reveals the process for the preparation of crystalline or mixture of crystalline and amorphous forms of atorvastatin calcium from atorvastatin lactone or diol protected ester compound.
- WO 01/28999A (US 2004063969 and US 6,646,133) teaches the preparation of amorphous atorvastatin calcium by crystallization from lower alkanol or mixtureof such lower alkanols by heating and cooling.
- CA Patent no: 2450820 (WO 03/016317A 1 ) provides a process for preparation of statin calcium salts from ester or protected ester derivative of atorvastatin by contacting with calcium hydroxide or an acid and then followed by calcium hydroxide and in presence of a phase transfer catalyst.
- US Patent Publication no. 2004024046 (CA 2392025) describes a process for converting crystalline atorvastatin calcium into amorphous form using solvents of two different types namely polar and non-polar.
- WO 03/099785 deals with the preparation of amorphous atorvastatin calcium from crystalline form 1 or mixture of crystalline and amorphous atorvastatin by dissolving in aliphatic acyclic ketone, filtering the solution and removing the solvent.
- WO 03/093233 describes the preparation of amorphous atorvastatin calcium from crude amorphous atorvastatin calcium by dissolving in water miscible solvent and adding the same to water under stirring.
- US Patent publication no. 2003212279 and US patent publication no. 20022183378 teaches the preparation of various crystalline forms of atorvastatin calcium and also amorphous form from any form of atorvastatin calcium by treatment with an organic solvent namely acetone or acetonitrile.
- WO 03/68739 teaches the preparation of amorphous atorvastatin calcium from diol protected ester of atorvastatin by hydrolysis, extraction with C 1 - C 5 ester solvent and precipitation using hydrocarbon or ether solvent.
- US Patent no. 6,528,660 (US Patent publication no. 2003149279) deals with the preparation of amorphous atorvastatin calcium by dissolving crystalline atorvastatin calcium in non-hydroxylic solvent and precipitating with non-polar hydrocarbon anti- solvent.
- WO 02/083638 teaches the preparation of amorphous atorvastatin calcium from diol protected ester of atorvastatin by obtaining first crude amorphous atorvastatin calcium comtaminated with calcium hydroxide, which is further subjected to purification using aqueous ethylacetate and non-polar hydrocarbon solvent to obtain the required product.
- Indian application no. 949/MAS/2001 provides a process for the preparation of amorphous atorvastatin calcium from atorvastatin butylester in acetonitrile solvent, hydrolyzing with an alkali hydroxide, followed by addition of aqueous calcium acetate, stirring the reaction mixture, distilling the solvent to obtain a residue which is dissolved in non-hydroxylic polar solvent and adding non-polar hydrocarbon solvent.
- US Patent no. 6,274,740 Bl teaches preparation of amorphous atorvastatin calcium starting from atorvastatin lactone to obtain crystalline form I which is dissolved in tetrahydrofuran, adding toluene and evaporating the solution over a period of four days to obtain desired percentage level of tetrahydrofuran and toluene in the residue and isolating amorphous atorvastatin calcium.
- Tetrahedron letters Vol.33,No,17,PP 2283-2284,1992 describes the preparation of amorphous Atorvastatin calcium starting from (4R-cis)-l,l-dimethylethyl 6- ⁇ 2[2-(4- fluorophenyl)-5( 1 -methylethyl)-3 -phenyl-4[(phenylamino)carbonyl] - 1 H-pyrrol- 1 - yl]ethyl ⁇ -2,2-dimethyl-l,3-dioxan-4-acetate( herein further referred to as ATV-I) by treating with aqueous hydrochloric acid, base hydrolysis followed by addition of calcium acetate .
- ATV-I aqueous hydrochloric acid, base hydrolysis followed by addition of calcium acetate
- Atorvastatin calcium is a substance which is very slightly water soluble, and it has been found that the crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability " of atorvastatin in the body. It has been found that the production of amorphous atorvastatin calcium according to the previously disclosed process was not consistently reproducible, and therefore a process has been developed for converting the crystalline forms of atorvastatin calcium (formed in the synthesis of atorvastatin) to the amorphous form.
- pure amorphous atorvastatin calcium salt is prepared from crystalline atorvastatin calcium, mixture of crude and amorphous atorvastatin calcium or crude amorphous atorvastatin calcium. None of the prior art processes teaches the preparation of amorphous atorvastatin directly without obtaining any one of the forms mentioned above as an intermediate. Surprising results of the present invention is achieved by directly obtaining amorphous atorvastatin calcium with enhanced yield from compound of formula (1) by obviating the formation of any of the above mentioned forms as an intermediate in the process steps adopted. The pure amorphous atorvastatin calcium is directly obtained from the reaction mixture by seeding resulting in precipitation of the required product.
- the process of present invention involves the crucial steps of apportioned addition of appropriately selected aqueous solution of calcium salt namely calcium acetate in combination with seeding using amorphous atorvastatin calcium to achieve the desired outcome of the process.
- aqueous solution of calcium salt namely calcium acetate
- seeding using amorphous atorvastatin calcium to achieve the desired outcome of the process.
- any one of these steps always led to the formation of mixture of crystalline and amorphous atorvastatin calcium salt and the result has been illustrated with examples.
- the process of present invention to obtain amorphous atorvastatin calcium salt from compound of formula (1) is novel and inventive.
- An object of the present invention is to provide a process for the preparation of amorphous atorvastatin calcium obviating all the disadvantages associated with the prior art processes.
- Another object of the present invention is to provide a process for the preparation of consistently homogenous amorphous atorvastatin calcium.
- Yet another object of the present invention is to provide a process which obviates the preparation of crude amorphous atorvastatin calcium, crystalline form of atorvastatin calcium or mixture of crystalline and amorphous form of atorvastatin calcium.
- Still another object of the present invention is to provide a process for the preparation of amorphous atorvastatin calcium which is economical and commercially viable.
- Still yet another object of the present invention is to provide a process to obtain pure amorphous atorvastatin calcium directly from the reaction mixture containing atorvastatin calcium.
- Further object of the invention is to provide a process with optimized condition for the preparation of amorphous atorvastatin calcium in high yield and required purity.
- the present invention relates to a novel process for the preparation of pure amorphous form of atorvastatin calcium from the compound of formula (1) which is also an intermediate for the preparation of atorvastatin lactone and several other crystalline forms of atorvastatin calcium salt. Accordingly, the present invention discloses a novel one pot process for the preparation of amorphous atorvastatin calcium on commercial scale from compound of formula (1)
- Figure I X-Ray diffraction pattern of amorphous atorvastatin calcium
- Figure II X-Ray diffraction pattern of crystalline atorvastatin calcium
- Figure III X-Ray diffraction pattern of mixture of crystalline and amor-
- Figure V IR spectrum of crystalline atorvastatin calcium
- Figure VI IR spectrum of mixture of crystalline and amorphous
- the process provided eliminates the problem of prior art.
- the invention also discloses for the first time a process for preparing amorphous atorvastatin calcium on a large scale from compound of formula (1) without obtaining intermediate product namely crude amorphous atorvastatin calcium or any crystalline form of atorvastatin calcium or mixture of crystalline and amorphous atorvastatin calcium.
- the present invention does not make use of any crystalline form, mixture of crystalline and amorphous form or crude amorphous form to obtain pure amorphous atorvastatin calcium like other prior arts.
- the pure amorphous atorvastatin calcium is isolated by adopting any conventional method, preferably centrifugation.
- the compound of formula (1) is treated with aqueous hydrochloric acid preferably in the range of 25 to 35 w/v and more preferably 28 - 32 w/v.
- the molar ratio of compound of formula (1) and aqueous hydrochloric acid used is 1 : 1.5 to 2.5, preferably 2.0
- the compound of formula (1) is contacted with to
- the polar organic solvent use is selected from the group consisting of N,N-dimethylforamide, dimethylsulphoxide acetonitrile, methanol, and sulfolane. Still yet another embodiment, the preferred polar water miscible organic solvent is methanol.
- the aqueous sodium hydroxide solution used for neutralization of hydrochloric acid ranges from 8 to 12 % w/v, preferably 10% w/v.
- the mole of aqueous sodium hydroxide solution used is in the range of 2.5 to 3.5, preferably 3.0.
- the pH of the reaction mixture is maintained between 7.5-9.5, preferably between 7.5 and 8.5 and should be always greater than 7.0.
- the aqueous calcium acetate solution used is in the range of 8 to 15 w/v.
- the moles of aqueous calcium acetate solution used is in the range of 1 to 1.2, preferably 1.0
- the precipitated material is cooled to 1O 0 C to 35 0 C, preferably in the range of
- step (b) contacting the compound of formula (1) with a polar water miscible organic solvent to obtain a clear solution
- steps b) treating the steps (a) solution with aqueous mineral acid under stirring at a temperature ranging between 25 0 C to40°C for a time period of 2h to 4 h c) neutralizing, hydrolyzing the ester function by treating step (b) solution with aqueous alkali hydroxide solution at a temperature ranging between 15 0 C to 35 0 C for a period of 2 h to 4h
- step (c ) reducing the volume of step (c ) to one fourth of its original volume, followed by addition of water , polar organic solvent used in step (a), an ethereal solvent, stirred for Ih to 2 h, separating aqueous and organic layer, e) extracting the aqueous layer of step (d) with a mixture of alkane and alkyl ester solvent, separating layers,
- step (e) with aqueous hydrochloric acid under stirring, heating the mixture to a temperature ranging between 40° to 55 0 C for 1 h to 4 h, g) adding 8 to 15 % of aqueous calcium acetate solution of the total quantity, maintaining the temperature between 40 0 C to 55 0 C stirred for up to an hour to obtain a turbidity, h) seeding the turbid solution of step (g) with amorphous atorvastatin calcium followed by addition of remaining quantity of aqueous calcium acetate solution over a period of Ih to 2h, continued stirring for further 4h, and i) separating the precipitated solid of step (h) by conventional method, drying the solid to obtain amorphous calcium.
- the x-ray diffractions show that the atorvastatin calcium obtained is in the amorphous form.
- Example 6 Dissolve the compound (4R-Cis)-1 -1-dimethylyl 6-[2[2-(4-fluorophenyl)-5-(l- methylethyl)-3 -phenyl-4 [(phenylamino carbonyl] - 1 H-pyrral- 1 -yl] ethyl] -2,2-dimethyl- l,3-dioxane-4-acetate ⁇ ATV-1, formula(l)) in methanol at an ambient temperature. Add IN aqueous hydrochloric acid solution and stir for 2h to 4h, followed by addition of 10% aqueous sodium hydroxide and continued stirring.
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Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IN1379/DEL/2004 | 2004-07-26 | ||
IN1379DE2004 | 2004-07-26 |
Publications (1)
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WO2006011155A1 true WO2006011155A1 (fr) | 2006-02-02 |
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PCT/IN2004/000331 WO2006011155A1 (fr) | 2004-07-26 | 2004-10-21 | Procede en enceinte unique pour calcium d'atorvastatine amorphe |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2075246A1 (fr) * | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | Procédé de préparation de forme amorphe de sel hémicalcium atorvastanine |
WO2011131601A1 (fr) * | 2010-04-19 | 2011-10-27 | Dsm Ip Assets B.V. | Production d'atorvastatine à faible teneur en impuretés lactones |
CN103108863A (zh) * | 2010-04-19 | 2013-05-15 | 中化帝斯曼制药有限公司荷兰公司 | 低醚杂质的阿托伐他汀的制备 |
WO2021105934A1 (fr) * | 2019-11-29 | 2021-06-03 | Dr. Reddy’S Laboratories Limited | Procédé de fabrication continue de statines |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002059087A1 (fr) * | 2001-01-23 | 2002-08-01 | Lek Pharmaceutical And Chemical Company D.D. | Preparation de calcium d'atorvastatine non cristallin |
WO2003068739A1 (fr) * | 2002-02-01 | 2003-08-21 | Zentiva A.S. | Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine) |
WO2003093233A1 (fr) * | 2002-04-29 | 2003-11-13 | Chemi S.P.A. | Procede de preparation de la forme amorphe d'un sel d'atorvastatine calcique |
US20030212279A1 (en) * | 2000-11-30 | 2003-11-13 | Limor Tessler | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
WO2004089895A1 (fr) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Procede de preparation d'un sel d'atorvastatine calcique amorphe |
WO2005005384A1 (fr) * | 2003-07-15 | 2005-01-20 | Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S. | Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline |
-
2004
- 2004-10-21 WO PCT/IN2004/000331 patent/WO2006011155A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030212279A1 (en) * | 2000-11-30 | 2003-11-13 | Limor Tessler | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
WO2002059087A1 (fr) * | 2001-01-23 | 2002-08-01 | Lek Pharmaceutical And Chemical Company D.D. | Preparation de calcium d'atorvastatine non cristallin |
WO2003068739A1 (fr) * | 2002-02-01 | 2003-08-21 | Zentiva A.S. | Procede de fabrication d'une forme amorphe du sel d'hemicalcium d'acide (3r, 5r) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-l-yl]-3, 5-dihydroxyheptanoique (atorvastatine) |
WO2003093233A1 (fr) * | 2002-04-29 | 2003-11-13 | Chemi S.P.A. | Procede de preparation de la forme amorphe d'un sel d'atorvastatine calcique |
WO2004089895A1 (fr) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Procede de preparation d'un sel d'atorvastatine calcique amorphe |
WO2005005384A1 (fr) * | 2003-07-15 | 2005-01-20 | Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S. | Procede de preparation d'atorvastatine calcique amorphe sans interconversion d'une forme cristalline |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2075246A1 (fr) * | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | Procédé de préparation de forme amorphe de sel hémicalcium atorvastanine |
WO2011131601A1 (fr) * | 2010-04-19 | 2011-10-27 | Dsm Ip Assets B.V. | Production d'atorvastatine à faible teneur en impuretés lactones |
US20130041163A1 (en) * | 2010-04-19 | 2013-02-14 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Production of atorvastatin low in lactone impurities |
CN103108863A (zh) * | 2010-04-19 | 2013-05-15 | 中化帝斯曼制药有限公司荷兰公司 | 低醚杂质的阿托伐他汀的制备 |
CN103108863B (zh) * | 2010-04-19 | 2015-08-19 | 中化帝斯曼制药有限公司荷兰公司 | 低醚杂质的阿托伐他汀的制备 |
WO2021105934A1 (fr) * | 2019-11-29 | 2021-06-03 | Dr. Reddy’S Laboratories Limited | Procédé de fabrication continue de statines |
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