WO2002083638A1 - Procede de production d'atorvastatine calcique sous forme amorphe - Google Patents

Procede de production d'atorvastatine calcique sous forme amorphe Download PDF

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Publication number
WO2002083638A1
WO2002083638A1 PCT/IN2001/000111 IN0100111W WO02083638A1 WO 2002083638 A1 WO2002083638 A1 WO 2002083638A1 IN 0100111 W IN0100111 W IN 0100111W WO 02083638 A1 WO02083638 A1 WO 02083638A1
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WO
WIPO (PCT)
Prior art keywords
atorvastatin calcium
aqueous
calcium
employed
solution
Prior art date
Application number
PCT/IN2001/000111
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English (en)
Inventor
Virendra Kumar Agarwal
Manish Harshadbhai Vakil
Kanwal Pandita
Nirogi Venakata Satya Ramakrishna
Pankaj Ramanbhai Patel
Satish Champaklal Manakiwala
Original Assignee
Cadila Healthcare 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.)
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Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2002083638A1 publication Critical patent/WO2002083638A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 novel process for the production of atorvastatin calcium.
  • the present invention relates to a novel process for the production of amorphous atorvastatin calcium.
  • the present invention relates to a novel process for the production of amorphous atorvastatin calcium from a diol protected tert- butyl ester (a).
  • atorvastatin is known to be therapeutically useful compound.
  • Atorvastatin calcium a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. Open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized.
  • R-form of the ring opened acid form has surprising inhibition of the biosynthesis of cholesterol.
  • Atorvastatin in its calcium salt form i.e. [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l- methylethyl) -3-phenyl-4- [(phenylarnino)carbonyl] - 1 H-pyrrole- 1 -heptanoic acid calcium salt (2: 1) having formula 1:
  • Atorvastatin is preferably prepared as its calcium salt, i.e. [R- (R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]- lH-pyrrole- l-heptanoic acid calcium salt (2 : 1) since the calcium salt is desirable and it enables easy formulation of atorvastatin for example, tablets, capsules, lozenges, powder and the like for oral administration.
  • PCT application WO 00/711 16 describes the procedure for converting the crystalline form-I by dissolving it in a non-hydroxylic solvent like tetrahydrofuran and precipitating amorpnous aiorvasiaun calcium by the addition of nonpolar hydrocarbon like, n-hexane cyclohexane or n-heptane.
  • the method disclosed in this PCT application is not suitable for large scale production of amorphous atorvastatin calcium as the process requires very large amount of non polar hydrocarbon solvents making the process uneconomical on the commercial scale.
  • an object of the present invention to provide a process for the preparation of amorphous atorvastatin calcium which avoids all the disadvantages of the prior arts.
  • the present invention discloses a novel process for the preparation of amorphous atorvastatin calcium from the above mentioned intermediate (a) on commercial scale, while in earlier prior arts, crystalline form - I of atorvastatin calcium is employed for the preparation of amorphous atorvastatin calcium.
  • the present invention also discloses a novel process of converting form - I of atorvastatin calcium into amorphous form, which is suitable for converting all the crystalline forms of atorvastatin calcium in to amorphous form on commercial scale.
  • the process of the present invention eliminates the problems of prior arts.
  • the present invention also discloses for the first time a process of manufacturing amorphous atorvastatin calcium directly from diol protected tert-butyl ester (a) as in scheme- 1.
  • the crude stage may contain some amount of calcium hydroxide, which is easily removed completely in the subsequent purification stage.
  • atorvastatin calcium produced by the process of the present invention was found to be amorphous as revealed by X-ray powder diffraction data (figure -1, 2, 3 & 4).
  • the present invention does not make use of any crystalline form to get amorphous atorvastatin calcium like other prior arts.
  • the present invention provides a process for the preparation of atorvastatin calcium in amorphous form which comprises treating diol protected tert-butyl ester of the following structure (a)
  • the aqueous acid is selected from hydrochloric acid , sulphuric acid, and formic acid; aqueous hydrochloric acid is being most preferred.
  • the aqueous hydroxide solution is seiecie ⁇ irom so ⁇ ium hydroxide, potassium hydroxide, and lithium hydroxide; In a most preferred embodiment, aqueous sodium hydroxide is employed.
  • the crude salt as well as the purified products are isolated by filtration and then dried.
  • the diol protected tert-butyl ester (a) is treated with 20 - 40 times w/v methanol. More preferably, the amount of methanol employed is 28 times w/v.
  • the HC1 employed is preferably 2 -6% aqueous w/v, more preferably 4% w/v in a molar ratio of 1.5 - 4, preferably 2.0.
  • the reaction temperature is maintained at a range of from 20-40°C preferably, 30 -35°C for 8 - 20 hours preferably for 15 hours.
  • the dilute aqueous sodium hydroxide solution employed ranges from 5 - 20% w/v, preferably 10% w/v in molar ratio of 1 - 1.5, more preferably, 1.35, (after calculating the amount of sodium hydroxide required for neutralization of hydrochloric acid present in the reaction mixture).
  • the reaction mass is stirred for 2 - 6 hours, preferably, for 5 hours.
  • the pH of the reaction mixture is maintained 7.0 - 9.5, preferably
  • pH is always maintained at a level > 7.0.
  • the aqueous calcium chloride solution is employed in the range of 2 - 6% w/v preferably 4 - 5 % in the molar ratio of 1 - 2, preferably 1.65.
  • the reaction temperature is maintained at a temperature in the range of 50 - 55°C for 15 - 60 minutes preferably for 60 minutes.
  • the precipitated material is preferably cooled to 25 - 40°C, more preferably to 30 - 35°C, which is further cooled to 0 - 20°C preferably, to 10 - 15°C.
  • the stirring is continued for 30 - 120 minutes preferably, for 60 minutes at 10 - 15°C
  • the material is centrifuged easily and is preferably washed with D.M. Water to remove excess calcium chloride.
  • the present invention describes the method of converting diol protected tert-butyl ester (a) of atorvastatin directly into crude amorphous atorvastatin calcium which contains some amount oi calcium hydroxide which is removed in subsequent purification step.
  • the whole process consists of following key operations
  • pH of the reaction mixture is adjusted between 7.0 - 9.5, preferably 8.5 by addition of 4% w/v aqueous hydrochloric acid, pH lower than 7.0 results in the formation of lactone compound (d) in the final product, this also results in the decrease oi ⁇ ne caicium content below the required amount i.e. 3.50 % w/w on dry basis.
  • the volume of the reaction mixture is then reduced to approximately 50% by distillation under reduced pressure below 60°C 5) The volume of the reaction mixture is measured and the content of methanol and water are determined v/v
  • the volume of the reaction mixture is then adjusted so that it contains 5 - 15 times, preferably 10 times methanol and 5 - 10 times, preferably 7 times water with respect to diol protected tert-butyl ester (a) initially taken.
  • reaction mixture is then washed with 5 - 15 times preferably 10 times as that of diol protected tert-butyl ester (a) taken for reaction, with organic solvents insoluble in water such as toluene, xylene, diisopropyl ether, diethyl ether, dichloromethane preferably diisopropyl ether to remove starting material unreacted diol protected tert-butyl ester (a).
  • organic solvents insoluble in water such as toluene, xylene, diisopropyl ether, diethyl ether, dichloromethane preferably diisopropyl ether to remove starting material unreacted diol protected tert-butyl ester (a).
  • Aqueous calcium chloride solution in the range of 2 - 6% w/v preferably 4 - 5 % in the molar ratio of 1 - 2 preferably 1.65 is added during 30 - 90 minutes preferably 60 minutes at 50 - 55°C with the smooth and uniform precipitation of atorvastatin calcium. If mode of addition is reversed, a sticky material is obtained under similar condition of operations.
  • the precipitated material is stirred at 50 - 55°C for 15 - 60 minutes preferably for 60 minutes.
  • the precipitated material is cooled to 25 - 40°C preferably to 30 - 35°C, which is further cooled to 0 - 20°C preferably to 10 - 15°C. 12) The stirring is continued for 30 - 120 minutes preferably for 60 minutes at 10 - 15°C. 13) The material is centrifuged easily and is was ⁇ cu w ⁇ n u.ivi. water to remove excess calcium chloride.
  • the solution is then treated with activated carbon for 30 minutes and filtered to get absolutely clear transparent solution of atorvastatin calcium in a aqueous ethyl acetate, devoid of calcium hydroxide.
  • the material is precipitated by adding non-polar hydrocarbon solvent which is soluble in ethyl acetate such as n- hexane, n-heptane, cyclohexane etc. at a temperature 15 - 40°C preferably at 25 - 35°C.
  • non-polar hydrocarbon solvent results in the precipitation of the material which is cooled to 0 - 20°C, preferably to 10 - 15°C for 15 - 90 minutes preferably for 60 minutes.
  • the material is recovered by filtration and dried at 20 - 70°C preferably 50 - 60°C for 5 - 20 hours preferably for 8 - 10 hours.
  • the volume of filtered aqueous ethyl acetate solution of atorvastatin calcium is adjusted to 7 - 15 times, more preferably 10 times in volume as that of crude amorphous atorvastatin calcium by adding filtered ethyl acetate.
  • the water content in aqueous ethyl acetate solution of atorvastatin calcium after make up with fresh ethyl acetate is adjusted 2 -7%, more preferably 3.5 - 4.0% v/v before the addition of non polar hydrocarbon solvent to precipitate pure material.
  • the amount of non polar hydrocarbon solvent to precipitate the material from aqueous ethyl acetate solution of atorvastatin calcium is 0.5 - 5 times, more preferably 1 - 2 times in volume as that of aqueous ethyl acetate solution of atorvastatin calcium.
  • Residual solvent levels in the final product is well below the allowable limits i.e. n-hexane 2000 - 2250 ppm, ethyl acetate 200 - 250 ppm.
  • Figure 1 depicts X-ray Powder diffractogram of crude amorphous atorvastatin calcium.
  • the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Figures 2, 3 85 4 shows X-ray powder diffractograms of purified amorphous atorvastatin calcium.
  • the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Figure 5 shows X-ray powder diffractogram of form - I of atorvastatin calcium.
  • the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Figure 6 teaches X-ray powder diffractogram of amorphous atorvastatin calcium prepared by converting form - I of atorvastatin calcium.
  • the horizontal axis presents 2 ⁇ and the vertical axis corresponds to peak intensity.
  • Scheme 1 describes schematic representation and distribution of the intermediates formed during the treatment of methanolic solution of diol protected tert-butyl ester (a) with dilute hydrochloric aci ⁇ ana subsequent conversion of all the intermediates (b,c,d 8s e) as in scheme-I into a single product atorvastatin sodium (f) and then to atorvastatin calcium.
  • reaction mixture is washed with 200 It. of diisopropylether.
  • Aqueous methanolic solution containing atorvastatin sodium is charged into another S.S. Reactor and finally pH is checked and if necessary adjusted to 8.5 and the contents are heated to 50 - 55°C to which a aqueous solution of 2.8 Kg. calcium chloride in b ⁇ it.
  • Example 2 The examples disclosed herein are purification stages in which calcium hydroxide present in atorvastatin calcium is being removed-
  • atorvastatin calcium is dissolved in aqueous ethyl acetate solution resulting in a hazy solution to which 5 g activated carbon is added and the reaction mixture is stirred for 50 - 55°C for 30 minutes.
  • the mixture is cooled to 30 - 35°C then it is filtered through hyflow bed with 2 x 200 ml ethyl acetate wash.
  • the combined filtrate is then passed through 5 micron filter.
  • the volume of the filtrate is then adjusted to 1 It. by adding filtered fresh ethyl acetate.
  • the water content in ethyl acetate solution of atorvastatin calcium is adjusted to 3.5 - 4.0 % v/v if necessary.
  • Example 3 The example disclosed herein is a convenient procedure to convert crystalline forms of atorvastatin calcium in to amorphous atorvastatin calcium, exemplified here by converting form - I of atorvastatin calcium in to amorphous form.
  • atorvastatin calcium form - I 25 g is stirred with 200 ml ethyl acetate containing 9.0 ml D.M.Water at 50- 55°C.
  • the resulting hazy solution is stirred with 1.0 g activated carbon at 50 - 55°C tor 15 mm.
  • the solution is then cooled to 30 - 35°C and filtered through hyflow bed, with 2 x 25 ml ethyl acetate wash.
  • the combined filtrate is passed through 5 micron filter to get a clear solution.
  • the total volume of the filtrate is adjusted to 250 ml by adding fresh ethyl acetate.
  • the water content of filtrate is adjusted to 3.5 - 4% v/v, if necessary.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'atorvastatine calcique sous forme amorphe. Ce procédé consiste (i) à traiter un ester de tert-butyle à protection de diol avec une solution méthanolique, en présence d'un acide aqueux; (ii) à ajouter une solution aqueuse d'hydroxyde au mélange réactionnel et à retirer un ester de tert-butyle à protection de diol non réagi (a) par le biais d'une extraction de solvant ; (iii) à traiter le produit obtenu à l'étape (ii) avec une solution de chlorure de calcium afin d'obtenir un sel d'atorvastatine calcique amorphe; (iv) à isoler ledit sel brut; (v) à traiter le produit brut isolé selon la description avec du charbon actif dans de l'acétate d'éthyle aqueux ; (vi) à récupérer le produit par le biais de l'ajout d'une filtration de solvant d'hydrocarbure polaire et à effectuer un séchage pour produire de l'atorvastatine calcique amorphe pure.
PCT/IN2001/000111 2001-04-11 2001-06-13 Procede de production d'atorvastatine calcique sous forme amorphe WO2002083638A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN334MU2001 IN190564B (fr) 2001-04-11 2001-04-11
IN334/MUM/01 2001-04-11

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Cited By (22)

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Publication number Priority date Publication date Assignee Title
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)
EP1577297A1 (fr) * 2004-03-17 2005-09-21 Ranbaxy Laboratories, Ltd. Procede de production d'atorvastatine calcique sous forme amorphe
US6992194B2 (en) 2000-11-30 2006-01-31 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7122681B2 (en) 2002-02-19 2006-10-17 Teva Pharmaceutical Industries, Ltd. Desolvation process for the production of atorvastatin hemi-calcium essentially free of bound organic solvent
US7144915B2 (en) 2001-06-29 2006-12-05 Warner-Lambert Company, Llc Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
WO2007052296A2 (fr) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd Procede de preparation de calcium d'atorvastatine amorphe
EP1784389A1 (fr) * 2004-08-27 2007-05-16 Biocon Limited Processus pour calcium d'atorvastatine amorphe
WO2007057755A1 (fr) 2005-11-21 2007-05-24 Warner-Lambert Company Llc Nouvelles formes d’acide [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoique magnesium
EP1793815A2 (fr) 2004-09-30 2007-06-13 Dr. Reddy's Laboratories Ltd. Atorvastatine calcique amorphe
CZ298382B6 (cs) * 2004-03-10 2007-09-12 Zentiva, A. S. Zpusob prípravy amorfní formy hemivápenaté soli atorvastatinu a její stabilizace
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
EP1977738A1 (fr) 2003-06-12 2008-10-08 Warner-Lambert Company LLC Compositions pharmaceutiques d'atorvastatine, qui sont produites sans procédé de granulation
US7501450B2 (en) 2000-11-30 2009-03-10 Teva Pharaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7534810B2 (en) 2004-05-05 2009-05-19 Pfizer Inc. Salt forms of [R—(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid
WO2009082362A1 (fr) * 2007-11-05 2009-07-02 Ulkar Kimya San. Ve Tic. A.S. Procédé de procution de statines sous forme pure
WO2009090544A2 (fr) * 2008-01-16 2009-07-23 Matrix Laboratories Limited Procédé de production d'atorvastatine calcique amorphe
WO2009139730A1 (fr) * 2008-05-13 2009-11-19 Ulkar Kimya San. Ve Tic. A.S. Fabrication de nouvelles formes non cristallines d'atorvastatine calcique
US7655692B2 (en) 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
US7939675B2 (en) 2004-10-28 2011-05-10 Pfizer, Inc. Process for forming amorphous atorvastatin
US8026376B2 (en) 2004-07-20 2011-09-27 Pfizer, Inc. Forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1)
US9034913B2 (en) 2005-09-21 2015-05-19 Pfizer Inc. Process for annealing amorphous atorvastatin
CN114213270A (zh) * 2021-12-17 2022-03-22 江苏阿尔法药业股份有限公司 一种利用连续流微通道反应器合成阿托伐他汀钙中间体的方法

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GB0218781D0 (en) 2002-08-13 2002-09-18 Astrazeneca Ab Chemical process
GB0312896D0 (en) 2003-06-05 2003-07-09 Astrazeneca Ab Chemical process
US7790197B2 (en) 2003-06-09 2010-09-07 Warner-Lambert Company Llc Pharmaceutical compositions of atorvastatin
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
UY28501A1 (es) 2003-09-10 2005-04-29 Astrazeneca Uk Ltd Compuestos químicos
GB0324791D0 (en) 2003-10-24 2003-11-26 Astrazeneca Ab Chemical process
WO2006048888A1 (fr) * 2004-11-01 2006-05-11 Jubilant Organosys Limited Nouveau procede de preparation du sel de calcium d’atorvastatine amorphe
ES2263370B1 (es) * 2005-02-16 2007-12-01 Ercros Industrial, S.A. Atorvastatina calcica amorfa estabilizada y procedimiento para su obtencion.
ES2270722B1 (es) * 2005-09-15 2008-03-01 Ercros Industrial, S.A. Procedimiento para la obtencion de atorvastatina calcica amorfa.
US20090111997A1 (en) * 2005-11-23 2009-04-30 Aaron Cote Method of Generating Amorphous Solid for Water-Insoluble Pharmaceuticals
US20100260851A1 (en) * 2007-07-11 2010-10-14 Actavis Group Ptc Ehf Novel Polymorph of Atorvastatin Calcium and Use Thereof for the Preparation of Amorphous Atorvastatin Calcium
EP2075246A1 (fr) 2007-12-27 2009-07-01 M. J. Institute of Research Procédé de préparation de forme amorphe de sel hémicalcium atorvastanine
CN113321607A (zh) * 2020-02-28 2021-08-31 北京福元医药股份有限公司沧州分公司 一种阿托伐他汀钙中间体的纯化方法

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US7732623B2 (en) 1999-11-17 2010-06-08 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
US7342120B2 (en) 2000-11-30 2008-03-11 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7189861B2 (en) 2000-11-30 2007-03-13 Teva Pharmaceutical Industries, Ltd. Processes for preparing amorphous atorvastatin hemi-calcium
US6992194B2 (en) 2000-11-30 2006-01-31 Teva Pharmaceutical Industries, Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
US7256212B2 (en) 2000-11-30 2007-08-14 Teva Pharmaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
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