WO2007096751A1 - Procédé de préparation d'atorvastatine calcique - Google Patents

Procédé de préparation d'atorvastatine calcique Download PDF

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Publication number
WO2007096751A1
WO2007096751A1 PCT/IB2007/000426 IB2007000426W WO2007096751A1 WO 2007096751 A1 WO2007096751 A1 WO 2007096751A1 IB 2007000426 W IB2007000426 W IB 2007000426W WO 2007096751 A1 WO2007096751 A1 WO 2007096751A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
atorvastatin
dimethyl
butyl ester
acetic acid
Prior art date
Application number
PCT/IB2007/000426
Other languages
English (en)
Inventor
Dhimant Jasubhai Patel
Rajiv Kumar
Shri Prakash Dhar Dwivedi
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.)
Filing date
Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2007096751A1 publication Critical patent/WO2007096751A1/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

Definitions

  • the present invention relates to an improved process for the preparation of atorvastatin protected diol which is used to produce atorvastatin calcium 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).
  • Atorvastatin protected diol has the Fo ⁇ nula-I given below.
  • Atorvastatin Calcium is a pharmaceutical
  • Statins are known as potent lipid lowering agents. Statins suppress cholesterol biosynthesis by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase, which catalyzes the conversion of HMG-CoA to mevalonate, which is the rate-determining step in the biosynthesis of cholesterol. They are currently the most therapeutically effective drugs available for the treatment of hyperlipidemia and hypercholesterolemia both of that are risk factors for arteriosclerosis and coronary heart disease.
  • Atorvastatin calcium is currently sold as Lipitor ® having the chemical name [R- (R*,R*)]-2-(4-fluorophenyl- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyrj-lH-pyrrole-1-heptanoic acid calcium salt (2:1). Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase.
  • Atorvastatin calcium is a potent lipid lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, Benign Prostatic Hyperplasia (BPH), and Alzheimer's disease.
  • the reference is silent in disclosing the melting point of the product and the crystal form of the product is not mentioned either.
  • WO 03/024959 discloses the process for the preparation- of intermediate polymorph Form - 1 and Form - II.
  • Paal-Knoor synthesis i.e. condensation of compound of Formula - II and Formula - III in the solvent ratio 1:4:1 of toluene, heptane and THF in presence of pivalic acid as a catalyst which is a known prior art to obtain compound of Formula - 1.
  • Another object of the present invention is to use the reagents i.e., amino side chain and stetter compound as the starting material in the mole ratio of 4:1 in order to obtain high yield of atorvastatin protected diol, thereby developing an industrially important process for the recovery of excess amino side chain.
  • the present invention provides pure atovastatin calcium in high yield by using atorvastatin protected diol. Summary of the Invention The present invention shows an improved process for the synthesis of
  • Atorvastatin Calcium The invention further discloses the use of Stetter Compound and Amino side chain as the starting substrates for the route of synthesis.
  • the reaction between Stetter Compound and amino side chain in the presence of cyclohexane, THF and Pivalic acid forms Atorvastatin protected diol, which is further, converted to final API, Atorvastatin Calcium.
  • This present invention provides process for the preparation of atorvastation protected diol by reacting amino side chain and stetter compound in the mole ratio of
  • the reaction can be preferably carried out in presence of inert organic solvent like cyclohexane, THF, and the like or mixtures there of. This reaction is also carried out in inert solvent like toluene, heptane, THF, and the like or mixtures there of in an appropriate mole ratio.
  • reaction is carried out in presence of catalytic amount of pivalic acid.
  • pH of the reaction mixture is adjusted by using liquor ammonia and the aqueous layer is extracted with the help of MDC.
  • reaction mixture is crystallized with mixture of IPA and water.
  • the present invention discloses the use of amino side chain and stetter intermediate in the improved mole ratio to get high yield and recovery of excess of amino side chain by an industrially useful procedure.
  • Example - 1 Step-1 Preparation of (4R-cis)-6-[-2-[3-phenyI-4-(phenyI-carbamoyl)-2-(4-flouro phenyl)-5-(l-methyl-ethyl)-pyrrol-l-yI]-ethyl]-2,2-dimethyl-[l,3]dioxane-4-yI- acetic acid-tertriay butyl ester
  • Stetter compound i.e. 4-(4-Fluorophenyl)-2-isobutryl-4-oxo-N- phenyl butryl amide (100 g, 0.24 mole) and Amino side chain i.e. [6-(2-aminoethyl)-
  • 2,2-dimethyl-[l,3]dioxan-4-yl]-acetic acid tert-butyl ester (261.9 g, 0.96 mole) was added at 25-35 0 C.
  • 100 ml THF and Pivalic acid (11.0 g, 0.11 mole) were added under same temperature condition.
  • the reaction mixture was heated up to reflux temperature 70-85 °C and the reflux was maintained for 18 hrs. After cooling the reaction mixture to room temperature (25-35 0 C), 500 ml water was added and stirred for 20 min.
  • Liq. Ammonia was added to adjust the pH between 8.5-9.5 and stirred for 30 min. at room temperature.
  • aq. layer is extracted with 2 x 500 ml MDC. From the combined MDC and cyclohexane layer, MDC and cyclohexane were distilled out. At this stage weight of the residue was 389.0 g.
  • step - 1 In a 2 L round bottom flask equipped with a mechanical stirrer and temperature as well as pH monitoring facility mother liquor (step - 1) and 429 ml water at 25 to 35 0 C temperature were taken. 100 ml of acetic acid was added at 25 to 35°C temperature. The reaction mixture was washed with 2 x 400 ml of toluene at room temperature. Organic layer was washed with 2 x 100 ml of 20% acetic acid solution at room temperature. The organic layer was discarded. Liquid ammonia was added by combining all the aqueous layer to adjust the pH 9 to 9.5 at 10 to 20 0 C. The reaction mixture was extracted with 3 x 400 ml of MDC. Combining all the MDC layer, MDC v/v at 45 to 5O 0 C was distilled out. Oily residue was obtained. Weight 200 g. Yield: 79.12% (considering the recovery of the amino side chain).
  • Example-2 Example-2:
  • Step-1 Preparation of [R-(R*,R*)]-2-(4-fluorophenyI- ⁇ , ⁇ -dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt (2:1) [Atorvastatin Calcium]
  • 50 g of atorvastatin protected diol and 500 ml methanol were added at 25-35 0 C. The temperature of the reaction mixture was raised up to 50-55 0 C.
  • the filtrate was transferred into 3 L round bottom flask at 25 - 35 °C.
  • the temperature of calcium chloride solution was raised up to 50 - 55 0 C.
  • Aqueous layer collected before was added into the calcium chloride solution at same temperature within 2 to 3 hrs.
  • the temperature of the reaction was maintained at the same temperature for next 1 hour.
  • the reaction mixture was cooled to room temperature 25 - 35 0 C and stirred for 1 hour. It was further cooled down to 10 - 15 0 C and stirred for 2 hrs.
  • the reaction mass was filtered and washed with water 50 ml x 3. The material was dried till constant weight was obtained at 50 - 55 0 C.
  • the yield of crude atorvastatin calcium obtained was 45.5g.
  • Step - 2 Purification of Atorvastatin calcium: -
  • the present invention provides an improved process for the synthesis of (4R-cis)- 6-[-2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-flourophenyl)-5-(l-methyl-ethyl)- pyrrol-l-yl]-ethyl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tert-butyl ester (Atorvastatin protected diol) with high yield as an important intermediate for preparation of atorvastatin calcium.
  • amino side chain used to obtain atorvastatin protected diol in the range of 1:1 to 1:10 of molar ratio to improve the yield.

Abstract

L'invention concerne un procédé de préparation d'atorvastatine calcique. Le procédé constitue une nouvelle technique de synthèse d'un produit intermédiaire chimique important de diol protégé d'atorvastatine, le composé (4R-cis)-6-[-2-[3-phényl-4-(phényl-carbamoyl)-2-(4-fluorophényl)-5-(1-méthyl-éthyl)-pyrrol-1-yl]-éthyl]-2,2-diméthyl- [1,3]dioxane-4-yl-acide acétique-butyl ester tertiaire pour atorvastatine calcique, c.-à-d. le sel calcique d'acide [R- (R*,R*)]-2-(4-fluorophényl-β,δ-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino) carbonyl]-1H-pyrrole-1-heptanoïque (2:1). L'invention concerne l'utilisation de la chaîne latérale amino [6-(2-aminoéthyl)-2,2,-diméthyl- [1,3]dioxan-4-yl]-acide acétique tert-butyl ester et du composé de Stetter 4-(4- fluorophényl)-2-isobutryl-4-oxo-N-phényl butryl amide comme matières premières importantes pour la préparation d'un diol protégé d'atorvastatine à haut rendement, et l'extraction de la chaîne latérale amino au moyen d'un procédé applicable au niveau industriel.
PCT/IB2007/000426 2006-02-21 2007-02-21 Procédé de préparation d'atorvastatine calcique WO2007096751A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN245/MUM/2006 2006-02-21
IN245MU2006 2006-02-21

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US13/495,233 Division US8479512B2 (en) 2006-11-23 2012-06-13 Internal combustion engine comprising an exhaust gas recirculation system

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WO2007096751A1 true WO2007096751A1 (fr) 2007-08-30

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102344401A (zh) * 2011-09-15 2012-02-08 景德镇市富祥药业有限公司 一种无定形阿托伐他汀钙的制备方法
CN101492405B (zh) * 2008-01-25 2012-05-09 石药集团中奇制药技术（石家庄）有限公司 阿伐他汀钙的制备方法
CN105693587A (zh) * 2016-01-15 2016-06-22 安徽悦康凯悦制药有限公司 一种阿托伐他汀钙的生产工艺
CN109180633A (zh) * 2018-10-09 2019-01-11 河南师范大学 一种阿托伐他汀钙中间体ats-9的纯化方法
CN109232355A (zh) * 2018-10-09 2019-01-18 河南师范大学 一种有效去除阿托伐他汀钙粗品中杂质阿托伐他汀缩合物的方法
CN115466196A (zh) * 2022-08-30 2022-12-13 宿迁阿尔法科技有限公司 一种阿托伐他汀钙中间体的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330172A2 (fr) * 1988-02-22 1989-08-30 Warner-Lambert Company Procédé de préparation de trans-6-[2-(pyrol-1-yl substitué)alkyl]pyran-2-one comme inhibiteurs de la synthèse du cholestérol
US5273995A (en) * 1989-07-21 1993-12-28 Warner-Lambert Company [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330172A2 (fr) * 1988-02-22 1989-08-30 Warner-Lambert Company Procédé de préparation de trans-6-[2-(pyrol-1-yl substitué)alkyl]pyran-2-one comme inhibiteurs de la synthèse du cholestérol
US5273995A (en) * 1989-07-21 1993-12-28 Warner-Lambert Company [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
K. L. BAUMANN ET AL: "The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase", TETRAHEDRON LETTERS, vol. 33, no. 17, 1992, pages 2283 - 2284, XP002443772 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101492405B (zh) * 2008-01-25 2012-05-09 石药集团中奇制药技术（石家庄）有限公司 阿伐他汀钙的制备方法
CN102344401A (zh) * 2011-09-15 2012-02-08 景德镇市富祥药业有限公司 一种无定形阿托伐他汀钙的制备方法
CN105693587A (zh) * 2016-01-15 2016-06-22 安徽悦康凯悦制药有限公司 一种阿托伐他汀钙的生产工艺
CN109180633A (zh) * 2018-10-09 2019-01-11 河南师范大学 一种阿托伐他汀钙中间体ats-9的纯化方法
CN109232355A (zh) * 2018-10-09 2019-01-18 河南师范大学 一种有效去除阿托伐他汀钙粗品中杂质阿托伐他汀缩合物的方法
CN115466196A (zh) * 2022-08-30 2022-12-13 宿迁阿尔法科技有限公司 一种阿托伐他汀钙中间体的制备方法
CN115466196B (zh) * 2022-08-30 2024-03-26 宿迁阿尔法科技有限公司 一种阿托伐他汀钙中间体的制备方法

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