WO2011127599A1 - Préparation de butyrate de clévidipine - Google Patents

Préparation de butyrate de clévidipine Download PDF

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Publication number
WO2011127599A1
WO2011127599A1 PCT/CA2011/050191 CA2011050191W WO2011127599A1 WO 2011127599 A1 WO2011127599 A1 WO 2011127599A1 CA 2011050191 W CA2011050191 W CA 2011050191W WO 2011127599 A1 WO2011127599 A1 WO 2011127599A1
Authority
WO
WIPO (PCT)
Prior art keywords
butyrate
clevidipine
water
clevidipine butyrate
heptane
Prior art date
Application number
PCT/CA2011/050191
Other languages
English (en)
Inventor
Fabio Souza
Ming PAN
Original Assignee
Alphora Research Inc.
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 Alphora Research Inc. filed Critical Alphora Research Inc.
Publication of WO2011127599A1 publication Critical patent/WO2011127599A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • This invention relates to clevidipine butyrate, a pharmaceutically active dihydropyridine calcium channel blocker used as a fast acting intravenous antihypertensive in critical care settings, and processes for its preparation.
  • Compound 1 is prepared by basic hydrolysis of cyanoethyl ester 2, which can be in turn prepared via the Hantzsch reaction (condensation of two moles of a ⁇ -dicarbonyl compound with one mole of an aldehyde in the presence of ammonia, to form a dihydropyridine), or the corresponding Knoevenagel-Fries modification.
  • Preparation of clevidipine as reported in US patents 5,856,346 and 6,350,877 involves reacting a salt of 1 - either generated in situ or pre-formed - with chloromethyl butyrate.
  • the salt of 1 is generated by reaction with an inorganic base, so that the cation is an inorganic cation (specifically sodium or potassium).
  • yields range from 66-90%, with purity ranging from 98.8-99.6%, with the best results being reported to be obtained when pre-formed salt of 1 is employed.
  • pre-forming and isolating the salt of 1 add additional steps to the process, with adverse effects on costs and yields.
  • TMAH tetramethylammonium hydroxide
  • organic base tetramethylammonium hydroxide
  • Yield and purity of the crude material produced are typically greater than 80% and 99.3%, respectively.
  • Use of TMAH eliminates the need to pre-form salt 1.
  • the procedure of the invention is robust with respect to the tolerance of high levels of impurities. Starting materials of purity as low as 92.5% can be used, and a pharmaceutically acceptable product obtained.
  • a process of preparing clevidipine butyrate which comprises reacting an acid of formula 1 : with tetramethylammonium hydroxide and chloromethyl butyrate.
  • the free acid form of compound 1 is suitably prepared by basic hydrolysis of cyanoethyl ester 2, described above. Then the free acid can be reacted with solid TMAH, optionally in the form of a hydrate, in dioxane solvent. It is also preferred to add a small amount of water, e.g. 2-10% v/v, to the reaction, so as to obtain crude material of suitable quality.
  • This reaction to produce the tetramethylammonium salt of compound 1 can be conducted at room temperature, with stirring. After substantial completion of the reaction, the chloromethyl butyrate is preferably added to the same reaction vessel, without recovering the carboxylate. The alkylation process proceeds under reflux conditions. When the reaction is complete, the reaction mixture is allowed to cool to some degree, and the organic phase containing the desired solid product is subjected to filtration to recover the solids. After suitable washing and drying, crude clevidipine butyrate is obtained.
  • clevidipine butyrate 40. Og, 88 mmol
  • isopropanol 400ml_
  • deionized water 400ml_
  • the precipitated solids were collected by filtration and washed with a mixture of deionized water and isopropanol, followed by heptane. Drying under high vacuum at 40°C gave clevidipine butyrate as an off white solid (36.6g, 80 mmol, 91 % yield).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un procédé permettant de préparer du butyrate de clévidipine O3-(butanoyloxyméthyl)-O5-méthyl-4-(2,3-dichlorophényl)- 2,6-diméthyl-1,4-dihydropyridine-3,5-dicarboxylate par l'alkylation de 4-(2,3-dichlorophényl)-1,4-dihydro-2,6-diméthyl-5-méthoxycarbonyl-3-pyridine acide carboxylique avec de l'hydroxyde de tétraméthylammonium et du butyrate de chlorométhyle dans un solvant dioxane/eau. Le produit final est purifié par cristallisation dans un système de solvant mixte constitué de dichlorométhane/héptane ou d'isopropano/eau.
PCT/CA2011/050191 2010-04-12 2011-04-12 Préparation de butyrate de clévidipine WO2011127599A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA2,701,087 2010-04-12
CA 2701087 CA2701087A1 (fr) 2010-04-12 2010-04-12 Preparation de butyrate de clevidipine

Publications (1)

Publication Number Publication Date
WO2011127599A1 true WO2011127599A1 (fr) 2011-10-20

Family

ID=44786869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2011/050191 WO2011127599A1 (fr) 2010-04-12 2011-04-12 Préparation de butyrate de clévidipine

Country Status (2)

Country Link
CA (1) CA2701087A1 (fr)
WO (1) WO2011127599A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103382175A (zh) * 2012-05-04 2013-11-06 上海医药工业研究院 一种丁酸氯维地平晶型ⅱ的制备方法
CN105198797A (zh) * 2015-11-12 2015-12-30 华仁药业股份有限公司 丁酸氯维地平的纯化方法
CN107449834A (zh) * 2016-05-31 2017-12-08 江苏正大丰海制药有限公司 一种氯维地平及其脂肪乳注射液中有关物质的检测方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856346A (en) * 1993-11-05 1999-01-05 Astra Aktiebolag Short-acting dihydropyridines
CA2349195A1 (fr) * 1998-11-23 2000-06-02 Astrazeneca Ab Nouveau procede de fabrication

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856346A (en) * 1993-11-05 1999-01-05 Astra Aktiebolag Short-acting dihydropyridines
CA2349195A1 (fr) * 1998-11-23 2000-06-02 Astrazeneca Ab Nouveau procede de fabrication

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103382175A (zh) * 2012-05-04 2013-11-06 上海医药工业研究院 一种丁酸氯维地平晶型ⅱ的制备方法
CN103382175B (zh) * 2012-05-04 2016-02-24 上海医药工业研究院 一种丁酸氯维地平晶型ⅱ的制备方法
CN105198797A (zh) * 2015-11-12 2015-12-30 华仁药业股份有限公司 丁酸氯维地平的纯化方法
CN107449834A (zh) * 2016-05-31 2017-12-08 江苏正大丰海制药有限公司 一种氯维地平及其脂肪乳注射液中有关物质的检测方法
CN107449834B (zh) * 2016-05-31 2020-04-07 江苏正大丰海制药有限公司 一种氯维地平及其脂肪乳注射液中有关物质的检测方法

Also Published As

Publication number Publication date
CA2701087A1 (fr) 2011-10-12

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