WO2008035379A2 - Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants - Google Patents

Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants Download PDF

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Publication number
WO2008035379A2
WO2008035379A2 PCT/IN2007/000414 IN2007000414W WO2008035379A2 WO 2008035379 A2 WO2008035379 A2 WO 2008035379A2 IN 2007000414 W IN2007000414 W IN 2007000414W WO 2008035379 A2 WO2008035379 A2 WO 2008035379A2
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WIPO (PCT)
Prior art keywords
alkyl
acid
compound
hydrogen
chloro
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PCT/IN2007/000414
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English (en)
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WO2008035379A3 (fr
Inventor
Venkata Subbaraju Gottumukkala
Satyanarayana Chava
Someswara Rao Casukhela
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Aptuit Laurus Private Limited
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Publication of WO2008035379A2 publication Critical patent/WO2008035379A2/fr
Publication of WO2008035379A3 publication Critical patent/WO2008035379A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • the present invention provides a novel method of producing Montelukast sodium and novel intermediates therefore.
  • Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. It has been found that antagonists to leukotrienes can perform valuable functions in the treatment or amelioration of certain disease states, particularly those associated with inflammation.
  • Montelukast sodium is an important leukotriene antagonist and useful in the treatment of asthma and other related disorders.
  • the compound synthesized by this method has the following structural formula (VII') and the method comprises:
  • the malonate comprises one or more of potassium alkyl malonate or diethylmalonate. Such a reaction may occur in the presence of a base to produce a ⁇ -Keto ester.
  • methylbenzoate to form alkyl 3-bromomethylbenzoate.
  • 3-methylbenzoic acid reacts with an alcohol in the presence of a strong acid
  • alkyl 3-methylbenzoate for example sulphuric acid
  • Any suitable alcohol may be used, but preferably it is selected from one or more of methyl, ethyl, propyl, butyl or benzyl alcohol.
  • Bromination according to this aspect of the invention may be carried out in any suitable fashion. However, it has been found advantageous to carry it out with one or more of N- bromosuccinimide or l,3-Dibromo-5,5-dimethyl hydantoin and a suitable organic solvent.
  • the organic solvent is preferably selected from one or more of dichioromethane, chloroform, acetonitrile or carbon tetrachloride.
  • Conversion into a formyl group may occur by any suitable means. According to one preferred embodiment, conversion is in the presence of one or more of hexamine or manganese dioxide and a suitable solvent.
  • the solvent may be any suitable solvent, and preferably selected from one or more of acetic acid, aqueous acetic acid or water..
  • the condensation may be carried out in any suitable fashion. According to one preferred embodiment, it is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, (d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene.
  • the condensation temperature may be any suitable temperature required for the reaction. Preferably it is maintained between 80- 15O 0 C and more particularly between 100-130 0 C.
  • VI comprising hydrolysing alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate to give 3- [((7- Chloro-2-quinolinyl)ethenyl)]benzoic acid.
  • hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide.
  • the acid is treated with one or more of the thionyl chloride, thionyl chloride and triethylarnine. oxalyl chloride or DMF and POCI 3 to form the corresponding acid chloride.
  • the compound synthesized by this method has the following structural formula (VII') and the method comprises;
  • VU' converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; reacting 3-methylbenzoate to form alkyl 3-bromomethylbenzoate; converting alkyl 3-bromomethylbenzoate into alkyl 3-formylbenzoate; condensing alkyl 3-formylbenzoate with 7-Chioroquinaldine to give alkyl 3-[((7-Chloro-2-quinoliny)ethenyl)] benzoate; hydrolysing alkyl 3-[((7-Chloro- 2-quinolinyl)ethenyl)] benzoate to give 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoic acid; and reacting 3-[((7-Chloro-2-quinolinyl)ethenyl))benzoic acid with Potassium alkyl malonate to obtain a compound of structural formula VII'.
  • R 1 is substituted or unsubstituted alkoxyl, carbonyl, alkyl, alkenyl, ring structure, or hydrogen, or halogen, or alcohol
  • R 2 is substituted or unsubstituted alkoxyl, carbonyl, alkyl, alkenyl, ring structure, or a halogen, or alcohol
  • R 3 is substituted or unsubstituted alkoxyl, carbonyl, akyl, alkenyl, ring structure, or hydrogen, or halogen or alcohol.
  • Preferred compounds of the seventh aspect are those in which R 1 is a C1-C3 alcohol, R 2 is substituted or unsubstituted carbonyl; and R 3 is hydrogen. More preferably, Ri is CHO; and R 2 is carboxyl.
  • Ri is methyl, R 2 is carboxyl; and R 3 is Hydrogen; or ,
  • Ri is methyl, R 2 is COOR and R is lower alkyl or lower alkenyl and R 3 is Hydrogen; or
  • Ri is a halogen substituted methyl
  • R 2 is COOR and R is lower alkyl or lower alkenyl and R 3 is hydrogen; or
  • Ri is substituted alkyl or alkenyl; R 2 is substituted carbonyl; and R 3 is hydrogen or lower alkyl.
  • Ri is a compound of structural formula II and:
  • R 2 is substituted lower alkyl carboxyl; R 3 is hydrogen or lower alkyl; R 4 is C1-C5 alkyl or alkenyl; and R 5 is halogen, hydroxy or lower alkyl.
  • R 2 is COOR and R is hydrogen or lower alkyl, R 3 is hydrogen, R 4 is C2 alkenyl, and R 5 is halogen.
  • R 2 is
  • R 3 is hydrogen, R 4 is a 2 to 10 carbon-chain alkenyl group, R 5 is halogen and R 6 is halogen or hydroxyl.
  • R 4 comprises a 2 carbon alkenyl group; and R 6 is hydroxyl.
  • the product contains some dibromo derivative also.
  • Benzoyl peroxide could be used as a radical initiator.
  • Methyl 3-bromomethylbenzoate (220 g) was dissolved in an aqueous solution of acetic acid (1:1, 800 ml) and hexamine added (250 g, 1.8 mol) and heated at 60-65° for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice (3 Kg) under stirring. The solid precipitated was filtered, washed with water and dried under vacuum at room temperature.
  • Methyl 3-formylbenzoate (90 g, 0.55 mol) and 7-chloroquinaldine (89 g, 0.5 mol) were dissolved in a mixture of acetic acid (100 ml), toluene (80 ml) and pyridine (40 ml) and refluxed for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and diluted with hexane (500 ml) under stirring. The precipitated solid was filtered, washed with hexane (50 ml) and dried under vacuum. Brown solid, 145 g (89%, yield)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention concerne un procédé de synthèse d'un β- cétoester de formule (VII) qui consiste : (a) à transformer de l'acide 3-méthylbenzoïque en alkyle 3-méthylbenzoate; (b) à faire réagir le 3-méthylbenzoate afin d'obtenir de l'alkyle 3-bromométhylbenzoate; (c) à transformer l'alkyle 3-bromométhylbenzoate en alkyle 3-formylbenzoate; (d) à condenser l'alkyle 3-formylbenzoate avec de la 7-chioroquinaldine afin d'obtenir de l'alkyle 3-[((7-chloro-2-quinolinyl)éthényl)]benzoate; (e) à hydrolyser l'alkyle 3-[((7-chloro-2-quinolinyl)éthényl)]benzoate afin d'obtenir de l'acide 3-[((7-chloro-2-quinolinyl)éthényl)]benzoïque; puis (f) à mettre en réaction l'acide 3-[((7-chloro-2-quinolinyl)éthényl)]benzoïque avec du malonate afin d'obtenir un composé de formule développée VII.
PCT/IN2007/000414 2006-09-19 2007-09-14 Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants WO2008035379A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1710/CHE/2006 2006-09-19
IN1710CH2006 2006-09-19

Publications (2)

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WO2008035379A2 true WO2008035379A2 (fr) 2008-03-27
WO2008035379A3 WO2008035379A3 (fr) 2010-02-18

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7812168B2 (en) 2005-07-05 2010-10-12 Teva Pharmaceutical Industries Ltd. Purification of montelukast
CN101891649A (zh) * 2010-07-06 2010-11-24 荆州市腾飞化工有限公司 一种制备3-氰基苯甲酸甲酯的新生产方法
CN102617460A (zh) * 2012-03-29 2012-08-01 中国科学院上海有机化学研究所 一种合成孟鲁司特钠所需中间体的合成方法
WO2017060148A1 (fr) 2015-10-05 2017-04-13 Basf Se Dérivés de pyridine pour lutter contre des champignons phytopathogènes
WO2018065182A1 (fr) 2016-10-04 2018-04-12 Basf Se Composés de quinoléine réduits en tant qu'agents antifuni
WO2018134127A1 (fr) 2017-01-23 2018-07-26 Basf Se Composés de pyridine fongicides
WO2019115343A1 (fr) 2017-12-15 2019-06-20 Basf Se Mélange fongicide comprenant des pyridines substituées
US11064697B2 (en) 2015-07-24 2021-07-20 Basf Se Pyridine compounds useful for combating phytopathogenic fungi
US11317628B2 (en) 2015-09-03 2022-05-03 BASF Agro B.V. Microparticle compositions comprising saflufenacil

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021974A1 (fr) * 2004-08-23 2006-03-02 Morepen Laboratories Limited Procede pour synthetiser un diol (viii), intermediaire du sodium de montelukast
WO2008058118A2 (fr) * 2006-11-06 2008-05-15 Dr. Reddy's Labortories, Ltd. Préparation de montélukast et de ses sels
WO2009001374A2 (fr) * 2007-06-25 2008-12-31 Aptuit Laurus Pvt Ltd Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006021974A1 (fr) * 2004-08-23 2006-03-02 Morepen Laboratories Limited Procede pour synthetiser un diol (viii), intermediaire du sodium de montelukast
WO2008058118A2 (fr) * 2006-11-06 2008-05-15 Dr. Reddy's Labortories, Ltd. Préparation de montélukast et de ses sels
WO2009001374A2 (fr) * 2007-06-25 2008-12-31 Aptuit Laurus Pvt Ltd Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
OKAMOTO ET AL.: 'A Novel Dual Antagonist of Thromboxane A2 and Leukotriene D4 Receptors: Synthesis and Structure-Activity Relationships of Chloroquinolylvinyl Derivatives' CHEMICAL & PHARMACEUTICAL BULLETIN vol. 54, no. 5, 2006, pages 603 - 610 *
The Combined Chemical Dictionary *
'Vogel's Textbook of Practical Organic Chemistry', LONGMAN SCIENTIFIC & TECHNICAL page 738, 999 *
WIERENGA W. ET AL.: 'ALIPHATIC AND AROMATIC beta-KETO ESTERS FROM MONOETHYL MALONATE: ETHYL 2- BUTYRYLACETATE' ORGANIC SYNTHESES, [Online] vol. 61, 1983, pages 5 - 8 Retrieved from the Internet: <URL:http://www.orgsyn.org/orgsyn/pdfs/CV7P0213.pdf> *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7812168B2 (en) 2005-07-05 2010-10-12 Teva Pharmaceutical Industries Ltd. Purification of montelukast
CN101891649A (zh) * 2010-07-06 2010-11-24 荆州市腾飞化工有限公司 一种制备3-氰基苯甲酸甲酯的新生产方法
CN101891649B (zh) * 2010-07-06 2013-05-08 荆州市腾飞化工有限公司 一种制备3-氰基苯甲酸甲酯的生产方法
CN102617460A (zh) * 2012-03-29 2012-08-01 中国科学院上海有机化学研究所 一种合成孟鲁司特钠所需中间体的合成方法
US11064697B2 (en) 2015-07-24 2021-07-20 Basf Se Pyridine compounds useful for combating phytopathogenic fungi
US11317628B2 (en) 2015-09-03 2022-05-03 BASF Agro B.V. Microparticle compositions comprising saflufenacil
WO2017060148A1 (fr) 2015-10-05 2017-04-13 Basf Se Dérivés de pyridine pour lutter contre des champignons phytopathogènes
WO2018065182A1 (fr) 2016-10-04 2018-04-12 Basf Se Composés de quinoléine réduits en tant qu'agents antifuni
WO2018134127A1 (fr) 2017-01-23 2018-07-26 Basf Se Composés de pyridine fongicides
WO2019115343A1 (fr) 2017-12-15 2019-06-20 Basf Se Mélange fongicide comprenant des pyridines substituées

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