WO2009001374A2 - Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast - Google Patents

Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast Download PDF

Info

Publication number
WO2009001374A2
WO2009001374A2 PCT/IN2008/000398 IN2008000398W WO2009001374A2 WO 2009001374 A2 WO2009001374 A2 WO 2009001374A2 IN 2008000398 W IN2008000398 W IN 2008000398W WO 2009001374 A2 WO2009001374 A2 WO 2009001374A2
Authority
WO
WIPO (PCT)
Prior art keywords
chloro
amine
alkyl
formula
ethenyl
Prior art date
Application number
PCT/IN2008/000398
Other languages
English (en)
Other versions
WO2009001374A3 (fr
Inventor
Ventaka Subba Raju Gottumukkala
Someswara Rao Casukhela
Satyanarayana Chava
Seeta Ramanjaneyulu Gorantla
Original Assignee
Aptuit Laurus Pvt Ltd
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 Aptuit Laurus Pvt Ltd filed Critical Aptuit Laurus Pvt Ltd
Publication of WO2009001374A2 publication Critical patent/WO2009001374A2/fr
Publication of WO2009001374A3 publication Critical patent/WO2009001374A3/fr

Links

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 improved methods for preparing ⁇ - ketoester derivatives which are key intermediate for producing leukotriene antagonists and their pharmaceutically acceptable salts.
  • the invention provides improved methods for preparing ⁇ - ketoester derivatives which are key intermediate for producing Montelukast.
  • 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 desired ⁇ -Keto ester ( ⁇ i) has been obtained through a sequence of steps consisting of the condensation of 7- chloroquinaldine and isophthalaldehyde in presence of acetic anhydride the reaction of the resulting aldehyde with methyl magnesium halide to produce a secondary alcohol, oxidation of the secondary alcohol to give an aromatic ketone and reaction of the aromatic ketone with dialkylcarbonate.
  • the main object of the invention is to provide a method of synthesizing a compound of formula III:
  • R is alkyl, alkenyl, aryl or arylalkyl.
  • the compound synthesized by this method has the following structural formula and the method comprises;
  • Wherin R 1 and R are individually alkyl, alkenyl, aryl or arylalkyl.
  • Another object of the invention is to provide an alternate, safer and scalable process for synthesizing the ⁇ -Keto ester of formula (in):
  • R is alkyl, alkenyl, aryl or arylalkyl.
  • the compound synthesized by this method has the following structural formula and the method comprises;
  • R is alkyl, alkenyl, aryl or arylalkyl.
  • the present invention provides a process for synthesizing ⁇ - ketoester (m) an intermediate of Montelukast sodium which comprises:
  • the reaction in step (a) may be carried out in an organic solvent alone or in the presence of an organic amine or in presence of an amine and an organic acid.
  • the organic amine used is selected from primary amine, secondary amine, tertiary amine and mixtures thereof.
  • the oraganic acid used is selected from acetic acid, pivalic acid or benzoic acid.
  • the organic solvent used is selected but not restricted from the groups aliphatic hydrocarbons, aromatic hydrocarbons, esters, halogenated hydrocarbons and mixture thereof, at a temperature ranging from room temperature to reflux temperature of the solvent, preferably above 80 0 C.
  • the reaction can also be carried out in the organic amine alone, wherein the organic amine itself is used both as a base and reaction medium.
  • the reaction in step (b) may be carried out in presence of a base which is selected from hydrides and alkoxides of alkali metals and alkaline earth metals, preferable base is sodium hydride.
  • a base which is selected from hydrides and alkoxides of alkali metals and alkaline earth metals, preferable base is sodium hydride.
  • the reaction being carried out in presence of an ester including but not restricted to methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate or mixture thereof at a temperature ranging from room temperature to boiling point of the solvent.
  • the reaction in step (a) may be carried out in presence of an organic solvent in the presence of an organic amine.
  • the organic amine used is selected from primary amine, secondary amine, tertiary amine and mixtures thereof.
  • the organic solvent used is selected but not restricted from the groups aliphatic hydrocarbons, aromatic hydrocarbons, esters, halogenated hydrocarbons and mixture thereof, at a temperature ranging from room temperature to reflux temperature of the solvent.
  • reaction in step (b) may be carried out in presence of ⁇ -haloester of the structural formula XCH 2 COOR wherein X is chloro or bromo.
  • R is alkyl, alkenyl or aryl and a metal catalyst selected but not restricted to Zn, Al, In, Sn or mixtures thereof.
  • the reaction in step (c) may be carried out in presence of Collins reagent wherein the Collins reagent is being made from MnO 2 , chromium salts or chromium complexes.
  • Ethyl 3-formylbenzoate (48 g, 0.269 mol) and 7-chloroquinaldine (43.5g, 0.2451mol) were suspended in toluene (240 ml), added piperidine (4.9 ml; 0.049 mol) then heated to reflux for 10 hrs by collecting water azetropically. After completion of the reaction, distilled 50% of toluene from reaction mass under vacuum at below 70 0 C. The obtained residue was cooled to 20-25 0 C and stirred for 1 hr. The reaction mass was further cooled to O 0 C for and stirred for another 2 hrs at 0-5 0 C.
  • reaction mass was cooled to 0-5 0 C and acetic acid (70 ml) was added slowly drop wise by maintaining temperature below 5 0 C to adjust the reaction mass PH at 5-6.
  • Distilled THF from the reaction mixture and the obtained residue was suspended in a mixture of water (500 ml) and toluene (500 ml), then filtered through celite bed and washed with toluene (50 ml). Organic layer was separated and athe aq.layer was extracted with toluene (100 ml). The combined toluene layers were washed with water (250 ml) distilled around 75-80% of solvent.
  • Isophthaldehyde (8.3 g, 0.0619 mol), 7-chloroquinaldine (10.0g, 0.05629 mol) and piperidine (0.95 g; 0.01115 mol) were suspended in toluene (50 ml) then heated to reflux for 12 h by collecting water azeotropically. After completion of the reaction, reaction mass was cooled to 20-25 0 C and stirred for 1 hr. The reaction mass was further cooled to 0-5 0 C and stirred for another 1-2 h at 0-5 0 C. The precipitated product was filtered and washed with n-hexane (12 ml). The product was dried at 55-60 0 C for 6 h (wt: 10.0 g; 60% of yield).
  • Example-4 Preparation of Ethyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phenyl]-3- hydroxy propanoate:
  • reaction mass was cooled to 20 0 C 5 separated the upper solvent phase and lower solid phase was dissolved in 10% aq. HCl (200 ml) and stirred for another 2 hrs at room temperature.
  • Compound was extracted into ethylacetate, washed with 10% aq. Sodium bicarbonate solution (50 ml) followed by vacuum salt (50 ml). Separated the organic layer, dried on sodium sulphate, filtered and concentrated to give the product (wt: 12g; 46% of yield).
  • reaction mass was stirred at 20-25 0 C for 12 hrs. After completion of the reaction, reaction mass was diluted with water (10 ml). Organic layer was separated and washed with 10% aq. HCl (10 ml) followed by vacuum salt (10 ml). The organic layer was dried on sodium sulphate and concentrated to give the product (0.2g, 40% of yield).

Landscapes

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

Abstract

L'invention porte sur un procédé de préparation de β- cétoester de formule (III) qui consiste à : (a) condenser alkyl 3- formylbenzoate avec 7-Chloroquinaldine pour obtenir alkyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzoate; et (b) faire réagir alkyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzoate avec un ester alkylique en présence d'hybrides métalliques/alcoxydes métalliques pour obtenir un composé β- cétoester de formule structurale (III) ou (a) condenser l'isophthalaldéhyde avec 7-Chloroquinaldine pour obtenir Ethyl 3-[((7-chloro-2- quinolinyl) ethenyl)] benzaldéhyde; (b) faire réagir Ethyl 3-[((7-chloro-2-quinolinyl) ethenyl)] benzaldéhyde avec un α-halo ester en présence d'un catalyseur métallique pour obtenir Ethyl 3'-[((7-chloro- 2-quinolinyl) ethenyl)phenyl] -3 -hydroxy propanoate; et (c) traiter Ethyl 3'-[((7-chloro-2- quinolinyl)ethenyl)phenyl]-3-hydroxy propanoate avec un réactif de Collins dans un solvant organique pour obtenir un composé β- cétoester de formule structurale (III).
PCT/IN2008/000398 2007-06-25 2008-06-24 Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast WO2009001374A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1353/CHE/2007 2007-06-25
IN1353CH2007 2007-06-25

Publications (2)

Publication Number Publication Date
WO2009001374A2 true WO2009001374A2 (fr) 2008-12-31
WO2009001374A3 WO2009001374A3 (fr) 2011-06-30

Family

ID=40186130

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000398 WO2009001374A2 (fr) 2007-06-25 2008-06-24 Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast

Country Status (1)

Country Link
WO (1) WO2009001374A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035379A2 (fr) * 2006-09-19 2008-03-27 Aptuit Laurus Private Limited Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants
WO2012020271A1 (fr) 2010-08-11 2012-02-16 Richter Gedeon Nyrt. Procédé pour la préparation de montélukast sodique
WO2014081616A1 (fr) * 2012-11-21 2014-05-30 Merck Sharp & Dohme Corp. Préparation de précurseurs d'antagonistes de leucotriène
CN104109122A (zh) * 2013-04-16 2014-10-22 浙江奥翔药业有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN116375639A (zh) * 2023-04-19 2023-07-04 南京欧信医药技术有限公司 一种微通道法制备孟鲁司特钠中间体的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375348A1 (fr) * 1988-12-23 1990-06-27 Smithkline Beecham Corporation Antagonistes de leukotriène
EP0480716A1 (fr) * 1990-10-12 1992-04-15 Merck Frosst Canada Inc. Acides hydroxyalkylquinoliniques saturés comme antagonistes de leukotriène
US5869673A (en) * 1997-02-28 1999-02-09 Merck & Co., Inc. Process for 3-(2-(7-chloro-2-quinolinyl)ethenyl) - benzaldehyde
US20030195201A1 (en) * 2001-12-10 2003-10-16 Bo Yunxin Y. Vanilloid receptor ligands and their use in treatments

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375348A1 (fr) * 1988-12-23 1990-06-27 Smithkline Beecham Corporation Antagonistes de leukotriène
EP0480716A1 (fr) * 1990-10-12 1992-04-15 Merck Frosst Canada Inc. Acides hydroxyalkylquinoliniques saturés comme antagonistes de leukotriène
US5869673A (en) * 1997-02-28 1999-02-09 Merck & Co., Inc. Process for 3-(2-(7-chloro-2-quinolinyl)ethenyl) - benzaldehyde
US20030195201A1 (en) * 2001-12-10 2003-10-16 Bo Yunxin Y. Vanilloid receptor ligands and their use in treatments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OKARNOTO ET AL.: 'A Novel Dual Antagonist of Thromboxane A2 and Leukotriene D4 Receptors: Synthesis and Structure-Activity Relationships of Chioroquinolylvinyl Derivatives' CHEMICAL & PHARMACEUTICAL BULLETIN vol. 54, no. 5, 2006, pages 603 - 610 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035379A2 (fr) * 2006-09-19 2008-03-27 Aptuit Laurus Private Limited Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants
WO2008035379A3 (fr) * 2006-09-19 2010-02-18 Aptuit Laurus Private Limited Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants
WO2012020271A1 (fr) 2010-08-11 2012-02-16 Richter Gedeon Nyrt. Procédé pour la préparation de montélukast sodique
WO2014081616A1 (fr) * 2012-11-21 2014-05-30 Merck Sharp & Dohme Corp. Préparation de précurseurs d'antagonistes de leucotriène
CN104109122A (zh) * 2013-04-16 2014-10-22 浙江奥翔药业有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN104109122B (zh) * 2013-04-16 2017-03-29 浙江奥翔药业股份有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN116375639A (zh) * 2023-04-19 2023-07-04 南京欧信医药技术有限公司 一种微通道法制备孟鲁司特钠中间体的方法
CN116375639B (zh) * 2023-04-19 2024-05-28 南京欧信医药技术有限公司 一种微通道法制备孟鲁司特钠中间体的方法

Also Published As

Publication number Publication date
WO2009001374A3 (fr) 2011-06-30

Similar Documents

Publication Publication Date Title
US8759525B2 (en) Process and intermediates for preparing integrase inhibitors
US7417149B2 (en) Process for the preparation of Montelukast
WO2009001374A2 (fr) Préparation de éthyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phényl]-3-oxopropanoate, clé intermédiaire pour le sodium de montelukast
WO2008035379A2 (fr) Procédé de production d'antagonistes de leucotriène et produits intermédiaires correspondants
CN112110828A (zh) 一种贝派地酸的合成方法及其中间体
CN101490005B (zh) 孟鲁司特的纯化方法
CN109503380A (zh) 4-烷氧基乙酰乙酸酯类化合物的合成方法
US20030105329A1 (en) Process for the production of piperidine derivatives
CN111004121A (zh) 一种4-烷氧基乙酰乙酸酯类化合物的制备方法
TWI588135B (zh) 用於製備特定４－羥－２－側氧基－２，５－二氫呋喃－３－羧酸酯類鹼金屬鹽之多階段方法
TW201231159A (en) Recyclable catalysts for esterification or acylation of alcohols
KR100301335B1 (ko) 알파-아릴-감마-부티로락톤의제조방법
CN113072471B (zh) 一种利非司特中间体及其制备方法
JPH0841029A (ja) ３−置換キノリン−５−カルボン酸誘導体およびその製造法
JP2001302658A (ja) ３−イソクロマノン類の製造方法
US9593086B2 (en) Process for the preparation of deferasirox
US20080300404A1 (en) Process for the Preparation of Mycophenolate Mofetil
JP6256469B2 (ja) スピロ［２．５］オクタン−５，７−ジオンの調製プロセス
CN115417793A (zh) 一种制备(E)-2-甲基-α-甲氧亚胺基苯乙酸甲酯的方法
EP0245913B1 (fr) Procédé pour la préparation de l'acide 6,7-dihydro-5,8-diméthyl-9-fluoro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylique
CN116606250A (zh) 一种孟鲁司特钠关键中间体的制备方法
JP4427661B2 (ja) ２−アルキリデン−４−ブロモアセト酢酸エステル類の製造方法
JPS6212784B2 (fr)
JPH06107599A (ja) 芳香族ジカルボン酸モノエステル類の製造方法
JP2893883B2 (ja) アセチレンジカルボン酸エステルの製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08789903

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 13.04.2010.)

122 Ep: pct application non-entry in european phase

Ref document number: 08789903

Country of ref document: EP

Kind code of ref document: A2