WO2008115912A1 - Synthèse régiospécifique de l'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique - Google Patents

Synthèse régiospécifique de l'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique Download PDF

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Publication number
WO2008115912A1
WO2008115912A1 PCT/US2008/057336 US2008057336W WO2008115912A1 WO 2008115912 A1 WO2008115912 A1 WO 2008115912A1 US 2008057336 W US2008057336 W US 2008057336W WO 2008115912 A1 WO2008115912 A1 WO 2008115912A1
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WIPO (PCT)
Prior art keywords
methyl
thiophene
propoxy
carboxylic acid
effected
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PCT/US2008/057336
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English (en)
Inventor
Gregory G. Kubiak
David J. Lythgoe
Yong Yu
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Sanofi-Aventis
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Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Publication of WO2008115912A1 publication Critical patent/WO2008115912A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
    • C07D333/48—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom by oxygen atoms

Definitions

  • This invention is directed to a two step regio-selective Ullmann synthesis of 4-bromo-3-methyl-5- propoxy-thiophene-2-carboxylic acid.
  • the invention is also directed to several intermediates leading to the 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid.
  • WO2001/13811 discloses compounds including [(benzylamine)-piperidin-l-yl] (aryl or heteroaryl)methanone as tryptase inhibitors, and describes potential uses for such compounds due to tryptase being implicated in a variety of biological processes, including degradation of vasodilating and bronchorelaxing neuropeptides (Caughey, et al., J. Pharmacol. Exp. Then, 1988, 244, pages 133- 137; Franconi, et al., J. Pharmacol. Exp. Then, 1988, 248, pages 947-951; and Tarn, et al., Am. J. Respir. Cell MoI. Biol., 1990, 3, pages 27-32) and modulation of bronchial responsiveness to histamine (Sekizawa, et al., J. Clin. Invest, 1989, 83, pages 175-179).
  • WO2005/097780 more particularly discloses the (benzylamine)-piperidin-l-yl thienylmethanone compound of formula A,
  • WO2005/097780 also discloses that the compound of the formula A is prepared through the coupling of the following compounds 16 and 10, and subsequent deprotection of the coupled product.
  • Compound 16 was prepared according to following multistep preparation
  • the present invention is directed to a regio-specific synthesis of 4-bromo-3-methyl-5-propoxy- thiophene-2-carboxylic acid compound of formula 16 comprising the steps of acetalating 3-methyl-thiophene-2-carbaldehyde in an alcohol solvent; iodinating the acetalated 3-methyl-thiophene-2-carbaldehyde in an non-protic polar or hydrocarbon solvent to yield the corresponding iodinated and acetalated 3-methyl- thiophene-2-carbaldehyde product; treating the iodinated and acetalated product with water to yield the corresponding 5- iodo-3-methyl-thiophene-2-carbaldehyde; oxidizing the S-iodo-S-methyl-thiophene-l-carbaldehyde to the corresponding 5-iodo- 3-methyl-thiophene-2-carboxylic acid in ketone solvent;
  • the invention is further directed to the following compounds
  • Acetalating means reacting with an alcohol such as MeOH, EtOH, or 1,2-ethylenediol or alcohol source such as trimethyl orthoformate under non-aqueous acidic conditions such as using dry HCl or tetrabutyl tribromide.
  • an alcohol such as MeOH, EtOH, or 1,2-ethylenediol or alcohol source such as trimethyl orthoformate under non-aqueous acidic conditions such as using dry HCl or tetrabutyl tribromide.
  • Alcohol solvent means MeOH, EtOH, or 1 ,2-ethylenediol, or the like.
  • Alkali metal means lithium, sodium, potassium or cesium.
  • Alkali metal propoxide salt means the salt form by the treatment of propanol with a strong base such as Cs 2 CO 3 , alkali metal base such as NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA), or alkylmetal such as alkyllithium, alkylpotassium, alkylsodium and alkylmagnesium wherein the alkyl is Ci_ 5 alkyl, more preferably butyl, i.e., CsOPr, NaOPr, LiOPr or KOPr.
  • Bromination organic solvent means a polar or inert organic solvent acceptable for effecting a bromination reaction, such as acetonitrile, organic acid such as acetic or propanoic acid or halogenated solvent such as methylene chloride or chloroform.
  • brominating means reacting with Br 2 or appropriate bromine source such as NBS.
  • Copper catalyst means a copper catalyst capable of effecting an Ullmann coupling is selected from the group consisting of CuSCN, CuBr, CuI, CuCl, CuBF 4 , CuPF 6 , CuOTf, CuPF 6 , CuBr 2 , CuCl 2 , and Cu 2 O.
  • Coupling co-solvent means an additional inert organic solvent such as THF, toluene, 2- methylTHF, or dimethoxyethane that could be combined with the propanol coupling solvent.
  • “Esterifying” means the conversion of the carboxylic group to its corresponding ester under esterification conditions such as reacting the acid with an alcohol in the presence of an acid or alkylating the acid converted to its corresponding carboxylic anion by treatment with base and with an alkylating agent such as Me 2 SO 4 , benzylbromide and MeI.
  • “Hydrolyzing co-solvent” means an inert polar organic solvent such as an ether such as 1 ,4-Dioxane, t-butyl methyl ether (TBME), isopropyl ethyl ether and diethyl ether.
  • Base hydrolyzing means using alkali metal hydroxides such as lithium, sodium or potassium hydroxides, or alkaline earth hydroxide to effect the hydrolysis.
  • Iodinating agent means I 2 , diiodoethylene, ICl or NIS.
  • Iodinating means reacting with I 2 , ICl or appropriate iodinating agent such as NBI in the presence of a strong base such as an alkyllithium base such as cyclohexyllithium, sec-butyllithium, n-butyllithium or lithium diisopropylamide, or the like.
  • a strong base such as an alkyllithium base such as cyclohexyllithium, sec-butyllithium, n-butyllithium or lithium diisopropylamide, or the like.
  • Iodinating solvent means a non-protic polar or hydrocarbon solvent, wherein a non-protic polar solvent is ether, t-butyl methyl ether (TBME), isopropyl ethyl ether, THF, 1,4-dioxane or 1,3- dioxolane, or the like, or hydrocarbon solvent such as toluene, xylene or heptane, or the like.
  • a non-protic polar solvent is ether, t-butyl methyl ether (TBME), isopropyl ethyl ether, THF, 1,4-dioxane or 1,3- dioxolane, or the like, or hydrocarbon solvent such as toluene, xylene or heptane, or the like.
  • Ketone solvent means a C 3 _ 5 such as acetone.
  • Oxidizing means treating with NaClO 2 / NaH 2 PO 4 « H 2 O/sulfamic acid, NaC10 2 /additives at a pH 1 ⁇ 10, KMnO 4 , silver oxide, H 2 O 2 or ozone.
  • the bromination organic solvent is acetic acid.
  • the acetal formation is effected at about - 10 0 C to about 20 0 C.
  • the iodinating is effected in THF.
  • the strong base used in the iodinating is n-BuLi.
  • the iodination agent is I 2 , diiodoethylene, ICl or NIS.
  • the iodinating is effected at about -80 0 C to about 0 0 C.
  • the oxidizing is effected using NaClO 2 / NaH 2 PO 4 « H 2 O/sulfamic acid.
  • the ketone solvent is acetone
  • the oxidizing is effected at about -1O 0 C to about 3O 0 C.
  • the alkali metal propoxide salt is CsOPr, NaOPr, LiOPr and KOPr.
  • the copper catalyst is CuOTf, CuSCN, CuBr, or CuI.
  • the coupling is carried out with heating at about 70 0 C to about 120 0 C depending on the solvent used and pressure utilized.
  • the brominating is effected from about O 0 C to about 10O 0 C, more particular at 75°C.
  • the brominating is effected using Br 2 .
  • the alkali metal propoxide salt is sodium propoxide.
  • the copper catalyst is CuSCN, CuBr, or CuI.
  • the temperature for hydrolyzing is effected from about O 0 C to about 5O 0 C.
  • the coupling is effected with a coupling co-solvent such as THF, toluene, 2-methylTHF, or dimethoxy ethane.
  • a coupling co-solvent such as THF, toluene, 2-methylTHF, or dimethoxy ethane.
  • the acetal is dissolved in THF (5.0 L), cooled to -60 0 C and n-BuLi (1.37 L, 2.5 M in hexane, 3.42 mol) is added over 75 minutes. The mixture is stirred at -60 0 C for 45 min. To this solution is added a THF solution of iodine (871 g, in 1.5 L THF, 3.42 mol) at -60 0 C over 40 minutes. The iodination is judged complete after 5 minutes (HPLC). After quenching with methanol (0.350 L) at -60 0 C, the reaction mixture is warmed to 15 0 C and held overnight. The dark-yellow reaction mixture is concentrated on rotary evaporator to afford a dark-yellow oil.
  • reaction mixture is concentrated by rotary evaporation to afford 587 g of dark-yellow solid.
  • 1,4-Dioxane (5.5 L) and water (4.6 L) are added, following by LiOH (223 g, 9.33 mol) at 3 0 C.
  • the reaction mixture is stirred at room temperature for 20 hr. After quenching with HCl (1.4 L, 6 N) at 2 0 C, water (1.1 L) is added.
  • the suspension is then filtered and the reactor and cake are washed with: 1100 mL dioxane/water (2:3), 3 x 600 mL of n-heptane, and 1100 mL acetone/n-heptane (1 :5).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Cette invention se rapporte à une synthèse régiospécifique en cinq étapes d'un acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique de formule 16 comprenant les étapes consistant à acétaler le 3-méthyl-thiophène-2-carbaldéhyde dans un solvant alcool ; à ioder le 3-méthyl-thiophène-2-carbaldéhyde acétalé dans un solvant polaire non-protique ou un solvant hydrocarboné pour produire le 3-méthyl-thiophène-2-carbaldéhyde iodé et acétalé correspondant ; à traiter le produit iodé et acétalé avec de l'eau pour produire le 5-iodo-3-méthyl-thiophène-2-carbaldéhyde correspondant ; à oxyder le 5-iodo-3-méthyl-thiophène-2-carbaldéhyde en acide 5-iodo-3-méthyl-thiophène-2-carboxylique correspondant dans un solvant cétone ; à effectuer une réaction de couplage d'Ullmann de l'acide 5-iodo-3-méthyl-thiophène-2-carboxylique avec un sel de propoxyde d'un métal alcalin en utilisant un catalyseur de cuivre dans du propanol pour produire l'acide 3-méthyl-5-propoxy-thiophène-2-carboxylique ; à estérifier l'acide 3-méthyl-5-propoxy-thiophène-2-carboxylique pour produire le 3-méthyl-5-propoxy-thiophène-2-carboxylate d'alkyle correspondant ; à bromer l'acide 3-méthyl-5-propoxy-thiophène-2-carboxylique pour produire le 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylate d'alkyle correspondant ; et effectuer une hydrolyse basique du 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylate d'alkyle avec une base pour produire l'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique.
PCT/US2008/057336 2007-03-21 2008-03-18 Synthèse régiospécifique de l'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique WO2008115912A1 (fr)

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US89610907P 2007-03-21 2007-03-21
US60/896,109 2007-03-21

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WO2008115912A1 true WO2008115912A1 (fr) 2008-09-25

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AR (1) AR065793A1 (fr)
TW (1) TW200902510A (fr)
WO (1) WO2008115912A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015052065A1 (fr) 2013-10-07 2015-04-16 Bayer Pharma Aktiengesellschaft Thiénouracile-carboxamides cycliques et utilisation associée
CN105085469A (zh) * 2015-09-11 2015-11-25 沧州那瑞化学科技有限公司 一种5-氯噻吩-2-羧酸的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097780A1 (fr) * 2004-03-26 2005-10-20 Aventis Pharmaceuticals Inc. [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2-yl)-methanone hydrochlorure tenant lieu d'inhibiteur de la mastocyte tryptase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097780A1 (fr) * 2004-03-26 2005-10-20 Aventis Pharmaceuticals Inc. [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2-yl)-methanone hydrochlorure tenant lieu d'inhibiteur de la mastocyte tryptase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; STEINKOPF, WILHELM ET AL: "Thiophene series. XLIX. Constitution of indophenins", XP002489932, retrieved from STN Database accession no. 1940:4694 *
JUSTUS LIEBIGS ANNALEN DER CHEMIE , 541, 238-60 CODEN: JLACBF; ISSN: 0075-4617, 1939 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015052065A1 (fr) 2013-10-07 2015-04-16 Bayer Pharma Aktiengesellschaft Thiénouracile-carboxamides cycliques et utilisation associée
US9604996B2 (en) 2013-10-07 2017-03-28 Bayer Pharma Aktiengesellschaft Cyclic thienouracil-carboxamides and use thereof
CN105085469A (zh) * 2015-09-11 2015-11-25 沧州那瑞化学科技有限公司 一种5-氯噻吩-2-羧酸的制备方法

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TW200902510A (en) 2009-01-16

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