WO2008109786A2 - Synthèse d'ullmann régio-sélective de l'acide 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylique - Google Patents

Synthèse d'ullmann régio-sélective de l'acide 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylique Download PDF

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Publication number
WO2008109786A2
WO2008109786A2 PCT/US2008/056112 US2008056112W WO2008109786A2 WO 2008109786 A2 WO2008109786 A2 WO 2008109786A2 US 2008056112 W US2008056112 W US 2008056112W WO 2008109786 A2 WO2008109786 A2 WO 2008109786A2
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WO
WIPO (PCT)
Prior art keywords
thiophene
methyl
carboxylic acid
propoxy
bromo
Prior art date
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PCT/US2008/056112
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English (en)
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WO2008109786A3 (fr
Inventor
Timothy A. Ayers
Ann Marie Gelormini
John J. Shay, Jr.
Adam W. Sledeski
Yong Yu
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Sanofi-Aventis
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Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Publication of WO2008109786A2 publication Critical patent/WO2008109786A2/fr
Publication of WO2008109786A3 publication Critical patent/WO2008109786A3/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
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention is directed to a two step regio-selective Ullmann synthesis of 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. Ther., 1988, 244, pages 133-137; Franconi, et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947- 951; and Tarn, et al., Am. J. Respir. Cell MoL 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, its preparation, and use for treating disease states capable of being modulated by the inhibition of tryptase.
  • 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 two step regio-selective Ullmann synthesis of 4-bromo- S-methyl-S-propoxy-thiophene-l-carboxylic acid compound of formula 16 comprising the steps of brominating 3-methyl-thiophene-2-carboxylic acid to yield 4,5-dibromo-3-methyl- thiophene-2-carboxylic acid in appropriate bromination organic solvent, and then effecting the selective Ullmann coupling of the 4,5-dibromo-3-methyl-thiophene-2-carboxylie acid with alkali metal propoxide salt using copper catalyst in propanol to yield the compound of formula 16.
  • Alkali metal of the alkali metal propoxide salt includes lithium, sodium and potassium, more particularly sodium.
  • Alkali metal propoxide salt means the salt form by the treatment of propanol with a strong alkali meal base such as NaH, NaHMDS, KHMDS, and LiHMDS.
  • Bromination organic solvent menas 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 mean a copper catalyst capable of effecting an Ullmann coupling inclusive of CuSCN, CuBr, CuI, CuOTf, CuPF 6 and Cu 2 O, more particular CuSCN, CuBr, and CuI.
  • Coupling cosolvent means an additional inert organic solvent such as THF, toluene, 2- methylTHF, or dimethoxyethane that could be combined with the propanol coupling solvent.
  • the bromination organic solvent is acetic acid.
  • the bromination is effected from about room temperature to about 100 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 coupling is effected with heating at about 70 °C to 110 °C depending on the solvent combination and pressure utilized, more particular at about 95 0 C.
  • the coupling is effected with a coupling cosolvent such as THF, toluene, 2-methylTHF, or dimethoxyethane.
  • a coupling cosolvent such as THF, toluene, 2-methylTHF, or dimethoxyethane.
  • the starting materials and intermediates may be prepared by the application or adaptation of known methods or their obvious chemical equivalents.
  • Example which is exemplary of the invention.
  • the following example is presented in order to more fully illustrate a particular embodiment of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
  • NMR nuclear magnetic resonance spectra
  • a 3-L jacketed cylindrical reactor equipped with overhead stirring, thermocouple, nitrogen purge, addition funnel and reflux condenser is purged with nitrogen for 10 minutes, using the bottom drain valve as the outlet.
  • the reactor is charged with 4,5-dibromo-3-methylthiophene- 2-carboxylic acid (110 g, 360 mmol) and copper (I) bromide (7.89 g, 53.9 mmol, 0.15 equiv). The reactor is purged for an additional 20 minutes.
  • the pH is adjusted with concentrated HCl (52 mL) to pH 4.4, which gives turbidity progressing to slight solid precipitation.
  • the pH is further adjusted (7 mL cone HCl) to 2.6, resulting in increased precipitation.
  • the mixture is cooled to it and then to ⁇ 5 °C over 1 hr and is held cold for a further 1 hr.
  • the pH is adjusted to 1.4 by addition of 24 mL cone HCl and the mixture is held cold for 30 minutes.
  • the product is filtered and the cake is washed with cold 9:10 propanol/water.
  • the cake is air dried overnight and the off-white crude (91 A%) product is slurried in 385 mL 9/10 propanol/water (8 parts). The mixture is refluxed (87-89 °C) for 3h, cooled to rt and then to ⁇ 5 °C, and held for 1 h. The product is filtered and the cake is washed with 2 x 60 mL cold 9/10 propanol/water to give white crystals. The product is dried at 5 in Hg and 50 °C overnight to give 40.6 g title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un synthèse régiosélective en deux étapes de composé d'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique de formule (16) comprenant les étapes de bromuration de l'acide 3-méthyl-thiophène-2-carboxylique pour produire de l'acide 4,5-dibromo-3-méthyl- thiophène-2-carboxylique dans un solvant organique approprié de bromuration, suivie du couplage d'Ullmann sélectif de l'acide 4,5-dibromo-3-méthyl- thiophène-2-carboxylique avec un sel de propoxyde de métal alcalin au moyen d'un catalyseur dans du propanol pour produire un composé de formule (16).
PCT/US2008/056112 2007-03-07 2008-03-07 Synthèse d'ullmann régio-sélective de l'acide 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylique WO2008109786A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US89349507P 2007-03-07 2007-03-07
US60/893,495 2007-03-07

Publications (2)

Publication Number Publication Date
WO2008109786A2 true WO2008109786A2 (fr) 2008-09-12
WO2008109786A3 WO2008109786A3 (fr) 2008-12-11

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PCT/US2008/056112 WO2008109786A2 (fr) 2007-03-07 2008-03-07 Synthèse d'ullmann régio-sélective de l'acide 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylique

Country Status (3)

Country Link
AR (1) AR065616A1 (fr)
TW (1) TW200844100A (fr)
WO (1) WO2008109786A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020007902A1 (fr) 2018-07-05 2020-01-09 Bayer Aktiengesellschaft Thiophènecarboxamides et analogues substitués utilisés en tant qu'agents antibactériens
WO2021001331A1 (fr) 2019-07-03 2021-01-07 Bayer Aktiengesellschaft Thiophène carboxamides substitués et leurs dérivés comme microbicides
WO2021123051A1 (fr) 2019-12-20 2021-06-24 Bayer Aktiengesellschaft Thiophène carboxamides substitués, acides thiophène carboxyliques et leurs dérivés

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 (3)

* Cited by examiner, † Cited by third party
Title
BUCK E ET AL: "Ullmann diaryl ether synthesis: rate aceleration by 2,2,6,6-tetramethylheptane-3,5-dione" ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, COLUMBUS, OH; US, vol. 4, no. 9, 1 January 2002 (2002-01-01), pages 1623-1626, XP002403679 ISSN: 1523-7060 *
KEEGSTRA M A ET AL: "COPPER(I) HALIDE CATALYSED SYNTHESIS OF ALKYL ARYL AND ALKYL HETEROARYL ETHERS" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 48, no. 17, 1 January 1992 (1992-01-01), pages 3633-3652, XP001053311 ISSN: 0040-4020 *
STEINKOPF, WILHELM ET AL: "Thiophene series. XXXVII. Iodine derivatives of 3-thiotolene" JUSTUS LIEBIGS ANNALEN DER CHEMIE , 532, 236-49 CODEN: JLACBF; ISSN: 0075-4617, 1937, XP009107181 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020007902A1 (fr) 2018-07-05 2020-01-09 Bayer Aktiengesellschaft Thiophènecarboxamides et analogues substitués utilisés en tant qu'agents antibactériens
US11884643B2 (en) 2018-07-05 2024-01-30 Bayer Aktiengesellschaft Substituted thiophenecarboxamides and analogues as antibacterials agents
US11952359B2 (en) 2018-07-05 2024-04-09 Bayer Aktiengesellschaft Substituted thiophenecarboxamides and analogues as antibacterials agents
WO2021001331A1 (fr) 2019-07-03 2021-01-07 Bayer Aktiengesellschaft Thiophène carboxamides substitués et leurs dérivés comme microbicides
WO2021123051A1 (fr) 2019-12-20 2021-06-24 Bayer Aktiengesellschaft Thiophène carboxamides substitués, acides thiophène carboxyliques et leurs dérivés

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WO2008109786A3 (fr) 2008-12-11
TW200844100A (en) 2008-11-16
AR065616A1 (es) 2009-06-17

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