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WO2008121666A1 - Utilisation de 2,5-dioxo-pyrrolidin-1-yl ester d'acide 4-bromo-3-méthyl-5-propoxythiophène-2-carboxylique pour la préparation d'un inhibiteur de tryptase [4-(5-aminométhyl-2-fluoro-phényl)-pipéridin-1-yl]-(4-bromo-3-méthyl-5-propoxy-thiophén-2-yl)-méthanone - Google Patents

Utilisation de 2,5-dioxo-pyrrolidin-1-yl ester d'acide 4-bromo-3-méthyl-5-propoxythiophène-2-carboxylique pour la préparation d'un inhibiteur de tryptase [4-(5-aminométhyl-2-fluoro-phényl)-pipéridin-1-yl]-(4-bromo-3-méthyl-5-propoxy-thiophén-2-yl)-méthanone Download PDF

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Publication number
WO2008121666A1
WO2008121666A1 PCT/US2008/058341 US2008058341W WO2008121666A1 WO 2008121666 A1 WO2008121666 A1 WO 2008121666A1 US 2008058341 W US2008058341 W US 2008058341W WO 2008121666 A1 WO2008121666 A1 WO 2008121666A1
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WIPO (PCT)
Prior art keywords
methyl
thiophene
bromo
propoxy
carboxylic acid
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Ceased
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PCT/US2008/058341
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English (en)
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Ann Marie Gelormini
Adam W. Sledeski
John Joseph Shay, Jr.
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Sanofi Aventis France
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Sanofi Aventis France
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • This invention is directed to the use of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester as an intermediate in preparing the tryptase inhibitor [4- (5 -aminomethyl-2-fluoro-phenyl)-piperidin- 1 -yl]-(4-bromo-3 -methyl-5 -propoxy-thiophen-2- yl)-methanone.
  • 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 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 ([4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l- yl]-(4-bromo-3 -methyl-5 -propoxy-thiophen-2-yl)-methanone), 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 as follows
  • the invention is directed to the method of preparing the tryptase inhibitor [4-(5-aminomethyl- 2-fluoro-phenyl)-piperidin- 1 -yl] -(4-bromo-3 -methyl-5 -propoxy-thiophen-2-yl)-methanone comprising amidization coupling 4-bromo-3 -methyl-5 -propoxythiophene-2-carboxylic acid 2,5- dioxo-pyrrolidin-1-yl ester with 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)- acetamide hydrochloride and strong base or tertiary amine base in alcohol solvent to yield 2,2,2-trifluoro-N- ⁇ 3-[l-(4-Bromo-3-methyl-5-propoxy-thiophene-2-carbonyl)- piperidin-4-yl]-4-fluoro-benzyl ⁇ -acetamide; and deprotecting 2,
  • 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.
  • a strong base such as Cs 2 CO 3
  • alkali metal base such as NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA)
  • alkylmetal such as alkyllithium, alkylpotassium, alkylsodium and alkylmagnesium wherein the alkyl is Ci_ 5 alkyl, more preferably butyl, i.
  • brominating agent means a bromine source such as Br 2 or 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.
  • Coupling agent means a compound useful for effecting an esterification selected from the group consisting of CDI, DCC, PFP, HOBT and HBTU, and the like.
  • 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.
  • Baseic 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 NBI.
  • Iodinating means reacting with an iodinating agent in the presence of a strong base.
  • Non-protic polar solvent means a solvent such ether, t-butyl methyl ether (TBME), isopropyl ethyl ether, THF, 1,4-dioxane or 1,3-dioxolane, or the like.
  • Hydrocarbon solvent means a solvent such as toluene, xylene or heptane, or the like.
  • Halohydrocarbon solvent means a C 3 _ 5 halo, preferably fluoro or chloro, substituted hydrocarbon such as chloroform or methylene chloride.
  • “Inert solvent” means an non-protic polar solvent, hydrocarbon solvent, halohydrocarbon solvent, nitrile solvent such as acetonitrile, or organic acid solvent such as acetic or propanoic acid.
  • “Strong base” means an alkali metal base such as NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA), or alkylmetal base such as alkyllithium, alkylpotassium, alkylsodium and alkylmagnesium wherein the alkyl is Ci_ 6 alicyclic (straight, branched or cyclic alkyl), more preferably butyl.
  • Ci_5 organic base wherein the nitrogen thereof does not bear a hydrogen, such as triethylamine.
  • the iodinating is effected in THF.
  • the strong base used in the iodinating is LDA.
  • the iodination agent is I 2 .
  • the iodinating is effected at about -8O 0 C to about O 0 C.
  • the alkali metal propoxide salt is NaOPr.
  • the copper catalyst is 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 solvent used for carrying out the coupling with CO 2 is effected in THF.
  • the strong base used for coupling with CO 2 is n-BuLi.
  • the coupling with CO 2 is carried out at a temperature below -14°C, more particular from about - 22°C to about -14°C.
  • the solvent for the esterifying is dichloromethane.
  • the coupling agent used for the esterifying is ⁇ iV-carbonyldiimidazole. In another particular embodiment of the method according to the present invention, the esterifying is carried out at about rt.
  • the inert solvent for bromination is halohydro carbon; more particularly dichloromethane.
  • the brominating is effected from about O 0 C to about 100 0 C.
  • the brominating agent is Br 2 .
  • the alcohol solvent for the amidization coupling is ethanol.
  • the amidization coupling is effected at about rt to about 3O 0 C.
  • the base for the amidization coupling is triethylamine.
  • the deprotecting is effected using aqueous base; aqueous NaOH.
  • the deprotecting is effected from about 5 0 C to about 3O 0 C.
  • iodine (454 g, 1.3 equiv) is dissolved in THF (1.65 L), stirred at rt for 20 min to ensure complete dissolution and cooled to -20 0 C. By the time the solution had cooled to -10 0 C, iodine began to precipitate.
  • the anion solution is brought to 0 0 C and cannulated over 40 minutes into a solution of the iodide, adjusting the rate as necessary to keep the reaction at or below -15°C.
  • the mixture is allowed to warm to 10 0 C over 2h.
  • the reaction is diluted with MTBE (1.0 L) and the reaction is quenched with 1 A sat'd ammonium chloride (500 mL).
  • the organic layer is washed with 0.5 N sodium thiosulfate (2 x 750 mL), 2 x 1 L water (2 x IL) and brine (200 mL).
  • the organic layers are allowed to sit in the separator for 4h and any separated water is drawn-off.
  • the organic layers are concentrated by rotary evaporation at 30 0 C and 175 mbar to 1.2 L. Essentially no product is detected by HPLC in either the aqueous phase or distillates. A small and unquantif ⁇ able amount of unreacted 3-methylthiophene is lost to the washes and evaporation. Based on recovered starting material, off-isomer formation, and the absence of product in either washings or rotovap distillates, the yield for this reaction is calculated as 73% for the purposes of estimating the reagents for the Ullmann coupling.
  • Example 2 In a 3 L 3N flask equipped with a reflux condenser atop a Dean-Stark trap, overhead stirring, headspace thermocouple, and nitrogen in/outlets, the 1.2 L of solution from Example 1 is combined with n-propanol. (1 L). The mixture is heated to reflux and distillates drawn-off and partially replaced with n-propanol (ca 1.2 L removed and 500 mL n-propanol added) until the head temperature reached 96 0 C. The mixture is cooled to 50 0 C and sodium t-butoxide (192 g, 2 mol, ca 2 equiv) is added as a solid causing an exotherm to ca 75 0 C.
  • sodium t-butoxide 192 g, 2 mol, ca 2 equiv
  • the mix is held between 75 and 85°C until all solids dissolved.
  • the reaction mixture is re-cooled to 50 0 C and freshly prepared copper iodide 1 (100 mmol, 19 g) in n-propanol (50 ml) is added as a slurry..
  • the mixture is heated to 95 0 C.
  • An HPLC assay at 30 minutes after the reaction temperature is reached showed the reaction to be complete.
  • the mixture is diluted with heptane (1 L). Celite (190 g) is added and the resulting slurry is stirred for 60 min while cooling to rt. The mixture is filtered and the cake washed with heptane (500 mL).
  • the combined filtrates and washings are washed with 5% aqueous disodium EDTA, (3 x 500 mL), water (3 x 500 mL) and brine (500 mL), to give a very dark organic layer which is concentrated to ⁇ 200 mL (170 mbar ,60 0 C) to give 159 g of a dark brown liquid that is 51A% desired compound by 1 H NMR.
  • the major impurities are heptane, ethylbenzene (from commercial LDA) and 2-iodo- 3 -methy lthiophene .
  • N-hydroxysuccinimide (68.3 g, 1.4 equiv) and dichloromethane (700 mL) and stirred at rt. to give a brown solution and a 3°C endotherm on mixing.
  • the cooling bath is filled with rt water and is present only to mitigate a slight exotherm.
  • JV,jV-carbonyldiimidazole (104 g, 1.1 equiv) is added as a solid in four 26.0 g portions spaced 10 min apart. Each addition is followed by a 2-3°C exotherm and gentle gas evolution. After the final addition, the mixture is stirred a rt for 3h or overnight.
  • the mixture is quenched with half saturated ammonium chloride (200 mL) and is washed with water (3 x 150 mL) and brine (150 mL).
  • the product is isolated by solvent exchange with heptane at 170 mbar and 30 0 C. After solid formed, the mixture is cooled to rt and then to 5°C to give a bright yellow solid which is isolated by filtration through cloth, washed with heptane, air dried on a frit for 20 min and further dried (30 0 C, 1.5 in Hg) to give 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester (104 g, 83%).
  • the organic phases are dried (Na 2 SO 4 ) and concentrated (30 0 C, 125 mbar) to give a brown solid which is re-dissolved in DCM (700 mL) and treated at 5°C with bromine (4 mL, 78 mmol, 0.3 equiv) in heptane (20 mL) to complete the reaction.
  • the organic phase is partitioned against 250 mL 1 N aq sodium thiosulfate (250 mL) and washed with water (2 x 250 mL) and brine (250 mL).
  • the solvent volume is reduced (30 0 C, 125 mbar) to 300 mL and 400 mL heptane is added (effecting some crystallization).
  • the reaction mixture is stirred for 18 h, and then partitioned between 1.5 L of water and 1.5 L of TBME.
  • the organic phase is washed with water (2 x 0.5 L), 1 N aq HCl (0.5 L) and brine (0.2 L).
  • the solution is cooled to 7 0 C, and 194 mL of aq. 50% NaOH is added causing an exotherm that warms the mixture to 24 0 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne la synthèse spécifique à une région, en cinq étapes, d'un composé d'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique représenté par la formule générale 16, comprenant les étapes d'acétalation d'un 3-méthyl-thiophène-2-carbaldéhyde dans un solvant à base d'alcool; d'iodation du 3-méthyl-thiophène-2-carbaldéhyde soumis à l'acétalation dans un solvant hydrocarboné ou polaire non protique pour l'obtention du produit 3-méthyl-thiophène-2-carbaldéhyde soumis à l'acétalation et à l'iodation correspondant; de traitement à l'eau du produit soumis à l'acétalation et à l'iodation pour l'obtention du 5-iodo-3-méthyl-thiophène-2-carbaldéhyde correspondant; d'oxydation du 5-iodo-3-méthyl-thiophène-2-carbaldéhyde en acide 5-iodo-3-méthyl-thiophène-2-carboxylique dans un solvant cétonique; de couplage par réaction d'Ullmann de l'acide 5-iodo-3-méthyl-thiophène-2-carboxylique avec un sel de peroxyde de métal alcalin à l'aide d'un catalyseur à base de cuivre dans du propanol pour l'obtention d'acide 3-méthyl-5-propoxy-thiophène-2-carboxylique; d'estérification de l'acide 3-méthyl-5-propoxy-thiophène-2-carboxylique pour l'obtention du 3-méthyl-5-propoyxy-thiophène-2-carboxylate d'alkyle correspondant; de bromuration de l'acide 3-méthyl-5-propoxy-thiophène-2-carboxylique pour l'obtention du 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylate d'alkyle correspondant; et d'hydrolyse basique du 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylate d'alkyle avec une base pour l'obtention d'acide 4-bromo-3-méthyl-5-propoxy-thiophène-2-carboxylique.
PCT/US2008/058341 2007-03-29 2008-03-27 Utilisation de 2,5-dioxo-pyrrolidin-1-yl ester d'acide 4-bromo-3-méthyl-5-propoxythiophène-2-carboxylique pour la préparation d'un inhibiteur de tryptase [4-(5-aminométhyl-2-fluoro-phényl)-pipéridin-1-yl]-(4-bromo-3-méthyl-5-propoxy-thiophén-2-yl)-méthanone Ceased WO2008121666A1 (fr)

Applications Claiming Priority (2)

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US90884407P 2007-03-29 2007-03-29
US60/908,844 2007-03-29

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AR (1) AR065858A1 (fr)
TW (1) TW200904811A (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011124930A1 (fr) 2010-04-08 2011-10-13 Respivert Limited Inhibiteurs de la map kinase p38
WO2011158044A2 (fr) 2010-06-17 2011-12-22 Respivert Limited Formulations respiratoires et composés destinés à être utilisés dans ces formulations
JP2012500794A (ja) * 2008-08-22 2012-01-12 サノフイ 肥満細胞トリプターゼインヒビターとしての［４−（５−アミノメチル−２−フルオロ−フェニル）−ピペリジン−１−イル］−［７−フルオロ−１−（２−メトキシ−エチル）−４−トリフルオロメトキシ−１ｈ−インドール−３−イル］−メタノン
US9242960B2 (en) 2009-04-03 2016-01-26 Respivert, Ltd. P38MAP kinase inhibitors

Citations (1)

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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 (1)

* Cited by examiner, † Cited by third party
Title
CLINE, GARY W. ET AL: "The aminolysis of N-hydroxysuccinimide esters. A structure-reactivity study", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY , 109(10), 3087-91 CODEN: JACSAT; ISSN: 0002-7863, 1987, XP002486129 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012500794A (ja) * 2008-08-22 2012-01-12 サノフイ 肥満細胞トリプターゼインヒビターとしての［４−（５−アミノメチル−２−フルオロ−フェニル）−ピペリジン−１−イル］−［７−フルオロ−１−（２−メトキシ−エチル）−４−トリフルオロメトキシ−１ｈ−インドール−３−イル］−メタノン
US20120283445A1 (en) * 2008-08-22 2012-11-08 Sanofi [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1h-indol-3-yl]-methanone as an inhibitor of mast cell tryptase
US8497379B2 (en) * 2008-08-22 2013-07-30 Sanofi Method and intermediates for the preparation of 2,2,2-trifluoro-N-(4-fluoro-3-pyridin-4-yl-benzyl)-acetamide hydrochloride
CN103508936A (zh) * 2008-08-22 2014-01-15 赛诺菲-安万特 用于制备吲哚苄胺化合物的中间体
AU2009282884B2 (en) * 2008-08-22 2014-01-23 Sanofi [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indol-3-yl]-methanone as an inhibitor of mast cell tryptase
US9242960B2 (en) 2009-04-03 2016-01-26 Respivert, Ltd. P38MAP kinase inhibitors
WO2011124930A1 (fr) 2010-04-08 2011-10-13 Respivert Limited Inhibiteurs de la map kinase p38
US9024041B2 (en) 2010-04-08 2015-05-05 Respivert Ltd. P38 MAP kinase inhibitors
WO2011158044A2 (fr) 2010-06-17 2011-12-22 Respivert Limited Formulations respiratoires et composés destinés à être utilisés dans ces formulations
US8933228B2 (en) 2010-06-17 2015-01-13 Respivert, Ltd. Respiratory formulations and compounds for use therein
US10358445B2 (en) 2010-06-17 2019-07-23 Respivert, Ltd. Respiratory formulations and compounds for use therein

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