WO2008109786A2 - Regio-selective ullmann synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid - Google Patents
Regio-selective ullmann synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid Download PDFInfo
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- 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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- thiophene
- methyl
- carboxylic acid
- propoxy
- bromo
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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
This invention is directed to a two step regio-selective Ullmann synthesis of 4-bromo-3- methyl-5-propoxy-thiophene-2-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-carboxylic cid with alkali metal propoxide salt using copper catalyst in propanol to yield the compound of formula 16.
Description
Regio-Selective Ullmann Synthesis of 4-Bromo-3-methyl-5-propoxy-thiophene-2- carboxylic acid
FIELD OF THE INVENTION
This invention is directed to a two step regio-selective Ullmann synthesis of 4-bromo-3- methyl-5-propoxy-thiophene-2-carboxylic acid.
BACKGROUND OF THE INVENTION
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
While the aforesaid procedure works to prepare intermediate 16, however it utilizes a number of steps, employs acyclic intermediates exhibiting unpleasant odor characteristics, and doesn't start from a readily available thienyl starting material.
SUMMARY OF THE INVENTION
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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be better appreciated by reference to the following detailed description.
Definitions
As used above, and throughout the description of the invention including the appended claims, the following abbreviations and terms, unless otherwise indicated, are understood to have the following meanings:
"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 Br2 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, CuPF6 and Cu2O, 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.
Particular Embodiments
In a particular embodiment of the method according to the present invention, the bromination organic solvent is acetic acid.
In another particular embodiment of the method according to the present invention, the bromination is effected from about room temperature to about 1000C, more particular at 75°C.
In another particular embodiment of the method according to the present invention, the brominating is effected using Br2.
hi another particular embodiment of the method according to the present invention, the alkali metal propoxide salt is sodium propoxide.
hi another particular embodiment of the method according to the present invention, the copper catalyst is CuSCN, CuBr, or CuI.
hi another particular embodiment of the method according to the present invention, 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 950C.
hi another particular embodiment of the method according to the present invention, the coupling is effected with a coupling cosolvent such as THF, toluene, 2-methylTHF, or dimethoxyethane.
Preparatory Details
The starting materials and intermediates may be prepared by the application or adaptation of known methods or their obvious chemical equivalents.
Example The present invention may be better understood by reference to the following non-limiting
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.
In the nuclear magnetic resonance spectra (NMR), reported infra, the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: br = broad, dd = double doublet, s = singlet; m = multiplet.
Example 1 - 4,5-dibromo-3-methyl-thiophene-2-carboxylic acid
To a 3 L jacketed reactor is added 15O g (1.056 mol) of 3-methyl-2-thiophene-carboxylic acid from Tyger Scientific and 1.8 L of glacial acetic acid. To this solution is added 165 mL (3.22 mol) of bromine over 15 minutes. During this time the temperature is increased from 20 0C to 33 °C. The temperature is increased to 80 °C over 40 minutes. During this time a precipitate is formed. The reaction is judged complete after 6 h. The mixture is cooled to 20 0C and held overnight. To the mixture is added 900 mL of water, which increases the temperature from 23 0C to 29 °C. The mixture is cooled to 22 °C and stirred for Ih. The mixture is then filtered and the reactor and cake are washed with; 1 x 900 mL of a 67/33 v/v water/acetic acid solution, 1 x 900 mL water, and 1 x 900 mL n-heptane. The solid is dried to afford 280.2 g (89% yield) of the desired 4,5-dibromo-3-methyl-thiophene-2-carboxylic acid.
Mp 233-234 °C; lH NMR (DMSO-d6) δ 13.6 (s, IH), 2.49 (s, 3H) 13CNMR 5 161.7; 143.6, 129.1, 119.1, 116.5, 16.1; LCMS (ESI) m/z 296.87 (M-H); Anal. Calcd. For C6H4Br2O2S: C, 24.02; H, 1.34; S, 10.69. Found: C, 24.25; H, 1.60; S, 10.34.
Example 2 - 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid
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. 1-propanol (825 mL) and 2,2,6,6- tetramethyl-3,5-heptanedione (15.1 mL, 71.8 mmol, 0.2 equiv) to give a green slurry, which iss stirred for 45 minutes. The reaction is brought to 20 0C. A solution of 19 wt% sodium n-propoxide (454 g, 1053 mmol, 2.94 equiv) is added in a thin stream over 16 minutes ( 6 °C exotherm) to give a green/gray slurry which is warmed to 95 0C and held for 20 h, by which time, HPLC analysis indicated that <10% starting material remained. The mixture (brown
slurry) is cooled to 60 °C and water (1.08 L) is added in a thin stream over 20 min (final temp 42 °C) to give a brown solution with fine brown suspended solid. Celite (40 g) is added to the mixture and the reaction is cooled to <5 °C and held for 2 h. The mixture is filtered through a 15 g celite bed to give a clear brown solution and gray celite cake. The cake is washed with 500 mL 9:10 propanol/water. The combined filtrates and washings are returned to the reactor and brought to 30 0C. While maintaining a temperature between 30 and 35 0C, 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.
Mp 162-163 °C; 1H NMR (CDCl3) δ 4.01 (2H, t), 2.39 (3H, s), 1.75 (3H, s), 0.95 (3H5 1). 13CNMR (CDCl3) δ 163.6; 161.6, 143.6, 112.6, 96.2, 75.9, 21.8, 15.1, 9.6 ; LCMS (ESI) m/z 278.95 (M+H); Anal. Calcd. For C9H11BrO3S: C, 38.72; H, 3.97; Br, 28.60. Found: C, 38.74; H, 3.35; Br, 28.60.
Claims
1. A method for preparing 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid 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- carboxylic acid with alkali metal propoxide salt using copper catalyst in propanol to yield the 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid.
2. The method according to claim 1 wherein the bromination organic solvent is acetic acid.
3. The method according to claim 1 wherein the bromination is effected from about room temperature to about 1000C.
4. The method according to claim 1 wherein the brominating is effected using Br2.
5. The method according to claim 1 wherein the alkali metal propoxide salt is sodium propoxide.
6. The method according to claim 1 wherein the_copper catalyst is CuSCN, CuBr, or CuI.
7. The method according to claim 1 wherein the coupling is effected with heating at about 700C to 110°.
8. The method according to claim 1 wherein the coupling is effected with a coupling cosolvent such as THF, toluene, 2-methylTHF, or dimethoxyethane.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89349507P | 2007-03-07 | 2007-03-07 | |
| US60/893,495 | 2007-03-07 |
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| Publication Number | Publication Date |
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| WO2008109786A2 true WO2008109786A2 (en) | 2008-09-12 |
| WO2008109786A3 WO2008109786A3 (en) | 2008-12-11 |
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| PCT/US2008/056112 WO2008109786A2 (en) | 2007-03-07 | 2008-03-07 | Regio-selective ullmann synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid |
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|---|---|
| AR (1) | AR065616A1 (en) |
| TW (1) | TW200844100A (en) |
| WO (1) | WO2008109786A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020007902A1 (en) | 2018-07-05 | 2020-01-09 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
| WO2021001331A1 (en) | 2019-07-03 | 2021-01-07 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides and derivatives thereof as microbicides |
| WO2021123051A1 (en) | 2019-12-20 | 2021-06-24 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005097780A1 (en) * | 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 hydrochloride as an inhibitor of mast cell tryptase |
-
2008
- 2008-03-06 AR ARP080100924 patent/AR065616A1/en not_active Application Discontinuation
- 2008-03-07 TW TW97107970A patent/TW200844100A/en unknown
- 2008-03-07 WO PCT/US2008/056112 patent/WO2008109786A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005097780A1 (en) * | 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 hydrochloride as an inhibitor of mast cell tryptase |
Non-Patent Citations (3)
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020007902A1 (en) | 2018-07-05 | 2020-01-09 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
| 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 (en) | 2019-07-03 | 2021-01-07 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides and derivatives thereof as microbicides |
| WO2021123051A1 (en) | 2019-12-20 | 2021-06-24 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AR065616A1 (en) | 2009-06-17 |
| TW200844100A (en) | 2008-11-16 |
| WO2008109786A3 (en) | 2008-12-11 |
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