WO2007054668A1 - Synthèse de dérivés de méthylsulfonylbenzène - Google Patents

Synthèse de dérivés de méthylsulfonylbenzène Download PDF

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Publication number
WO2007054668A1
WO2007054668A1 PCT/GB2006/004090 GB2006004090W WO2007054668A1 WO 2007054668 A1 WO2007054668 A1 WO 2007054668A1 GB 2006004090 W GB2006004090 W GB 2006004090W WO 2007054668 A1 WO2007054668 A1 WO 2007054668A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
sulfonic acid
group
acid
Prior art date
Application number
PCT/GB2006/004090
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English (en)
Inventor
Raymond Fisher
Original Assignee
Peakdale Molecular Limited
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 Peakdale Molecular Limited filed Critical Peakdale Molecular Limited
Priority to EP06808388A priority Critical patent/EP1945608A1/fr
Publication of WO2007054668A1 publication Critical patent/WO2007054668A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups

Definitions

  • the present invention relates to a process for the preparation of compounds of formula (I) which are useful as intermediates in the synthesis of, inter alia, pharmaceutical products.
  • the inventors have developed a simplified process for the synthesis of l-substituted-2- fluoro-4-methylsulfonylphenyl compounds .
  • R is optionally substituted C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is halogen (other than F), Cl-6 alkyl, Cl-6 haloalkyl, cyclohydrocarbyl, heterocyclyl, OR 2 , SR 2 , NO 2 , CN, NR 2 R 2 , NR 2 NR 2 2 , CO 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 , NHCO 2 R 2 , COR 2 , CONR 2 , S(O)R 2 , SO 2 NR 2 2 OrNR 2 S(O) 2 R 2 ;
  • R 2 is hydrogen, Tf (triflouromethyl sulphonyl), Cl-6 alkyl, Cl-6 haloalkyl, aryl or heteroaryl;
  • radicals R 2 when a group as defined above contains two or more radicals e.g. the radical R 2 as for example in NR 2 R 2 , the radicals R 2 may be the same or different.
  • halogen includes F, Cl, Br and I.
  • alkyl relates to both straight chain and branched alkyl radicals, for example, of 1 to 6 carbon atoms, e.g. 1, 2, 3, 4, 5, 6, carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, n-hexyl.
  • alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • haloalkyl relates to an alkyl group substituted with one or more halogen atoms.
  • Cyclic group means a hydrocarbon ring or ring system, which may be unsaturated or partially unsaturated but is usually saturated, typically containing 5 to 13 ring-forming atoms, for example a 5- or 6- membered ring.
  • a cyclic group includes cyclohydrocarbyl and heterocyclyl.
  • Cyclohydrocarbyl relates to a saturated, partly unsaturated or unsaturated 3 - 10, for example, 5, 6, 7, 8, 9 or 10, membered hydrocarbon ring, including aryl. Cyclohydrocarbyl includes aliphatic and aromatic cyclic groups.
  • Aryl means an aromatic, for example, C6 to 10 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated hydrocarbon.
  • Aryl may include phenyl, indenyl, naphthyl, tetrahydronaphthyl, anthracenyl, phenanthracenyl.
  • Heterocyclyl means, for example, a C3-10, for example 5 or 6, membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl.
  • the heterocyclyl system may contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl may be fully saturated, partially saturated or unsaturated.
  • Heteroaryl means an aromatic, for example, 5-10 membered aromatic ring containing one or more heteroatoms selected from N, O or S such as indole, and containing one ring which is optionally fused to one or more saturated or unsaturated rings.
  • cyclohydrocarbyl or heterocyclyl groups include but are not limited to phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxane, dioxolane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isooxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine,
  • Halogen means Cl, Br, or I.
  • the halogen is I or Br.
  • R is methyl, ethyl, propyl, isopropyl or chloromethyl.
  • R is methyl.
  • R 1 is halogen (other than F), aliphatic hydrocarbyl, OR 2 , SR 2 , NO 2 , CN, NR 2 R 2 , NR 2 NR 2 2 , CO 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 , NHCO 2 R 2 , COR 2 , CONR 2 , S(O)R 2 , SO 2 NR 2 2 or NR 2 S(O) 2 R 2 and R 2 is hydrogen, Tf (triflouromethyl sulphonyl), or aliphatic hydrocarbyl.
  • R 1 is halogen (other than F), Cl-6 alkyl, Cl-6 haloalkyl, OR 2 , SR 2 , NO 2 , CN, NR 2 R 2 , NR 2 NR 2 2 , CO 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 , NHCO 2 R 2 , COR 2 , CONR 2 , S(O)R 2 , SO 2 NR 2 2 or NR 2 S(O) 2 R 2 and R 2 is hydrogen, Tf (triflouromethyl sulphonyl), C 1 -6 alkyl or Cl-6 haloalkyl.
  • Tf triflouromethyl sulphonyl
  • R 1 is OR 2 , SR 2 , NR 2 R 2 or NR 2 NR 2 2 and R 2 is hydrogen, Tf or Cl -6 alkyl.
  • R is NR R each of the radicals R may together form a cyclic group, for example carbocyclyl or heterocarbocyclyl such as cycloalkyl.
  • R 1 is OH or NHNH 2 .
  • R 1 is NHNH 2 .
  • R is methyl and R 1 is OH or NHNH 2 .
  • the sulfonic acid is of the formula R-SO 3 H wherein R is as defined herein.
  • R is methyl.
  • the sulfonic anhydride is produced by reaction of a sulfonic acid and a dehydrating agent.
  • the sulfonic acid is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, isopropanesulfonic acid and chloromethanesulfonic acid.
  • the sulfonic acid is a methanesulfonic acid.
  • the sulfonic anhydride is methane sulfonic anhydride.
  • dehydrating agent is intended to encompass any agent capable of converting an acid to the respective anhydride via a dehydration step.
  • the dehydrating agent may be selected from the group consisting OfAlCl 3 , PCl 5 , PCl 3 , POCl 3 , SOCl 2 (thionyl chloride) and SO 2 Cl 2 .
  • the dehydrating agent is SOCl 2 .
  • the catalyst may be AlCl 3 ortrifluoromethane sulfonic acid.
  • the catalyst is trifluoromethane sulfonic acid.
  • step (i) comprises the step of (a) mixing the sulfonic acid and dehydrating agent prior to reaction with the compound of formula (II) in the presence of the catalyst.
  • the sulfonic acid and the dehydrating agent react to form a sulfonic anhydride.
  • the sulfonic acid is methanesulfonic acid.
  • the dehydrating agent is thionyl chloride.
  • the thionyl chloride reacts with methanesulfonic acid to form methanesulfonic anhydride.
  • the step of mixing the sulfonic acid and the dehydrating agent may take place at room temperature (for example whilst stirring) or the mixture may be heated, for example to a temperature of up to 13O 0 C, for example up to 9O 0 C.
  • the mixture may be heated to 9O 0 C for over 10 hours, for example at least 24 hours.
  • step (i) further comprises the step of (b) heating, for example to a temperature up to 12O 0 C, the solution resulting from step (a) prior to reaction with a solution of the compound of formula (II) in the presence of the catalyst.
  • the solution of the compound of formula (II) and the catalyst may be added drop wise for over 2hrs to the solution resultant from step (a).
  • the mixture is heated at 12O 0 C for 6hrs.
  • the catalyst is trifluromethanesulfonic acid.
  • step (i) (a) is catalysed by the trifluoromethane sulfonic acid in a Friedel-Crafts reaction to give the desired methylsulfonyl compound of formula III.
  • the product of step (i) is 1,2 -difluoro-4-(methylsulfonyl) benzene.
  • nucleophile in step (ii) of the process is any nucleophile capable of displacing the F para to the sulphonyl group.
  • nucleophile is an anion of R 1 or R 1 group having an unshared pair of electrons.
  • the nucleophile may be selected from the group consisting of OR 2" , halide ion (e.g I “ , Br “ or Cl " ), NR 2 R 2" , R 2 OH, R 2 SH, CN " , C 1-6 alkyl, C 1-6 haloalkyl, carbocyclyl, heterocyclyl, NR 2 2 NR 2 2 , NR 2 3 or a nucleophile capable of displacing the F para to the sulphonyl group with any of the following groups CO 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 , NHCO 2 R 2 , COR 2 , CONR 2 , S(O)R 2 , SO 2 NR 2 2 or NR 2 S(O) 2 R 2 ; wherein R 2 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, aryl or heteroaryl.
  • R 2 is hydrogen, C 1-6 alkyl, C 1-6 halo
  • the nucleophile is selected from the group consisting of OR 2" , halide ion (e.g I “ , Br “ or Cl " ), NR 2 R 2" , R 2 OH, R 2 SH 5 CN “ , C 1-6 alkyl, C 1-6 haloalkyl, NR 2 2 NR 2 2 , NR 2 3 or a nucleophile capable of displacing the F para to the sulphonyl group with any of the following groups CO 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 , NHCO 2 R 2 , COR 2 , CONR 2 , S(O)R 2 , SO 2 NR 2 2 or NR 2 S(O) 2 R 2 ; wherein R 2 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl.
  • R 1 is OTf
  • the OTf group is made by an additional process step (iii) which involves reacting a compound of formula (I) where
  • the nucleophile is a hydrazine.
  • the hydrazine is of formula NH 2 NH 2 .
  • the hydrazine may be in a protected form, for example acethydrazide or t-butyl carbazate where the acetyl group or t-butoxy carbonyl group is removed by a subsequent de-protection step.
  • the hydrazine is hydrated.
  • step (ii) comprises the step of (a) heating a solution of hydrazine hydrate in an o ⁇ ganic solvent that does not react with the hydrazine, for example methanol, ethanol or methylated spirits.
  • a solution of hydrazine hydrate in an o ⁇ ganic solvent that does not react with the hydrazine for example methanol, ethanol or methylated spirits.
  • the solutions are refluxed, for example at a temperature between room temperature and 200 0 C.
  • step (ii) further comprises the step of (b) reacting the compound of formula (III) with the solution resultant from step (a).
  • step (b) is carried out whilst heating under reflux.
  • the solution is heated under reflux for 24 hours before cooling to O 0 C.
  • Compounds of formula (I) are useful in the preparation of pharmaceutically active compounds, for example compounds shown to be useful in the treatment of metabolic disorders.
  • Examples of compounds that are derived from the intermediates of formula (I) are described in WO2005007647 and WO2005007658.
  • the following compound was obtained (see WO2005007658 for details of its synthesis) from a compound of formula wherein R is methyl and R 1 is NHNH 2 .
  • reaction mixture was heated at 12O 0 C for a further 4 h, cooled to 50 0 C, and divided into 2 equal portions. Each portion was carefully added to water (50 kg) at 5O 0 C, causing the temperature of the mixture to rise to ca.70 0 C. The mixture was then cooled to 35°C and the product was extracted with dichloromethane (9.47 kg). The combined organic fractions derived from the two portions were separated, dried, and concentrated to a thick slush.

Abstract

La présente invention concerne un procédé de synthèse de dérivés 2-fluoro-4-méthylsulfonylphénylés substitués en 1.
PCT/GB2006/004090 2005-11-09 2006-11-02 Synthèse de dérivés de méthylsulfonylbenzène WO2007054668A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06808388A EP1945608A1 (fr) 2005-11-09 2006-11-02 Synthèse de dérivés de méthylsulfonylbenzène

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0522846.5 2005-11-09
GB0522846A GB0522846D0 (en) 2005-11-09 2005-11-09 Process

Publications (1)

Publication Number Publication Date
WO2007054668A1 true WO2007054668A1 (fr) 2007-05-18

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Country Status (3)

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EP (1) EP1945608A1 (fr)
GB (1) GB0522846D0 (fr)
WO (1) WO2007054668A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140092A1 (fr) 2009-06-05 2010-12-09 Pfizer Inc. Derives de l-(piperidin-4-yl)-pyrazole utilises en tant que modulateurs du gpr 119

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496630A1 (fr) * 1991-01-25 1992-07-29 Rhone-Poulenc Agriculture Ltd. Herbicides à base de 2-cyano-1,3-dione

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496630A1 (fr) * 1991-01-25 1992-07-29 Rhone-Poulenc Agriculture Ltd. Herbicides à base de 2-cyano-1,3-dione

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KEITH SMITH ET.AL.: "Study of regioselective methanesulfonylation of simple aromatics with methanesulfonic anhydride in the presence of zeolite catalysts", ORG. BIOMOL. CHEM., vol. 2, 2004, pages 3150 - 3154, XP002419098 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140092A1 (fr) 2009-06-05 2010-12-09 Pfizer Inc. Derives de l-(piperidin-4-yl)-pyrazole utilises en tant que modulateurs du gpr 119

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EP1945608A1 (fr) 2008-07-23
GB0522846D0 (en) 2005-12-21

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