Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/13—Dicarboxylic acids
  • C07C57/15—Fumaric acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
  • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
  • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
  • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the subject of the present invention is a process for the preparation of the compound of formula (I):
• a cis / trans mixture is obtained and the compound of formula (I) (trans isomer) is obtained and separated from the cis isomer by chromatography on silica.
• a compound of formula (I) is prepared via the formation of the compound of general formula (IA):
• the process for preparing the compound of formula (IA) comprises the reaction of a compound of formula (II) with a compound of formula (III),
• reaction is followed by a salification step by addition of fumaric acid.
• the process for preparing the compound of formula (I) comprises the step of adding base to the compound of formula (IA).
• the reaction of the compound of formula (II) with the compound of formula (III) can be carried out as described in WO 02/44139.
• This reaction may be carried out in an organic solvent at a temperature between room temperature and the reflux temperature of the solvent.
• ambient temperature is meant a temperature of between 18 ° C and 25 ° C.
• a solvent there may be mentioned ethanol or trimethylorthoformate.
• sodium borohydride (NaBH 4 ) or a derivative thereof (such as NaBH 3 CN) is added.
• the reaction mixture is preferably stirred at a temperature between 0 ° C. and room temperature.
• the reaction mixture obtained can be used as it is for the following of the reaction or can be extracted using an organic solvent, such as ethyl acetate, washed, dried and evaporated according to routine methods to be engaged in the subsequent salification step.
• the salification step may be carried out in an organic solvent at a temperature between room temperature and the reflux temperature of the solvent.
• a solvent there may be mentioned ethanol.
• the compound of formula (I) can be obtained according to the methods known to those skilled in the art, for example by addition of base, in an organic solvent.
• organic bases such as a solution of ammonia or NH 4 OH.
• organic solvent there may be mentioned (C1-C4) alkyl acetates, esters, aromatic solvents such as toluene, ethers such as isopropyl-ether or tert-butyl-methyl-ether (TBME) dichloromethane, methyl tetrahydrofuran (THF) and methoxycyclopropane.
• the process for preparing the compound of formula (I) may be carried out directly or may comprise the step of separating the compound of formula (IA) after the salification and before the addition of base. This separation can be carried out by any technique known per se, such as filtration, and optionally washing the precipitate with a suitable solvent, wherein the compound of formula (IA) is not soluble. It is thus possible to use the solvent used for the salification step.
• the present invention also relates to the compound of formula (IA):
• This compound is useful as an intermediate in the preparation of the compound of formula (A), by application or adaptation of the methods described in WO 02/44139, WO 03/099819 and WO 03/099772.
• the present application also relates to a process for the preparation of the compound of formula (A) or a pharmaceutically acceptable salt thereof, comprising the preparation of the compound of formula (I) from the compound of formula (IA) as described above.
• the process for preparing the compound of formula (A) or a pharmaceutically acceptable salt thereof also comprises the step of preparing the compound of formula (IA) as described above.
• the process for preparing the compound of formula (A) further comprises the following steps:
• Pg represents a protecting group of the alcohol function
• Pg ' represents a hydrogen atom or an amino function protecting group
• Diagram 1 The present invention also relates to the use of the compound of formula (IA) for the preparation of the compound of formula (A) or a pharmaceutically acceptable salt thereof.
• protecting group is intended to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the reactive function. intact at the end of synthesis. Examples of protecting groups and methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 2nd Edition (John Wiley & Sons, Inc., New York).
• the mass spectra are measured in the so-called Electrospray (ES) ionization mode.
• the signals observed in NMR are expressed as follows: s: singlet; it is: widened singlet; d: doublet; d.d: double doublet; t: triplet; td: split triplet; q: quadruplet; m: massive; mt: multiplet.
• Mass spectra were obtained using a Thermoelectron LCQ DecaXP MCX ion trap spectrometer equipped with an ESI source.
• reaction medium is heated under nitrogen for 12 hours, then it is returned to ambient temperature and then evaporated with the rotavapor until an oil is obtained. The residue is engaged as such in the next step.
• the imine formed is taken up in 50 ml of ethanol. It is cooled to 5 ° C. and 0.460 g (12.18 mmol, 1 eq) of sodium borohydride are added under nitrogen for 15 minutes. The reaction medium is left stirring for 2 hours at 5 ° C. 15 ml of water are then added, the mixture is stirred for 15 minutes and then extracted with ethyl acetate (50 ml). The organic phase is washed with 15 ml of water and then with 15 ml of a saturated solution of sodium chloride. It is dried over magnesium sulphate, filtered and then evaporated with a rotavapor.
• the oily residue (trans / cis mixture in an 85/15 ratio of the two amines) is used as it is in the salification step.
• the crude reaction product is taken up in 50 ml of ethanol. It is heated to 50 ° C. 0.710 g (0.5 eq) of fumaric acid are added. The medium becomes soluble and is allowed to return to ambient temperature. The precipitate obtained is cooled to 5 ° C. The mixture is filtered and the crystals are washed with 2 times 5 ml of ice-cold ethanol. It is dried under vacuum at 50 ° C. 2.40 g is obtained 4- [trans-4 - [(phenylmethyl) amino] cyclohexyl] benzoic acid ethyl ester fumarate salt.
• Step 2 Synthesis of the compound of formula (I) ethyl ester of the acid
• the compound thus obtained can be used to prepare the compound of formula (A) by application or adaptation of the methodologies described in WO 02/44139, WO 03/099772 and WO 03/099819, or according to the following steps 3 and 4.
• Step 3 Synthesis of 4-Trans-4- (phenylmethyl) - (2S) -3- (4-benzyloxy-3-methanesulfonylamino-phenoxy) -2-hydroxy-propyl-amino-cyclohexyl-4-ethyl ester benzoic:
• Crystallization of the product begins when the concentrate is returned to room temperature. The crystallized mixture was stirred at 5 0 C for 90 minutes, the product was filtered, washed with toluene (6 L) and dried in vacuo at 50 0 C. Yield: 12.84 kg, colorless crystals, Melting point: 99- 100 0 C.
• Step 4 Synthesis of the hydrochloride of the compound of formula (A) (4-Ftrans-4 - [(S) -2-Hydroxy-3- (4-hydroxy-3-methanesulfonylamino) ethyl ester hydrochloride phenoxy) -propylaminol-cyclohexyl benzoic acid):

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2008
  • 2008-08-21 FR FR0804665A patent/FR2935141B1/fr not_active Expired - Fee Related
• 2009
  • 2009-08-18 JP JP2011523435A patent/JP2012500251A/ja not_active Withdrawn
  • 2009-08-18 WO PCT/FR2009/001013 patent/WO2010020719A1/fr active Application Filing
  • 2009-08-18 EP EP09737019A patent/EP2331492A1/de not_active Withdrawn
  • 2009-08-18 US US13/059,871 patent/US20110190529A1/en not_active Abandoned

Non-Patent Citations (1)

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