EP1805167A2 - Novel product, method and intermediates for the preparation of azetidine derivatives - Google Patents

Novel product, method and intermediates for the preparation of azetidine derivatives

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Publication number
EP1805167A2
EP1805167A2 EP05809232A EP05809232A EP1805167A2 EP 1805167 A2 EP1805167 A2 EP 1805167A2 EP 05809232 A EP05809232 A EP 05809232A EP 05809232 A EP05809232 A EP 05809232A EP 1805167 A2 EP1805167 A2 EP 1805167A2
Authority
EP
European Patent Office
Prior art keywords
bis
methyl
chlorophenyl
azetidin
methylsulfonamide
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05809232A
Other languages
German (de)
French (fr)
Inventor
Stéphane Mutti
Michel Lavigne
Luc Grondard
Joël 77 Allée Arnoul Greban MALPART
Joerg Rieke-Zapp
Véronique Crocq
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
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Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Publication of EP1805167A2 publication Critical patent/EP1805167A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the process for the preparation of azetidine derivatives such as N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide and its N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide dihydrochloride and N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin -3-yl ⁇ -N- (3,5-difluorophenyl) methylsulfonamide.
  • azetidine derivatives such as N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide and its N- ⁇ 1- [bis- (4
  • N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide in its base form and N- ⁇ 1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (3,5-difluorophenyl) -methylsulphonamide are described in patent application WO0164634 and are known to have a high affinity for cannabinoid receptors and particularly those of CBl type . They are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system and disorders of reproduction.
  • these compounds can be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, trauma. cranial, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, compulso-obsessive disorder , senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers, drug-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia) xie), obesity, memory problems, withdrawal from chronic treatment and abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines, for
  • the present invention relates to the development of a method for the synthesis of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide and N-1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (3,5-difluorophenyl) methylsulfonamide, compatible with large scale production.
  • This method of production made it possible to eliminate all the purification steps and all the isolations of intermediates or of the finished product by chromatography on silica and to use crystallization techniques.
  • the present invention also relates to the use of N-dihydrochloride
  • this compound can be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, head trauma, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, compulso - Obsessive, senile dementia, mood disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced movement disorder, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia) , obesity, memory problems, withdrawal from chronic treatment and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators the an
  • Patent application WO 0164634 describes a method for the general synthesis of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (aryl or heteroaryl) methylsulfonamide.
  • Aryl is understood to mean a phenyl, naphthyl and indenyl radical, these aryls being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOaIk, amide. alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, hydroxyalkyl.
  • heteroaryl is meant benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromannyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3, 4-tetrahydroisoquinolyl, thiazolyl and thienyl, which heteroaryls may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOaIk, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkyl
  • Patent application WO 0164634 describes the synthesis of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (aryl or heteroaryl) methylsulfonamide from an intermediate common to N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (3,5-difluorophenyl) methylsulfonamide and N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin]; 3-yl ⁇ -N-quinol-6-yl-methylsulfonamide which is 1-
  • the present invention relates to a process improvement of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-yl-methylsulfonamide for a scaling up with isolations allowing to obtain a high purity of the products without chromatography.
  • the present invention has also made it possible to obtain a new product, a new salt of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-yl-methylsulfonamide dihydrochloride salt.
  • This salt of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-yl-methylsulfonamide dihydrochloride is obtained in the presence of hydrochloric acid in isopropanol and preferably in the presence of 5-6N isopropanol in hydrochloric acid.
  • N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-yl-methylsulfonamide dihydrochloride 7 and N- ⁇ 1 - [bis- (4 chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (3,5-difluorophenyl) methylsulfonamide 9 is prepared according to the synthetic scheme (I):
  • N [bis (4-chlorophenyl) methyl] -acetamide 2 is obtained from 4,4'-dichlorobenzophenone 1 in the presence of sodium borohydride in tetrahydrofuran and then acetonitrile in the presence of sulfuric acid.
  • 1,1-bis (p-chlorophenyl) methylamine is obtained from N [bis (4-chlorophenyl) methyl] acetamide 2 in the presence of hydrochloric acid and butanol and is isolated in the form of a hydrochloride. 3.
  • toluene is preferable with a temperature of between 40 and 60 ° C., preferably between 50 and 60 ° C., and makes it possible to eliminate the chromatography step, in particular for N- ⁇ 1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide.
  • the present invention has made it possible to obtain a process for the synthesis of N- ⁇ 1 ⁇ [bis-
  • the present invention has made it possible to obtain a synthesis of N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-yl-methylsulfonamide dihydrochloride, characterized in that
  • N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-ylmethylsulfonamide is converted into N- ⁇ 1- [bis- (4- chlorophenyl) methyl] azetidin-3-yl ⁇ -N-quinol-6-yl-methylsulfonamide (preferentially in the presence of HCl in isopropanol) which is isolated.
  • the present invention has also made it possible to obtain a synthesis of N- ⁇ 1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl ⁇ -N- (3,5-difluoro-phenyl) - methanesulfonamide 9 characterized in that the reaction of hydrobromide of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol with N- (3,5-difluoro-phenyl) -methanesulfonamide in the presence of DIAD, triphenylphosphine in the presence of toluene to form N- ⁇ 1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl ⁇ -N- (3,5-difluoro-phenyl) -methanesulfonamide which is isolated.
  • the temperature of the medium is then raised to 100 ⁇ 5 ° C. so as to distil about 550 ml.
  • 200 ml of purified water are again introduced and the distillation is resumed in order to distil about 100 ml.
  • the reaction medium is then used to cool naturally to 20 ⁇ 5 ° C for 3-4 hours.
  • the suspension thus obtained is cooled to 5 ⁇ 5 ° C., before being filtered.
  • the cake is then washed with 80 ml of purified water, drained and dried in an oven under vacuum (40-45 0 C / 5 mmHg) to constant weight. 74.1 g of 1,1-bis (p-chlorophenyl) -methylamine hydrochloride are thus obtained with a yield of 96%.
  • the temperature of the medium is brought to 30 ⁇ 5 ° C. before introducing 100 ml of toluene and 100 ml of purified water.
  • the mixture is stirred for 30 minutes and then the aqueous phase is removed.
  • the organic phase is then washed with twice 50 ml of purified water. 4 ml of a 48% aqueous hydrobromic acid solution are introduced into the organic phase and the mixture is stirred for about 30 minutes until a crystallization primer is observed.
  • the suspension is then cooled to 10 ⁇ 5 ° C, before being filtered.
  • the cake is then washed with 3 times 15 ml of toluene, drained and dried in an oven under vacuum (50-55 0 C / 10 mmHg), to constant weight.
  • the medium becomes red blood and at the end of casting, the temperature of the medium is at 12 ° C.
  • the cold bath is removed and allowed to return to room temperature.
  • the medium thickening is then added 450 ml of dichloromethane.
  • the environment becomes more agitable.
  • the end of the reaction is obtained after about 24 hours of contact at room temperature.
  • the mixture is cooled to 14 ° C. ⁇ 2 ° C. and 499 ml of tap water are added over 5 minutes.
  • the addition of sodium hydroxide is weakly exothermic + 4 ° C.
  • the pH of end of pouring of the soda must be at 12, if it is not the case to make an addition of soda to reach this value.
  • the mixture is stirred and heated for 1.5 hours at 50 ° C. until a homogeneous biphasic medium is obtained.
  • the basic aqueous phase is reextracted with toluene 300 ml.
  • the organic phases are combined and washed with deionized water twice 1138 ml.
  • the toluene phase is distilled in order to eliminate traces of water. Under a pressure of 155 mbar, 730 ml of a toluene / water mixture are distilled at 57 ° C.
  • the diisopropylazodicarboxylate (178.5 ml) is introduced over 1 hour.
  • the reaction is exothermic, the temperature of the reaction medium at the end of casting is 54 ⁇ 2 ° C. A red solution is observed.
  • the additional heating time is maintained at 54 ⁇ 2 ° C.
  • the heating is stopped and an HPLC check is carried out to ensure the end of the reaction.
  • 1500 ml of demineralized water are washed twice. 2.330 ml of a toluene / water mixture are distilled under 173 mbar and at 59 ° C. ⁇ 2 ° C. The distillation is stopped and 3 liters of isopropanol are added. Distillation is continued.
  • a dark yellow solution is observed at the end of introduction of the hydrochloric acid solution in isopropanol. We stop the heating.
  • a primer is introduced at 30 ⁇ 2 ° C. It is allowed to return to room temperature for 18 hours. After 18 hours of contact at room temperature, a fine beige suspension is obtained.
  • the reaction medium is cooled to 5 ⁇ 2 ° C. This temperature is maintained for 1 hour.
  • the mixture is washed with 350 ml of methanol previously cooled to 5 ⁇ 20 ° C.
  • the mixture is dried in a vacuum oven at 100 ° C. for 10 minutes at constant weight.
  • the reactor is charged with 14.0 kg of 3,5-difluoroaniline and 56 L of THF. To the stirred solution was added 9.6 kg of pyridine. The reaction medium is cooled to 0 ° C. and 13.10 kg of methanesulphonyl chloride are added while maintaining the temperature between 0 ° -10 ° C during one hour and a half. At the end of the introduction of methane sulphonyl chloride, the reaction medium is warmed at 25 ° C. for 2 hours. To the reaction medium are added 29L of demineralised water and then 6.6kg of hydrochloric acid (30% w / w).
  • the reactor is charged with 6.66 kg of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide, toluene and 28L of deionized water. To this mixture are added 3.46 kg of a solution of sodium hydroxide (30% w / w). The reaction mixture is stirred for 1 hour at 45 ° C and then cooled to 25 ° C, after decantation the organic phase is recovered and washed 3 times with 28L of demineralized water. The organic phase is added to a reactor charged with 4.87 kg of triphenylphosphine and 3.50 kg of N- (3,5-difluoro-phenyl) -methanesulfonamide.
  • the solid obtained is charged in a reactor in the presence of 112L of 2-propanol, the reaction medium is heated under reflux until a clear solution is obtained.
  • the solution is filtered on a pre-heated filter at 80 ° C. expected product crystallizes on cooling at 20 ° C. The crystallization is maintained for 12-24 hours.
  • the product is filtered and washed 3 times with 1L of 2-propanol.
  • the solid is dried under vacuum (32mbar) at 50 ° C.

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Abstract

The invention relates to a novel method for the preparation of azetidine derivatives such as N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-6-yl- methylsulphonamide and the dichlorhydrate thereof and N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulphonamide.

Description

NOUVEAU PRODUIT, PROCEDE ET INTERMEDIAIRES DE PREPARATION NEW PRODUCT, METHOD AND INTERMEDIARY PREPARATION
DE DERIVES D'AZETIDINE.OF AZETIDINE DERIVATIVES.
La présente invention concerne le procédé de préparation de dérivés d'azétidine tels que le N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6- yl-méthylsulfonamide et de son dichlorhydrate N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide et de N-{1- [bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-(3,5-difluorophényl)- méthylsulfonamide. Le produit N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N- quinol-6-yl-méthylsulfonamide sous sa forme de base et le N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3 -yl} -N-(3 ,5-difluorophényl)-méthylsulfonamide sont décrits dans la demande de brevet WOOl 64634 et sont connus pour présenter une forte affinité pour les récepteurs cannabinoïdes et particulièrement ceux de type CBl. Ils sont donc utiles dans le traitement et la prévention des désordres touchant au système nerveux central, au système immunitaire, au système cardio-vasculaire ou endocrinien, au système respiratoire et aux désordres de la reproduction. C'est ainsi que ces composés peuvent être utilisés pour le traitement ou la prévention des psychoses y compris la schizophrénie, des troubles anxieux, de la dépression, de Pépilepsie, de la neurodégénération, des désordres cérébelleux et spinocérébelleux, des désordres cognitifs, du trauma crânien, des attaques de panique, des neuropathies périphériques, des glaucomes, de la migraine, de la maladie de Parkinson, de la maladie d'Alzheimer, de la chorée de Huntington, du syndrome de Raynaud, des tremblements, du désordre compulso-obsessionnel, de la démence sénile, des désordres thymiques, du syndrome de Tourette, de la dyskinésie tardive, des désordres bipolaires, des cancers, des désordres du mouvement induit par les médicaments, des dystonies, des chocs endotoxémiques, des chocs hémorragiques, de l'hypotension, de l'insomnie, des maladies immunologiques, de la sclérose en plaques, des vomissements, de l'asthme, des troubles de l'appétit (boulimie, anorexie), de l'obésité, des troubles de la mémoire, dans le sevrage aux traitements chroniques et abus d'alcool ou de médicaments (opioides, barbituriques, cannabis, cocaïne, amphétamine, phencyclide, hallucinogènes, benzodiazépines par exemple), comme analgésiques ou potentialisateurs de l'activité analgésique des médicaments narcotiques et non narcotiques.The present invention relates to the process for the preparation of azetidine derivatives such as N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide and its N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide dihydrochloride and N- {1- [bis- (4-chlorophenyl) methyl] azetidin -3-yl} -N- (3,5-difluorophenyl) methylsulfonamide. The product N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide in its base form and N- {1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulphonamide are described in patent application WO0164634 and are known to have a high affinity for cannabinoid receptors and particularly those of CBl type . They are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system and disorders of reproduction. Thus, these compounds can be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, trauma. cranial, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, compulso-obsessive disorder , senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers, drug-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia) xie), obesity, memory problems, withdrawal from chronic treatment and abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines, for example), as analgesics or potentiators of the analgesic activity of narcotic and non-narcotic drugs.
La présente invention concerne le développement d'un procédé de synthèse du N- { 1 -[bis-(4-chlorophényl)méthyl]azétidin-3-yl} -N-quinol-6-yl- méthylsulfonarnide et du N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-(3,5- difluorophényl)-méthylsulfonamide, compatible avec une production à grande échelle. Ce procédé d'obtention a permis de supprimer toutes les étapes de purification et tous les isolements d'intermédiaires ou du produit fini par chromatographie sur silice et d'utiliser des techniques de cristallisation.The present invention relates to the development of a method for the synthesis of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide and N-1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, compatible with large scale production. This method of production made it possible to eliminate all the purification steps and all the isolations of intermediates or of the finished product by chromatography on silica and to use crystallization techniques.
La présente invention concerne également l'utilisation du dichlorhydrate N-The present invention also relates to the use of N-dihydrochloride
{ 1 -[bis-(4-chlorophényl)méthyl]azétidin-3-yl} -N-quinol-6-yl-méthylsulfonamide dans le traitement et la prévention des désordres touchant au système nerveux central, au système immunitaire, au système cardio-vasculaire ou endocrinien, au système respiratoire et aux désordres de la reproduction. C'est ainsi que ce composé peut être utilisé pour le traitement ou la prévention des psychoses y compris la schizophrénie, des troubles anxieux, de la dépression, de l'épilepsie, de la neurodégénération, des désordres cérébelleux et spinocérébelleux, des désordres cognitifs, du trauma crânien, des attaques de panique, des neuropathies périphériques, des glaucomes, de la migraine, de la maladie de Parkinson, de la maladie d'Alzheimer, de la chorée de Huntington, du syndrome de Raynaud, des tremblements, du désordre compulso- obsessionnel, de la démence sénile, des désordres thymiques, du syndrome de Tourette, de la dyskinésie tardive, des désordres bipolaires, des cancers, des désordres du mouvement induit par les médicaments, des dystonies, des chocs endotoxémiques, des chocs hémorragiques, de l'hypotension, de l'insomnie, des maladies immunologiques, de la sclérose en plaques, des vomissements, de l'asthme, des troubles de l'appétit (boulimie, anorexie), de l'obésité, des troubles de la mémoire, dans le sevrage aux traitements chroniques et abus d'alcool ou de médicaments (opioides, barbituriques, cannabis, cocaïne, amphétamine, phencyclide, hallucinogènes, benzodiazépines par exemple), comme analgésiques ou potentialisateurs de l'activité analgésique des médicaments narcotiques et non narcotiques, dans le traitement du syndrome métabolique, de l'obésité viscérale, la dyskinésie induite par la levodopa.{1 - [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide in the treatment and prevention of disorders affecting the central nervous system, immune system, cardio system vascular or endocrine, respiratory system and reproductive disorders. Thus this compound can be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, head trauma, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, compulso - Obsessive, senile dementia, mood disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced movement disorder, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia) , obesity, memory problems, withdrawal from chronic treatment and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators the analgesic activity of narcotic and non-narcotic drugs narcotics, in the treatment of metabolic syndrome, visceral obesity, levodopa-induced dyskinesia.
La demande de brevet WO 0164634 décrit une méthode de synthèse générale de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-(aryl ou heteroaryl) méthylsulfonamide.Patent application WO 0164634 describes a method for the general synthesis of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (aryl or heteroaryl) methylsulfonamide.
On entend par aryle un radical phényle, naphtyle et indényle, ces aryles étant non substitués ou substitués par un ou plusieurs halogène, alkyle, alcoxy, formyle, hydroxy, trifluorométhyle, trifluorométhoxy, -CO-alk, cyano, -COOH, COOaIk, amide, alkylsulfanyle, alkylsulfinyle, alkylsulfonyle, alkylsulfanylalkyle, alkylsulfmylalkyle, alkylsulfonylalkyle, hydroxyalkyle. On entend par hétéroaryle les cycles benzofuryle, benzothiazolyle, benzothiényle, benzoxazolyle, chromannyle, 2,3-dihydrobenzofuryle, 2,3-dihydrobenzothiényle, furyle, imidazolyle, isochromannyle, isoquinolyle, pyrrolyle, pyridyle, pyrimidyle, quinolyle, 1,2,3,4- tétrahydroisoquinolyle, thiazolyle et thiényle, ces hétéroaryles pouvant être non substitués ou substitués par un halogène, alkyle, alcoxy, hydroxy, trifluorométhyle, trifluorométhoxy, cyano, -COOH, COOaIk, alkylsulfanyle, alkylsulfinyle, alkylsulfonyle, alkylsulfanylalkyle, alkylsulfïnylalkyle, alkylsulfonylalkyle ou hydroxyalkyle.Aryl is understood to mean a phenyl, naphthyl and indenyl radical, these aryls being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOaIk, amide. alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, hydroxyalkyl. By heteroaryl is meant benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromannyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3, 4-tetrahydroisoquinolyl, thiazolyl and thienyl, which heteroaryls may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOaIk, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl .
La demande de brevet WO 0164634 décrit la synthèse de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-(aryl ou heteroaryl) méthylsulfonamide à partir d'un intermédiaire commun au N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3- yl}-N-(3,5-difluorophényl)-méthylsulfonamide et au N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide qui est le 1-Patent application WO 0164634 describes the synthesis of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (aryl or heteroaryl) methylsulfonamide from an intermediate common to N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide and N- {1- [bis- (4-chlorophenyl) methyl] azetidin]; 3-yl} -N-quinol-6-yl-methylsulfonamide which is 1-
[bis-(4-chlorophenyl)méthyl]azetidin-3-ol et du N-(aryl ou heteroaryl) méthylsulfonamide en présence de triphénylphosphine et diethylazodicarboxylate[bis- (4-chlorophenyl) methyl] azetidin-3-ol and N- (aryl or heteroaryl) methylsulfonamide in the presence of triphenylphosphine and diethylazodicarboxylate
(DEAD) dans un solvant inerte tel que le tétrahydrofuranne. Ces produits sont obtenus après une ou deux chromatographies sur silice et/ou cristallisation.(DEAD) in an inert solvent such as tetrahydrofuran. These products are obtained after one or two chromatographies on silica and / or crystallization.
La présente invention concerne une amélioration de procédé de synthèse de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide pour une montée en échelle avec des isolements permettant d'obtenir une grande pureté des produits sans chromatographie. La nouvelle synthèse réalisée dans le toluène concernant la réaction de Mitsunobu au lieu du THF permet de simplifier le procédé en éliminant les chromatographies sur silice , les changements de solvants, les séchages statiques des solutions organiques sur produits desséchants (remplacés par des distillations azéotropiques) et permet de cristalliser directement le N-{l-[bis- (4-chlorophényl)méthyl]azétidin-3-yl}-N-(3,5-difluorophényl)-méthylsulfonamide et le N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl- méthylsulfonamide dans Pisopropanol sans chromatographie sur colonne préalable.The present invention relates to a process improvement of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide for a scaling up with isolations allowing to obtain a high purity of the products without chromatography. The new synthesis carried out in toluene concerning the Mitsunobu reaction instead of THF makes it possible to simplify the process by eliminating silica chromatography, solvent changes, static drying of organic solutions on desiccants (replaced by azeotropic distillations) and allows to crystallize directly N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide and N- {1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide in isopropanol without prior column chromatography.
La présente invention a également permis l'obtention d'un nouveau produit, nouveau sel dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N- quinol-6-yl-méthylsulfonamide. Ce sel de dichlorhydrate de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide est obtenu en présence d'acide chlorhydrique dans l'isopropanol et préférentiellement en présence d'isopropanol 5-6N en acide chlorhydrique.The present invention has also made it possible to obtain a new product, a new salt of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride salt. . This salt of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride is obtained in the presence of hydrochloric acid in isopropanol and preferably in the presence of 5-6N isopropanol in hydrochloric acid.
L'obtention du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin- 3-yl}-N-quinol-6-yl-méthylsulfonamide 7 et du N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-(3,5-difluorophényl)-méthylsulfonamide 9 est réalisée selon le schéma de synthèse (I) : Obtaining N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride 7 and N- {1 - [bis- (4 chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide 9 is prepared according to the synthetic scheme (I):
HCIaq / n-butanol HCI aq / n-butanol
Schéma (I)Scheme (I)
Selon le mode opératoire décrit dans le schéma de synthèse (I), le N[bis(4- chlorophenyl)methyl]-acétamide 2 est obtenu à partir du 4, 4'-dichlorobenzophenone 1 en présence de borohydrure de sodium dans le tétrahydroruranne puis d'acétonitrile en présence d'acide sulfurique.According to the procedure described in the synthesis scheme (I), N [bis (4-chlorophenyl) methyl] -acetamide 2 is obtained from 4,4'-dichlorobenzophenone 1 in the presence of sodium borohydride in tetrahydrofuran and then acetonitrile in the presence of sulfuric acid.
Le l,l-bis(p-chlorophenyl)-méthylamine est obtenu à partir de N[bis(4- chlorophenyl)methyl]-acétamide 2 en présence d'acide chlorhydrique et de butanol et est isolé sous la forme d'un chlorhydrate 3.1,1-bis (p-chlorophenyl) methylamine is obtained from N [bis (4-chlorophenyl) methyl] acetamide 2 in the presence of hydrochloric acid and butanol and is isolated in the form of a hydrochloride. 3.
Le bromhydrate de l-[bis-(4-chlorophenyl)méthyl]azetidin-3-ol 4 est préparé à partir de Pépibromhydrine et du chlorhydrate de [bis(4-chlorophényl)méthyl] aminé 3 en présence d'éthanol, de bicarbonate de sodium puis dans du toluène en présence d'acide bromhydrique.1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide is prepared from epibromhydrin and [bis (4-chlorophenyl) methyl] amine hydrochloride 3 in the presence of ethanol, bicarbonate of sodium then in toluene in the presence of hydrobromic acid.
L'avantage d'utiliser le bromhydrate de l~[bis-(4- chlorophenyl)méthyl]azetidin-3-ol 4 est qu'il est possible de diversifier la chaîne en position 3 de l'azétidine en faisant réagir un N-(aryl ou heteroaryl) methylsulfonamide de type 5 ou 8 en présence de triphénylphosphine et diisopropylazodicarboxylate (DIAD) dans le toluène avec le l-[bis-(4- chlorophenyl)méthyl]azetidin-3-ol. Il est généralement décrit dans WO0164634 que le solvant utilisé est le THF au reflux avec du DEAD. Il a maintenant été trouvé que le toluène est préférable avec une température comprise entre 40 et 6O0C préférentiellement entre 50 et 60°C et permet d'éliminer l'étape de chromatographie en particulier pour N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl- méthylsulfonamide. Lorsque la réaction est terminée, une distillation azéotropique toluéne/isopropanol permet d'éliminer le toluène conduisant ainsi à une cristallisation du N- { 1 -[bis-(4-chlorophényl)méthyl] azétidin-3 -yl } -N-quinol-6-yl- méthylsulfonamide sans faire précipiter l'oxyde de triphénylphosphine. Cette amélioration permet ainsi d'envisager une production à grande échelle de tels produits non réalisables précédemment avec des purifications par chromatographie.The advantage of using [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide 4 is that it is possible to diversify the chain by position 3 of azetidine by reacting a N- (aryl or heteroaryl) methylsulfonamide type 5 or 8 in the presence of triphenylphosphine and diisopropylazodicarboxylate (DIAD) in toluene with 1- [bis- (4-chlorophenyl) methyl] azetidine -3-ol. It is generally described in WO0164634 that the solvent used is refluxing THF with DEAD. It has now been found that toluene is preferable with a temperature of between 40 and 60 ° C., preferably between 50 and 60 ° C., and makes it possible to eliminate the chromatography step, in particular for N- {1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide. When the reaction is complete, a toluene / isopropanol azeotropic distillation makes it possible to eliminate toluene, thus leading to crystallization of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol 6-yl-methylsulfonamide without precipitating triphenylphosphine oxide. This improvement thus makes it possible to envisage a large-scale production of such products not previously achievable with purifications by chromatography.
La présente invention a permis d'obtenir un procédé de synthèse de N- { 1 ~[bis-The present invention has made it possible to obtain a process for the synthesis of N- {1 ~ [bis-
(4-chlorophényl)méthyl]azétidin-3-yl}-N-(aryl ou hétéroaryl)-méthylsulfonamide caractérisé en ce que(4-chlorophenyl) methyl] azetidin-3-yl} -N- (aryl or heteroaryl) methylsulfonamide characterized in that
a) réaction de bromhydrate de l-[bis-(4-chlorophenyl)méthyl]azetidin-3-ol avec N-(aryl ou hétéroaryl)-methanesulfonamide en présence de DIAD, triphénylphosphine dans du toluène pour former le N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-(aryl ou hétéroaryl)-méthylsulfonamide qui est isolé.a) reaction of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide with N- (aryl or heteroaryl) -methanesulfonamide in the presence of DIAD, triphenylphosphine in toluene to form N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (aryl or heteroaryl) methylsulfonamide which is isolated.
La présente invention a permis d'obtenir une synthèse du dichlorhydrate de N- { 1 -[bis-(4-chlorophényl)méthyl]azétidin-3-yl} -N-quinol-6-yl-méthylsulfonamide caractérisé en ce queThe present invention has made it possible to obtain a synthesis of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride, characterized in that
a) réaction de bromhydrate de l-[bis-(4-chlorophenyl)méthyl]azetidin-3-ol avec N-Quinolin-6-yl-methanesulfonamide en présence de DIAD, triphénylphosphine dans du toluène pour former le N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N- quinol-6-yl-méthylsulfonamide (préférentiellement la réaction se fait à une température situé entre 40 et 600C) puisa) reaction of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide with N-quinolin-6-yl-methanesulfonamide in the presence of DIAD, triphenylphosphine in toluene to form N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- quinol-6-yl-methylsulfonamide (preferentially the reaction is carried out at a temperature of between 40 and 60 ° C.) and then
b) le N- { 1 -[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl- méthylsulfonamide est transformé en dichlorhydrate de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide (préférentiellement en présence de HCl dans de l'isopropanol) qui est isolé.b) N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide is converted into N- {1- [bis- (4- chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide (preferentially in the presence of HCl in isopropanol) which is isolated.
La présente invention a également permis d'obtenir une synthèse de N-{1- [Bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-N-(3,5-difluoro-phenyl)- methanesulfonamide 9 caractérisé en ce que la réaction de bromhydrate de l-[bis-(4- chlorophenyl)méthyl]azetidin-3-ol avec N-(3,5-difluoro-phenyl)-methanesulfonamide en présence de DIAD, triphénylphosphine dans du toluène pour former le N-{l-[Bis- (4-chloro-phenyl)-methyl]-azetidin-3-yl}-N-(3,5-difluoro-phenyl)- methanesulfonamide qui est isolé.The present invention has also made it possible to obtain a synthesis of N- {1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluoro-phenyl) - methanesulfonamide 9 characterized in that the reaction of hydrobromide of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol with N- (3,5-difluoro-phenyl) -methanesulfonamide in the presence of DIAD, triphenylphosphine in the presence of toluene to form N- {1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methanesulfonamide which is isolated.
La présente invention est illustrée dans les exemples de synthèse qui suivent :The present invention is illustrated in the following synthesis examples:
Exemple 1Example 1
Préparation du N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl- méthylsulfonamide et de ses intermédiaires selon le schéma (I) :Preparation of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide and its intermediates according to Scheme (I)
Préparation de l'intermédiaire N-[Bis-(4-chloro-phenyl)-methyl]-acetamide.Preparation of N- [Bis- (4-chloro-phenyl) -methyl] -acetamide Intermediate
Dans un tricol de 500 ml équipé d'une agitation mécanique, d'un thermomètre, d'une ampoule de coulée isobare de 25 ml et d'une colonne de distillation sont chargés 0,87 g de borohydrure de sodium et 40 ml de THF, qui sont portés à 65±5°C. 20 g de 4,4'-dichlorobenzophenone en solution dans 120 ml de THF sont alors additionnés sous agitation. A la solution obtenue sont additionnés 16,5 ml de chlorure de méthylsulfonyle, sur une période de 60 minutes. La température de la masse est maintenue 1 heure supplémentaire à 65±5°C. Une fois la réaction complète, la masse réactionnelle est refroidie à 20±5°C avant de couler 84 ml d'une solution molaire d'acide chlorhydrique. La phase aqueuse est éliminée, la phase organique est alors chauffée à 70±5°C et environ 100 ml de THF sont éliminés par distillation. Sur la masse réactionnelle préalablement refroidie à 50±5°C sont chargés 120 ml d'acétonitrile. La température du milieu réactionnel est alors portée à 80±5°C de manière à distiller environ 100 ml. 15,3 g d'acide sulfurique à 95 % en solution dans 8,5 ml d'eau purifiée sont alors introduits en 30 minutes. La température est maintenue à 80±5°C pendant 3-4 heures. Une fois la réaction complète, 300 ml d'eau purifiée sont coulés sur la masse réactionnelle à 70±5°C, avant d'être refroidie et maintenue 30-40 minutes à 50±5°C (jusqu'à apercevoir une amorce de cristallisation). Le milieu est alors refroidi à 5-100C. La suspension est alors filtrée. Le gâteau est alors lavé par 30 ml d'eau purifiée, essoré et séché à l'étuve sous vide (40-450C / 5 rnmHg), jusqu'à poids constant.In a three-necked 500 ml equipped with a mechanical stirrer, a thermometer, a 25 ml isobaric dropping funnel and a distillation column are charged with 0.87 g of sodium borohydride and 40 ml of THF. , which are brought to 65 ± 5 ° C. 20 g of 4,4'-dichlorobenzophenone dissolved in 120 ml of THF are then added with stirring. To the resulting solution are added 16.5 ml of methylsulfonyl chloride over a period of 60 minutes. The temperature of the mass is maintained an additional hour at 65 ± 5 ° C. Once the reaction is complete, the reaction mass is cooled to 20 ± 5 ° C. before pouring 84 ml of a molar solution of hydrochloric acid. The aqueous phase is removed, the organic phase is then heated to 70 ± 5 ° C and about 100 ml of THF are distilled off. On the reaction mass previously cooled to 50 ± 5 ° C are charged 120 ml of acetonitrile. The temperature of the reaction medium is then raised to 80 ± 5 ° C. so as to distil about 100 ml. 15.3 g of 95% sulfuric acid dissolved in 8.5 ml of purified water are then introduced in 30 minutes. The temperature is maintained at 80 ± 5 ° C for 3-4 hours. Once the reaction is complete, 300 ml of purified water are poured on the reaction mass at 70 ± 5 ° C., before being cooled and maintained for 30-40 minutes at 50 ± 5 ° C. (until a primer of crystallization). The medium is then cooled to 5-10 ° C. The suspension is then filtered. The cake is then washed with 30 ml of purified water, drained and dried in an oven under vacuum (40-45 0 C / 5 mmHg) to constant weight.
23.3 g de N[bis(4-chlorophenyl)méthyl]-acétamide sont ainsi obtenus avec un rendement de 91,1 %.23.3 g of N [bis (4-chlorophenyl) methyl] acetamide are thus obtained with a yield of 91.1%.
Préparation de l'intermédiaire chlorhydrate de l,l-bis(p-chlorophenyl)- méthylaminePreparation of the Intermediate 1,1-bis (p-chlorophenyl) -methylamine Hydrochloride
Dans un réacteur de 2-litres équipé d'une agitation mécanique, d'un thermomètre, d'une ampoule de coulée isobare de 250 ml et d'un réfrigérant surmonté d'un compte-bulles sont chargés 78,3 g de N[bis(4-chlorophenyl)méthyl]- acétamide, 200 ml de n-butanol et 235 ml d'eau purifiée. 214 ml d'acide chlorhydrique 36 % sont alors introduits en 15 minutes via l'ampoule, à une température de 20±5°C. La température de la masse réactionnelle est alors portée à 90±5°C pour une durée de 10 à 15 heures. Une fois la réaction complète, 200 ml d'eau purifiée sont coulés sur la masse réactionnelle. La température du milieu est alors portée à 100±5°C de manière à distiller environ 550 ml. 200 ml d'eau purifiée sont à nouveau introduits et la distillation est reprise afin de distiller environ 100 ml. Le milieu réactionnel est alors utilisé à refroidir naturellement jusqu'à 20±5°C pendant 3-4 heures. La suspension ainsi obtenue est refroidie à 5±5°C, avant d'être filtrée. Le gâteau est alors lavé par 80 ml d'eau purifiée, essoré et séché à l'étuve sous vide (40-450C / 5 rnmHg), jusqu'à poids constant. 74,1 g de chlorhydrate de l,l-bis(p-chlorophenyl)-méthylamine sont ainsi obtenus avec un rendement de 96 %.In a 2-liter reactor equipped with a mechanical stirrer, a thermometer, a 250 ml isobaric dropping funnel and a condenser surmounted by a bubble counter are charged 78.3 g of N [ bis (4-chlorophenyl) methyl] acetamide, 200 ml n-butanol and 235 ml purified water. 214 ml of 36% hydrochloric acid are then introduced in 15 minutes via the ampoule, at a temperature of 20 ± 5 ° C. The temperature of the reaction mass is then raised to 90 ± 5 ° C for a period of 10 to 15 hours. Once the reaction is complete, 200 ml of purified water are poured onto the reaction mass. The temperature of the medium is then raised to 100 ± 5 ° C. so as to distil about 550 ml. 200 ml of purified water are again introduced and the distillation is resumed in order to distil about 100 ml. The reaction medium is then used to cool naturally to 20 ± 5 ° C for 3-4 hours. The suspension thus obtained is cooled to 5 ± 5 ° C., before being filtered. The cake is then washed with 80 ml of purified water, drained and dried in an oven under vacuum (40-45 0 C / 5 mmHg) to constant weight. 74.1 g of 1,1-bis (p-chlorophenyl) -methylamine hydrochloride are thus obtained with a yield of 96%.
Préparation de l'intermédiaire bromhydrate de l-[bis-(4- chlorophenyl)méthyl] azetidin-3 -ol :Preparation of intermediate 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide:
Dans un réacteur de 1 -litre équipé d'une agitation mécanique, d'un thermomètre, d'une ampoule de coulée isobare de 25 ml et d'un réfrigérant surmonté d'un compte-bulles sont chargés 20 g de chlorhydrate de l,l-bis(p-chlorophenyl)- méthylamine, 120 ml d' éthanol et 12,2 g d'hydrogénocarbonate de sodium. La masse réactionnelle est alors chauffée à 80±5°C pour une durée de 1 heure, avant d'être refroidie à 55±5°C. 16,7 g d'épibromhydrine sont introduits en 30 minutes via l'ampoule de coulée et la masse réactionnelle est maintenue à une température de 55±5°C pendant 4-5 heures, avant d'être portée au reflux pendant 4-5 heures supplémentaires. Une fois la réaction terminée, la température du milieu est ramenée à 30±5°C avant d'introduire 100 ml de toluène et 100 ml d'eau purifiée. Le mélange est agité 30 minutes, puis la phase aqueuse est éliminée. La phase organique est alors lavée par 2 fois 50 ml d'eau purifiée. Sur la phase organique obtenue sont introduits 4 ml d'une solution aqueuse d'acide bromhydrique à 48 % et l'on laisse agiter environ 30 minutes jusqu'à observer une amorce de cristallisation. La suspension est alors refroidie à 10±5°C, avant d'être filtrée. Le gâteau est alors lavé par 3 fois 15 ml de toluène, essoré et séché à l'étuve sous vide (50-550C / 10 rnmHg), jusqu'à poids constant.In a 1-liter reactor equipped with a mechanical stirrer, a thermometer, a 25 ml isobaric dropping funnel and a condenser surmounted by a bubble counter are charged with 20 g of l-hydrochloride. 1-bis (p-chlorophenyl) methylamine, 120 ml of ethanol and 12.2 g of sodium hydrogencarbonate. The reaction mass is then heated to 80 ± 5 ° C for a period of 1 hour, before being cooled to 55 ± 5 ° C. 16.7 g of epibromohydrin are introduced in 30 minutes via the dropping funnel and the reaction mass is maintained at a temperature of 55 ± 5 ° C. for 4-5 hours, before being refluxed for 4-5 hours. overtime. Once the reaction is complete, the temperature of the medium is brought to 30 ± 5 ° C. before introducing 100 ml of toluene and 100 ml of purified water. The mixture is stirred for 30 minutes and then the aqueous phase is removed. The organic phase is then washed with twice 50 ml of purified water. 4 ml of a 48% aqueous hydrobromic acid solution are introduced into the organic phase and the mixture is stirred for about 30 minutes until a crystallization primer is observed. The suspension is then cooled to 10 ± 5 ° C, before being filtered. The cake is then washed with 3 times 15 ml of toluene, drained and dried in an oven under vacuum (50-55 0 C / 10 mmHg), to constant weight.
22,6 g de bromhydrate de l-[bis-(4-chlorophenyl)méthyl]azetidin-3-ol sont ainsi obtenus avec un rendement de 83,9 %.22.6 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide are thus obtained in a yield of 83.9%.
Préparation de N-Quinolin-6-yl-methanesulfonamidePreparation of N-Quinolin-6-yl-methanesulfonamide
Dans un ballon tricol de 5-litres muni d'une agitation mécanique, d'une ampoule d'introduction de 250 ml et d'une arrivée d'azote, on introduit la 6- aminoquinoline 150 g, 3000 ml de dichlorométhane puis la pyridine 90,5 g. On obtient une solution jaune limpide. On agite et on refroidit le milieu à 5°C±2°C. On coule en 30 minutes à 5±2°C le chlorure de méthane sulfonyle 123.9 g soit 1.06 eq.In a 5-liter three-necked flask equipped with a mechanical stirrer, a 250 ml introduction funnel and a nitrogen inlet, the 6-aminoquinoline 150 g, 3000 ml of dichloromethane and then the pyridine are introduced. 90.5 g. A clear yellow solution is obtained. The mixture is stirred and cooled at 5 ° C. ± 2 ° C. The methane sulphonyl chloride (123.9 g, 1.06 eq) is cast in 30 minutes at 5 ± 2 ° C.
Le milieu devient rouge sang et à la fin de coulée, la température du milieu est à 12°C.The medium becomes red blood and at the end of casting, the temperature of the medium is at 12 ° C.
Après 10' de fin de coulée et toujours à 5 ±2°C, le milieu réactionnel s'épaissit brutalement (milieu réactionnel rosé hétérogène).After 10 'of end of casting and still at 5 ± 2 ° C, the reaction medium thickens abruptly (heterogeneous pink reaction medium).
Après 15' de fin de coulée, on retire le bain froid et on laisse revenir à température ambiante. Le milieu s' épaississant, on ajoute alors 450 ml de dichlorométhane. Le milieu devient plus agitable. La fin de la réaction est obtenue après environ 24 heures de contact à température ambiante. On refroidit à 14°C ± 2°C et on ajoute en 5 minutes 499 ml d'eau de ville. Puis on coule en 30' 408 ml de soude 5N. L'addition de soude est faiblement exothermique +4°C.After 15 'end casting, the cold bath is removed and allowed to return to room temperature. The medium thickening is then added 450 ml of dichloromethane. The environment becomes more agitable. The end of the reaction is obtained after about 24 hours of contact at room temperature. The mixture is cooled to 14 ° C. ± 2 ° C. and 499 ml of tap water are added over 5 minutes. Then poured into 30 '408 ml of 5N sodium hydroxide. The addition of sodium hydroxide is weakly exothermic + 4 ° C.
Le pH de fin de coulée de la soude doit être à 12, si ce n'est pas le cas faire un rajout de soude pour atteindre cette valeur.The pH of end of pouring of the soda must be at 12, if it is not the case to make an addition of soda to reach this value.
On décante. On obtient 2 phases limpides jaunes. La phase aqueuse est lavée avec 3*300 ml de dichlorométhane. La phase aqueuse est refroidie à 14°C ± 2°C. On coule en 30 min de l'acide chlorhydrique 6N. Dès les premiers ml versés, on observe une précipitation jaune épaisse. En fin de coulée, la solution rouge précipite brusquement. On agite à 10°C 30 min supplémentaires et on laisse revenir à température ambiante. On coule en 30 min à température ambiante 990 ml de bicarbonate de sodium 10 % dans l'eau. A la fin de la coulée, le pH doit être compris entre 8 et 9, si ce n'est pas le cas, il faut faire un ajustement. On observe un milieu épais rosé qui mousse. On laisse agiter une nuit à température ambiante puis on refroidit à 2 +2°C pendant lheure avant de filtrer.We decant. We obtain 2 clear yellow phases. The aqueous phase is washed with 300 ml of dichloromethane. The aqueous phase is cooled to 14 ° C ± 2 ° C. The hydrochloric acid 6N is poured in 30 minutes. From the first ml poured, a thick yellow precipitation is observed. At the end of the casting, the red solution precipitates suddenly. Stirred at 10 ° C for an additional 30 minutes and allowed to warm to room temperature. 990 ml of 10% sodium bicarbonate are poured into the water during 30 min at ambient temperature. At the end of the pour, the pH must be between 8 and 9, if it is not the case, it is necessary to make an adjustment. There is a thick pink medium that foam. It is left to stir overnight at room temperature and then cooled to 2 ± 2 ° C for 1 hour before filtering.
On rince avec de l'eau de ville 3*150 ml et on place le solide rosé en étuve sous vide (100 mmbars) à 350C jusqu'à poids constant. On obtient 182,8 g de N- Quinolin-6-yl-methanesulfonamide soit un rendement de 80,6 %. Spectre RMN IH (300MHz ) - δ en ppm - dans le DMSO-d6 : 3,12 (s, 3H) ; 7,51 (dd, J =4,5 et 8,5 Hz, IH) ; 7,63 (dd, J = 2,5 et 9,0 Hz, IH) ; 7,75 (d, J = 2,5 Hz, IH) ; 8,01 (d, J = 8,5 Hz, IH) ; 8,32 (d large, J = 8,5 Hz, IH) ; 8,82 (dd, J = 2,0 et 4,5 Hz, IH) ; 10,2 (s large, IH) .Rinsed with tap water 3 * 150 ml and placed the pink solid in an oven under vacuum (100 mmbars) at 35 0 C to constant weight. 182.8 g of N-quinolin-6-yl-methanesulphonamide is obtained, a yield of 80.6%. 1H NMR Spectrum (300MHz) - δ in ppm - in DMSO-d6: 3.12 (s, 3H); 7.51 (dd, J = 4.5 and 8.5 Hz, 1H); 7.63 (dd, J = 2.5 and 9.0 Hz, 1H); 7.75 (d, J = 2.5 Hz, 1H); 8.01 (d, J = 8.5 Hz, 1H); 8.32 (d, J = 8.5 Hz, 1H); 8.82 (dd, J = 2.0 and 4.5 Hz, 1H); 10.2 (broad s, 1H).
Préparation de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6- yl-méthylsulfonamide :Preparation of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide:
Dans un réacteur de 5-litres équipé d'une agitation mécanique, d'un thermomètre, d'une ampoule de coulée isobare de 250 ml et d'un réfrigérant surmonté d'un compte-bulles sont chargés à 2O0C 299,4 g de bromhydrate de l-[bis- (4-chlorophenyl)méthyl]azetidin-3-ol, 130,8 ml de soude ION et 3 litres de toluène.In a 5-liter reactor equipped with a mechanical stirrer, a thermometer, a 250 ml isobaric dropping funnel and a refrigerant surmounted by a bubble counter are charged at 20 ° C. 299.4 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide, 130.8 ml of ION sodium hydroxide and 3 liters of toluene.
On obtient une suspension.A suspension is obtained.
On agite et on chauffe pendant lh30 à 50°C jusqu'à l'obtention d'un milieu biphasique homogène. On décante. La phase aqueuse basique est réextraite par du toluène 300 ml. On rassemble les phases organiques et lave par de l'eau déminéralisée 2 fois 1138 ml. La phase toluénique est distillée afin d'éliminer les traces d'eau. On distille sous 155 mbars et à 57°C 730ml d'un mélange toluène/eau. Sur le milieu réactionnel à 20±2°C, on ajoute en une seule fois la triphénylphosphine 224,2 g, la N-Quinolin-6-yl-methanesulfonamide 179,9 g et enfin 700 ml de toluène. On observe une suspension orange. On chauffe le milieu réactionnel à 50 +20C.The mixture is stirred and heated for 1.5 hours at 50 ° C. until a homogeneous biphasic medium is obtained. We decant. The basic aqueous phase is reextracted with toluene 300 ml. The organic phases are combined and washed with deionized water twice 1138 ml. The toluene phase is distilled in order to eliminate traces of water. Under a pressure of 155 mbar, 730 ml of a toluene / water mixture are distilled at 57 ° C. On the reaction medium at 20 ± 2 ° C., triphenylphosphine (224.2 g), N-quinolin-6-yl-methanesulfonamide (179.9 g) and finally 700 ml of toluene are added in one go. An orange suspension is observed. The reaction medium is heated at 50 ± 20 ° C.
On introduit en 1 heure le diisopropylazodicarboxylate 178,5 ml. La réaction est exothermique, la température du milieu réactionnel en fin de coulée est de 54±2°C. On observe une solution rouge. On maintient le chauffage lh30 supplémentaire à 54±2°C. On stoppe le chauffage et on réalise un contrôle HPLC pour s'assurer de la fin de réaction. On lave par de 2 fois 1500 ml d'eau déminéralisée. On distille sous 173 mbars et à 590C ± 2°C 2330 ml d'un mélange toluène/eau. On stoppe la distillation et on rajoute 3 litres d'isopropanol. On poursuit la distillation. On distille sous 192 mbars et à 44 ±2°C 2700 ml d'un mélange toluène/isopropanol. On stoppe la distillation et on vérifie la teneur du toluène dans l'isopropanol (ne pas dépasser 10 % vol/vol). On ajoute sous agitation et en maintenant la température du milieu réactionnel à 44°C 2600 ml d'isopropanol. On stoppe le chauffage et on introduit une amorce à 31±2°C. On laisse revenir à température ambiante et sous agitation lente toute la nuit.The diisopropylazodicarboxylate (178.5 ml) is introduced over 1 hour. The reaction is exothermic, the temperature of the reaction medium at the end of casting is 54 ± 2 ° C. A red solution is observed. The additional heating time is maintained at 54 ± 2 ° C. The heating is stopped and an HPLC check is carried out to ensure the end of the reaction. 1500 ml of demineralized water are washed twice. 2.330 ml of a toluene / water mixture are distilled under 173 mbar and at 59 ° C. ± 2 ° C. The distillation is stopped and 3 liters of isopropanol are added. Distillation is continued. Under a pressure of 192 mbar, 2700 ml of a toluene / isopropanol mixture are distilled at 44 ± 2 ° C. Distillation is stopped and the toluene content in isopropanol is checked (do not exceed 10% vol / vol). With stirring and maintaining the temperature of the reaction medium at 44 ° C., 2600 ml of isopropanol are added. The heating is stopped and a primer is introduced at 31 ± 2 ° C. Allowed to warm to room temperature and slow stirring overnight.
Après 18h d'agitation à 18+2°C, on obtient une suspension orange-crème. On refroidit le milieu réactionnel à 13±2°C pendant Ih, on filtre, on empâte le gâteau puis on rince celui-ci par 2*381 ml d'isopropanol prérefroidi à 10±2°C. On essore et on sèche sous vide et à 35±2°C jusqu'à poids constant. On obtient 178,1 g de N-(I- [bis-(4-chlorophényl)méthyl] azétidin-3 -yl} -N-quinol-6-yl-méthylsulfonamide soit un rendement de 45 %.After stirring for 18 h at 18 ± 2 ° C., an orange-cream suspension is obtained. The reaction medium is cooled to 13 ± 2 ° C. for 1 h, filtered and the cake is impasted and rinsed with 2 * 381 ml of isopropanol pre-cooled to 10 ± 2 ° C. It is filtered off and dried under vacuum and at 35 ± 2 ° C. until constant weight. 178.1 g of N- (1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl] -N-quinol-6-yl-methylsulphonamide are obtained, ie a yield of 45%.
Spectre RMN IH (400MHz ) - δ en ppm - dans le DMSO-d6 :1H NMR spectrum (400MHz) - δ in ppm - in DMSO-d6:
2,76 (m, 2H) ; 3,02 (s, 3H) ; 3,42 (m, 2H) ; 4,40 (s, IH) ; 4,85 (m, IH) ; 7,31 (d large, J = 8,5 Hz, 4H) ; 7,36 (d large, J = 8, 5 Hz, 4H) ; 7,59 (dd, J = 4,5 et 8,5 Hz, IH) ; 7,71 (dd, J = 2,5 et 9,0 Hz, IH) ; 7,97 (d, J = 2,5 Hz, IH) ; 8,04 (d, J = 9,0 Hz, IH) ; 8,39 (dd, J = 1 ,5 et 8,5 Hz, IH) ; 8,94 (dd, J = 2,0 et 4,5 Hz, IH).2.76 (m, 2H); 3.02 (s, 3H); 3.42 (m, 2H); 4.40 (s, 1H); 4.85 (m, 1H); 7.31 (broad d, J = 8.5 Hz, 4H); 7.36 (broad d, J = 8.5 Hz, 4H); 7.59 (dd, J = 4.5 and 8.5 Hz, 1H); 7.71 (dd, J = 2.5 and 9.0 Hz, 1H); 7.97 (d, J = 2.5 Hz, 1H); 8.04 (d, J = 9.0 Hz, 1H); 8.39 (dd, J = 1.5 and 8.5 Hz, 1H); 8.94 (dd, J = 2.0 and 4.5 Hz, 1H).
Préparation du dichlorhydrate de N-(l-[bis-(4-chlorophényl)méthyl]azétidin- 3 -yl} -N-quinol-6-yl-méthylsulfonamidePreparation of N- (1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl] -N-quinol-6-yl-methylsulfonamide dihydrochloride
Dans un ballon tricol de 3-litres, muni d'une agitation mécanique, d'une ampoule d'introduction de 500 ml et d'une arrivée d'azote, on charge à 20 ± 20C 351,5 g de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl- méthylsulfonamide puis 1760 ml de methanol. On chauffe le milieu réactionnel à 50±2°C. On coule en 5 minutes 302 ml d'une solution d'acide chlorhydrique dans Pisopropanol (fraîchement dosée 4,9 N). On n'observe pas d'exothermie. On observe une solution jaune foncé à la fin d'introduction de la solution d'acide chlorhydrique dans l'isopropanol. On stoppe le chauffage. On introduit une amorce à 30±2°C. On laisse revenir à température ambiante pendant 18h. Au bout de 18h de contact à température ambiante, on obtient une suspension beige fine.In a three-necked flask of 3-liter provided with a mechanical stirrer, a 500 ml introduction funnel and a nitrogen inlet was charged at 20 ± 2 0 C. 351.5 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide followed by 1760 ml of methanol. The reaction medium is heated at 50 ± 2 ° C. 302 ml of a solution of hydrochloric acid in isopropanol (freshly measured 4.9 N) are poured in over 5 minutes. No exotherm is observed. A dark yellow solution is observed at the end of introduction of the hydrochloric acid solution in isopropanol. We stop the heating. A primer is introduced at 30 ± 2 ° C. It is allowed to return to room temperature for 18 hours. After 18 hours of contact at room temperature, a fine beige suspension is obtained.
On refroidit le milieu réactionnel à 5 ± 2°C. On maintient 1 heure à cette température. On filtre sur verre frite. On lave avec 2*350 ml de méthanol préalablement refroidi à 5 + 20C. On sèche en étuve sous vide lOmmbars à 600C jusqu'à poids constant.The reaction medium is cooled to 5 ± 2 ° C. This temperature is maintained for 1 hour. We filter on fried glass. The mixture is washed with 350 ml of methanol previously cooled to 5 ± 20 ° C. The mixture is dried in a vacuum oven at 100 ° C. for 10 minutes at constant weight.
On obtient ainsi 322,9 g de dichlorhydrate de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide (poudre cristalline blanche) soit un rendement de 80 %.322.9 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulphonamide dihydrochloride (white crystalline powder) are thus obtained, ie a yield of 80%.
Point de fusion du dichlorhydrate de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide : 125°CMelting point of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide dihydrochloride: 125 ° C
Spectre RMN IH (400MHz ) - δ en ppm - dans le DMSO-d6 avec mélange de conformères 75 % - 25 % : 3,12 (s, 2,2H) et 3,30 (s, 0,8H) ; de 3,92 à 4,23 (m, 4H) ; 5,22 (m, 0,7H) et 5,60 (m, 0,3H) ; 5,99 (m large, 0,7H) et 6,26 (m large, 0,3H) ; 7,47 (d large, J = 8,5 Hz, 4H) ; 7,72 (d large, J = 8,5 Hz, 4H) ; de 7,95 à 8,09 (m, 2H) ; 8,25 (s large, 0,7H) et 8,38 (s large, 0,3H) ; 8,42 (d, J = 9,0 Hz, IH) ; 8,95 (d large, J = 8,5 Hz, IH) ; 9,23 (d large, J = 5,0 Hz, IH) ; 13,2 (m étalé, 0,3H) et 13,5 (m très étalé, 0,7H).1H NMR spectrum (400MHz) - δ in ppm - in DMSO-d6 with mixture of 75% -25% formers: 3.12 (s, 2.2H) and 3.30 (s, 0.8H); from 3.92 to 4.23 (m, 4H); 5.22 (m, 0.7H) and 5.60 (m, 0.3H); 5.99 (broad m, 0.7H) and 6.26 (m wide, 0.3H); 7.47 (d, J = 8.5 Hz, 4H); 7.72 (d, J = 8.5 Hz, 4H); from 7.95 to 8.09 (m, 2H); 8.25 (br s, 0.7H) and 8.38 (br s, 0.3H); 8.42 (d, J = 9.0 Hz, 1H); 8.95 (broad d, J = 8.5 Hz, 1H); 9.23 (broad d, J = 5.0 Hz, 1H); 13.2 (m spread, 0.3H) and 13.5 (very spread m, 0.7H).
Exemple 2Example 2
Préparation du N-{l-[Bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-N-(3,5-difluoro- phenyl)-methanesulfonamide. La préparation de l'intermédiaire bromhydrate de 1- [bis-(4-chlorophenyl)méthyl]azetidin-3-ol est commune à l'exemple 1.Preparation of N- {1- [Bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -methanesulfonamide. The preparation of the intermediate 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide is common to Example 1.
Préparation de N-(3,5-difluoro-phenyl)-methanesulfonamidePreparation of N- (3,5-difluoro-phenyl) -methanesulfonamide
Le réacteur est chargé avec 14,0kg de 3,5-difluoroaniline et 56L de THF. A la solution agitée, on ajoute 9,6kg de pyridine. Le milieu réactionnel est refroidi à 00C et 13,10kg de chlorure méthane sulfonyle sont additionnés en maintenant la température entre 0°-10°C pendant une lh30. A la fin de l'introduction du chlorure méthane sulfonyle, le milieu réactionnel est réchauffé à 250C pendant 2 heures. Au milieu réactionnel sont ajoutés 29L d'eau déminéralisée puis 6.6kg d'acide chlorhydrique (30 % w/w). On distille 6OL de solvant à pression atmosphérique en présence d'un bain extérieur maintenu à 100°C, le milieu réactionnel est alors refroidi à 20°C. La suspension résultante est filtrée et le solide est lavé avec au total 2OL d'eau déminéralisée. Le solide est séché sous vide (20 mbar) à 40°C jusqu'à obtenir une teneur en eau<0.5 %. On obtient ainsi un solide cristallin légèrement jaune 19,48kg (87 %) (mp: 1210C)The reactor is charged with 14.0 kg of 3,5-difluoroaniline and 56 L of THF. To the stirred solution was added 9.6 kg of pyridine. The reaction medium is cooled to 0 ° C. and 13.10 kg of methanesulphonyl chloride are added while maintaining the temperature between 0 ° -10 ° C during one hour and a half. At the end of the introduction of methane sulphonyl chloride, the reaction medium is warmed at 25 ° C. for 2 hours. To the reaction medium are added 29L of demineralised water and then 6.6kg of hydrochloric acid (30% w / w). 6OL solvent is distilled at atmospheric pressure in the presence of an external bath maintained at 100 ° C, the reaction medium is then cooled to 20 ° C. The resulting suspension is filtered and the solid is washed with a total of 2% demineralized water. The solid is dried under vacuum (20 mbar) at 40 ° C until a water content <0.5%. This gives a slightly yellow crystalline solid 19.48 kg (87%) (mp: 121 ° C.)
N-{l-[Bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-N-(3,5-difluoro-phenyl)- methanesulfonamideN- {1- [Bis- (4-Chloro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methanesulfonamide
Le réacteur est chargé avec 6,66kg de bromhydrate de l-[Bis-(4-chloro- phenyl)-methyl]-azetidin-3-ol, 84L toluène et 28L d'eau déminéralisée. A ce mélange sont ajoutés 3.46kg d'une solution d'hydroxide de sodium (30 % w/w). Le milieu réactionnel est agité pendant 1 heure à 45°C puis refroidi à 25°C, après décantation la phase organique est récupérée et lavée 3 fois par 28L d'eau déminéralisée. La phase organique est ajoutée à un réacteur chargé par 4,87kg de triphenylphosphine et 3,50kg of N-(3,5-difluoro-phenyl)-methanesulfonamide. 16L de solvant sont alors distillés sous vide avec un bain extérieur de 360C. Le milieu réactionnel est chauffé à 5O0C. Puis 3,96kg de diisopropylazodicarboxylate (DIAD) sont ajoutés pendant une 1 heure et on poursuit le chauffage 1 heure supplémentaire à 500C. 54L de solvant sont distillés sous vide avec un bain extérieur à 550C puis 100L de 2-propanol sont additionnés au milieu réactionnel suivi d'une distillation de 6OL de solvant sous pression atmosphérique avec un bain extérieur de 9O0C. Le milieu réactionnel est refroidi à 2O0C et agité à cette température pendant 2 heures. Le produit attendu cristallise dans le milieu réactionnel, on filtre et le solide est lavé 2 fois avec du 2-propanol (2* 10L). Le solide obtenu est chargé dans un réacteur en présence de 112L de 2-propanol, le milieu réactionnel est chauffé à reflux jusqu'à obtenir une solution claire. La solution est filtrée sur un filtre pré-chauffé à 800C. Le produit attendu cristallise lors du refroidissement à 200C. On maintient la cristallisation pendant 12-24 heures. Le produit est filtré et lavé 3 fois par 1OL de 2- propanol. Le solide est séché sous vide (32mbar) à 50°C.The reactor is charged with 6.66 kg of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide, toluene and 28L of deionized water. To this mixture are added 3.46 kg of a solution of sodium hydroxide (30% w / w). The reaction mixture is stirred for 1 hour at 45 ° C and then cooled to 25 ° C, after decantation the organic phase is recovered and washed 3 times with 28L of demineralized water. The organic phase is added to a reactor charged with 4.87 kg of triphenylphosphine and 3.50 kg of N- (3,5-difluoro-phenyl) -methanesulfonamide. 16L of solvent are then distilled under vacuum with an outside bath of 36 ° C. The reaction medium is heated to 50 ° C. Then 3.96 kg of diisopropylazodicarboxylate (DIAD) are added for one hour and heating is continued for an additional hour. 50 0 C. 54L of solvent are distilled in vacuo with an outer bath at 55 0 C and then 100 L of 2-propanol are added to the reaction medium followed by a solvent 6OL distillation under atmospheric pressure with an external bath 9O 0 C. The reaction medium is cooled to 20 ° C. and stirred at this temperature for 2 hours. The expected product crystallizes in the reaction medium, is filtered and the solid is washed twice with 2-propanol (2 * 10L). The solid obtained is charged in a reactor in the presence of 112L of 2-propanol, the reaction medium is heated under reflux until a clear solution is obtained. The solution is filtered on a pre-heated filter at 80 ° C. expected product crystallizes on cooling at 20 ° C. The crystallization is maintained for 12-24 hours. The product is filtered and washed 3 times with 1L of 2-propanol. The solid is dried under vacuum (32mbar) at 50 ° C.
Rendement : 5.72kg (68 %) d'un solide cristallin légèrement jaune (mp: 159°C) Yield: 5.72kg (68%) of a slightly yellow crystalline solid (mp: 159 ° C)

Claims

REVENDICATIONS
1. Nouveau produit le dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin- 3-yl}-N-quinol-6-yl-méthylsulfonamide1. New product N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride
2. Produit selon la revendication 1 caractérisé en ce que son point de fusion est 125°C.2. Product according to claim 1 characterized in that its melting point is 125 ° C.
3. Produit selon la revendication 1 caractérisé en ce qu'il est cristallisé avec une solution d'acide chlorhydrique dans Pisopropanol.3. Product according to claim 1 characterized in that it is crystallized with a solution of hydrochloric acid in isopropanol.
4. Procédé de synthèse du dichlorhydrate de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide caractérisé en ce que4. Process for the synthesis of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride, characterized in that
a) réaction de brornhydrate de l-[bis-(4-chlorophenyl)méthyl]azetidin-3-ol avec N-Quinolin-6-yl-methanesulfonamide en présence de DIAD, triphénylphosphine dans du toluène pour former le N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N- quinol-6-yl-méthylsulfonamide puisa) reaction of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide with N-quinolin-6-yl-methanesulfonamide in the presence of DIAD, triphenylphosphine in toluene to form N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide followed by
b) le N-{l-[bis-(4-chloroρhényl)méthyl]azétidin-3-yl}-N-quinol-6-yl- méthylsulfonamide est transformé en dichlorhydrate de N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-quinol-6-yl-méthylsulfonamide qui est isolé.b) N- {1- [bis- (4-chloro-phenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide is converted into N- {1- [bis- (4- (4-dihydrochloride salt); chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide which is isolated.
5. Procédé selon la revendication 4 caractérisé en ce que l'étape a) se fait à une température située entre 40 et 600C.5. Method according to claim 4 characterized in that step a) is at a temperature between 40 and 60 0 C.
6. Procédé selon la revendication 4 caractérisé en ce que l'étape a) se fait à une température située entre 50 et 600C.6. Method according to claim 4 characterized in that step a) is at a temperature between 50 and 60 0 C.
7. Procédé selon la revendication 4 caractérisé en ce que l'étape b) est réalisé en présence de HCl dans de Pisopropanol.7. Process according to claim 4, characterized in that step b) is carried out in the presence of HCl in isopropanol.
8. Procédé selon la revendication 3 caractérisé en ce que l'isopropanol est 5-6 N en acide chlorhydrique. 8. Process according to claim 3, characterized in that the isopropanol is 5-6 N in hydrochloric acid.
9. Procédé de synthèse de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}-N-(aryl ou hétéroaryl)-méthylsulfonamide caractérisé en ce que9. Process for the synthesis of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (aryl or heteroaryl) -methylsulfonamide characterized in that
a) réaction de bromhydrate de l-[bis-(4-chlorophenyl)méthyl]azetidin-3-ol avec N-(aryl ou hétéroaryl)-methanesulfonamide en présence de DIAD, triphénylphosphine dans du toluène pour former le N-{l-[bis-(4- chlorophényl)méthyl]azétidin-3-yl}-N-(aryl ou hétéroaryl)-méthylsulfonamide qui est isolé.a) reaction of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol hydrobromide with N- (aryl or heteroaryl) -methanesulfonamide in the presence of DIAD, triphenylphosphine in toluene to form N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (aryl or heteroaryl) methylsulfonamide which is isolated.
10. Utilisation du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3- yl}-N-quinol-6-yl-méthylsulfonamide pour la fabrication d'un médicament10. Use of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride for the manufacture of a medicament
11. Utilisation du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3- yl}-N-quinol-6-yl-méthylsulfonamide pour la fabrication d'un médicament pour le traitement du syndrome métabolique.11. Use of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride for the manufacture of a medicament for the treatment of metabolic syndrome .
12. Utilisation du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3- yl}-N-quinol-6-yl-méthylsulfonamide pour la fabrication d'un médicament pour le traitement de la maladie d'Alzheimer.12. Use of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride for the manufacture of a medicament for the treatment of the disease Alzheimer.
13. Utilisation du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3- yl}-N-quinol-6-yl-méthylsulfonamide pour la fabrication d'un médicament pour le traitement de la schizophrénie.13. Use of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride for the manufacture of a medicament for the treatment of schizophrenia .
14 Utilisation du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}- N-qumol-6-yl-méthylsulfonamide pour la fabrication d'un médicament pour le traitement de la dyskinésie induite par la levodopa.Use of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-qumol-6-yl-methylsulfonamide dihydrochloride for the manufacture of a medicament for the treatment of induced dyskinesia by the levodopa.
15 Utilisation du dichlorhydrate de N-{l-[bis-(4-chlorophényl)méthyl]azétidin-3-yl}- N-quinol-6-yl-méthylsulfonamide pour la fabrication d'un médicament pour le traitement de l'obésité. Use of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide dihydrochloride for the manufacture of a medicament for the treatment of obesity .
EP05809232A 2004-10-14 2005-10-10 Novel product, method and intermediates for the preparation of azetidine derivatives Withdrawn EP1805167A2 (en)

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