EP2114874A2 - Procede de preparation de sulfanylamides et sulfinamidines fluores et leurs utilisations - Google Patents

Procede de preparation de sulfanylamides et sulfinamidines fluores et leurs utilisations

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Publication number
EP2114874A2
EP2114874A2 EP08761839A EP08761839A EP2114874A2 EP 2114874 A2 EP2114874 A2 EP 2114874A2 EP 08761839 A EP08761839 A EP 08761839A EP 08761839 A EP08761839 A EP 08761839A EP 2114874 A2 EP2114874 A2 EP 2114874A2
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EP
European Patent Office
Prior art keywords
optionally substituted
aryl
groups
alkyl
heteroaryl
Prior art date
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EP08761839A
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German (de)
English (en)
French (fr)
Inventor
Eric Bacque
Youssef El-Ahmad
Thierry Billard
Bernard Langlois
Aurélien FERRY
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.)
Centre National de la Recherche Scientifique CNRS
Aventis Pharma SA
Original Assignee
Centre National de la Recherche Scientifique CNRS
Rhone Poulenc Rorer SA
Aventis Pharma SA
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Publication of EP2114874A2 publication Critical patent/EP2114874A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/08—Sulfenic acids; Derivatives thereof
    • C07C313/18—Sulfenamides
    • C07C313/20—Sulfenamides having sulfur atoms of sulfenamide groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/08—Sulfenic acids; Derivatives thereof
    • C07C313/18—Sulfenamides
    • C07C313/26—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C313/30—Y being a hetero atom
    • C07C313/32—X and Y not being nitrogen atoms, e.g. N-sulfenylcarbamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/06—Compounds containing sulfur atoms only bound to two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms

Definitions

  • the present invention relates to a process for the preparation of fluorinated sulfanylamides and sulfinamidines.
  • the present invention relates to a process for the preparation of novel polyfluorinated sulfanylamides and sulfinamidines and their precursors and the potential use of these sulfanylamides as possible substitutes for hydrophobic groups or carboxylic acids contained in certain bioactive molecules or as a perfluoroalkylsulfanylation agent.
  • Fluorine chemistry has undergone a spectacular development in recent decades due to the importance of fluorinated molecules in fields as diverse as polymers, battery salts, surfactants, dyes, liquid crystals , coolants, agrochemistry and pharmacy [(a) Topics in Applied Chemistry. Organofluorine Chemistry, Principles and Commercial Applications. R. E. Banks, B.E. Smart and J. C. Tatlow. Plenum Press, New York, 1994 (b) Chem. Organic. Chem., 2004, No. 5, Special Issue "Fluorin in Life Sciences” (c) Chemistry of Organic Fluorine Compounds. Compounds II. A Critical Review. Mr. Hudlicky and A. E. Pavlath. ACS Washington, 1995 (d) Organofluorine Compounds. Chemistry and Applications. T. Hiyama. Springer, 2000].
  • the figures show that the number of molecules comprising at least one fluorine atom and in pre-clinical or clinical development has been multiplied by 2.5 in twenty years [Inventory of Industrial Fluoro-Biochemicals. A. Becker. Eyrolles, Paris, 1996].
  • the corresponding therapeutic indications range from the central nervous system to anti-cancer, including antibiotics, anti-diabetics, anti-inflammatories and antihypertensives [Bioorganic and Medicinal Fluorine Chemistry, JP Bégué, D. Bonnet-Delpon, CNRS Editions , 2005].
  • trifluoromethylsulfanylamides may have various biological properties as illustrated by the molecules below [Bayer AG Patents (WO2002006277, 2002; DE2045441, 1972; DE2103199, 1972); Boehringer-Mannheim patent (DE2727550, 1979); Merck Patents (GB2266527, 1993; EP481671, 1992; EP199630, 1986)].
  • This reagent is itself prepared from SF 4 , a difficult-to-handle compound, which explains the limited number of known trifluoromethylsulfinamidines.
  • the present invention relates to a process for the preparation of the sulfanylamide compound of formula (I) and of the sulfinamidine compound formula (II)
  • R 1 represents:
  • R 2 represents a perfluorofluoroalkyl or difluoromethylene group substituted with a -S-aryl, -S-heteroaryl or benzoxazol-2-yl group.
  • the aryl, heteroaryl and benzoxazole groups are optionally substituted,
  • R 3 and R 4 represent, independently of one another, an alkyl, alkoxyalkyl or cycloalkyl group, or else R 3 and R 4 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocycle; 3- to 7-membered ring optionally comprising another heteroatom (such as piperidinyl, pirrolidinyl or morpholinyl);
  • optionally substituted aryl means an aryl group optionally substituted with one or more groups (for example from 1 to 3) groups, identical to or different from one another, chosen from the following atoms and groups:
  • Fluoroalkyl fluoroalkoxy
  • R a and R b are independently selected from hydrogen, a (C 1 - C 4) optionally substituted alkyl, (C 1 -C 4) fluoroalkyl, cycloalkyl, optionally substituted aryl, heteroaryl optionally substituted, heterocycloalkyl and R c takes the values of R a except hydrogen, or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated 3 to 7-membered heterocycle, comprising possibly another heteroatom.
  • heteroaryl optionally substituted, is understood to mean a heteroaryl group optionally substituted with one or more groups (for example 1 to 3) groups, identical to or different from each other, chosen from the following atoms and groups:
  • optionally substituted alkyl denotes an alkyl group optionally substituted with one or more groups (for example 1 to 3) groups, identical to or different from one another, chosen from the following atoms and groups: • halogen,
  • R a , Rb and R c are as previously defined;
  • a halogen atom a fluorine, a chlorine, a bromine or an iodine.
  • an alkyl group a saturated aliphatic group comprising from 1 to 12 carbon atoms (advantageously from 1 to 6 carbon atoms) and being linear or branched.
  • an alkoxy group an -O-alkyl radical in which the alkyl group is as defined above.
  • an alkoxyalkyl group a radical of formula alkyl-O-alkyl, in which the alkyl groups, which are identical to or different from one another, are as defined previously.
  • a fluoroalkyl group an alkyl group as defined above and comprising between 1 and 13 fluorine atoms, preferentially from 1 to 5.
  • a fluoroalkyl group an alkyl group as defined above and comprising between 1 and 13 fluorine atoms, preferentially from 1 to 5.
  • the group is said perfluoroalkyl when each hydrogen atom of the alkyl group is replaced by a fluorine atom as in -CF 2 CF 3 .
  • a fluoroalkoxy group an alkoxy group as defined above and comprising between 1 and 9 fluorine atoms.
  • the group is perfluoroalkoxy when each hydrogen atom of the alkyl group is replaced by a fluorine atom as in -OCF 2 CF 3 .
  • an alkylene group a linear or branched hydrocarbon group having one or more unsaturations and having 2 to 12 carbon atoms, preferably between 2 and 6 carbon atoms.
  • an alkynyl group a linear or branched hydrocarbon substituent having at least two unsaturations borne by a pair of vicinal carbon atoms having from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms.
  • the substituents ethynyl, prop-1-ynyl, prop-2-ynyl, and but-1-ynyl are examples of alkynyl substituents.
  • a cycloalkyl group a saturated or partially unsaturated mono or polycyclic hydrocarbon group having from 3 to 12 carbon atoms, preferably between 3 and 12 carbon atoms;
  • cycloalkyl substituents examples include cycloalkyl substituents.
  • a heterocycloalkyl group a cyclic carbon group comprising between 4 and 8 members and between 1 and 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
  • This heterocycloalkyl group may be substituted, at any position, including on ring nitrogen atoms, with one or more groups, which are identical or different from one another, chosen from fluorine and optionally substituted alkyl or alkoxy groups.
  • morpholine pyrrolidine, piperidine, piperazine, 2-pyrrolidinone, 2-piperidinone, imidazoline, and imidazolidine-2,4-dione groups.
  • an aryl group a mono- or polycyclic aromatic substituent having from 6 to 14 carbon atoms.
  • the substituents phenyl, naphth-1-yl, naphth-2-yl, anthracen-9-yl, 1, 2,3,4-tetrahydronaphth-5-yl and 1,2,3,4-tetrahydronaphth-6-yl are examples of aryl substituents.
  • a heteroaryl group a mono- or polycyclic heteroaromatic substituent having from 1 to 13 carbon atoms and from 1 to 4 heteroatoms.
  • the substituents pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, indolyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl, azaindolyl, quinolyl, isoquinolyl, carbazolyl and acridyl are examples of heteroaryl substituents. -
  • R 1 represents:
  • Fluoroalkyl fluoroalkoxy
  • R 3 and R b are independently selected from a hydrogen atom, a (dC 4) alkyl, optionally substituted (C 1 -C 4) fluorooalkyle, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocycloalkyl and R c takes the values of R 3 except hydrogen, or R 3 and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated 3 to 7-membered heterocycle optionally comprising another heteroatom ; or a heteroaryl optionally substituted with one or more (for example 1 to 3) groups, identical or different from each other, chosen from the following atoms and groups: • halogen,
  • Fluoroalkyl fluoroalkoxy
  • Halogen optionally substituted aryl
  • R a , R b and R c are as previously defined;
  • alkyl is optionally substituted with one or more groups (for example 1 to 3) groups, which are identical to or different from each other, chosen from the following atoms and groups:
  • R a , R b and R c are as defined above.
  • aryl optionally substituted with one or more groups (for example 1 to 3) groups, which are identical or different from one another, chosen from a halogen atom (such as Cl and F), a - (C 1 -C 4 JaIkVIe, - (C 1 - C 4) alkoxy, - (C ⁇ C ⁇ perfluoroalkyl, - (C 1 -C 4) perfluoroalkoxy, -NO 2, - (C 3 - C 6) optionally substituted heterocycle, -N ( R a ) (R b ), -N (R a ) CO (R b ), -
  • R a and R b are independently selected from a hydrogen atom, an optionally substituted - (C 1 -C 4) JaKyIe or (C 1 -C 4 ) perfluoroalkyl group and R c has the values of R 3 except for hydrogen, - or -SO 2 -aryl wherein the aryl is optionally substituted by one or more (e.g.
  • an aryl optionally substituted with one or more groups for example 1 to 3) groups, which are identical to or different from each other, chosen from a halogen atom (such as Cl and F) and a - (CrC 4 ) alkyl group - (C 1 -C 4 ) alkoxy, -CF 3 , -NO 2 , -NHCOR d (with R d , as defined above), - CO (C 1 -C 4 ) alkyl, - (C 3 -C 6 ) heterocycloalkyl optionally substituted with one or more groups, identical or different from each other, selected from an oxo group and (C r C 2 ) alkyl optionally substituted with a heteroaryl;
  • groups for example 1 to 3 groups, which are identical to or different from each other, chosen from a halogen atom (such as Cl and F) and a - (CrC 4 ) alkyl group - (C 1 -C 4 ) alk
  • aryl is optionally substituted with one or more (for example 1 to 3) groups, which are identical to or different from each other, chosen from a halogen atom, a - (C 1 -C 4 alkyl, - (C 1 -C 4 ) alkoxy, - (C 1 -C 4 ) perfluoroalkyl, - (C 1 -C 4 ) PeIfIuOrOaClOXy;
  • a heteroaryl optionally substituted with one or more groups (for example 1 to 3) groups, identical or different from one another, chosen from a halogen atom, a - (C 1 -C 4 ) alkyl group, - (C 1 - C 4 ) perfluoroalkyl, - (C 1 -C 4 ) PePfIuOrOaClOXy, - (C 1 -C 4) JaICOXy,
  • CN, -COR b , -COOR c wherein R b and R c are as previously defined; is an alkyl optionally substituted with one or more (for example 1 to 3) groups, identical or different from each other, selected from a fluorine atom, a - (CrC 4) perfluoroalkyl group (such as -CF 3 , -CF 2 CF 3 ), - NO 2 , -CN, optionally substituted aryl, optionally substituted heteroaryl or -NR d R e , where R d and R e are H or - (C r C 4 ) alkyl.
  • the present invention relates to a preparation method as defined above for which R 2 represents a - (C 1 -C 2 ) perfluoroalkyl group.
  • the present invention also preferably relates to a preparation method as defined above for which R 3 and R 4 represent, independently of one another, an alkyl or alkoxyalkyl group or else R 3 and R 4 together form, with the nitrogen atom to which they are attached, a morpholinyl group.
  • the subject of the present invention is a preparation method as defined above for which R 5 , R 6 and R 7 represent a methyl group.
  • the compound of formula (III) is obtained by reaction of the compounds of formula (IV), and (V), preferably in a ratio (IV) / (V) between 1 and 2 equivalents, at a temperature of between -40 ° C. and 40 ° C., in the presence of preferably from one to two equivalents, of a tertiary amine (such as triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-lutidine), in an organic solvent preferably a non-polar solvent such as dichloromethane.
  • a tertiary amine such as triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-lutidine
  • the sulfanylamides of formula (I) and the sulfinamidines of formula (II) are obtained by adding, to the preceding reaction mixture containing the compound of formula (III), a compound of formula RiNH 2 , preferably an equivalent, at a temperature between -40 0 C and 40 0 C.
  • the sulfinamidine intermediate of formula (II) When the sulfinamidine intermediate of formula (II) is isolable and stable, it can be converted to the sulfanylamide compound of formula (I) by reaction in an organic solvent such as dichloromethane, in the presence of an organic or inorganic acid, by for example, trifluoroacetic acid, at a temperature between 0 ° C. and the boiling point of the solvent.
  • an organic solvent such as dichloromethane
  • an organic or inorganic acid by for example, trifluoroacetic acid
  • the present invention also relates to the process for preparing a compound of formula (l b i S) in which Ro is an alkyl, alkylene, alkynyl, optionally substituted, obtained by alkylation of compounds of formula (I), wherein R 1 and R 2 are as defined above.
  • the compounds of formula (I) are reacted with an alkylating agent of formula R 0 X or R 0 OSO 2 R, where X is a halogen atom and R is an alkyl or aryl group optionally substituted, in the presence of an organic or inorganic base such as sodium hydride NaH, in a polar aprotic solvent such as dimethylformamide, at a temperature in particular between -20 ° C. and 60 ° C.
  • an alkylating agent of formula R 0 X or R 0 OSO 2 R where X is a halogen atom and R is an alkyl or aryl group optionally substituted, in the presence of an organic or inorganic base such as sodium hydride NaH, in a polar aprotic solvent such as dimethylformamide, at a temperature in particular between -20 ° C. and 60 ° C.
  • the present invention also relates to the intermediate compounds of formula (I), (II) and (III):
  • the molecules below are inhibitors of the IGF1-R tyrosine kinase [Baserga, R. Exp. IECI. Res., 1999, 253, 1-6 for a review on this kinase]:
  • Sulfanylamides (I) in which R 1 is of the type -SO 2 -aryl, -SO 2 -heteroaryl, -SO 2 -fluoroalkyl, -CO 2 -alkyl, -CO 2 -aryl or -CO 2 -heteroaryl, where the groups aryl, heteroaryl and alkyl may be optionally substituted, may find applications in the field of pharmacy, as substitutes for molecules containing a carboxylic acid function by replacing said carboxylic acid with a group -SO 2 -NH-SR 2 or - OCO-NH-SR 2 as described in the present invention and with R 2 defined as above.
  • the compound P-CH 3 -C 6 H 4 -SO 2 -NH-SCF 3 has a measured pKa of 5.4 (titration with D-Pas in MeOH / KCl 0.15M at 25 ° C. C), while the pKa of benzoic acid is 4.2.
  • the sulfanylamides (I) or (1 b ⁇ s ) where R 1 is an aryl group (advantageously phenyl), R 2 is a trifluoromethyl group and for the compound of formula (1 b ⁇ s ) R 0 is a methyl group can be used as a perfluoroalkylsulfanylation - preferentially trifluoromethyl- and pentafluoroethyl-sulfanylation of compounds aromatic, heteroaromatic, alkenyl and alkynyl, according to the three equations below.
  • the present invention also relates to the use of compounds of formula (I) and (la) as perfluoroalkylsulfanylation agent compounds aryl, heteroaryl, alkenyl and alkynyl as defined below.
  • the unsaturated substrate and the compound (I) in equimolar quantity, are reacted in the presence of either an excess of sulphonic acid (preferably para-toluenesulphonic acid or camphorsulphonic acid) or of hydrochloric acid in ether, either an excess of a sulphonic acid salt (preferably the sodium salt of para-toluenesulphonic acid) and a Lewis acid (such as ethyl trifluoroborate). ), in an apolar solvent such as dichloromethane and at a temperature between 0 ° and 40 0 C, to give compounds having an SR 2 function.
  • sulphonic acid preferably para-toluenesulphonic acid or camphorsulphonic acid
  • hydrochloric acid in ether
  • the resulting polyfluorinated compounds are potentially interesting compounds for various applications, including agrochemistry and pharmacy, for example as building blocks for building more complex bioactive molecules.
  • the starting compounds and reagents when their method of preparation is not described below, are commercially available or described in the literature or may be prepared according to methods described therein or which are known in the art. 'Man of the art. The invention is also described by the following examples, given by way of illustration of the invention.
  • 0.137 ml of morpholinosulfur trifluoride are added dropwise to a solution of 0.130 g of ⁇ -diisopropylethylamine in 2 ml of anhydrous dichloromethane, under an inert atmosphere of nitrogen and at a temperature in the region of -20 ° C.
  • the reaction medium is stirred at this same temperature for 10 minutes before the addition of 0.150 ml of trifluoromethyltrimethylsilane. After 1 hour, with stirring at -20 ° C, a 19 F NMR assay of the reaction medium is carried out.
  • 1- (4 - ⁇ [(trifluoromethyl) thio] amino ⁇ phenyl) ethanone can be prepared according to the following procedure: to the reaction mixture of step 2.1, it is added at -20 ° C, 0.135 g of 1- (4-aminophenyl) ethanone dissolved in 2 ml of anhydrous dichloromethane. The reaction medium is then stirred at room temperature for 4 hours before being washed with an aqueous solution (6%) of NaHCO 3 and dried over Na 2 SO 4 . After filtration and evaporation under reduced pressure, the crude The reaction mixture is solubilized in 2 ml of anhydrous dichloromethane and then cooled to a temperature of 0 ° C.
  • step 2.1 To the reaction mixture of step 2.1, 0.151 g of benzyloxycarbamate dissolved in 2 ml of anhydrous dichloromethane is added at -20 ° C. The reaction medium is then stirred at room temperature for 48 hours. The reaction crude is subsequently washed with an aqueous solution (6%) of NaHCO 3 before being dried over Na 2 SO 4 .
  • Example 6 4-Nitro- ⁇ / - [(trifluoromethyl) thio] aniline (Compound 17) 6.1: N, N-diethyl-1,1,1-trifluoro-N '- (4-nitrophenyl) methane sulfinimidamide (Compound 33)
  • step 2.1 To the reaction mixture of step 2.1, 0.175 ml of N, N-diisopropylethylamine is added at -20 ° C. and then, 5 minutes later, against the stream of N 2 , 0.140 g of 4-nitroaniline. The reaction medium is subsequently stirred at 0 ° C. for 3 hours. Finally, the crude reaction product is washed with an aqueous solution (6%) of NaHCO 3 and then dried over
  • 0.135 ml of diethylaminosulfur trifluoride are added dropwise to a solution of 0.130 g of ⁇ -diisopropylethylamine in 2 ml of anhydrous dichloromethane, under an inert nitrogen atmosphere and at a temperature of -20 ° C.
  • the reaction medium is stirred at this same temperature for 10 minutes before the addition of 0.241 g of 2- [difluoro (trimethylsilyl) methyl] -1,3-benzoxazole. After 1 hour, with stirring at room temperature, a 19 F NMR assay of the reaction medium is carried out.
  • 0.135 ml of diethylaminosulfur trifluoride are added dropwise to a solution of 0.130 g of ⁇ -diisopropylethylamine in 2 ml of anhydrous dichloromethane under an inert atmosphere of nitrogen and at a temperature in the region of -20 ° C. ( DAST).
  • the reaction medium is stirred at this same temperature for 10 minutes before the addition of 0.180 ml of (pentafluoroethyl) trimethylsilane. After 1 hour, with stirring at -20 ° C., a 19 F NMR assay of the reaction medium is carried out.
  • Example 11 4-Chloro-N - [(trifluoromethyl) thio] aniline (Compound 11) At a temperature of -20 ° C., 0.127 g of 4-chloroaniline is added to the reaction mixture of step 2.1 in the counterflow of N 2 . The reaction medium is subsequently stirred at room temperature for 12 hours. Finally, the crude reaction product is washed with an aqueous solution (6%) of NaHCO 3 and then dried over Na 2 SO 4 .
  • step 2.1 To the reaction mixture of step 2.1, 0.175 ml of N 1 N-diisopropylethylamine is added at 20 ° C., then 5 minutes later, against a current of N 2 , 0.242 g of benzyl (4-aminophenyl) carbamate. The reaction medium is subsequently stirred at 0 ° C. for 3 hours before being washed with an aqueous solution (6%) of NaHCO 3 and dried over Na 2 SO 4 . After filtration and evaporation under reduced pressure, the crude reaction product is solubilized in 2 ml of anhydrous dichloromethane and then cooled to a temperature of 0 ° C. 0.030 ml of trifluoroacetic acid is then added dropwise.
  • Example 13 ⁇ T- ⁇ 3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -1H-pyrazol-5-yl ⁇ -1,1,1-trifluoro- ⁇ / ⁇ / bis (2-methoxyethyl) methane sulfinimidamide (Compound 27)
  • 0.135 ml of diethylaminosulfur trifluoride is added dropwise to a solution of 0.130 g of ⁇ -diisopropylethylamine in 2 ml of anhydrous dichloromethane under an inert atmosphere of nitrogen and at a temperature in the region of -20 ° C.
  • Example 21 3 - [(trifluoromethyl) thio] indole (Compound 80)
  • a solution of 2 ml of dichloromethane containing 0.193 g of N- [(trifluoromethyl) thio] aniline (Compound 9, Example 10) is added 0.117 g of indole.
  • 0.485 g of para-toluenesulphonic acid monohydrate is added and the reaction mixture is then heated for 18 hours at 50 ° C.
  • the reaction crude is finally extracted with an Et 2 O / H 2 O mixture.
  • the organic phase is separated, dried over Na 2 SO 4 and then concentrated under vacuum.
  • [(trifluoromethyl) thio] aniline (Compound 9, Example 10) is added 0.134 g of 1,3-dimethoxybenzene. After 5 minutes, 0.485 g of para-toluenesulphonic acid monohydrate is added and the reaction mixture is then heated for 18 hours at 50 ° C. The reaction crude is finally extracted with an Et 2 O / H 2 O mixture. The organic phase is separated, dried over Na 2 SO 4 and then concentrated under vacuum.
  • the compounds 1 to 23 below were prepared from the intermediate compounds III (themselves prepared according to the step or example indicated), either directly or after reaction with trifluoroacetic acid (TFA), as indicated.
  • TFA trifluoroacetic acid

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