FR2827858A1 - New fluorinated sufonamides and their preparation, useful in the resolution of racemic chiral amines - Google Patents

Abstract

Process for the resolution of a chiral amine in a racemic mixture or enriched in one of the stereoisomers by contact of the mixture with a defined fluorinated sulfonatmide reactant. The reactant conforms to the general formula (I) :- - in which R1 asterisk = a chiral group; Rf = 1 - 20C hydrocarbyl optionally comprising at least one halogen, preferably F; E = an electrophilic group(sulfonyl, carbonyl or phosphoryl). - contact enables recovery of one of the stereoisomers, the other being in a form in which one H atom of the amine function is replaced by E. Independent claims are also included for the reactants and their preparation.

Description

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NOVEL SULFONAMIDES, THEIR PREPARATION AND THEIR USE
FOR THE SPLITTING OF A RACEMIC CHIRAL AMINE.

 The present invention relates to new sulfonamides, their preparation and their use for the resolution of a racemic chiral amine.

 The invention relates more particularly to fluorinated sulfonamides.

 The production of pure optically active compounds is a problem which arises in many technical fields such as for example, pharmacy, agrochemistry, the food industry (food additives, flavorings) and also in the perfume industry.

 It is expected that this problem will take on increasing importance because, more and more, we note that in a given application, only one of the stereomers has the desired property.

 In particular, optically pure amines are required in the synthesis of compounds for therapeutic purposes such as alkaloids or amino acids.

 Kinetic resolution is an effective method for obtaining optically pure molecules.

 Up to now, the kinetic resolution of amines has mainly been carried out by the enzymatic route.

 Two types of chemical resolution are described.

 Murakami et al. (Synlett, 1998,725-726) describe the use of a triacetylated binaphthyldiamine as an enantioselective acetylation reagent. The results obtained are not entirely satisfactory because the best enantiomeric excesses are 44% for a reagent / substrate ratio equal to 0.25.

 Slightly higher enantiomeric excesses are obtained by Yutaka le and Gregory C. Fu (Chem. Commum., 2000, 119-120 and Angew.

Chem. 2001.40 (1) 234-236), by enantioselective acylation of amines using a chiral ferrocene derivative of 4-pyrrolidinopyridine as an acylating agent.

The disadvantage of this separation lies in the fact that the reaction temperature must be very low (-78 C) to obtain good enantiomeric excesses.

 The object of the present invention is a process for the resolution of a racemic chiral amine using a new resolution reagent.

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 Another object of the invention is to provide new chemical compounds capable, among other things, of being used as reagents for chial resolution.

 Another object of the invention is the process for obtaining said compounds.

dans ladite formule (1) : - Ri* représente un groupement chiral, - Rf représente un groupement hydrocarboné ayant de 1 à 20 atomes de carbone comprenant ou non au moins un atome d'halogène, de préférence un atome de fluor, - E représente un groupement électrophile choisi parmi les groupes sulfonyl, carbonyle, ou phosphoryle, ce qui permet d'obtenir l'un des stéréomères, l'autre se trouvant sous une forme dans laquelle un atome d'hydrogène de la fonction amine est remplacé par un groupement électrophile E. The subject of the invention is precisely a process for splitting a chiral amine in the form of a racemic mixture or enriched in one of the stereomers characterized in that the said mixture is brought into contact with a resolution reagent corresponding to the general formula (1):

in said formula (1): - Ri * represents a chiral group, - Rf represents a hydrocarbon group having from 1 to 20 carbon atoms comprising or not comprising at least one halogen atom, preferably a fluorine atom, - E represents an electrophilic group chosen from sulfonyl, carbonyl or phosphoryl groups, which makes it possible to obtain one of the stereomers, the other being in a form in which a hydrogen atom of the amine function is replaced by a group electrophile E.

 In formula (1), Ri * represents a chiral group, that is to say a hydrocarbon group having at least one element of asymmetry such as for example, an asymmetric carbon atom or an atropoisomerism.

 The invention contemplates the case where Ri * has more than one asymmetric carbon atom, namely two, three or even more.

In formula (1), the electrophilic group E more particularly represents one of the following groups: - S02Rf - CORs - C02R6 - PORRs or PO (OR7) (ORg)
In the different formulas, Rf has the meaning given above and Rg to Rg, identical or different, represent a hydrocarbon group having from 1 to 20 carbon atoms, and more particularly: - an alkyl group, linear or branched, having from 1 to 12 carbon atoms,

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 - a linear or branched alkenyl or alkynyl group having from 2 to 12 carbon atoms, - a cycloalkyl or cycloalkenyl group, having from 3 to 8 carbon atoms, - an aryl group having from 6 to 20 carbon atoms, preferably a phenyl group or a naphthyl group, an arylalkyl group having from 7 to 20 carbon atoms, preferably a benzyl group.

 The various groups mentioned above, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or arylalkyl may be substituted by any substituent insofar as they do not interfere with the reaction. As more specific examples of substituents, mention may be made inter alia of halogen atoms, preferably fluorine, chlorine, bromine.

 Among the aforementioned groups Rg to Rs, it is preferably an alkyl group having from 1 to 4 carbon atoms, a phenyl group, a trifluoromethyl, trichloromethyl, trifluoroethyl group, a trifluoromethylphenyl group.

Sulfonamides and derivatives.

dans ladite formule : - Rf et E ont la signification donnée précédemment, - Y représente un groupement

dans lequel : - Ra et R'a représentent un groupement hydrocarboné quelconque ayant de
1 à 20 atomes de carbone dans la mesure où ils ne comprennent pas de groupements nucléophiles, comprenant ou non un groupement électro- attracteur, - les groupes Ra et R'a peuvent être liés entre eux pour former un hétérocycle azoté, The invention relates, as new products, to the resolution reagents corresponding to the following formula (f):

in said formula: - Rf and E have the meaning given above, - Y represents a group

in which: - Ra and R'a represent any hydrocarbon group having
1 to 20 carbon atoms insofar as they do not comprise nucleophilic groups, which may or may not include an electron-withdrawing group, - the groups Ra and R'a can be linked together to form a nitrogen heterocycle,

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dans les formules (la) et (lob) : - R'et R" représentent indépendamment l'un de l'autre un groupe hydrocarboné ayant de 1 à 20 atomes de carbone qui peut être un groupe aliphatique acyclique saturé ou insaturé, linéaire ou ramifié ; un groupe carbocyclique ou hétérocyclique saturé, insaturé ou aromatique, monocyclique ou polycyclique ; un enchaînement des groupes précités ; - ou encore, R'et R"peuvent être liés de manière à constituer avec les atomes de carbone qui les portent un groupe carbocyclique ou hétérocyclique ayant de 4 à 20 atomes, saturé, insaturé, monocyclique ou polycyclique, - Ar et Ar2 symbolisent, indépendamment l'un de l'autre deux cycles aromatiques, carbocycliques ou hétérocycliques, substitués ou non, condensés ou non et portant le cas échéant un ou plusieurs hétéroatomes, - x et y repèrent respectivement les deux liaisons établies entre le squelette symbolisé par A et les groupements sulfonamide et Y. - and if Ra or R'a represents a hydrogen atom then R'a or Ra represents an electro-attractor group S02 Rf, Rf having the meaning given above, - A symbolizes a skeleton of general formula (la) or (lob )

in formulas (la) and (lob): - R'and R "independently of one another represent a hydrocarbon group having from 1 to 20 carbon atoms which can be an acyclic saturated or unsaturated, linear or aliphatic aliphatic group branched; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the abovementioned groups; - or alternatively, R ′ and R ″ may be linked so as to constitute, with the carbon atoms carrying them, a carbocyclic group or heterocyclic having 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic, - Ar and Ar2 symbol, independently of one another two aromatic, carbocyclic or heterocyclic rings, substituted or not, condensed or not and carrying the case where appropriate one or more heteroatoms, - x and y respectively identify the two bonds established between the skeleton symbolized by A and the sulfonamide and Y groups.

 For the purposes of the present invention, it is intended to cover the compounds of formula (1 ′) as well as their racemic mixtures and their optically active isomers.

In formula (1), the chiral group Ri * is symbolized by the formula:

r groupement électro-attracteur. g In formula (1), Ra and R'a represent any hydrocarbon group having from 1 to 20 carbon atoms insofar as they do not comprise nucleophilic groups, comprising or not a

r electro-attractor group. g

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 Ra and R'a must not comprise nucleophilic groups, that is to say groups more nucleophilic than the nitrogen atom of the mixture of amines to be resolved.

 The term “electron-attracting group” is understood to mean a group as defined by H. C. BROWN in the work of Jerry MARCH-Advanced Organic Chemistry, 4th edition, John Wiley and Sons, 1992, chapter 9, pp. 273-292.

 It is preferably: - a C1 to C10 alkyl or C3 to C10 cycloalkyl mono-, poly- or per-halogenated group, - a phenyl group substituted by at least one C1 to Ciao alkyl group, preferably in C1 to C4, mono-, poly- or per-halogenated or a nitro or nitrile group, - of a phenyl group mono-, poly- or per-halogenated, - of a functional group such as -CO- R3, - CO-NR3R4, - COOR3, in which Rg, R4, identical or different, represent a C 10 -C 10 alkyl group; preferably C1 to C4, mono-, poly- or per-halogenated; a phenyl group; a phenyl group substituted with at least one C1-Ciao, preferably C1-C4 alkyl, mono-, poly- or perhalogenated group or a nitro or nitrile group; a mono-, poly- or per-halogenated phenyl group.

 As mentioned above, the groups Ra and R'a can be linked together to form a nitrogen heterocycle comprising from 5 to 7 atoms.

 More specifically, in formulas (1) or (1 '), Rf represents a hydrocarbon group having from 1 to 20 carbon atoms and more particularly:. a C1 to C, o, preferably C1 to C4 alkyl group, and more preferably a methyl or ethyl group. a C1-Ciao, preferably C1-C4, mono-, poly- or per-halogenated alkyl group having from 1 to 23 halogen atoms, preferably a CF3 group,. a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclohexyl group,. an optionally mono-, poly- or per-halogenated cycloalkyl group having from 3 to 8 carbon atoms,. a phenyl group,. a mono-, poly- or per-halogenated phenyl group.

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ou par un ou plusieurs groupements a) ky ! e en Ci-Cg mono-, po) y- ou per-f) uoré. . a phenyl group substituted with at least one C1 to C4, preferably C1 to C4, optionally mono-, poly- or per-halogenated or a nitro or nitrile group; . an optionally mono-, poly- or per-halogenated aryl group having from 6 to 12 carbon atoms,
More preferably, Rf represents a group CFg, C4Fg or a phenyl group substituted by one or more halogen atoms, preferably fluorine,

or by one or more groups a) ky! e in Ci-Cg mono-, po) y- or per-f) uoré.

The preferred sulfonyl groups are: - your tosytes (p-to) uènesu! fony) e) -SO-CgH-CHg - tes brosy! es (p-bromobenzènesutfony) e) -SO-CgH-Br - tes nosytes (p-nitrobenzènesu) fony) e) -SO-CgH-NO - tes mesés) es (méthanesu) fonyte) -SO-CHg - trif) y) es (trif) uorométhanesu! fony) e) -SO-CFg - your nonaftytes (nonaf) uorobutanesu) fony) e) -SOg-CFg - trésyles (2, 2, 2-trifluroéthanesulfonyle). -S02-CH2-CF3
As regards the definition of Y, it is more particularly a sulfonamide-N (SO 2 Rf) group (RJ in which Ra represents in particular: - a hydrogen atom, - an alkyl chain, preferably Ci to Ciao, optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl group (s), - an alkenyl or alkynyl chain, preferably in C2 to Co, possibly interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atom (s) or carboxyl group (s), - a group aryl, preferably C6 to C12, optionally substituted by one or more halogen atom (s) or C1 to Ciao alkyl, alkenyl or C2 to Ciao alkynyl group,
In the preceding general formulas which follow, the halogen atom (s) mentioned as a substituent are preferably represented by a fluorine atom.

 According to a first variant of the invention, the compounds of general formula (@ ') correspond to the general formula (I'b)

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dans laquelle : - Rf, Ra, E, (x), (y) sont tels que définis précédemment et Ar, et Ar2 figurent ensemble un groupement aromatique qui peut être un carbocycle ayant de 6 à 12 atomes de carbone ou un hétérocycle ayant de 5 à 12 atomes.

in which: - Rf, Ra, E, (x), (y) are as defined above and Ar, and Ar2 together represent an aromatic group which can be a carbocycle having from 6 to 12 carbon atoms or a heterocycle having 5 to 12 atoms.

 In the description which follows of the present invention, the term "aromatic" is understood to mean a classic notion of aromaticity as defined in the literature, in particular by J. March Advanced Organic Chemistry, 4 ed., John Wiley & Sons, 1992, pp 40 and following.

 In the context of the present invention, the aromatic derivative can be monocyclic or polycyclic.

 In the case of a monocyclic derivative, it can comprise, at the level of its cycle, one or more heteroatoms chosen from nitrogen, phosphorus, sulfur and oxygen atoms. According to a preferred mode, these are nitrogen atoms not substituted by a hydrogen atom.

 By way of illustration of the monocyclic heteroaromatic derivatives which are suitable for the present invention, mention may in particular be made of the pyridine, pyrimidine, pyridazine and pyrazine derivatives.

 The carbon atoms of the aromatic derivative can also be substituted. Two vicinal substituents present on the aromatic ring can also form together with the carbon atoms which carry them a hydrocarbon ring, preferably aromatic and comprising, where appropriate, at least one heteroatom. The aromatic derivative is then a polycyclic derivative.

 By way of illustration of this type of compound, mention may in particular be made of naphthalene, quinoline and isoquinoline derivatives.

soit un groupement dérivant du diphényl-2, 2'-diyle, soit un groupement dinaphtyle-2, 2'-diyle. As a representative of the compounds corresponding to the general formula (I'b), mention may more particularly be made of those in iesqueis Ar and Ar2 appearing together

either a group derived from 2,2-diphenyl, 2'-diyl, or a dinaphthyl-group 2, 2'-diyl.

In the case where Ar1 and Ar2 together represent a 2,2-diphenyl group, 2'diyle, the two phenyl rings are substituted so as to block the

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 configuration of the corresponding structure with substituents such as a C1 to C6, preferably C1 to C4 alkyl, alkoxy or alkylthio group: said groups are preferably in position 3 and 3 '.

 The compounds of general formula () ') in which A symbolizes a skeleton of formula (la) prove in fact very particularly interesting.

dans laquelle - Rf, Rg, E, (x), (y) sont tels que définis ci-dessus en formule générale (1'), - R'et R"représentent indépendamment l'un de l'autre un groupe carbocyclique ou hétérocyclique, saturé, insaturé ou aromatique, monocyclique ou polycyclique, - ou R'et R"peuvent être liés de manière à constituer avec les atomes de carbone qui les portent un groupe carbocyclique ou hétérocyclique ayant de 4 à 20 atomes, saturé, insaturé, monocyclique ou polycyclique. More preferably, these compounds correspond to the general formula (a):

in which - Rf, Rg, E, (x), (y) are as defined above in general formula (1 '), - R'and R "independently of one another represent a carbocyclic group or heterocyclic, saturated, unsaturated or aromatic, monocyclic or polycyclic, - or R'and R "can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic.

 In the general formulas (la) and (a), R'and R ", identical or different, can take various meanings. Different examples are presented below, but they are in no way limiting.

 Thus, R ′ and R ″ can represent, independently of one another, an acyclic aliphatic group, saturated or unsaturated, linear or branched.

 More precisely, R ′ and R ″ preferably represent a linear or branched saturated acyclic aliphatic group preferably having from 1 to 12 carbon atoms, and even more preferably from 1 to 4 carbon atoms.

 The invention does not exclude the presence of an unsaturation on the hydrocarbon chain such as one or more double bonds which can be conjugated or not.

 The hydrocarbon chain can optionally be interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group insofar as the latter does not react and mention may in particular be made of a group such as in particular -CO-.

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 The hydrocarbon chain may optionally carry one or more substituents (for example, halogen, ester) insofar as they do not interfere.

 The acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent. By cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.

 The acyclic aliphatic group can be linked to the ring by a valential bond, a heteroatom or a functional group such as oxy, carbonyl, carboxyl, sulfonyl etc ...

 As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention. Mention may in particular be made of alkyl and alkoxy groups having from 1 to 4 carbon atoms.

 Among the aliphatic groups carrying a cyclic substituent, more particularly targeted are cycloalkylalkyl groups, for example, cyclohexylalkyl or arylkyl groups having from 7 to 12 carbon atoms, in particular benzyl or phenylethyl.

 In the general formulas (la) and (a), the groups R'and R "can also represent, independently of one another, a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 with 8 carbon atoms, preferably 6 carbon atoms in the ring, said ring being able to be substituted As preferred examples of this type of groups, mention may be made of cyclohexyl groups optionally substituted by linear or branched alkyl groups, having 1 to 4 carbon atoms.

un groupe hydrocarboné aromatique, et notamment benzénique répondant à la formule générale le :

The groups R'and R "can represent independently of each other,

an aromatic, and in particular benzene, hydrocarbon group corresponding to the general formula:

dans laquelle : - n'représente un entier de 0 à 5 et

in which: - does not represent an integer from 0 to 5 and

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 - Q a group chosen from:. a linear or branched alkyl group having from 1 to 6 carbon atoms,. a linear or branched alkoxy group having from 1 to 6 carbon atoms,. a linear or branched alkylthio group having from 1 to 6 carbon atoms,. a group-NO2,. a group-CN,. a halogen atom,. a CFg group.

 R'and R "can also represent, independently of one another, a polycyclic aromatic hydrocarbon group with the cycles which can form between them ortho-condensed, ortho-and pericondensed systems. Mention may more particularly be made of a naphthyl group; said cycle can be substituted.

 R'and R "can also represent, independently of each other, a heterocyclic group, saturated, unsaturated or aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen atoms (unsubstituted by a hydrogen atom), sulfur and oxygen; the carbon atoms of this heterocycle can also be substituted.

 R'and R "can also represent a heterocyclic polycyclic group defined as being either a group consisting of at least two aromatic heterocyclic rings or not containing at least one heteroatom in each cycle and forming between them ortho-or ortho-and peri-systems condensed, or either a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them orthoor ortho-and peri-condensed systems; the carbon atoms of said cycles can optionally be substituted.

 By way of examples of heterocyclic R ′ and R ″ groups, mention may be made, inter alia, of the furyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl and quinolyl, napthyridinyl, benzopyrannyl groups, benzofuranyl.

 The number of substituents present on each cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturation on the cycle. The maximum number of substituents capable of being carried by a cycle is easily determined by a person skilled in the art.

 R'and R "can also be linked to represents, carbocyclic or heterocyclic, mono- or poly-cyclic, saturated, unsaturated or aromatic, preferably bicyclic, groups which means that at least two rings have two carbon atoms in common In the case of compounds

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 polycyclic, the number of carbon atoms in each cycle preferably varies between 3 and 6.

---------- ---------

By way of illustration of this type of structure, the following cyclic groups can be mentioned in particular:

---------- ---------

Of particular interest are the compounds of general formula (a) in which: - R'and R "both represent a phenyl group, - R'and R" are linked together so as to constitute with the carbon atoms which carry them a cyclohexyl group.

 As mentioned above, the compounds of general formula (1) or (1 ') are all the more advantageous when they are presented in an optically active form.

 To this end, the two carbons of the general formula (1) involved respectively at the level of the connections symbolized by (x) and (y) constitute two centers of chirality which are preferably of the same configuration.

1

dans ladite formule, - Rf1 représente un groupe alkyle ayant de 1 à 10 atomes de carbone, un groupe phényle, un groupe phényle substitué par un groupe alkyle ayant de 1 à 10 atomes de carbone, de 1 à 5 atomes de fluor ou un groupe trifluorométhyle, - Ra'représente un groupe alkyle ayant de 1 à 10 atomes de carbone, - Rb'représente un atome d'hydrogène ou un groupe alkyle ayant de 1 à 10 atomes de carbone, - Re représente un atome d'hydrogène ou un groupe alkyle ayant de 1 à 4 atomes de carbone. The preferred reagents according to the invention correspond to the following formula (I'c)

1

in said formula, - Rf1 represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms or a group trifluoromethyl, - Ra'represent an alkyl group having from 1 to 10 carbon atoms, - Rb'represent a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms, - Re represents a hydrogen atom or a alkyl group having 1 to 4 carbon atoms.

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------------------------------------------------------------------------1 1 1 1 Une autre classe préférée de réactifs sont ceux qui répondent à la formule ------------------------------------------------------------------i

dans ladite formule, - Rf1 représente un groupe alkyle ayant de 1 à 10 atomes de carbone, un groupe phényle, un groupe phényle substitué par un groupe alkyle ayant de 1 à 10 atomes de carbone, de 1 à 5 atomes de fluor ou un groupe trifluorométhyle, - R2'représente un groupe alkyle ayant de 1 à 10 atomes de carbone, - Rb'représente un atome d'hydrogène ou un groupe alkyle ayant de 1 à 10 atomes de carbone, - Re représente un atome d'hydrogène ou un groupe alkyle ayant de 1 à 4 atomes de carbone.

-------------------------------------------------- ---------------------- 1 1 1 1 Another preferred class of reagents are those which have the formula ----------- -------------------------------------------------- ----- i

in said formula, - Rf1 represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms or a group trifluoromethyl, - R2'represent an alkyl group having from 1 to 10 carbon atoms, - Rb'represent a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms, - Re represents a hydrogen atom or a alkyl group having 1 to 4 carbon atoms.

sulfonamido)cyclohexane, le (18, 28) -N-acétyl-1, 2-bis (p-trifluorométhylbenzènesulfonamido) cyclohexane, le (lS, 2S)-N-propionyl-1, 2-bis (trifluorométhanesulfonamido) cyclohexane, le (18, 28) -N-isobutyryl-1, 2-bis (trifluorométhanesulfonamido) cyclohexane, le (18, 28) -N-acétyl-1, 2-bis (trifluorométhanesulfonamido) diphényléthane, le (18, 28) -N-acétyl-N-méthyl-1, 2-bis (trifluorméthanesulfonamido) cyclohexane, le (1S, 2S)-N-acétyl-1,2-bis(méthane- sulfonamido)cyclohexane, le (1S, 2S)-N-acétyl-1,2-bis (benzènesulfonamido)cyclohexane. Mention may in particular be made, as representative of the compounds of the invention, of (1S, 2S) -N-acetyl-1,2-bis (trifluoromethane-sulfonamido) cyclohexane, (1S, 2S) -N-acetyl-1 , 2-bis (pentafluorobenzene-

sulfonamido) cyclohexane, le (18, 28) -N-acetyl-1, 2-bis (p-trifluoromethylbenzenesulfonamido) cyclohexane, le (lS, 2S) -N-propionyl-1, 2-bis (trifluorométhanesulfonamido) cyclohexane 18, 28) -N-isobutyryl-1, 2-bis (trifluoromethanesulfonamido) cyclohexane, le (18, 28) -N-acetyl-1, 2-bis (trifluoromethanesulfonamido) diphenylethane, (18, 28) -N-acetyl -N-methyl-1,2-bis (trifluormethanesulfonamido) cyclohexane, le (1S, 2S) -N-acetyl-1,2-bis (methane-sulfonamido) cyclohexane, le (1S, 2S) -N-acetyl-1 , 2-bis (benzenesulfonamido) cyclohexane.

Preparation of sulfonamides.

 In accordance with the process of the invention, the sulfonamides of formula (1) or () ') are preferably obtained (a) to (I'd) by reacting an amino compound carrying a chiral group (II) and a reagent providing the sulfonyl group.

 More precisely, the amino compound can be symbolized by the formula (II): Ri * -NH (H) in said formula, R * has the meaning given above.

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 As more specific examples of amines, there may be mentioned, inter alia (1S, 2S) -1,2-cyclohexanediamine, (1S, 2S) -1,2-diphenylethylenediamine.

 In accordance with the process of the invention, the amino compound of formula (II) is reacted with a compound providing the electro-attractor group - SO-Rf.

dans ladite formule (ici) : - Rf a la signification donnée précédemment, - Z représente : . un atome d'halogène, de préférence un atome de chlore ou de brome, . un groupe -O-SO2-Rf@ dans lequel Rf', identique ou différent de Rf, a la signification donnée pour Rf. More precisely, it can be represented by the formula (Ill):

in said formula (here): - Rf has the meaning given above, - Z represents:. a halogen atom, preferably a chlorine or bromine atom,. a group -O-SO2-Rf @ in which Rf ', identical or different from Rf, has the meaning given for Rf.

 The preferred compounds correspond to formula (III) in which Z represents a chlorine or bromine atom.

 As more specific examples of compounds of formula (III), there may be mentioned in particular: - mesyl chloride, - benzenesulfonyl chloride, - tosyl chloride, - trifluoromethanesulfonyl chloride, - pentafluorobenzenesulfonyl chloride, - chloride of p-trifluoromethylbenzenesulfonyl.

 A compound corresponding to formula (IV) is obtained: R, * -NH-S02-Rf () V) in said formula (IV), R1 * and Rf have the meaning given above.

- (lR, 2R)-1, 2-bîs (trifluorométhane sulfonamido) cyclohexane, - (lys, 2S)-1, 2-bis (trifluorométhanesulfonamido) -1, 2-diphényléthane, - /- ?, 2/-1, 2-bis (triftuorométhanesu) fonamido)-A/-méthyicyc) ohexane, - (1R, 2R)-1,2-bis (méthanesulfonamido)cyclohexane, - (1R, 2R)-1,2-bis (benzènesulfonamido)cyclohexane. As more specific examples of compounds of formula (IV), there may be mentioned in particular: - (1S, 2S) -1,2-bis (trifluoromethane sulfonamido) cyclohexane, - (1R, 2R) -1,2-bis (pentafluorobenzene sulfonamido ) cyclohexane,

- (lR, 2R) -1, 2-bîs (trifluoromethane sulfonamido) cyclohexane, - (lys, 2S) -1, 2-bis (trifluoromethanesulfonamido) -1, 2-diphenylethane, - / -?, 2 / -1, 2-bis (triftuoromethanesu) fonamido) -A / -methyicyc) ohexane, - (1R, 2R) -1,2-bis (methanesulfonamido) cyclohexane, - (1R, 2R) -1,2-bis (benzenesulfonamido) cyclohexane.

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 The reaction between the amino compound of formula (II) and the compound of formula (III) takes place in the optional presence of a base.

 Can therefore intervene in the process of the invention, a base which can be an inorganic or organic base whose role is to trap the acid formed during the reaction.

 You can use any type of base.

 A base is used whose pKa of the conjugated acid is greater than or equal to the pKa of the product obtained (IV).

 It should be noted that if the pKa of the product obtained is low (less than around 6), it is not necessary to use a base.

 PKa is defined as the ionic dissociation constant of the acid / base couple, when water is used as a solvent.

 For the choice of a base having a pKa as defined by the invention, reference may be made, inter alia, to the HANDBOOK OF CHEMISTRY AND PHYSICS, 66th edition, p. D-161 and D-162.

 Strong bases can be used such as alkali metal hydroxides, preferably sodium or potassium hydroxide or alkali metal salts, in particular carbonates, bicarbonates, phosphates, hydrogen phosphates, sulfates, acetates and trifluoroacetates alkali.

 The concentration of the basic starting solution is not critical. The alkali metal hydroxide solution used has a concentration generally between 10 and 50% by weight.

 A preferred variant of the invention consists in adding a base, preferably a tertiary amine in order to trap the released acid.

 Among the bases which can be used, mention should be made of tertiary amines and more particularly those corresponding to the general formula (VI) N- (R9) g (V!)! in which: the groups Rg, which are identical or different, represent hydrocarbon residues having from 1 to 20 carbon atoms, such as alkyl, cycloalkyl, aryl or heterocyclic groups; - 2 Rg groups form together and with the nitrogen atom a heterocycle having 4 to 5 atoms.

 More particularly: the symbols Rg represent an alkyl group having 1 to 10 carbon atoms and preferably 1 to 4 carbon atoms or a cyclopentyl or cyclohexyl group or a pyridinyl group;

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 - 2 Rg groups together and with the nitrogen atom form a piperidine or pyrrolidine cycle.

tripropylamine, la diisopropyléthylamine, la tributylamine, la méthyldibutylamine, la méthyldicyclohexylamîne, l'éthyldiisopropylamine, la tv, Ndiéthylcyclohexylamine, la diméthylamino-4-pyridine, la N-méthylpipéridine, la N- éthylpipéridine, la N-butylpipéridine, la 1, 2-diméthylpipéridine, la N- méthylpyrrolidine, la 1, 2-diméthylpyrrolidine, la diazabicycloundécène. As examples of such amines, mention may be made of triethylamine,

tripropylamine, diisopropylethylamine, tributylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, tv, Ndiethylcyclohexylamine, dimethylamino-4-pyridine, N-methylpiperidine, N- ethylpiperidine, N-ethylpiperidine dimethylpiperidine, N-methylpyrrolidine, 1,2-dimethylpyrrolidine, diazabicycloundecene.

 Aromatic amines such as, for example, pyridine are also suitable as bases.

 The reaction of the compounds (II) and (III) is carried out in the presence of a base, preferably in an organic solvent.

 Any type of polar or non-polar organic solvent or a mixture of organic solvents is used.

 It is also possible to use an organic solvent which is inert under the reaction conditions. Thus, it is possible to use aliphatic or cycloaliphatic hydrocarbons, halogenated or not such as, for example, hexane, cyclohexane, dichloromethane, dichloroethane or aromatic, halogenated or not such as benzene, toluene, xylenes, chlorobenzenes ; esters such as methyl benzoate, methyl terephthalate, methyl adipate, dibutyl phthalate; polyol esters or ethers such as tetraethylene glycol diacetate; aliphatic, linear or cyclic ethers such as isopropyl ether, tetrahydrofuran or dioxane; aliphatic or aromatic nitriles such as acetonitrile, propionitril, butanenitrile, isobutanenitrile, benzonitrile, benzyl cyanide.

 As for the various reagents and substrates, they are used in the quantities specified below.

 The concentration of the compound of formula (II) used in the solvent can vary within very wide limits. Generally, the concentration of the compound of formula (II) varies between 0.1 and 5 mol / L, preferably between 1.0 and 2.0 mol / L of solvent.

 The amount of base used, expressed by the ratio of the number of moles of base to the number of moles of compound of formula (III) can vary within wide limits. Thus, the base / compound molar ratio of formula (III) preferably varies between 1.0 and 2.0.

 The amount of compound of formula (III) used, expressed by the ratio between the number of moles of compound of formula (III)) and the number of

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 moles of compound of formula (II) advantageously varies between 1.0 and 1.5 and is preferably around 1.1.

 The temperature at which the reaction of the compounds (II) and (ill) is carried out is between -15 ° C. and 50 ° C., preferably between 00 ° C. and ambient temperature (most often between 150 ° C. and 25 ° C.).

 According to a practical embodiment of the invention, it is possible to carry out the mixing of all the reagents in any order.

 A preferred embodiment of the invention consists in adding the compound of formula (III) to a reaction medium comprising the base and the amino compound, optionally an organic solvent.

 At the end of the reaction, an acid treatment is generally carried out in order to reprotonate the nitrogen. For example, hydrochloric acid is used in an amount such that the pH is less than or equal to 6, preferably between 4 and 5.

 The compound of formula (IV) is separated by extraction using an organic solvent which dissolves the compound of formula (IV).

 As solvents which may be used, there may be mentioned ethers, and more particularly diisopropyl ether, methyl isobutyl ether, methyl tert-butyl ether.

 The product can optionally be dried over sodium sulfate.

 A crystalline product is recovered by evaporation of the solvent. Purification can optionally be carried out by recrystallization from toluene or by chromatography on a silica gel column.

In a following step, the electrophilic group is fixed on the nitrogen atom.
To this end, the compound of formula (IV) is reacted with a reagent providing the electrophilic group E.

This reagent corresponds to formula (V):
EW (V) in said formula (V), E has the meaning given above and W represents a halogen atom, preferably chlorine or bromine and an OE group.

 As more specific examples of compounds of formula M, there may be mentioned, among others, among: - sulfonyl halides or sulfonic anhydrides: mesyl chloride, tosyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride,

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 -acyl or benzoyl halides or carboxylic anhydrides: acetyl chloride, propionyl chloride, 2-methylethanoyl chloride, acetic anhydride, - alkyl haloformates: methyl chloroformate, - dialkylcarbonates: di-tert-butyldicarbonate.

 - dialkyl- or diaryl- or alkylaryl-phosphoric or phosphonic halides: dimethylphosphoric chloride.

 Among the compounds of formula (V), the acyl or benzoyl halides are preferably chosen, and more preferably acetyl chloride, propionyl chloride, butyryl chloride.

 The compounds (IV) and (V) are reacted in an organic solvent as mentioned above.

 The concentration of the compound of formula (IV) used in the solvent can vary within very wide limits. Generally, the concentration of the compound of formula (IV) varies between 0.1 and 5.0 mol / L and is preferably between 0.2 and 2.0 mol / L of solvent.

 The ratio between the number of moles of compound of formula (V) and the number of moles of compound of formula (IV) is at least 1, preferably between 1 and 2.

 The reaction is most often carried out in the presence of a base.

As bases, use may be made in particular of butyllithium, sodium hydride or one of the tertiary amines of formula (VI).

 The amount of base used is such that generally the ratio between the number of moles of base- and the number of moles of compound of formula (IV) varies between 1 and 2.

 The reaction is advantageously carried out between -800 ° C. and 50 ° C. like the preceding step, preferably at room temperature.

 This reaction is generally carried out under atmospheric pressure.

 At the end of the reaction, the compound of formula (1) is obtained.

 Acid treatment is usually done to remove excess base.

 As examples of acids, use is preferably made of the following mineral acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid. We especially choose hydrochloric acid.

 Use is made, for example, of a dilute hydrochloric acid solution, for example 1 N.

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 The quantity of mineral acid used expressed relative to the compound of formula (1) is determined so that the pH of the medium is less than or equal to 6, preferably between 2 and 6.

 The compound of formula (1) is collected in the organic phase. It can be isolated by removing the solvent from the organic phase, in particular by dry evaporation.

 The compound obtained is used as a chial resolving reagent.

Process for the resolution of a racemic chiral amine.

 According to the invention, one obtains from a chiral amine in the form of a racemic mixture (or enriched in one of the stereomers), one of the stereomers because the other stereomer reacts less quickly with the reagent of chial resolution. It is therefore a kinetic chiral resolution.

 The racemic mixture of amine to be split is brought into contact with the chiral resolving reagent of formula (1), preferably (la) or (nib).

 It can be symbolized by the formula (VII): Rc-NH-Rd (Vil) in which Rc, Rd, identical or different, represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms and at least one of the groups Rc and Rd represents a chiral group: the amino group may or may not be carried by the asymmetric carbon.

 In formula (VII), Rc and Rd represent a hydrocarbon group comprising at least 3 atoms, monovalent, substituted or unsubstituted, which may be an aliphatic, acyclic, saturated or unsaturated, linear or branched group; a carbocyclic or heterocyclic, saturated or unsaturated, monocyclic or polycyclic group; a sequence of two or more of the above groups.

 It will be specified, without however limiting the scope of the invention, that the compound of formula (VII) may be: - an aliphatic, saturated or unsaturated, linear or branched chiral amine, optionally carrying a cycle, - a chiral amine carbocyclic or heterocyclic, monocyclic, saturated or unsaturated, - a chiral carbocyclic or heterocyclic, polycyclic amine comprising at least two carbocycles, saturated and / or unsaturated and / or aromatic.

 The chiral amine which can intervene in the process of the invention more particularly corresponds to the formula (VII) in which Rc and Rd represent an acyclic aliphatic group, saturated or unsaturated, linear or branched.

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 More precisely, Rc and Rd represent an alkyl, alkenyl, alkadienyl, alkynyl, linear or branched group preferably having from 3 to 40 carbon atoms.

et/ou porteuse de l'un des substituants suivants: -COOR11, -CHO, -NO2, -X, -CF3: dans ces formules R10 représente de préférence un groupe alkyle linéaire 1 ou ramifié ayant de 1 à 4 atomes de carbone, de préférence un groupe méthyle

1 ou éthy ! e, R représente un atome d'hydrogène ou un groupe R1o. The hydrocarbon chain can possibly be interrupted by a heteroatom (for example, oxygen or sulfur) or by one of the groups! following: i

and / or carrying one of the following substituents: -COOR11, -CHO, -NO2, -X, -CF3: in these formulas R10 preferably represents a linear 1 or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl group

1 or ethy! e, R represents a hydrogen atom or an R1o group.

 Said acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent.

dans ces formules, Rio a la signification donnée précédemment. It can be linked to the cycle by a valid link or by one of the following groups:

in these formulas, Rio has the meaning given above.

 By cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.

 The nature of the cycle can be arbitrary.

 As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of one or more substituents. The preferred cyclic substituents are the benzene rings.

 In the amines corresponding to formula (VII), Re and Rd may represent a carbocyclic, monocyclic group. The number of carbon atoms in the ring can vary widely from 3 to 8 carbon atoms but it is preferably equal to 5 or 6 carbon atoms.

 The carbocycle can be saturated or comprising 1 or 2 double bonds.

 In the case where Re and Rd represent a carbocyclic, monocyclic, saturated or unsaturated group, it is possible that one or more of the carbon atoms of the ring are replaced by a heteroatom, preferably oxygen, nitrogen (not carrying a hydrogen atom) or sulfur not

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nucleophile or by a functional group, preferably carbonyl or ester, thus leading to a heterocyclic, monocylic compound. The number of atoms in the ring can vary widely from 3 to 8 atoms but it is preferably equal to 5 or 6 atoms.

R. and R groups The Rc and Rd groups can also be carbocyclic, preferably polycyclic bicyclic, which means that at least two rings have two carbon atoms in common. In the case of polycyclic groups, the number of carbon atoms in each cycle varies between 3 and 6: the total number of carbon atoms being preferably equal to 7.

Examples of bicyclic structure, commonly encountered:

The groups e and d can also be hererocyclic, polycyclic, preferably bicyclic, which means that at least two rings have two atoms in common. In this case, the number of atoms in each cycle varies between 3 and 6 and is more preferably equal to 5 or 6.

It should be noted that if the groups R. and R It should be noted that if the groups Re and Rd comprise any cycle, it is possible that this cycle carries a substituent. The nature of the substituent is arbitrary insofar as it does not interfere with the desired product. The substituents most often carried by the ring are one or more alkyl or alkoxy groups preferably having from 1 to 4 carbon atoms, preferably three methyl groups.

 The substrates preferably used in the process of the invention are the aliphatic, saturated or unsaturated, linear or branched amines, having from 3 to 30 carbon atoms, which may optionally carry a substituent, for example cyclic, and more particularly a group phenyl, a halogen atom, an amine or alkoxy group generally having from 1 to 4 carbon atoms.

 The reagent includes an electron-withdrawing group which is a sulfonyl group and an electrophilic group.

 The mixture of amines carries an amino group with at n. oins a hydrogen atom capable of reacting with the kinetic resolution reagent according to a stereoselective functionalization reaction of nitrogen.

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 The functional group of the reacting resolution reagent is either the sulfonyl group or the electrophilic group.

 The product obtained is a function of the more or less electro-attracting character of said groups.

moins électro-attracteur que le groupe électrophile :

R-SOE Rf SO2, E 1 R,-NH-Rd--R.-N-R+ R,-NH-F+ RfSO.-NH 1 1 R* 1 1 1 mélange d'énantiomères i 1 (1) (Vila) et (V) ! b) (V) !)) (V ! ta) ou (V)) b) ( ! V) 1 1

1 1 Généralement, on obtient un composé de formule (VIII) selon une réaction ! de carbamoylation, d'acylation (au sens large incluant la benzoylation), de sulfonylation ou phosphorylation. Without linking the interpretation of the scope of the patent to the following mechanisms, it is believed that a compound of formula (VIlla) is obtained if the sulfonyl type group is more electron-attracting than the electrophilic group or a compound of formula (Vlllb) if the sulfonyl group is

less electro-attractor than the electrophilic group:

R-SOE Rf SO2, E 1 R, -NH-Rd - R.-N-R + R, -NH-F + RfSO.-NH 1 1 R * 1 1 1 mixture of enantiomers i 1 (1) (Vila ) and V) ! b) (V)!)) (V! ta) or (V)) b) (! V) 1 1

1 1 Generally, a compound of formula (VIII) is obtained according to a reaction! carbamoylation, acylation (broadly including benzoylation), sulfonylation or phosphorylation.

 Among all these reactions, acylation reactions, in particular acetylation reactions, are preferred.

1 1 L---1

1 1 R--SO COr*H 1 N"'+R.-NH-R,---R.-N-Rd+R,-NH-R, + RfSO.-NH 1 mélange d'enantiomeres i (1) (Vlla) et (Vilb) (VIII) (Vlla) ou (Vllb) (IV) 1 1 1 Conformément à l'invention, on met en oeuvre le réactif de résolution en une quantité telle que le rapport molaire entre le nombre de moles d'amines de formule (VII) et de réactif de résolution de formule (1) est supérieur ou égal à 1, de préférence, supérieur ou égal à 2 et compris entre 2 et 10, de préférence, entre 2 et 5, et encore plus préférentiellement égal à 3. ! An example of such a reaction is as follows

1 1 L --- 1

1 1 R - SO COr * H 1 N "'+ R.-NH-R, --- R.-N-Rd + R, -NH-R, + RfSO.-NH 1 mixture of enantiomers i ( 1) (Vlla) and (Vilb) (VIII) (Vlla) or (Vllb) (IV) 1 1 1 According to the invention, the resolution reagent is used in an amount such that the molar ratio between the number moles of amines of formula (VII) and of resolution reagent of formula (1) is greater than or equal to 1, preferably, greater than or equal to 2 and between 2 and 10, preferably between 2 and 5, and even more preferably equal to 3.

 The reaction is advantageously carried out in an organic solvent. It can be any organic solvent, protic or aprotic, polar or apolar.

 As preferred examples of solvents, mention may be made of aprotic, polar organic solvents and mention may more particularly be made of linear or cyclic carboxamides such as N, N-dimethylacetamide (DMAC),

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le N, N-diéthylacétamide, le diméthylformamide (DMF), le diéthylformamide ou la 1-méthyl-2-pyrrolidinone (NMP) ; le diméthylsulfoxyde (DMSO) ; l'hexaméthylphosphoramide (HMPA), l'hexaméthylphosphotriamide (HMPT) ; la tétraméthylurée ; les composés nitrés tels que le nitrométhane, le nitroéthane, le 1-nitropropane, le 2-nitropropane ou leurs mélanges, le nitrobenzène ; les nitriles alphatiques ou aromatiques comme l'acétonitrile, le propionitrile, le butanenitrile, Ilisobutanenitrile, le benzonitrile, le cyanure de benzyle ; la tétraméthylène sulfone (sulfolane), la 1, 3-diméthyl-3, 4,5, 6-tétrahydro-2- (1, H) -pyrimidinone (DMPU).

N, N-diethylacetamide, dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP); dimethyl sulfoxide (DMSO); hexamethylphosphoramide (HMPA), hexamethylphosphotriamide (HMPT); tetramethylurea; nitro compounds such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane or their mixtures, nitrobenzene; alphatic or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, Ilisobutanenitrile, benzonitrile, benzyl cyanide; tetramethylene sulfone (sulfolane), 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2- (1, H) -pyrimidinone (DMPU).

 The amine concentration varies between 0.01 and 2 mol / L, preferably between 0.1 and 0.3.

 The reaction is carried out at a temperature between -50 ° C. and 100 ° C., preferably between -200 ° C. and 20 ° C.

 From a practical point of view, the racemic amine, the organic solvent are used and, generally, the resolution reagent is added gradually.

 The reaction is most often carried out under atmospheric pressure.

 The stereomer is obtained in solution.

 It is separated in a conventional manner, for example, washing is carried out using an acid, preferably hydrochloric acid, in aqueous solution, for example 0.5 to 2 M.

 The desired product is recovered by crystallization, distillation or any other means, for example column chromatography.

EXAMPLES
Examples of preparation of the new sulfonamides are given below, as well as a general procedure for transferring enantioselective acetyl onto a racemic mixture of amines (kinetic resolution).

 Before detailing the examples, a procedure is given for preparing the (18, 28) -1, 2-bis (trifluoromethane sulfonamido) cyclohexane used in the following examples.

 In an analogous manner, the (lus, 2S) -1, 2bis (trifluoromethanesulfonamido) -1, 2-diphenylethane is prepared.

 Preparation of (read, 2S) -1, 2-bis (trifluoromethane sulfonamido) cyclohexane.

 In a 100 ml three-necked flask, fitted with an addition funnel, a temperature probe and a magnetic bar with stirring by a magnetic stirrer:

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 - 1 g (8.75 mmol) of (lys, 2S) -1, 2-cyclohexanediamine, - 2.94 mL (17.5 mmol) of trifluoromethanesulfonyl anhydride, - 1.58 mL (11.38 mmol) of triethylamine - 20 mL of dichloromethane.

 We start by loading the diamine and dichloromethane, then establishing an atmosphere of inert gas (nitrogen).

 The reaction mixture is then cooled to a temperature of 00C using an ice bath.

 The sulfonylating agent is poured in slowly using an addition funnel, then the reaction mixture is allowed to return to ambient temperature with stirring for two hours.

 After two hours, a saturated solution of ammonium chloride is introduced into the medium, and the organic phase is extracted, then washed several times using a saturated solution of sodium chloride.

 The organic phase is then dried over magnesium sulphate then filtered and finally evaporated under vacuum.

 The residue is then chromatographed on silica gel. The disulfonylated compound is obtained with a yield greater than 85%.

Example 1
In this example, the reagent A is prepared, namely (1S, 2S) -N-acetyl-1, 2bis (trifluoromethanesulfonamido) cyclohexane, from S, 2S) -1, 2bis (trifluoromethane sulfonamido) cyclohexane and chloride d acetyl.

- 1 g (2, 64 mmol) de (lys, 2S)-1, 2-bis (trifluorométhane sulfonamido) cyclohexane, - 550 uL (3,96 mmol ; 1,5 éq. ) de triéthylamine, - 188 uL (2,64 mmol ; 1 éq. ) de chlorure d'acétyle, - 20 mL de diéthyléther. In a 50 mL flask fitted with a magnetic bar with agitation by magnetic stirrer, rigorously dry and then placed under an argon atmosphere, we load:

- 1 g (2.64 mmol) of (lys, 2S) -1, 2-bis (trifluoromethane sulfonamido) cyclohexane, - 550 uL (3.96 mmol; 1.5 eq.) Of triethylamine, - 188 uL (2 , 64 mmol; 1 eq.) Of acetyl chloride, - 20 mL of diethyl ether.

 We start by loading the disulfonamide and the diethyl ether under an inert atmosphere (argon), then the reaction mixture is cooled to a temperature of −20 ° C. using a dry ice bath in acetone.

 Triethylamine is poured in, then the acetylating agent (acid chloride) drop by drop, using a precision syringe.

 The reaction mixture is left under stirring at 0 ° C. for 3 hours, then the precipitate formed is filtered.

 The solvent is evaporated, and the residue chromatographed on silica gel.

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The desired compound is obtained with a yield of 85% and a purity greater than 95%.

OU \/ 10 Formule brute : 5 LCF3 6. CH4, N2, S2 6 2 Masse molaire : 7U'IL 1 s"S-CFg 420, 17 g/mol d/\ 9 Aspect : Solide blanc

Les analyses sont les suivantes : CCM Rf = 0, 76 (éluant : AcOEt/hexane : 2/8 ; révélateur : vert de bromocrésol) RMN 1H 300 MHz, CDOg ô (ppm) 1, 10-1, 60 (m, 3H, H, yole) ; 1, 70-2, 00 (m, 3H, H, e) ; 2, 05-2, 35 (m, 1 H, Hcvc, e) ; 2, 35-2, 60 (m, 1 H, Hcvc, e) ; 2, 52 (s, 3H, H1) ; 3, 60-4, 05 (m, 1 H, H4) ; 4, 10 à 4, 60 (m, 1 H, Ha) ; 5, 04 (d, 1H, H-H4=10Hz, N-H) RMN 13C 75 MHz, CDC'3 ô (ppm) 24,4 (C6) ; 25,5 (C7) ; 26,8 (C1) ; 29,1 (C5) ; 35,4 (C8) ; 54,5 (C4) ; 66,9(C3); 119,4(q, JC-F=321 Hz, C10); 119,5 (q, JC-F=322Hz, C9); 170,0(C2) IR Transmission, film (Csl) v (cm') : 3296 ; 3221 ; 2948 ; 2868 ; 1737 ; 1716 ; 1456 ; 1385 ; 1233 ;
1200 ; 1131 ; 1070 ; 1016 ; 971 ; 942 ; 918 ; 896 ; 736 ; 627 ; 611 ; 590 ;
532

pf 110 C aD +17, 46 (c = 1, 5 ; CHC ! g) SM IC (NHa) (m/z) : 438 [M+NHJ+ ; 456 [M+2NHJ+ Exemple 2 Dans cet exemple, on prépare le réactif B à savoir le (1S, 2S)-N-acétyl-1,2bis (pentafluorobenzènesulfonamido) cyclohexane, à partir de (lus, 2S)-1, 2- bis (pentafluorobenzène sulfonamido) cyclohexane et de chlorure d'acétyle. Reagent A is obtained which corresponds to the following form

OR \ / 10 Raw formula: 5 LCF3 6. CH4, N2, S2 6 2 Molar mass: 7U'IL 1 s "S-CFg 420, 17 g / mol d / \ 9 Appearance: White solid

The analyzes are as follows: TLC Rf = 0.76 (eluent: AcOEt / hexane: 2/8; developer: bromocresol green) 1 H NMR 300 MHz, CDOg ô (ppm) 1, 10-1, 60 (m, 3H , H, skiff); 1.70-2.00 (m, 3H, H, e); 2.05-2.35 (m, 1H, Hcvc, e); 2.35-2.60 (m, 1H, Hcvc, e); 2.52 (s, 3H, H1); 3.60-4.05 (m, 1H, H4); 4.10-4.60 (m, 1H, Ha); 5.04 (d, 1H, H-H4 = 10Hz, NH) 13C NMR 75 MHz, CDC'3 ((ppm) 24.4 (C6); 25.5 (C7); 26.8 (C1); 29.1 (C5); 35.4 (C8); 54.5 (C4); 66.9 (C3); 119.4 (q, JC-F = 321 Hz, C10); 119.5 (q, JC-F = 322Hz, C9); 170.0 (C2) IR Transmission, film (Csl) v (cm '): 3296; 3221; 2948; 2868; 1737; 1716; 1456; 1385; 1233;
1200; 1131; 1070; 1016; 971; 942; 918; 896; 736; 627; 611; 590;
532

mp 110 C aD +17.46 (c = 1.5; CHC! g) SM IC (NHa) (m / z): 438 [M + NHJ +; 456 [M + 2NHJ + Example 2 In this example, reagent B is prepared, namely (1S, 2S) -N-acetyl-1,2bis (pentafluorobenzenesulfonamido) cyclohexane, starting from (lus, 2S) -1, 2- bis (pentafluorobenzene sulfonamido) cyclohexane and acetyl chloride.

 The procedure of Example 1 is repeated.

 Reagent B, which corresponds to the following formula, is obtained with a yield of 82%:

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y/=s Formute brute : q 1F5 Formule brute : 6 \J CH,, FN, 0, S2 2 Masse molaire : 'r\ 616, 23 g/mol 0 0 Aspect : Solide blanc

Les analyses sont les suivantes : CCM Rf = 0, 47 (éluant : AcOEt/hexane : 2/8 ; révélateur : vert de bromocrésol) RMN'H 300 MHz, CDOg ô (ppm) 1, 05-1, 46 (m, 3H, H ycle) ; 1, 50-1, 85 (m, 3H, Hcyc, e) ; 1, 85-2, 15 (m, 1H, H,,) ; 2, 20-2, 61 (m, 1H, HJ ; 2, 41 (s, 3H, H1) ; 3, 75-4, 10 (m, 1 H, 1 H, Hcvcle) ; 2, 20-2, 61 (m, 1 H, Hr H4) ; 4, 15-4, 35 (m, 1 H, Ha) ; 4, 90-5, 40 (m, 1 H, N-H) RMN 13C 75 MHz, CDC13 ô (ppm) 24, 4 (C7) ; 25, 6 (C6) ; 26, 6 (C1) ; 29, 5 (C5) ; 35, 1 (C8) ; 53, 2 (C4) ; 65, 2 (C3) ; 116, 8 (m, CAr) ; 136, 5 (m, CAr) ; 139, 9 (m, CAr) ; 142, 8 (m, CAr) ; 146, 2 (m, CAr) ; 170, 5 (C2) IR Transmission, film (Csl) v (cm') : 3287 ; 2943 ; 1716 ; 1645 ; 1523 ; 1500 ; 1372 ; 1302 ; 1226 ; 1174 ; 1103 ; 993 ; 731 ; 608 ; 578 Pf 73-74 C SM IC (NHg) (m/z) : 634 [M+NHJ---------------------------Exemple 3 Dans cet exemple, on prépare le réactif C à savoir le (lus, 28) -N-acétyl-1, 2bis (p-trifluorométhylbenzènesulfonamido) cyclohexane à partir de (lus, 2S)-1, 2bis (p-trifluorométhylbenzènesulfonamido) cyclohexane et de chlorure d'acétyle.

y / = s Raw formula: q 1F5 Raw formula: 6 \ J CH ,, FN, 0, S2 2 Molar mass: 'r \ 616, 23 g / mol 0 0 Appearance: White solid

The analyzes are as follows: TLC Rf = 0.47 (eluent: AcOEt / hexane: 2/8; developer: bromocresol green) 1 H NMR 300 MHz, CDOg 6 (ppm) 1.05-1.46 (m, 3H, H ycle); 1.50-1.85 (m, 3H, Hcyc, e); 1.85-2.15 (m, 1H, H ,,); 2, 20-2, 61 (m, 1H, HJ; 2, 41 (s, 3H, H1); 3, 75-4, 10 (m, 1H, 1 H, Hcvcle); 2, 20-2, 61 (m, 1 H, Hr H4); 4, 15-4, 35 (m, 1 H, Ha); 4, 90-5, 40 (m, 1 H, NH) 13C 75 MHz NMR, CDC13 ô ( ppm) 24.4 (C7); 25.6 (C6); 26.6 (C1); 29.5 (C5); 35.1 (C8); 53.2 (C4); 65.2 (C3) ; 116, 8 (m, CAr); 136, 5 (m, CAr); 139, 9 (m, CAr); 142, 8 (m, CAr); 146, 2 (m, CAr); 170, 5 ( C2) IR Transmission, film (Csl) v (cm '): 3287; 2943; 1716; 1645; 1523; 1500; 1372; 1302; 1226; 1174; 1103; 993; 731; 608; 578 Pf 73-74 C SM IC (NHg) (m / z): 634 [M + NHJ --------------------------- Example 3 In this example, we prepare reagent C, namely (lus, 28) -N-acetyl-1, 2bis (p-trifluoromethylbenzenesulfonamido) cyclohexane from (lus, 2S) -1, 2bis (p-trifluoromethylbenzenesulfonamido) cyclohexane and acetyl chloride.

The procedure of Example 1 is repeated.

Reagent C, which corresponds to the following formula, is obtained with a yield of 84%:

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oo 9 10 0 9 10 Formule brute : C. HF. N. OA L JL. U 67u."l U~, 2 1 73N'/\ Masse molaire : QS/ 572, 37 g/mol 0 0 Aspect : Solide blanc
Les analyses sontles sulvantes CCM Rf = 0,25 (éluant : AcOEt/hexane : 2/8 ; révélateur : vert de bromocrésol) RMN H 300 MHz, CDCl3 # (ppm) 1,15-1,35 (m, 3H, Hcycle); 1,40-1, 58 (m, 1 H, HCYcle) ; 1,60-1, 82 (m,
2H, Hcvc, ; 1,95-2, 10 (m, 1 H, Hcvcle) ; 2,05 (s, 3H, H1) ; 2, 15-2,35 (m, 1 H,
Hcyc, ; 3,75-3, 95 (m, 1 H, H4); 3,96-4,16 (m, 1H, H3); 4,87 (d, H, JN-H- H4=9,03Hz, N-H); 7,82 (dd, 4H, JH9-H9=26,2Hz, JH9-H10=8,1Hz, H9); 7,80-
8,10 (m, 4H, H10) RMN C 75 MHz, CDCl3 ô (ppm) 24,5 (C7) ; 25,7 (C6) ; 26,6 (C1) ; 29,3 (C5) ; 36,1 (C8) ; 53, 1 (C4) ; 64,4 (C3) ; 124,6 (q, JC-F=270Hz, C11) ; 125,1 (q, JC-F=272Hz, C12) ; 126,1 (CAr) ; 126,9 (CAr) ; 127,8 (CAr) 170,2 (C2) IR Transmission, film (Csl) v (cm-1): 3366 ; 3155 ; 2942 ; 2863 ; 1794 ; 1705 ; 1609 ; 1467 ; 1360 ;

1323 ; 1233 ; 1171 ; 144 ; 1064 ; 909 ; 735 ; 651 ; 617 Pf 158-160 C aD + 18, 610 (c = 0, 63 ; CHC) s) SM IC (NHg) (m/z) : 590 [M+NHJ'----------------------------- Exemple 4
Dans cet exemple, on prépare le réactif D à savoir le (lS, 28) -N-propionyl- 1,2-bis (trifluorométhanesulfonamido) cyclohexane, à partir de (lus, 2S)-1, 2bis (trifluorométhane sulfonamido) cyclohexane et de chlorure de propionyle.

oo 9 10 0 9 10 Gross formula: C. HF. N. OA L JL. U 67u. "L U ~, 2 1 73N '/ \ Molar mass: QS / 572, 37 g / mol 0 0 Appearance: White solid
The analyzes are as follows CCM Rf = 0.25 (eluent: AcOEt / hexane: 2/8; developer: bromocresol green) NMR H 300 MHz, CDCl3 # (ppm) 1.15-1.35 (m, 3H, Hcycle ); 1.40-1.58 (m, 1H, HCYcle); 1.60-1.82 (m,
2H, Hcvc,; 1.95-2.10 (m, 1H, Hcvcle); 2.05 (s, 3H, H1); 2.15-2.35 (m, 1 H,
Hcyc,; 3.75-3.95 (m, 1H, H4); 3.96-4.16 (m, 1H, H3); 4.87 (d, H, JN-H-H4 = 9.03 Hz, NH); 7.82 (dd, 4H, JH9-H9 = 26.2Hz, JH9-H10 = 8.1Hz, H9); 7,80-
8.10 (m, 4H, H10) C-NMR 75 MHz, CDCl3 ô (ppm) 24.5 (C7); 25.7 (C6); 26.6 (C1); 29.3 (C5); 36.1 (C8); 53, 1 (C4); 64.4 (C3); 124.6 (q, JC-F = 270Hz, C11); 125.1 (q, JC-F = 272Hz, C12); 126.1 (CAr); 126.9 (CAr); 127.8 (CAr) 170.2 (C2) IR Transmission, film (Csl) v (cm-1): 3366; 3155; 2942; 2863; 1794; 1705; 1609; 1467; 1360;

1323; 1233; 1171; 144; 1064; 909; 735; 651; 617 Pf 158-160 C aD + 18.610 (c = 0.63; CHC) s) SM IC (NHg) (m / z): 590 [M + NHJ '----------- ------------------ Example 4
In this example, the reagent D is prepared, namely (lS, 28) -N-propionyl-1,2-bis (trifluoromethanesulfonamido) cyclohexane, from (lus, 2S) -1, 2bis (trifluoromethane sulfonamido) cyclohexane and propionyl chloride.

The procedure of Example 1 is repeated
Reagent D, which corresponds to the following formula, is obtained with a yield of 71%:

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0 0 \\//10 Formule brute : 5 JiN/S-CF3 CHN, 0,5S2 cr Il0 1 Masse molaire : 73M 7 3 N 434, 2 g/mol 1/\\ 9 00 Aspect : Solide blanc
Les analyses sont les suivantes : CCM Rf = 0,44 (éluant : AcOEt/hexane : 2/8 ; révélateur : vert de bromocrésol) RMN H 200 MHz, CDCl3 # (ppm) 1,17 (t, 3H, JH1-H2=7,34Hz, H1); 1,21-1,45 (m, 3H, Hcycle); 1,60-

1, 95 (m, 3H, Hr v 1, 95 (m, 3H, Hcvcle) ; 2, 15-2, 34 (m, 1 H, Hcvc, e) ; 2, 35-2, 59 (m, 1 H, Hcvc, e) ; 2, 61-2, 83 (m, 1 H, HJ ; 2, 84-3, 08 (m, 1 H, HJ ; 3, 62-3, 92 (m, 1 H, H4) ; 4, 18-4, 43 (m, 1 H, Ha) ; 5, 12 (d, 1H, 3JNH-H4=10Hz, NH) RMN C 50 MHz, CDCl3 # (ppm) 8,9 (C1); 24,4 (C6) ; 25,5 (C7) ; 29,3 (C5) ; 31, 9 (C2) ; 35,3 (C8) ; 54, 7 (C4) ; 66, 9 (C3) ; 119, 4 (q, JC-F=32lHz, C10) ; 119, 6 (q, Jc-
F=322Hz, C9) ; 174, 4 (C1 1) IR Transmission, film (Csl) v (cm-1): 3304 ; 3055 ; ; 2948 ; 1740 ; 1444 ; 1396 ; 1266 ; 1233 ;
1203 ; 1135 ; 980 ; 740 ; 610 Pu 102-1 05C

aD +20, 39 (c = 1, 02 ; CHCig) SM IC (NHs) (m/z) : 452 [M+NHJ----------------------------- Exemple 5
Dans cet exemple, on prépare le réactif E à savoir le (1S, 2S)-N-isobutyryl- 1,2-bis(trifluorométhanesulfonamido)cyclohexane à partir de (lS, 2S)-1, 2bis (trifluorométhanesulfonamido) cyclohexane et de chlorure de butyryle.

0 0 \\ // 10 Raw formula: 5 JiN / S-CF3 CHN, 0.5S2 cr Il0 1 Molar mass: 73M 7 3 N 434, 2 g / mol 1 / \\ 9 00 Appearance: White solid
The analyzes are as follows: TLC Rf = 0.44 (eluent: AcOEt / hexane: 2/8; developer: bromocresol green) H NMR 200 MHz, CDCl3 # (ppm) 1.17 (t, 3H, JH1-H2 = 7.34 Hz, H1); 1.21-1.45 (m, 3H, Hcycle); 1,60-

1.95 (m, 3H, Hr v 1.95 (m, 3H, Hcvcle); 2.15-2.34 (m, 1 H, Hcvc, e); 2.35-2.59 (m, 1 H, Hcvc, e); 2, 61-2, 83 (m, 1 H, HJ; 2, 84-3, 08 (m, 1 H, HJ; 3, 62-3, 92 (m, 1 H, H4); 4.18-4.43 (m, 1H, Ha); 5.12 (d, 1H, 3JNH-H4 = 10Hz, NH) C NMR 50 MHz, CDCl3 # (ppm) 8.9 (C1 ); 24.4 (C6); 25.5 (C7); 29.3 (C5); 31.9 (C2); 35.3 (C8); 54, 7 (C4); 66, 9 (C3) ; 119, 4 (q, JC-F = 32lHz, C10); 119, 6 (q, Jc-
F = 322Hz, C9); 174, 4 (C1 1) IR Transmission, film (Csl) v (cm-1): 3304; 3055; ; 2948; 1740; 1444; 1396; 1266; 1233;
1203; 1135; 980; 740; 610 Pu 102-1 05C

aD +20, 39 (c = 1.02; CHCig) SM IC (NHs) (m / z): 452 [M + NHJ -------------------- --------- Example 5
In this example, the reagent E is prepared, namely (1S, 2S) -N-isobutyryl- 1,2-bis (trifluoromethanesulfonamido) cyclohexane from (lS, 2S) -1, 2bis (trifluoromethanesulfonamido) cyclohexane and chloride butyryl.

 The procedure of Example 1 is repeated.

 Reagent E which corresponds to the following formula is obtained with a yield of 68%

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- -------------------------------------------------------------------------- 00 \\//10 Formule brute : 5 FION, C,, H1F, N, 0, S2 0 : 0 1 Masse molaire : 1 : t 7 3 N 448, 23 g/mol S-cog \\ 9 Aspect : 0 0 00 Solide blanc

Les analyses sont les suivantes : CCM Rf = 0, 64 (éluant : AcOEt/hexane : 2/8 ; révélateur : vert de bromocrésol) RMN 1H 300 MHz, CDOg ô (ppm) 1, 18 (d, 3H, aJH1-H2=8, 32Hz, H1) ; 1, 24 (d, 3H, aJH1-H2=6, 6Hz, H1) ; 1, 29-1, 43 (m, 3H, H, ye) ; 1, 74-1, 96 (m, 3H, Hcycle) ; 2, 19-2, 31 (m, 2H, Hcyc, e) ; 3, 22-3, 31 (qt, 1H, 2-H1=6, 57Hz, H2) ; 3, 61-3, 91 (m, 1H, HJ ; 4, 25-4, 61 (m, 1 H, Ha) ; 5, 09 (d, 1 H, 3JNH-H4=9, 1 Hz, NH) RMN 13C 75 MHz, CDCI, ô (ppm) 19, 8 (C1) ; 20, 3 (C1) ; 24, 3 (C6) ; 25, 4 (C7) ; 28, 9 (C5) ; 35, 8 (C8) ; 36, 7 (C2) ; 55, 7 (C4) ; 66, 2 (C3) ; 119, 4 (q, JC-F=321 Hz, C10) ; 120, 0 (q, Jc-F=322Hz, C9) ; 178, 4 (C11) IR Transmission, film (Csl) v (cm-1) : 3345 ; 3054 ; 2986 ; 1734 ; 1445 ; 1410 ; 1231 ; 1202 ; 1133 ; 939 ; 896 ; 767 ; 715 ; 696 ; 610 Pf 70-71OC aD +45, 96 (c = 1, 14 ; CHC) 3) SM IC (NHa) (m/z) : 466 [M+NHJ----------------------------Exemple 6 Dans cet exemple, on prépare le réactif F à savoir le (18, 28) -N-acétyl-1, 2bis (trifluorométhanesulfonamido) diphényléthane, à partir de (lS, 2S)-1, 2bis (trifluorométhanesulfonamido) -1, 2-diphényléthane et de chlorure d'acétyle.

- ------------------------------------------------- ------------------------- 00 \\ // 10 Gross formula: 5 FION, C ,, H1F, N, 0, S2 0: 0 1 Molar mass: 1: t 7 3 N 448, 23 g / mol S-cog \\ 9 Appearance: 0 0 00 White solid

The analyzes are as follows: TLC Rf = 0.64 (eluent: AcOEt / hexane: 2/8; developer: bromocresol green) 1 H NMR 300 MHz, CDOg ô (ppm) 1.18 (d, 3H, aJH1-H2 = 8.32Hz, H1); 1.24 (d, 3H, aJH1-H2 = 6.6Hz, H1); 1.29-1.43 (m, 3H, H, ye); 1.74-1.96 (m, 3H, Hcycle); 2, 19-2, 31 (m, 2H, Hcyc, e); 3.22-3.31 (qt, 1H, 2-H1 = 6.57Hz, H2); 3.61-3.31 (m, 1H, HJ; 4.25-4.61 (m, 1H, Ha); 5.09 (d, 1H, 3JNH-H4 = 9.1Hz, NH) 13 C NMR 75 MHz, CDCI, ô (ppm) 19, 8 (C1); 20, 3 (C1); 24, 3 (C6); 25, 4 (C7); 28, 9 (C5); 35, 8 ( C8); 36, 7 (C2); 55, 7 (C4); 66, 2 (C3); 119, 4 (q, JC-F = 321 Hz, C10); 120, 0 (q, Jc-F = 322Hz, C9); 178, 4 (C11) IR Transmission, film (Csl) v (cm-1): 3345; 3054; 2986; 1734; 1445; 1410; 1231; 1202; 1133; 939; 896; 767; 715 ; 696; 610 Pf 70-71OC aD +45, 96 (c = 1.14; CHC) 3) SM IC (NHa) (m / z): 466 [M + NHJ ---------- ------------------ Example 6 In this example, the reagent F is prepared, namely (18, 28) -N-acetyl-1, 2bis (trifluoromethanesulfonamido) diphenylethane, from (1S, 2S) -1, 2bis (trifluoromethanesulfonamido) -1, 2-diphenylethane and acetyl chloride.

The procedure of Example 1 is repeated.

Reagent F, which corresponds to the following formula, is obtained with a yield of 82%:

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Formule brute : 0 6 C, BH16F6N205S2 ! . S-CF3 4.,, NH Masse molaire : 0 518, 27 g/mol N1 3 Aspect : //\\ 5 Solide blanc 0 0 ,/-S-CF3 /'\\ 5 Solide blanc - O'Q s So) ideb) anc

Les analyses sont les suivantes : CCM Rf = 0, 64 (éludant : AcOEt/hexane : 2/8 ; révélateur : vert de bromocrésol) RMN'H 300 MHz, CDCI, ô (ppm) 1, 18 (d, 3H, aJH1-H2=8, 32Hz, H1) ; 1, 24 (d, 3H, i-H2=6, 6Hz, H,) ; 1, 29-1, 43 (m, 3H, Hcvc, e) ; 1, 74-1, 96 (m, 3H, Hcvc, e) ; 2, 19-2, 31 (m, 2H, Hcvc, e) ; 3, 22-3, 31 (qt, 1 H, aJH2-H1=6, 57Hz, HJ ; 3, 61-3, 91 (m, 1 H, H4) ; 4, 25-4, 61 (m, 1 H, Ha) ; 5, 09 (d, 1 H, aJNH-H4=9, 1 Hz, NH) RMN 1aC 75 MHz, CDCla ô (ppm) 19, 8 (C1) ; 20, 3 (C1) ; 24, 3 (C6) ; 25, 4 (C7) ; 28, 9 (C5) ; 35, 8 (C8) ; 36, 7 (C2) ; 55, 7 (C4) ; 66, 2 (C3) ; 119, 4 (q, JC-F=321 Hz, C10) ; 120, 0 (q, JC-F=322Hz, C9) ; 178, 4 (C11) IR Transmission, film (Csl) v (cm-1) : 3345 ; 3054 ; 2986 ; 1734 ; 1445 ; 1410 ; 1231 ; 1202 ; 1133 ; 939 ; 896 ; 767 ; 715 ; 696 ; 610 Pf 70-71OC aD +45, 960 (c = 1, 14 ; CHCI,) SM IC (NHg) (m/z) : 466 [M+NHJ+ Exemple 7 Dans cet exemple, on prépare le réactif G à savoir le (18, 28) -N-acétyl-Nméthyl-1, 2-bis (trifluorométhanesulfonamido) cyclohexane par methylation du composé A obtenu selon l'exemple 1.

Gross formula: 0 6 C, BH16F6N205S2! . S-CF3 4. ,, NH Molar mass: 0 518, 27 g / mol N1 3 Appearance: // \\ 5 White solid 0 0, / - S-CF3 / '\\ 5 White solid - O'Q s So ) ideb) anc

The analyzes are as follows: TLC Rf = 0.64 (eluent: AcOEt / hexane: 2/8; developer: bromocresol green) 1 H NMR 300 MHz, CDCI, ((ppm) 1.18 (d, 3H, aJH1 -H2 = 8.32Hz, H1); 1.24 (d, 3H, i-H2 = 6.6Hz, H,); 1.29-1.43 (m, 3H, Hcvc, e); 1.74-1.96 (m, 3H, Hcvc, e); 2, 19-2, 31 (m, 2H, Hcvc, e); 3, 22-3, 31 (qt, 1 H, aJH2-H1 = 6.57Hz, HJ; 3.61-3, 91 (m, 1 H, H4); 4.25-4, 61 (m, 1 H, Ha); 5.09 (d, 1 H, aJNH-H4 = 9.1 Hz, NH) 1aC NMR 75 MHz, CDCla ô (ppm) 19, 8 (C1); 20, 3 (C1); 24 , 3 (C6); 25, 4 (C7); 28, 9 (C5); 35, 8 (C8); 36, 7 (C2); 55, 7 (C4); 66, 2 (C3); 119, 4 (q, JC-F = 321 Hz, C10); 120, 0 (q, JC-F = 322Hz, C9); 178, 4 (C11) IR Transmission, film (Csl) v (cm-1): 3345 ; 3054; 2986; 1734; 1445; 1410; 1231; 1202; 1133; 939; 896; 767; 715; 696; 610 Pf 70-71OC aD +45, 960 (c = 1, 14; CHCI,) SM IC ( NHg) (m / z): 466 [M + NHJ + Example 7 In this example, the reagent G is prepared, namely (18, 28) -N-acetyl-Nmethyl-1, 2-bis (trifluoromethanesulfonamido) cyclohexane by methylation of compound A obtained according to Example 1.

First, an ethereal solution of diazomethane is prepared.

In a 50 ml plastic container fitted with a magnetic bar with stirring by magnetic stirrer, are loaded: - 560 mg (3.81 mmol) of 1-methyl-3-nitro-nitrosoguanidine, - 660 mg (11, 76 mmol; 3 eq.) of KOH, - 1 mL of H2O, - 428 mg (1.02 mmol; 0.25 eq.) of compound A,

<Desc / Clms Page number 30>

 - 10 + 20 mL of diethyl ether.

 We start by loading the diazomethane precursor (1-methyl-3-nitro-nitrosoguanidine) and the diethyl ether.

 The reaction mixture is cooled to a temperature of 00C using an ice bath, then an aqueous KOH solution is added dropwise.

 Gas evolution and the color of the ethereal phase (yellow) are instantly observed.

 The reaction mixture is left under stirring at 00C for ten minutes.

composé A à 0OC. The ethereal solution of diazomethane thus prepared is then poured dropwise into a second container containing an ethereal solution of

compound A at 0OC.

C o
The reaction mixture is left under stirring at 00C for thirty minutes, then a solution of acetic acid is poured into the reaction medium.

 The solvent is then evaporated under reduced pressure, and the residue chromatographed on silica gel.

l'ensemble des deux étapes : acétylation et methylation). Compound G is obtained, with a yield of 85% (i.e. 72% over

all of the two stages: acetylation and methylation).

: 11 0 1 HgC su/1 10 Formule brute : : 5 \N"S-CF3 C H 0 : 1 60 : "'" 11 16F6N2 SS2 1 r ! o 1 1 0 Masse molaire : 1 7 3 N 1 7 8'S-CF 434, 2 g/mol 8 S-CF3 9 00 Aspect Solide blanc : L----------------------------------J

Les analyses sont les suivantes : CCM Rf = 0, 19 (éludant AcOEt/hexane : 5/95 ; révélateur : vert de bromocrésol) RMN 1H 300 MHz, CDOg ô (ppm) 1, 00-1, 65 (m, 3H, Hcycle) ; 1, 68-2, 05 (m, 4H, H, ; 2,48(s, 3H, H1); 2, 40-2, 75 (m, 1H, Hcycle); 2,96 (s, 3H, H11); 4,02 (td, 1H, H4- H3=11,37Hz et JH4-H5=4,28Hz, H4); 5,58 (td, 1H, JH4-H3=10,95Hz et

JH4-H5=4,52Hz, H3) RMN 75 MHz, CDCI, ô (ppm) 24, 2 (C7) ; 25, 5 (C6) ; 27, 3 (C1) ; 28, 7 (C5) ; 30, 0 (C8) ; 30, 5 (C11) ; 57, 1 (C4) ; 62, 8 (C3) ; 119, 5 (q, Jc-F=321Hz, C10) ; The reagent G obtained corresponds to the following formula:!

: 11 0 1 HgC su / 1 10 Raw formula:: 5 \ N "S-CF3 CH 0: 1 60:"'"11 16F6N2 SS2 1 r! O 1 1 0 Molar mass: 1 7 3 N 1 7 8'S- CF 434, 2 g / mol 8 S-CF3 9 00 Appearance White solid: L -------------------------------- --J

The analyzes are as follows: TLC Rf = 0.19 (eluting AcOEt / hexane: 5/95; developer: bromocresol green) 1 H NMR 300 MHz, CDOg ô (ppm) 1.00-1.65 (m, 3H, Hcycle); 1.68-2.05 (m, 4H, H, 2.48 (s, 3H, H1); 2.40-2.75 (m, 1H, Hcycle); 2.96 (s, 3H, H11 ); 4.02 (td, 1H, H4- H3 = 11.37Hz and JH4-H5 = 4.28Hz, H4); 5.58 (td, 1H, JH4-H3 = 10.95Hz and

JH4-H5 = 4.52 Hz, H3) NMR 75 MHz, CDCI, ((ppm) 24, 2 (C7); 25.5 (C6); 27, 3 (C1); 28, 7 (C5); 30.0 (C8); 30.5 (C11); 57, 1 (C4); 62, 8 (C3); 119.5 (q, Jc-F = 321Hz, C10);

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v (cm-1) : 3455 ; 2950 ; 2869 ; 1740 ; 1398 ; 1190 ; 1131 ; 1098 ; 1065 ; 981 ; 951 ; 933 ; 895 ; 774 ; 609 ; 533 ; 491 Pf 38-40 C aD +6, 220 (c = 4, 1 ; CHC) a) SM IC (NHg) (m/z) : 452 [M+Nt-LT Exemple 8 On prépare dans cet exemple, le réactif H à savoir le (1S, 2S)-N-acétyl-1,2bis (méthanesulfonamido) cyclohexane à partir de (1S,2S)-1,2bis (méthanesulfonamido) cyclohexane et de chlorure d'acétyle. 120.2 (q, JC-F = 322Hz, C9); 169.9 (C2) IR Transmission, film (Csl)

v (cm-1): 3455; 2950; 2869; 1740; 1398; 1190; 1131; 1098; 1065; 981; 951; 933; 895; 774; 609; 533; 491 Pf 38-40 C aD +6, 220 (c = 4, 1; CHC) a) SM IC (NHg) (m / z): 452 [M + Nt-LT Example 8 The reagent is prepared in this example H, namely (1S, 2S) -N-acetyl-1,2bis (methanesulfonamido) cyclohexane from (1S, 2S) -1,2bis (methanesulfonamido) cyclohexane and acetyl chloride.

 - 1 g (3.70 mmol) of (lS, 2S) -1.2 is loaded into a 50 mL flask fitted with a magnetic bar with agitation by magnetic stirrer, rigorously dry and then placed under an argon atmosphere. -bis (methanesulfonamido) cyclohexane, - 775 ilL (5.55 mmol; 1.5 eq.) of triethylamine, - 135 mg (0.13 mmol; 0.3 eq) of dimethylaminopyridine (DMAP), - 265 uL (3 , 70 mmol; 1 eq.) Of acetyl chloride, - 20 mL of diethyl ether.

 We start by loading the disulfonamide, the DMAP and the diethyl ether under an inert atmosphere (argon).

 Then the reaction mixture is cooled to a temperature of −20 ° C. using a dry ice bath in acetone.

 Triethylamine is poured in, then slowly the acetylating agent (acid chloride) using a precision syringe.

 The reaction mixture is left under stirring at 0 ° C. for 3 hours, then the precipitate formed is filtered.

 The solvent is evaporated, and the residue chromatographed on silica gel.

 The desired compound is obtained with a yield of 79% and a purity greater than 95%.

 Reagent H is obtained which corresponds to the following formula:

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v--00 \//io Formule brute : , ÂHN ' CNH oN2,5S2 '\n, 0 43 JA1 Masse molaire : U. l 7 8 3 NI 312, 29 g/mol 11\\ 9 3 0 0 Aspect : Solide blanc

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Les analyses sont les suivantes : CCM Rf = 0,23 (éluant : AcOEt/Dichlorométhane : 8/2 ; révélateur : Vert de bromocrésol) RMN H 300 MHz, CDCl3

& (ppm) 1,10-1,50 (m, 3H, Hcycle); 1, 65-1, 95 (m, 3H, H, cl,) ; 2, 05-2, 30 (m, 1H, HJ ; 2, 31-2, 50 (m, 1H, HcJ ; 2, 47 (s, 3H, HJ ; 2, 96 (s, 3H, Hto) ; 3, 34 (s, 3H, Hg) ; 3, 65-4, 35 (2m, 2H, Hg et H) ; 4, 56 (d, 1H,'J =8, 6Hz, N-H) RMN 1aC 75 MHz, CDCla ô (ppm) 24,4 (C6) ; 25,4 (C7) ; 26,7 (C1) ; 30,0 (C5) ; 34,8 (C8) ; 40,8 (C10) ; 42,2 (C9) ; 51,7 (C4) ; 64,8 (C3) ; 171,3 (C2) IR Transmission, film (Csl) v (cm-1): 3282 ; 2938 ; 2862 ; 2258 ; 1697 ; 1449 ; 1416 ; 1349 ; 1323 ;
1242 ; 1162 ; 1079 ; 981 ; 959 ; 936 ; 913 ; 771 ; 733 ; 544 ; 522 Pi 114-115C aD +10,19 (c = 1, 6 ; CHC) 3) SM) IC (NH3)

(m/z): 330 [M+NH4]+ Exemple 9 Dans cet exemple, on préare le réactif 1 à savoir, le (1S, 2S)-N-acétyl-1,2- bis(benzènesulfonamido)cyclohexane à partir de (1S,2S)-1,2- bis (benzènesulfonamido) cyclohexane et de chlorure d'acétyle.

v - 00 \ // io Gross formula:, ÂHN 'CNH oN2,5S2' \ n, 0 43 JA1 Molar mass: U. l 7 8 3 NI 312, 29 g / mol 11 \\ 9 3 0 0 Appearance: Solid white

-------------------------------------------------- -------------------------
The analyzes are as follows: TLC Rf = 0.23 (eluent: AcOEt / Dichloromethane: 8/2; developer: Bromocresol green) NMR H 300 MHz, CDCl3

& (ppm) 1.10-1.50 (m, 3H, Hcycle); 1.65-1.95 (m, 3H, H, cl,); 2, 05-2, 30 (m, 1H, HJ; 2, 31-2, 50 (m, 1H, HcJ; 2, 47 (s, 3H, HJ; 2, 96 (s, 3H, Hto); 3 , 34 (s, 3H, Hg); 3.65-4.35 (2m, 2H, Hg and H); 4.56 (d, 1H, 'J = 8, 6Hz, NH) 1aC NMR 75 MHz, CDCla ô (ppm) 24.4 (C6); 25.4 (C7); 26.7 (C1); 30.0 (C5); 34.8 (C8); 40.8 (C10); 42.2 ( C9); 51.7 (C4); 64.8 (C3); 171.3 (C2) IR Transmission, film (Csl) v (cm-1): 3282; 2938; 2862; 2258; 1697; 1449; 1416 ; 1349; 1323;
1242; 1162; 1079; 981; 959; 936; 913; 771; 733; 544; 522 Pi 114-115C aD +10.19 (c = 1.6, CHC) 3) SM) IC (NH3)

(m / z): 330 [M + NH4] + Example 9 In this example, reagent 1 is prepared, namely (1S, 2S) -N-acetyl-1,2-bis (benzenesulfonamido) cyclohexane from (1S, 2S) -1,2- bis (benzenesulfonamido) cyclohexane and acetyl chloride.

 The procedure of Example 8 is repeated.

 Reagent 1, which corresponds to the following formula, is obtained with a yield of 72%:

<Desc / Clms Page number 33>

Formate brute : 0 0 10 il \\//9 C20H24N205S2 6 o e4N Masse molaire : 114 15 436, 43 g/mol 7"3N/\ 7 3 N Aspect : 8 s 16 //\\ 13 ! J Solide blanc 00

--------------------------------------------------------------------------Les analyses sont les suivantes : CCM Rf = 0, 47 (éluant : AcOEt/hexane : 5/5 ; révélateur : vert de bromocrésol) RMN'H 300 MHz, CDCig ô (ppm) 0, 95-1, 35 (m, 3H, HC, e) ; 1, 36-1, 52 (m, 1 H, HCYcle) ; 1, 53-1, 80 (m, 2H, Hcvcle) ; 1, 95-2, 10 (m, 1 H, Hcvcle) ; 2, 08 (s, 3H, H1) ; 2, 15-2, 35 (m, 1 H, Hcycle) ; 3, 65-3, 90 (m, 1 H, H4) ; 3, 90-4, 16 (m, 1 H, Ha) ; 4, 72 (d, 1 H, aJN-HH4=8, 4Hz, N-H) ; 7, 40-7, 75 (m, 6H, HAr) ; 7, 80-8, 10 (m, 4H, HAr) RMN 1aC 75 MHz, CDCI ô (ppm) 24, 5 (C7) ; 25, 8 (C6) ; 26, 8 (C1) ; 29, 1 (C5) ; 36, 2 (C8) ; 52, 5 (C4) ; 63, 9 (C3) ; 127, 3 (C12) ; 127, 4 (C16) ; 128, 9 (C11) ; 129, 6 (C15) ; 132, 2 (C10) ; 134, 0 (C14) ; 139, 4 (C9) ; 140, 9 (C13) ; 170, 4 (C2) IR Transmission, film (Csl) v (cm') : 3269 ; 2937 ; 1701 ; 1448 ; 1350 ; 1331 ; 1236 ; 1166 ; 1091 ; i 970 ; 937 ; 913 ; 890 ; 756 ; 736 ; 689 ; 608 ; 588 Pf 1570C aD +19, 69 (c=1, 09 ; CHC) 3) SM IC (NHg) (m/z) : 454 Exemples 10 à 16 Ces exemples illustrent la résolution cinétique de la phényléthylamine dans le toluène à température ambiante à l'aide du réactif A de l'exemple 1.

Raw format: 0 0 10 il \\ // 9 C20H24N205S2 6 o e4N Molar mass: 114 15 436, 43 g / mol 7 "3N / \ 7 3 N Appearance: 8 s 16 // \\ 13! J White solid 00

-------------------------------------------------- ------------------------ The analyzes are as follows: TLC Rf = 0.47 (eluent: AcOEt / hexane: 5/5; developer: green bromocresol) 1 H NMR 300 MHz, CDCl 6 (ppm) 0.95-1.35 (m, 3H, HC, e); 1.36-1.52 (m, 1H, HCYcle); 1.53-1.70 (m, 2H, Hcvcle); 1.95-2.10 (m, 1H, Hcvcle); 2.08 (s, 3H, H1); 2.15-2.35 (m, 1H, Hcycle); 3.65-3.90 (m, 1H, H4); 3.90-4.16 (m, 1H, Ha); 4.72 (d, 1H, aJN-HH4 = 8.4Hz, NH); 7.40-7.75 (m, 6H, HAr); 7.80-8.10 (m, 4H, HAr) 1aC NMR 75 MHz, CDCI ô (ppm) 24.5 (C7); 25.8 (C6); 26.8 (C1); 29, 1 (C5); 36, 2 (C8); 52.5 (C4); 63, 9 (C3); 127, 3 (C12); 127, 4 (C16); 128, 9 (C11); 129, 6 (C15); 132, 2 (C10); 134.0 (C14); 139, 4 (C9); 140.9 (C13); 170, 4 (C2) IR Transmission, film (Csl) v (cm '): 3269; 2937; 1701; 1448; 1350; 1331; 1236; 1166; 1091; i 970; 937; 913; 890; 756; 736; 689; 608; 588 Pf 1570C aD +19, 69 (c = 1.09; CHC) 3) SM IC (NHg) (m / z): 454 Examples 10 to 16 These examples illustrate the kinetic resolution of phenylethylamine in toluene at room temperature using reagent A of Example 1.

In a 5 mL flask, placed under an argon atmosphere, fitted with a magnetic bar with stirring by magnetic stirrer, are charged: - 31 μL (0.24 mm 3) of phenylethylamine, - 50 mg (0.12 mmol; 0, 5 eq.) Of reagent A, - 1 + 2 mL of toluene.

We start by loading the amine, then pouring 1 ml of anhydrous toluene under an argon atmosphere.

<Desc / Clms Page number 34>

 A solution of reagent A in 2 ml of toluene is then added, using a syringe. The reaction mixture is left stirring at room temperature until no more reagent is observed on thin layer chromatography.

 The solvent is then evaporated and the residue is chromatographed on silica gel.

 The samples obtained are then analyzed by high performance liquid chromatography on a chial column.

 In all reactions the transformation is total and the yield quantitative, without the formation of by-products.

 In Table (1) below are given the yields isolated by chromatography on a silica gel column.

 Table (1)

<Desc / Clms Page number 35>

Ref. Amide Colonne Conditions Temps de Temps de Rdt ee rétention rétention % % Ex isomère (R) isomère (min) (S) (min) 350C - t NHAc 10 0. 8 mL/min Chira cel Chntancei 38, 57 42, 75 87 90 OD 98/2 350C 11 NHAc 1 1 ml/min rY"Chiraicei,,. 13, 98 16, 85 85 86 OD 97/3 300C 0. SmL/min 12 NHAc 2. 2.

Ref. Amide Column Conditions Runtime Time retention ee retention%% Ex isomer (R) isomer (min) (S) (min) 350C - t NHAc 10 0. 8 mL / min Chira cel Chntancei 38, 57 42, 75 87 90 OD 98/2 350C 11 NHAc 1 1 ml / min rY "Chiraicei ,,. 13, 98 16, 85 85 86 OD 97/3 300C 0. SmL / min 12 NHAc 2. 2.

4 Chiralpa Trimethylpentane 8, 78 10, 93 90 72 kAD / EtOH: 95/5 350C g NHAc t 1 mL / min 'Chiraice) 16, 58 18, 98 86 69 00 hexane / EtOH 97/3 300C 300C Chiralcel Chiraicei 4, 00 5, 75 87 73 OD hexane / ETOH 85/15 350C -NHAc 15 cr! 1 ml / min Chiralcel 9, 92 11, 78 90 00 hexane / EtOH 95/5 350C 16 u0 "0.8.8 ml / min Chiralcel hexane / EtOH 20, 18 23, 5f 84 80 1 / HAC 00 NHAc '" - 97 / 3

Claims (5)

CLAIMS 1-Process for splitting a chiral amine in the form of a racemic mixture or enriched in one of the stereomers characterized in that said mixture is brought into contact with the resolution reagent corresponding to general formula 1 (1):

 in said formula (!): - * represents a chiral group, Rif represents a hydrocarbon group having from 1 to 20 carbon atoms, comprising or not at least one halogen atom, preferably a fluorine atom, - E represents a electrophilic group chosen from sulfonyl, carbonyl or phosphoryl groups, which makes it possible to obtain one of the stereomers, the other being in a form in which a hydrogen atom of the amine function is replaced by an electrophilic group E. 2. Method according to claim 1 characterized in that the resolution reagent corresponds to formula (1) in which the electrophilic group E represents one of the following groups: -SO2Rf - COR - C02R6 - POR7Ra or PO (OR7) (0 Ra) in said formulas, Rf has the meaning given above and Rg to Ra, identical or different, represent a hydrocarbon group having from 1 to 20 carbon atoms, and preferably: - an alkyl group, linear or branched, having from 1 to 12 carbon atoms, - a linear or branched alkenyl or alkynyl group having from 2 to 12 carbon atoms, - a cycloalkyl or cycloalkenyl group, having from 3 to 8 carbon atoms, - an aryl group having from 6 to 20 carbon atoms, preferably a phenyl group or a naphthyl group, <Desc / Clms Page number 37>  - an arylalkyl group having from 7 to 20 carbon atoms, preferably a benzyl group.  3 - Method according to one of claims 1 and 2 characterized in that the resolution reagent corresponding to the following formula (1 '):

 in said formula: - Rf and E have the meaning given above, - Y represents a group

 in which: - Ra and R'a represent any hydrocarbon group having 1 to 20 carbon atoms insofar as they do not comprise nucleophilic groups, whether or not comprising an electron-withdrawing group, - the groups Ra and R'a can be linked together to form a nitrogen heterocycle, - and if Ra or R'a represents a hydrogen atom then R'a or Ra represents an electro-attracting group SO2Rf, Rf having the meaning given previously, - A symbolizes a skeleton of general formula (Ia) or (Ib):

 in formulas (la) and (lob): - R'and R "independently of one another represent a hydrocarbon group having from 1 to 20 carbon atoms which can be an acyclic saturated or unsaturated, linear or aliphatic aliphatic group branched; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the aforementioned groups; <Desc / Clms Page number 38>  - or, R'and R "can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic, - Ar, and Ar2 symbolize , independently of one another two aromatic rings, carbocyclic or heterocyclic, substituted or not, condensed or not and carrying if necessary one or more heteroatoms, - x and y respectively identify the two bonds established between the skeleton symbolized by A and the sulfonamide and Y groups.  4 - Process according to claim 3 characterized in that the electron-withdrawing group is chosen from: - a C1 to C10 alkyl or C8 to C10 cycloalkyl group mono-, poly- or per-halogenated, - d ' a phenyl group substituted by at least one C1 to Ciao, preferably C1 to C4, mono-, poly- or per-halogenated alkyl group or a nitro or nitrile group, - of a phenyl mono-, poly- or per-halogenated, - of a functional group such as -CO-Rg, - CO-NRR ,, - COORs, in which Rg, R4, identical or different, represent a C1 to C10 alkyl group; preferably C1 to C4, mono-, poly- or per-halogenated; a phenyl group; a phenyl group substituted with at least one C1 to C11, preferably C1 to C4, mono-, poly- or perhalogenated alkyl group or a nitro or nitrile group; a mono-, poly- or per-halogenated phenyl group.  5 - Method according to one of claims 1 to 4 characterized in that the resolution reagent corresponds to formula (1) or (f) in which Rf represents a hydrocarbon group having from 1 to 20 carbon atoms and preferably :. a C1 to Ciao alkyl group, preferably a C1 to C4 alkyl group, and more preferably a methyl or ethyl group,. a C1 to Ciao, preferably C1 to C4, mono-, poly- or per-halogenated alkyl group having from 1 to 23 halogen atoms, preferably a CF3 group, <Desc / Clms Page number 39>  . a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclohexyl group,

 . an optionally mono-, poly- or per-halogenated cycloalkyl group, a gro having from 3 to 8 carbon atoms, a grou. a phenyl group,. a mono-, poly- or per-halogenated phenyl group.  . a phenyl group substituted with at least one C1 to C6 preferably C1 to C4 alkyl group, optionally mono-, poly- or per-halogenated or a nitro or nitrile group; . an optionally mono-, poly- or per-halogenated aryl group having from 6 to 12 carbon atoms, 6 - Process according to Claim 5, characterized in that the resolution reagent corresponds to the formula (1) or (1 ' ) in which Rf represents a group

 CF CFg, C4F9 or a phenyl group substituted by one or more halogen atoms, preferably fluorine, or by one or more mono-, poly- or per-fluorinated C1-C2 alkyl groups.  7 - Method according to one of claims 1 to 6 characterized in that the resolution reagent corresponds to formula (1) or (! ') In which Y represents a sulfonamide-N group (SO2Rf) (Ra) in which Ra represents in particular: - a hydrogen atom, - an alkyl chain, preferably C1 to C10, optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by a or more halogen atoms or carboxyl groups, - an aicenyie or alkynyl chain, preferably in C2 to C10, optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atom (s) or carboxyl group (s); - An aryl group, preferably C6 to 2, optionally substituted by one or more halogen atom (s) or C1 to Ce alkyl group (s) alkenyl or C2 to C10 alkynyl.  8 - Method according to one of claims 1 to 7 characterized in that the resolution reagent corresponds to the formula (I'b) <Desc / Clms Page number 40>

 in which: - Rf, Ra, E, (x), (y) are as defined above and Ar1 and Ar2 together represent an aromatic group which can be a carbocycle having from 6 to 12 carbon atoms or a heterocycle having from 5 to 12 atoms.  9 - Process according to claim 8 characterized in that the resolution reagent corresponds to the general formula (Ib) in which Ar1 and Ar2 appear together either a group deriving from diphenyl-2, 2 '-diyle, or a dinaphthyl group- 2, 2'-diyle. 10 - Process according to claim 3 to 6 characterized in that the resolution reagent corresponds to the general formula (a):

 -------------------------------------------------- -----------------------

 ------------------------------------------ in which - Rf, Rg, E , (x), (y) are as defined above in general formula (1 '), - R'and R "independently of one another represent a carbocyclic or heterocyclic group, saturated, unsaturated, aromatic, monocyclic or polycyclic, - or R'and R "can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic.  11 - Method according to claim 3 to 6 characterized in that the resolution reagent corresponds to the following formula (I'c): <Desc / Clms Page number 41>

 in said formula, - Rf1 represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms, a group trifluoromethyl, - R2'represent an alkyl group having from 1 to 10 carbon atoms, - Rb'represent a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms, - Re represents a hydrogen atom or a alkyl group having 1 to 4 carbon atoms.  12 - Process according to claim 3 to 6 characterized in that the resolution reagent corresponds to the following formula (I'd):

 in said formula, - Rf1 represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms, a group trifluoromethyl, - R're represents an alkyl group having from 1 to 10 carbon atoms, - Rb're represents a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms, - Re represents a hydrogen atom or a alkyl group having 1 to 4 carbon atoms.  13 - Process according to claim 1 characterized in that the resolution reagent is chosen from: (1S, 2S) -N-acetyl-1,2-bis (trifluoromethane-sulfonamido) cyclohexane, (1S, 2S) -N -acetyl-1,2-bis (pentafluorobenzene-sulfonamido) cyclohexane, le (1S, 2S) -N-acetyl-1,2-bis (p-trifluoromethylbenzene- <Desc / Clms Page number 42>  sulfonamido), cyclohexane le (1S, 2S) -N-propionyl-1,2-bis (trifluorométhanesulfonamido) cyclohexane, le (1S, 2S) -N-isobutyryl-1,2-bis (trifluorométhanesulfonamido) cyclohexane, le (1S, 2S) -N-acetyl-1,2-bis (trifluoromethanesulfonyloxy

 sulfonamido) diphenylethane, le (18, 28) -N-acetyl-N-methyl-1, 2-bis (trifluorméthanesulfonamido) cyclohexane, le (18, 2S) -N-acetyl-1, 2-bis (methanesulfonamido) cyclohexane, (18, 28) -N-acetyl-1, 2-bis (benzenesulfonamido) - cyclohexane.  14 - Process according to claim 1 characterized in that the racemic chiral amine is symbolized by the formula (VII): R-NH-Rd (V!!) In which Rc, Rd, identical or different, represent an atom d hydrogen or a hydrocarbon group having from 1 to 20 carbon atoms and at least one of the groups Rc and Rd represent a chiral group: the amino group may or may not be carried by the asymmetric carbon.  15 - Process according to claim 1 to 14 characterized in that one implements the resolution reagent in an amount such that the molar ratio between the number of moles of amines of formula (VII) and resolution reagent of formula (1) is greater than or equal to 1, preferably, greater than or equal to 2 and between 2 and 10, preferably between 2 and 5, and even more preferably equal to 3.  16 - Process according to claim 1 to 15 characterized in that the reaction is carried out at a temperature between -50 C and 100 C, preferably between - 200C and 20 C. 17-Reagent corresponding to the following formula (1 '):

 in said formula: - Rf and E have the meaning given above, - Y represents a group

 in which : <Desc / Clms Page number 43>  - Raet R'a represent any hydrocarbon group having 1 to 20 carbon atoms insofar as they do not comprise nucleophilic groups comprising or not comprising an electron-attracting group, - the groups Ra and R'a can be linked together to form a nitrogen heterocycle, - and if Ra or R'a represents a hydrogen atom then R'a or Ra represents an electro-attractor group S02Rf, Rf having the meaning given above, - A symbolizes a skeleton of general formula (la) or (lob):

 in formulas (la) and (lob): - R'and R "independently of one another represent a hydrocarbon group having from 1 to 20 carbon atoms which can be an acyclic saturated or unsaturated, linear or aliphatic aliphatic group branched; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the abovementioned groups; - or alternatively, R ′ and R ″ can be linked so as to constitute, with the carbon atoms carrying them, a carbocyclic group or heterocyclic having 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic, - Ar1 and Ar2 symbolize, independently of one another two aromatic rings, carbocyclic or heterocyclic, substituted or not, condensed or not and carrying the case where appropriate one or more heteroatoms, - x and y respectively identify the two bonds established between the skeleton symbolized by A and the sulfonamide and Y groups.  18 - Reagent according to claim 17 characterized in that the electron-withdrawing group is chosen from: - a C1 to C1 alkyl group) or a Cg to C1Q cycloalkyl group mono-, poly- or per-halogenated, <Desc / Clms Page number 44>  - a phenyl group substituted with at least one mono-, poly- or per-halogenated C1 to C10 alkyl group or a nitro or nitrile group, - a mono-, poly- or per-halogenated phenyl group, - a functional group such that -CO-R3, - CO-NR3R4, - COOR3, in which Rs, R4, identical or different, represent a C1 to C10 alkyl group; a mono-, poly- or per-halogenated C1 to C10 alkyl group; a phenyl group; a phenyl group substituted with at least one C1-C10 alkyl group mono-, poly- or per-halogenated or a nitro or nitrile group; a mono-, poly- or per-halogenated phenyl group.  19 - Reagent according to one of claims 17 and 18 characterized in that it corresponds to formula (I ') in which Rf represents a hydrocarbon group having from 1 to 20 carbon atoms and preferably:. a C1 to C10 alkyl group; preferably 1 to 4 carbon atoms and more preferably a methyl or ethyl group,

 . a mono-, poly- or per-halogenated C1 to C10 alkyl group having from 1 to 1 group 23 carbon atoms; preferably a CFg group,. a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclohexyl group,. an optionally mono-, poly- or per-halogenated cycloalkyl group having from 3 to 8 carbon atoms,

 a grou. a phenyl group,. a mono-, poly- or per-halogenated phenyl group.  . a phenyl group substituted by at least one C1 to C10 alkyl group optionally mono-, poly- or per-halogenated or a nitro or nitrile group; . an optionally mono-, poly- or per-halogenated aryl group having from 6 to 12 carbon atoms.  20 - Reagent according to claim 19 characterized in that it corresponds to formula (1 ') in which Rf represents a group CFg, C4Fg or a phenyl group substituted by one or more halogen atoms, preferably fluorine or by one or more mono-, poly- or perfluorinated C1-C2 alkyl groups. <Desc / Clms Page number 45>  21 - Reagent according to claim 17 characterized in that it corresponds to formula (I ') in which Y represents a sulfonamide-N group (SOs Rf) (RJ in which Ra represents: - an alkyl chain, preferably in C1 to Ciao, optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl groups, - an alkenyl or alkynyl chain, preferably in C2 to C11, optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atom (s) or carboxyl group (s); - a aryl group, preferably C6 to C12, optionally substituted by one or more halogen atom (s) or C1 to Calo alkyl group (s) C2 to C12 alkenyl or alkynyl - Reagent according to one of claims 17 to 21 characterized in that it r corresponds to formula (I'b):

 in which: - Rf, Ra, E, (x), (y) are as defined above and Ar, and Ar2 together represent an aromatic group which can be a carbocycle having from 6 to 12 carbon atoms or a heterocycle having 5 to 12 atoms.  23 - Reagent according to claim 22 characterized in that it corresponds to the general formula (I'b) in which Ar1 and Ar2 appear together either a group deriving from 2,2-diphenyl-diyl, or a dinaphthyl group- 2, 2'diyle. 24 - Reagent according to one of claims 17 to 21 characterized in that it corresponds to the general formula (a): <Desc / Clms Page number 46>

 in which - Rf, Ra, E, (x), (y) are as defined above in general formula () '), - R'and R "independently of one another represent a carbocyclic group or heterocyclic, saturated, unsaturated, aromatic, monocyclic or polycyclic, - or R'and R "can be linked so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic.  25 - Reagent according to one of claims 17 to 21 characterized in that the resolution reagent corresponds to the following formula (I'c):

 in said formula, - Rf1 represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms, a group trifluoromethyl, - R're represents an alkyl group having from 1 to 10 carbon atoms, - Rb're represents a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms, - Re represents a hydrogen atom or a alkyl group having 1 to 4 carbon atoms.  26 - Reagent according to one of claims 17 to 21 characterized in that the resolution reagent corresponds to the following formula (I'd) <Desc / Clms Page number 47>

 in said formula, - rif, represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms, a trifluoromethyl group, - R2 ′ represents an alkyl group having from 1 to 10 carbon atoms, - Rb're represents a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms, - Re represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.  27 - (? S, 2S) -N-acetyl-1,2-bis (trifluoromethanesulfonamido) cyclohexane, - (1S, 2S) -N-acetyl-1,2-bis (pentafluorobenzenesulfonamido) cyclohexane, - (( 1S, 2S) -N-acetyl-1,2-bis (p-trifluoromethylbenzenesulfonamido) cyclohexane, - le (1S, 2S) -N-propionyl-1,2-bis (trifluoromethanesulfonamido) cyclohexane, - le (1S, 2S) -N-isobutyryl-1,2-bis (trifluoromethanesulfonamido) cyclohexane,

 - (1S, 2S) -N-acetyl-1, 2-bis (trifluoromethanesulfonamido) diphenylethane, - (1S, 2S) -N-acetyl-N-methyl-1, 2-bis (trifluoromethanesutfonamido) cyclohexane, - le (1S, 2S) -N-acetyl-1, 2-bis (methanesulfonamido) cyclohexane, - le (1S, 2S) -N-acetyl-1,2-bis (benzenesulfonamido) cyclohexane. 28- A process for preparing a sulfonamide described in one of claims 17 to 27 characterized in that it consists in reacting an amino compound carrying a chiral group of formula (11) R, * -NHs ( N) in said formula, Ri * has the meaning given above and a reagent providing the sulfonyl group then a reagent providing the electrophilic group E.  29 - Process according to claim 28 characterized in that the reagent providing the sulfonyl group corresponds to the formula (alla): <Desc / Clms Page number 48>

 ----------------------------------------- in said formula (III): - Rf has the meaning given above, - Z represents:. a halogen atom, preferably a chlorine or bromine atom,. a group-O-SO-Rf in ieque! Rf, identical or different from Rf, has the meaning given for Rf.  30 - Process according to claim 29 characterized in that the reagent of formula (III) is chosen from: - mesyl chloride, - benzenesulfonyl chloride, - tosyl chloride, - trifluoromethanesulfonyl chloride, - chloride of pentafluorobenzenesulfonyl, - p-trifluoromethylbenzenesulfonyl chloride, 31 - Process according to claim 28 characterized in that the reaction between the amino compound of formula (II) and the compound of formula of formula (III) takes place in the presence of a base, preferably in an organic solvent.  32 - Method according to claim 28 characterized in that the reagent corresponds to formula (V): E-W (V) in said formula (V), E has the meaning given above and W represents a halogen atom, preferably chlorine or bromine and an O-E group.  33 - Process according to claim 32 characterized in that the electrophilic reagent is acetyl chloride, propionyl chloride, butyryl chloride.  34 - Process according to claim 31 characterized in that the compound obtained and the compound (V) are reacted in an organic solvent, in the presence of a base. <Desc / Clms Page number 49>  35 - Process according to claim 34 characterized in that the reaction is carried out between - 800C and 50 C, preferably at room temperature.  36 - Process according to claim 34 characterized in that the sulfonamide is recovered from the organic phase in which it is found.