Patent EA-002658-B1 (EA)
Title: Process for the preparation of phenylimidazolidine derivatives
Inventor: BOUCHET RAPHAEL
IPC: C07D233/72
Filed: 1996-11-14
Abstract: 1. Preparation process for the products of formula (I):   in which: R1 and R2, identical or different, are chosen from the hydrogen atom, halogen atoms and the following radicals: alkyl, alkenyl, alkynyl, comprising 1 to 6 carbon atoms, alkyloxy, alkenyloxy, alkynyloxy, comprising 1 to 6 carbon atoms, phenyl, phenoxy, nitro, trifluoromethyl, acyl, comprising 1 to 6 carbon atoms, cyano, amino, monoalkylamino, dialkylamino, comprising 1 to 6 carbon atoms, free, esterified, amidified or salified carboxy, R3 is chosen from the hydrogen atom and alkyl, alkenyl, alkynyl, comprising 1 to 6 carbon atoms, aryl or arylalkyl radicals, comprising up to 10 carbon atoms, all these radicals being optionally substituted by one or more substituents chosen from halogen atoms, the following radicals: optionally esterified, etherified or protected hydroxyl, alkoxy, alkenyloxy, alkynyloxy, comprising 1 to 6 carbon atoms, trifluoromethyl, mercapto, cyano, acyl, comprising 1 to 6 carbon atoms, acyloxy, free, esterified, amidified or salified carboxy, amino, mono- and dialkylamino, comprising 1 to 6 carbon atoms, arylthio and cyclic radicals containing 3 to 6 members; all the sulphur atoms being optionally oxidized in the form of the sulphoxide or sulphone; the aryl and aralkyl radicals being moreover optionally substituted by an alkyl, alkenyl or alkynyl radical, comprising 1 to 6 carbon atoms, R4 and R5: either are identical or different and represent a hydrogen atom or an alkyl, comprising 1 to 6 carbon atoms, optionally substituted by one or more substituents chosen from halogen atoms, the optionally esterified, etherified or protected hydroxyl, radical phenylthio and C1-C6 alkylthio radicals, in which the sulphur atom can be oxidized into the sulphoxide or sulphone and being optionally substituted by one or more radicals chosen from halogen atoms and optionally esterified, etherified or protected hydroxyl radicals, free, esterified, amidified or salified carboxy radicals, amino, mono- and dialkylamino radicals, comprising 1 to 6 carbon atoms, or form together: a heterocyclic radical   wherein T represents an oxygen or sulphur atom, X and Y, identical or different, represent an oxygen or sulphur atom, said products of formula (I) being in all possible racemic, enantiomeric or diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or mineral and organic bases of said products of formula (I), characterized in that: a compound of formula (A):   in which W represents a halogen atom or a hydantoin derivative of formula:   in which R'4 and R'5 have the meanings indicated above for R4 and R5 in which the optional reactive functions are optionally protected, a) halogenation with obtaining the compound of formula (F3):   in which Hal represents a halogen atom and W has the meaning determined above, b) the obtained compound is subjected to a substitution reaction on the halogen atom, by a metallic derivative of formula (VII):   in which M represents a metal and R'2 has the meanings indicated above for R2 in which the reactive functions are optionally protected, in order to obtain the product of formula (F4):   in which R'2 and W have the meanings indicated above, c) which can be subjected to the successive reaction of diazotation of the amino radical, then halogenation and finally substitution on the nitrogen atom by a metallic derivative of formula R'1-M (VI), in which M represents a metal and R'1 has the meanings indicated above for R1 in which the optional reactive functions are optionally protected, in order to obtain the product of formula F5:   in which R'1, R'2 and W have the meanings indicated above, d) further the compounds of formulae F3, F4, or F5, wherein W is a halogen atom, which is subjected to the reaction with a compound of formula (IV):   in which R'4 and R'5 have the meanings indicated above, in order to obtain the product of formula I':   in which R"1 and R"2 are such that: either R"2 represents a halogen atom and R"1 represents an amino radical or halogen atom or R''2 is R'2 radical as defined above, and R"1 represents an amino radical or R'1 as defined above, the compound of formulae (I'), if necessary is subjected to one or more of the following reactions: a) an elimination reaction of the optional protective groups which can be carried by R''1, R''2, R'4 and R'5; b) a conversion reaction of the >C=O into the >C=S group, c) the action of a reagent of formula Hal-R'3 in which R'3 has the values of R3 as defined above, with the exception of the hydrogen and in which the optional reactive functions are optionally protected and Hal represents a halogen atom, in order to obtain products of formula (I) as defined above, then, if desired, the action on these products of an agent for eliminating the optional protective groups which can be carried by R'3 or if appropriate, the action of an esterification, amidification or salification agent, a conversion reaction of the amino radical into a nitro radical. 2. The process for preparation of the compounds of formula (I), wherein the radicals have the meanings as defined in Claim 1, characterized in that the compound of formula A   in which W represents a halogen atom or a hydantoin derivative of formula:   in which R'4 and R'5 have the meanings indicated in Claim 1 for R4 and R5 in which the optional reactive functions are optionally protected, are subjected to halogenation with obtaining the compound of formula (F3):   in which Hal represents a halogen atom and W has the meaning determined above, and the obtained compound F3 is subjected to a diazotation-halogenation reaction in order to obtain the product of formula (F6):   in which the two halogen atoms represented by Hal are identical or different and W has the meaning indicated above, which can be subjected to a substitution reaction on the halogen atoms by the compound of formula (VI): R'1-M or (VII): R'2-M, wherein R'1 and R'2 are as defined in Claim 1, in order to obtain the product of formula (F5) as defined in Claim 1, in which R'1 and R'2 are identical, which products of formulae (F5) and (F6), wherein W represents a halogen atom, are put into reaction with the product of formula (IV), as defined above in order to obtain the product of formula (I') as defined above, which is subjected to the operations described in Claim 1. 3. The process for preparation of the compounds of formula (I), wherein the radicals have the meanings as defined in Claim 1, and wherein R2 is hydrogen atom, characterized in that the compound of formula A   in which W represents a halogen atom or a hydantoin derivative of formula:   in which R'4 and R'5 have the meanings indicated in Claim 1 for R4 and R5 in which the optional reactive functions are optionally protected, are subjected to diazotation with obtaining the compound of formula (V):   in which   represents an anion of a halogen atom or of a halogenated derivative and W has the meaning indicated above, which can be subjected to a halogenation reaction in order to obtain the product of formula (F1):   in which Hal and W have the meanings indicated above, hydantoin derivative of which, if necessary, is isolated as one of the desired products of formula I and for obtaining other derivatives of formula I, wherein R2 is hydrogen atom, can be subjected to a substitution reaction on the halogen atom by a metallic derivative of formula (VI):   in which M represents a metal and R'1 has the meaning indicated above for R1 in Claim 1, in which the optional reactive functions are optionally protected, in order to obtain the product of formula (F2):   in which R'1 and W have the meanings indicated above, the compounds of formulae F1, F2, wherein W is a halogen atom, which is subjected to the reaction with a compound of formula (IV):   in which R'4 and R'5 have the meanings of radicals R4 and R5 indicated in Claim 1, in which the optional reactive functions are optionally protected in order to obtain the product of formula I':   in which R"2 is hydrogen atom and R"1 is a halogen atom or R'1 determined in Claim 1, the compound of formulae (I'), if necessary is subjected to one or more of the following reactions: a) an elimination reaction of the optional protective groups which can be carried by R''1, R''2, R'4 and R'5; b) a conversion reaction of the >C=O into the >C=S group, c) the action of a reagent of formula Hal-R'3 in which R'3 has the values of R3 as defined above, with the exception of the hydrogen and in which the optional reactive functions are optionally protected and Hal represents a halogen atom, in order to obtain products of formula (I) as defined above, then, if desired, the action on these products of an agent for eliminating the optional protective groups which can be carried by R'3 or if appropriate, the action of an esterification, amidification or salification agent, a conversion reaction of the amino radical into a nitro radical. 4. The process according Claims 1, 3, wherein the compound of formula A is previously obtained by halogenation of o-trifluoromethylaniline of formula II:   with N-bromosuccinimide or mono- or dihalosubstituted dimethylhydantoin of formula III:   in which Hal represents a halogen atom and V represents hydrogen or halogen atom with obtaining a compound of formula A2:   in which Hal represents a bromine atom or another halogen atom, corresponding to the compound of formula A, wherein W represents a halogen atom and which is put into reaction with a compound of formula (IV):   in which R'4 and R'5 have the meanings indicated in Claim 1, in order to obtain the product of formula (A3):   corresponding to the product of formula (A) in which W represents the radical of hydantoin derivative. 5. The process according Claims 1 or 4, wherein o-trifluoromethylaniline is halogenated with dihalosubstituted dimethylhydantoin of formula III, described in Claim 4, and then the obtained compound is treated with the compound of formula