Patent EA-002883-B1 (EA)
Title: Method for preparing alkyloxy firanone derivatives, compounds obtained by said method and use of said compounds
Inventor: BOUCHET RAPHAEL
IPC: C07K5/06
Filed: 1998-07-09
Abstract: 1). Compounds of formula (IVa), (IVb), (IVc) or (IVd):   in which R1 is an alkyi group containing from 1 to 4 carbon atoms or a phenylalkyl group containing from 7 to 11 carbon atoms, as well as the addition salts thereof with acids. 2). Compound of the formula (IVd) as defined in Claim 1, as well as the addition salts thereof with acids. 3). Compound of the formula (IVd) according to Claim 2, in which R1 is an ethyl group, as well as the addition salts thereof with acids. 4). Process for preparing the compounds of the formula (IVa), (IVb), (IVc) or (IVd) as defined in Claim 1, characterized in that it comprises at least one of the following steps: a) action of an arylamine of the formula R3R4CHNH2, in which R3 is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms and R4 is an optionally substituted aryl, on the racemic alkoxyfuranone of the formula (II):   in which R1 is an alkyl group containing from 1 to 4 carbon atoms or a phenylalkyl group containing from 7, to 11 carbon atoms, and production of the trans isomer compounds (4R, 5R) and (4S, 5S) respectively, of the formulae (IIIa) and (IIIb)   which subsequently - are separated by crystallization, carrying out, if necessary, one or more salification reactions, - or, when R3 is a hydrogen atom, are resolved by the action of an optically active acid, b) where appropriate, epimerization reaction on the compound of the formula (IIIa) or (IIIb), in salified or non-salified form, in the presence of an acid, in order to obtain the cis isomer compounds (4R, 5S) or (4S, 5R) of the formula (IIIc) or (IIId), which are salified if necessary/   c) hydrogenolysis reaction, - either on the trans isomer (4R, 5R) or (4S, 5S) of the formula (IlIa) or (IIIb), in salified or non salified form/ in order to obtain the compound of the formula (IVa) or (IVb) in the form of the trans isomer (4R, 5R) or (4S, 5S) as defined above, which is then, if necessary, salified and/or protected, - or on the cis isomer (4R, 5S) or (4S, 5R) of the formula (IIIc) or (IIId), in salified or non salified form, in order to obtain the compound of the formula (IVc) or (IVd) in the form of the cis isomer (4R,5S) or (4S,5R), which is, if necessary salified, and/or protected. 5). Process according to Claim 4, characterized in that the protection reaction on the amines of the formula (IVa), (IVb), (IVc) or (IVd), in salified or non salified form, is carried out by the action of the chloroformate of the formula C1-CO-O-CH2-R2, R2 representing a tert-butyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl or phenyl radical, which may be substituted or unsubstituted, in order to obtain the compounds of the formula (la), (Ib), (Ic) or (Id) respectively, in the form of the trans-diastereoisomers (4R, 5R), (43, 5S) or cis-diastereoisomers (4R, 5S) and (4S, 5R), which if necessary are salified,   6). Process according to Claim 4, characterized in that the separation, by crystallization, of the compounds of the formulae (IIIa) and (IIIb), as defined in Claim 4, is carried out: a) by the action of trichloroacetic acid, in order to obtain the corresponding salt of the formula (IIIa) or (IIIb), b) and then by the action of monochloroacetic acid on the mother liquors in order to obtain the salt corresponding to the other diastereoisomer of the formula (IIIa) or (IIIb). 7). Process for preparing, according to Claim 4, the compounds of the formula (IVd) as defined in Claim 2 or the compounds of the formula (Id) as defined in Claim 5, characterized in that it comprises at least one of the following steps: a) action of the R phenylethylamine on the compound of the formula (II), in order to obtain the compounds of the formulae (III'a) and (III'b) below: '   b) resolution of trans sfcereoisoroers of the formulae (III'a) and (III'b) by the action of trichloroacetic acid, in order to obtain the stereoisomer (III'b) (4S, 5S) in the form of the trichloroacetic acid salt, followed by the action of monochloroacetic acid, in order to obtain the stereoisomer (III'a) (4R, 5R) in the form of the monochloroacetic acid salt, c) where appropriate, return to the free amine by the action of a base, d) epimerization reaction on the stereoisomer (4S, 5S) of the formula (III'b) in the presence of an acid, in order to obtain a cis stereoisomer (4S, 5R) of the formula (III'd):   e) if necessary, crystallization after salification by the action of monochloroacetic acid or dichloroacetic acid, f) where appropriate, return to the free amine by the action of a base, g) if necessary, recrystallization after salification, in particular in the form of the hydrochloride, h) hydrogenolysis of the cis stereoisomer (4S, 5R) of the formula (III'd), in order to obtain the compound of the formula (IVd) in the form of the cis diastereoisomer (48, 5R) i) where appropriate, the action of allyl chloroformate on the compound of the formula (IVd), in order to obtain the compound of the formula (Id) in the form of the cis diastereoisomer (4S, 5R), with R2 representing -CH=CH2. 8). Process for preparing, according to Claim 4, the compounds of the formula (IVd) as defined in Claim 2 or the compounds of the formula (Id) as defined in Claim 5, characterized in that it comprises at least one of the following steps: a) action of the S phenylethylamine on the compound of the formula (II) in order to obtain the compounds of the formulae (III"a) and ( III"b) below:   b) resolution of the trans stereoisomers of the formulae (III"a) and (III"b) by the action of trichloroacetic acid, in order, to obtain the stereoisomer (III"a) (4R, 5R) in the form of the trichloroacetic acid salt, followed by the action of monochloroacetic acid, in order to obtain the stereoisomer (III'"b) (4S, 5S) in the form of the monochloroacetic acid salt. c) if necessary, desalification by the action of a base, d) epimerization reaction on the stereoisomer (4S, 5S) of the formula (III"b) in the presence of an acid, in order to obtain the cis stereoisomer (4S, 5R) of the formula (III"d):   e) if necessary, crystallization after salification by the action of an acid, such as monochloroacetic acid or dichloro-acetic acid, f) where appropriate, return to the free amine by the action of a base, g) if necessary, recrystallization after salification, in particular in the form of the hydrochloride, h) hydrogenolysis of the cis stereoisomer (4S, 5R) of the formula (III"d), in order to obtain the compound of the formula (IVd) in the form of the cis diastereoisomer (4S, 5R), i) where appropriate, the action of allyl chloroformate on the compound of the formula (IVd), in order to obtain the compound of the formula (Id) in the form of the cis diastereoisomer (48,5R), R2 representing a -CH=CH2 radical. 9). Process as defined in any one of Claims 4 to 8, characterized in that the addition of the amine to the compound of the formula (II) as defined in Claim 4 is carried out in dimethylformamide or aqueous isopropanol. 10). Process as defined in any one of Claims 4 to 8, characterized in that the epimerization reaction is carried out with tin tetrachloride or methanesulphonic acid. 11). Process as defined in any one of Claims 4 to 8, characterized in that R1 is an ethyl radical. 12). Process as defined in any one of Claims 8 to 11, characterized in that the resolution of the trans stereo-isomers with trichloroacetic acid (step b) is carried out in aqueous isopropanol. 13). Process as defined in any one of Claims 8 to 11, characterized in that the epimerization reaction on the (4S.5S) stereoisomer of the formula (III"b, step d) is carried out in the presence of methanesulphonic acid in toluene. 14). Process as defined in any one of Claims 8 to 11, characterized in that the crystallization (step e) is carried out by the action of dichloroacetic acid in toluene. 15). Use: either of the compounds of the formula (IVa), (IVb), (IVc) or (IVd) as defined in Claim 1 or obtained from the process as defined in Claim 4, in amidation reactions, starting with the acid of the formula A-COOH to give a compound of the formula (V) below:   A representing any organic radical. 16). Use: the compounds of the formula (Ia), (Ib) (Ic) or (Id) obtained from the process as defined in Claim 5,  in amidation reactions, starting with the acid of the formula A-COOH to give a compound of the formula (V) below:   A representing any organic radical. 17). Use: the compounds of the formula (IYb) or (IYd) obtained from the process as defined in Claim 4, in the synthesis of the compounds of the formula (V), which have inhibitory activity on interleukin converting enzyme. 18). Use: the compounds of the formula (Ib) and (Id) obtained from the process as defined in Claim 5,  in the synthesis of the compounds of the formula (V), which have inhibitory activity on interleukin converting enzyme. 19). Use: the compounds of the formula (IVd) with R1 ( ethyl as defined in Claim 3 or obtained by from the process as defined in Claim 7 or 8, to obtain the compound of the formula (Y), which have inhibitory activity on interleukin converting enzyme. 20). Use as difined in Claim 19 of the formula (IYd) of Claim 19 in the preparation of the compound of the formula (V) with the following structure:   21). Use: the compounds of the formula (Id) with R1 ( ethyl as defined in Claim 5 to obtain the compound of formula (V), which have inhibitory activity on interleukin converting enzyme. 22). Use as defined in Claim 21 of the compounds of the formula (1d) of Claim 21 to obtain the compound of the formula (V) with the following structure:   23). The compounds of the formulae (IIIa), (IIIb), (IIIc), (IIId) as novel intermediate compounds as well as the addition salts thereof with acids, with the exception of the compounds of the formulae (III"a) and (III"b) as defined in Claim 8, in which R1 = methyl.