MXPA00000506A - Method for preparing alkyloxy furanone derivatives, compounds obtained by said method and use of said compounds - Google Patents

Abstract

The invention concerns a novel method for preparing compounds of formula (IV) or (I) from racemic alkoxyfuranone of formula (II) in which R1 and R2 are as defined in the description, the said novel compounds of formula (IV) and the intermediate compounds of said method, and the use of compounds of formula (IV) or (I) in the synthesis process of compounds inhibitors of interleukin-1beta converting enzyme.

Description

PROCEDURE FOR THE PREPARATION OF THE DERIVATIVES AMINATED FROM THE A L Q U I L O X I F U R A N N A N, COMPOUNDS OBTAINED BY THIS PROCEDURE AND USE OF THEMSELVES Description of the invention: The present invention has as its objective a new process for the preparation of ammonium derivatives of the alkyloxyfuranone, the compounds obtained from this process and the use of these compounds in synthesis of Inhibitors of the interleukin-beta conversion enzyme. Patent applications WO9535308, W09722619, W09722618, EP 19748, WO9633209, describe compounds that inhibit the conversion enzyme of interleukin-beta. The process for the preparation of certain compounds described in the patent applications cited above applies the compounds of the following formula (I): OR REF .: 32480 in which Rj represents an ethyl radical and R2 represents a radical -CH = CH2. The compounds of the formula (I) are prepared from the protected L-aspartic acid and need 4 synthesis steps: 1) acylation; 2) reduction; 3) oxidation; 4) cyclization (Chapman K.T., et al., Bioorg. Med. Chem. Lett. 2_ (6), 613-8 (1992)). This process has some important disadvantages, especially in the case where it is desired to obtain chiral compounds of the formula (I). It is necessary to start from a costly chiral reagent: the ß-tert-butylester of L-aspartic acid, and above all to use c r o m a t t o g r a f i c s to isolate and / or purify the different d i a te r m e r s. Then, the present invention aims to find another way of synthesis of the compounds of the formula (I), where it is avoided starting from this initial product and that does not need separations by chromatography. The applicant then proposes a new synthesis route, starting from the alkyloxy uranone, of the formula (II), in racemic form, which allows access to the new compounds of the formulas (IVa), (IVb), ( IVc) or (IVd), as defined below, salified or unsalified, which later, as the case may be, are protected in order to obtain, in particular, the compounds of the formula (I). This method has the advantage of being able to be applied on a large scale, starting from a compound of the formula (II), easily accessible and inexpensive, with the separation and / or purification steps that are carried out by means of crystallization, and not by chromatography Thus, each of the formulations (III), (IV) or (I) can be isolated. The present invention then has, on the one hand, as its objective, the following compounds of the formulas (IVa), (IVb), (IVc) or (IVd): (iva) (ivb) (ivc) (IVd) in which i is an alkyl group comprising from 1 to 4 carbon atoms, or a phenylalkyl group comprising from 7 to 11 carbon atoms, as well as their addition salts with the acids. The invention naturally includes the salts of the compounds of the formula (IVa), (IVb), (IVc) or (IVd), such as, for example, the salts formed with the mineral or organic acids on the amine. Then it can be hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulfonic acids, such as methane or ethane acids sulphonic, aryl, and their, such as benzene- or para-toluene sulfonic acids and arylcarboxylic acids. It can also be chloroacetic acid or t r i c I o r c a c e t i co. These are, in particular, salts with hydrochloric acid. When Ri is an alkyl group comprising 1 to 4 carbon atoms, it is especially methyl, ethyl, butyl or propyl and, more particularly, ethyl. The term "phenylalkyl" is preferably the benzyl group.

The invention relates more particularly to the compound of the formula (IVd), as defined above, as well as its addition salts with the acids. The invention has as its object, more particularly, the compound of the formula (IVd) in which Ri is an ethyl group, as well as its addition salts with the acids. On the other hand, the present invention aims at a process for the preparation of the compounds of the formula (IVa), (IVb), (IVc) or (IVd), as described above, characterized in that it comprises at least one of the following steps: a) the action of an arylamine, of the formula R 3 R 4 CHNH 2, wherein R 3 is a hydrogen atom or an alkyl group comprising 1 to 4 carbon atoms; and R 4 is an optionally substituted aryl, on the racemic (I), (i), (a), (a) or (ii): ("") wherein R 1 is an alkyl group comprising 1 to 4 carbon atoms, or phenylalkyl comprising 7 to 11 carbon atoms, and obtaining trans isomers (4R, 5R) and (4S , 5S), respectively, of the formulas (Illa) and (111 b): (Illa) (Illb) which, next: -are separated by crystallization, carrying out, if required, one or several salification reactions, or -when R3 is a hydrogen atom, are split by the action of an optically active acid; b) if required, the epimerization reaction of the compound of the formula (Illa) or (Illb), salified or non-salified, in the presence of an acid, to obtain the cis (4R, 5S) or (4S, 5R) isomeric compounds ), of the formula (lile) or (Illd), which are salified, if required, (Ule) Ciiid) c) Hydrogenolysis reaction, either on the trans isomer (4R, 5R) or (4S, 5S), of the formula (Illa) or (Illb), salified or non-salified, to obtain the compound of the formula (IVa) ) or (IVb), in the form of the trans (4R, 5R) or (4S, 5S) isomer, as defined above, which, if required, is salified and / or protected, either on the cis (4R) isomer , 5S) or (4S, 5R), of the formula (lile) or (Illd), salified or non-salified, to obtain the compound of the formula (IVc) or (IVd), in the form of the cis isomer (4R, 5S ) or (4S, 5R), as defined above, which, if required, is salified and / or protected. In particular, the protection reaction of the amines of the formula (IVa), (IVb), (IVc) or (IVd), salified or non-salified, is carried out by the action of the chloroformate, of the formula CI-CO-0- CH2-R, where R2 represents a terbutyl, alkenyl (C2-C4), alkynyl (C2-C4) or phenyl, substituted or unsubstituted radical, to obtain the compounds of the formula (Ia), (Ib), ( le) or (Id), respective entity, in the form of the isothermal days trans (4R, 5R), (4S, 5S) or cis (4R, 5S) or (4S, 5R), which, if required, they are salified, (le) (Id) The action of the arylamine of the formula R3R4CHNH2 on the racemic alkyloxyfuranone of the formula (II) is carried out according to the classical methods necessary for the Michael reaction, namely especially in a dipolar aprotic solvent, such as dimethylformamide, at room temperature . It is also possible to operate with water in aqueous isopropanol. The separation of the two trans isomers (4R, 5R) and (4S, 5S), namely, respectively, the compounds of the formulas (Illa) and (Illb), by crystallization, are carried out according to the methods known to those skilled in the art, concerning the isomer separations. As an example, it is preferred that the separation be effected by the action of the acid t r i c I o r c a t i co in a solvent such as the terbutyimethyl ether or aqueous isopropanol. The trans isomer (4R, 5R) (Illa) is crystallized in the form of the trichloroacetic acid salt, while the trans isomer (4S, 5S) (Illb) is recovered in the form of the monocyclic acid salt. by treatment of the mother liquors, in the presence of mon oc I or a c etic acid. When R3 is a hydrogen atom (non-chiral amine) the separation (cleavage) is then effected by means of a chiral acid such as tartaric acid, ca.sulfonic acid, salicylic acid, lithium dibenzoic acid, R + 2,4-hydroxyphenoxypropionic acid. . The epimerization reaction on one of the isomers (4 R, 5 R) or (4S, 5S), of the formula (Illa) or (Illb), is carried out in the presence of a Lewis acid, such as ferric chloride , titanium tetrachloride optionally complexed with tetrahydrofuran, boron trichloride, boron trifluoride etherate and tin tetrachloride or an organic acid such as methane sulphonic acid, trifluoroacetic acid and acid para te uensu If ó nor co. This is, preferably, tin tetrachloride, in the presence of a polar solvent, such as dichloromethane, or methanesulfonic acid in a solvent such as toluene.

The reaction of h i d r o g e n or I i s on the cis or trans d i s t e r e s or m e r s s, of the formula (Illa), (Illb), (lile) or (Illd), is carried out according to the classical methods known to those skilled in the art, for example, by the action of hydrogen in the presence of palladium on carbon at 10% in tetrahydrofuran. The acylation reaction with the cyclodextrin is preferably carried out in the presence of a base such as pyridine in a low polar solvent, such as dichloromethane. The formation of the base, from the corresponding salt, that is, the return to the free amine, as well as the salification methods with the acids, as defined above, is carried out according to the methods known to those trained in the art. .

Concerning the compounds of the formula (III), when R3 is an alkyl group comprising 1 to 4 carbon atoms, it is preferably methyl or ethyl and, when R 4 is an aryl group, it is preferably phenyl or naphthyl. As regards the compounds of the formula (I), when R2 is a (C2-C4) alkenyl group or (C2-C4) alkynyl, it is preferably a -CH = CH2, -C = CH, -CH = CH2-CH3, -C = C-CH3. The protective reactions of the compounds of the. formula (I) are carried out according to methods known to those trained in the art and especially referring to the work of Philip J. Kociens and, Protecting Groups Ed., Georg. Thieme Verlog Stuttgart New York, 1994. The object of the present invention is, more particularly, the process as defined above, characterized in that the separation by crystallization of the compounds of the formulas (Illa) and (IHb), is carried out: a ) by the action of the tricyclic acid, to obtain the corresponding salt of the formula (Illa) or (IHb), b) then, by the action of the monochloroacetic acid, on the mother liquors, to obtain the corresponding salt of the another diasteroi mere of the formula (Illa) or (III b). The subject of the present invention is, more particularly, a process for the preparation, as described above, of the compounds of the formula (IVd) or (Id), as defined above, characterized in that it comprises at least one of the following steps: a) action of the phenylethylamine R on the compound of the formula (II), to obtain the compounds of the following formulas (Ill'a) and (Ill'b): (Ill'a) (Ill'b) b) separation of the trans steroisomers, from the formulas (Ill'a) and (Ill'b), by the action of tric acid I oroac ti ti, to obtain the sterois or mere (Ill'b) (4 s, 5 s), in the form of the salt of trichloroacetic acid, then by the action of the monocytic acid, to obtain the thermal oil (Ill'a) (4 R, 5R), in the form of the salt of monochloroacetic acid; c) as required, return to the free amine by the action of a base; d) epimerisation reaction of the sulfur atom (4S, 5S), of the formula (Ill'b), in the presence of an acid, to obtain a sulfuric ester (4S, 5R), of the formula (Ill'd): e) as required, crystallization, after salification, by the action of an acid such as monochloroacetic or dichloroacetic acid; f) if required, return to the free zone by the action of a base; g) if required, the r e c a r i s a c t ion, after salification, especially in the form of a hydrochloride; h) hydrogenolysis of the cis (4S, 5R) steroisomer of the formula (IH'd) to obtain the compound of the formula (IVd) in the form of the cis diastereoisomer (4S, 5R); i) if required, action of the I oroformia to a I i I over the compound of the formula (IVd) to obtain the compound of the formula (Id) in the form of the days te roi só me ro cis (4S, 5R), where i represents -CH = CH2. The present invention also aims, more particularly, at a process for the preparation, as described above, of the compounds of the formula (IVd) or (Id), as defined above, characterized in that it comprises at least one of the following steps: a) action of the phenylethylamine S on the compound of the formula (II), to obtain the compounds of the following formulas (III "a) and (III" b): (III "a) (III" b) b) splitting of the trans steroids, of the formulas (III "a) and (III" b), by the action of the tric acid I oroac ti ti, to obtain the terrestrial ester (III "a) (4R , 5R), in the form of the salt of the tric acid and acetic acid, then by the action of the mon oc Ionic acid, to obtain the stereoisomer (III "b) (4S, 5S), in the form of salt of the acid mono I oroac ethico; c) as required, return to the free amine by the action of a base; d) reaction of epimerization of the stereoisomer (4S, 5S), of the formula (III "b), in the presence of an acid, to obtain a cis (4S, 5R) steroisomer of the formula (111") d): e) as required, crystallization, after salification, by the action of an acid such as acid or n o c 1 or r o a c e t i c o or o acetic acid; f) if required, return to the free amine by the action of a base; g) if required, recrystallization, after salification, especially in the hydrochloride form; h) h i d r o g e n i I s i s of the cis (4S, 5R) steroisomer, of the formula (III "d), to obtain the compound of the formula (IVd) in the form of the d i a s t e r i i s m e r o cis (4 S, 5 R); i) if required, the action of the allyl ion on the compound of the formula (IVd) to obtain the compound of the formula (Id) in the form of the d i a s te r or i s or m e r o cis (4S, 5R). The object of the invention is, more particularly, the process, as defined above, characterized in that the addition of an amine to the compound of the formula (II) is carried out in the dimethylformamide or in the aqueous isopropanol. The object of the invention is, more particularly, the process, as defined above, characterized in that the reaction of e p i m e r i za n is carried out with tin tetrachloride or methane sulphonic acid. The invention aims, more particularly, at the process, as defined above, characterized in that Ri is an ethyl radical. The object of the invention is, more particularly, the process, as defined above, characterized or in that the separation of the trans-stereoisomers, with acid t r i c I or r c a t i c o (step b) is carried out in aqueous isopropanol.

The invention has as its objective, more particularly, the process where phenylethylamine (R) is used, characterized in that the reaction of the stereoisomer (4S, 5D, of the formula (III "b) (step d) is The object of the invention is, more particularly, the process in which phenylethylamine () is used, characterized in that the crystallization (step e) is carried out by the action of dichloroacetic acid in toluene. The invention also aims at the use: either of the compounds of the formula (IVa), (IVb), (IVc) or (IVd), as defined above, or that are obtained from the process as described above; either the compounds of the formula (la), (Ib), (le) or (Id), produced by the process as described above, in the amidation reactions, from the acid of the formula A-COOH, to obtain a compound of the following formula (V): where A represents any organic radical. The invention also aims at the use: either of the compounds of the formula (IVb) or (IVd), as defined above, or that are obtained from the process as described above; either the compounds of the formula (Ib) or (Id), produced by the process as described above, for the synthesis of the compounds of the formula (V), which have inhibitory activity of the interleukin conversion enzyme. . These compounds of the formula (V) are especially described in the patent applications WO9535308, w or 9722619, EP0519748 and WO9633209. The invention aims, more particularly, to use: either the compound of the formula (IVd), Ri = ethyl, as defined above, or obtained from the process as described above; either the compound of the formula (Id) with R 1 = ethyl, obtained from the process as described above, for the preparation of a compound of the formula (V), which has an inhibitory activity of the interleukin conversion enzyme. The invention has as its object, more particularly, the use: either of the compound of the formula (IVd), with Rx = ethyl, as defined above, or obtained from the process as described above; either the compound of the formula (Id) with Ri = ethyl, obtained from the process as described above, for the preparation of a compound of the formula (V), having the following structure: This compound is described in patent application W09722619 (Pdt 412e).

The invention also aims at the compounds of the formulas (Illa), (Illb), (IIIc), (Illd), as well as their acid addition salts, as described above, as novel intermediate compounds, with the exception of the compounds of the formulas (111"a) and (III" b), with t = methyl. The compounds of the formula (II) are known or easily accessible from the me t-xifuranone, by the action of APTS (paratoluenesulfonic acid), in the presence of water, and after a reagent of the formula (R x O ) 3 CH, in the presence of an acid catalyst. The following examples illustrate the invention, without being limited in any way.

EXAMPLE 1: (2R-cis) (2 - e t o x i - t e t r a h i d r o - 5 - o x o - 3 -f u r a n i i) - c a r b a m a t 2-propenyl. Step 1: Addition of Michael 4 (R *) dihydro-5-ethoxy-4 [(1-phenylethyl) amino3-2 (3H) -furanone. They are added, in 30 minutes, at a temperature between 23 and 25 ° C, under in an inert atmosphere, 15 mL of R (+) 98% phenylethylamine, to 15 g of racemic ethoxyfuranone, in 75 mL of dimethylformamide; the obtained solution is stirred for 24 hours; then it is poured into the water-ice mixture. Isopropyl ether is added, extracted, washed and dried; and evaporated under reduced pressure to obtain 27 g of an oil corresponding to the expected 50/50 mixture of the trans isomers. NMR (CDCl3: 250 Hz 1.12, 1.22 (t) CH2CH_3 1.37 (dd) Ctb (-NH-CH (Ct) (Ph)) 2.13 (dd, 3 = 3.5 and 17.5); 2.35 (dd, 3 = 3 and 17.5); Cfch in 3 of the furanona 2.70 (dd, 3 = 7.5 and 17.5); 2.80 (dd, 3 = 7 and 17.5) 3.26 (m) CU in 4 of the furanone 3.30 to 3.90 (m) CH CH3 3.82 (m) CU (-NH-CJ ± (CH3) (Ph)) .00 (d, 3 = 1.5 and 5.32 (d, 3 = 1.5) CH in 5 of the furanone 7.2 to 7.4 (m) aromatic 5H Step 2 Objection of two trans-steroid diastere A) Obtaining trans (4S, 5S) trichloroacetate transdermal diastere of 4 (S) [4 a (S *), 5 b] - dihydro-5-ethoxy-4 - [(1-phenylethyl) amypo] -2 (3H) -furanone A solution of 10.6 g of trichloroacetic acid (99.5%) in 50 ml of methylbutyl ether is added in 20 minutes to 27 g of the mixture of dichloroacetic acid. The former was obtained in the previous stage, in 164 mL of methylterbutyl ether. The solution obtained is stirred for 2 hours at a temperature of 20-25 ° C, then 2 hours at 0-5 ° C. 12 g of the isomer (4S, 5S) are obtained in the form of the trichloroacetic acid salt. [aD] = + 71 ° (c = 1% CH3OH) NMR (CPCI3: 250 M H z) 1.75 (d, 3 = 7) Ctb (-NH-CH (Ctb) (Ph)) 2.78 (dd, 3 = 8.5 and 18.5); 3.05 (dd, 3 = 4 and 18.5); Ctb in 3 of the furanone 3.43 (ddd, 3 = 2-4 and 8.5) CH. in 4 of the furanone 3.59 (dq 1H) 3.79 (dq 1H) CH_2CH3 4.29 (q, J =)) (-NH-CH (CJ ± 3) (Ph)) .77 (d, 3 = 1.5) Cü in 5 of the furanone 7.42 to 7.57 5H aromatic 9.80 (large) H mobile B) obtaining the trans ore (4R, 5R) cioacetate diastere of 4 (R) [4a (R *), 5β] -dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 ( 3H) -furanone The mother liquors from the previous stage are washed with a saturated solution of sodium bicarbonate, then with water, then re-extracted once with isopropyl ether. After drying, it is evaporated under reduced pressure to obtain 15.45 g of the expected product in the form of an oil. 5 g of monochloroacetic acid are added to the 15.45 g of the product in 130 mL of isopropanol and heated to 40 ° C. A solution is observed, then a crystallization, then it is stirred for 1 hour at room temperature, then 2 hours at a temperature of 0-5 ° C. 11.98 g of the expected isomer (4R, 5R) are obtained in the form of a monochloroacetic acid salt.

Step to obtain the desalted compound (4S, 5S) 4 (S) [4a (S *), 5β] -dihydro-5-ethoxy-4 - [(1-fer? I) ethyl) amine] -2 ( 3H) -furanone 11.8 g of the salt obtained in step 2A and 120 ml of dichloromethane are mixed at room temperature, then 100 ml of a saturated solution of sodium bicarbonate are added. After stirring for 10 minutes, the mixture is extracted, washed, dried and evaporated under reduced pressure to obtain 7.1 g of the product of the product. [a] = + 114 ° (c = 1% CH3OH) Step 4: epimerization: obtaining the diastereoisomer (4S, 5R) 4 (S) [4a (S *) / 5a] -dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 (3H) -furanone In an inert atmosphere, in 1 hour, at a temperature of 4 ± 1 ° C, 28.6 mL of 1M tin tetrachloride, in dichloromethane, is added to 6.8 g of the desalated compound (4S, 5S) obtained in the Stage 3, in 135 mL of dichloromethane and stir 40 m inutes at this temperature. 11 mL of acetic acid are added immediately, the mixture is stirred at 5 ° C for 30 minutes, water / ice is poured into the mixture, washed, cyclohexane is added, and the pH is 7-8 with the addition of sodium bicarbonate. , it is extracted with cyclohexane, dried and evaporated under reduced pressure to obtain 4.39 g of the expected product in the form of an oil, corresponding to a cis / trans ratio of 90/10. [ao] = - 1 ° 5 (c = 1% CH3OH) NMR (CDCl3: 250 MHz1) 1.23 (t) CHzCHj 1.40 (d, 3 = 6.5) Cu, (-NH-CH (CiL3 ) (Ph)) 2.39 (dd, 3 = 11 and 17); 2.61 (dd, 3 = 8 and 17); Cfcb in 3 of the furanone 3.32 (m) CU in 4 of the furanone 3.77 (m) CH (-NH-CH (Ctb) (Ph)) 4.96 (d, 3 = 5) CtL in 5 of the furanone 7.20 to 7.40 (m) aromatic 5H The formation of the mono-sucrose-acetic acid monochloroacetic acid cis (4S, 5R) Coryloacetate of 4 (S) [4 a (S *), 5 a] - dihydro-5-ethoxy -4 - [(1-phenylethyl ) amino] -2 (3H) -furanone 1.82 g of monochloroacetic acid (96%) are added, in an inert atmosphere, at a temperature of 20-25 ° C, to 5 g of the cis diasterois obtained in the previous stage. , in 50 μL of terbutilmethyl ether. A solution is obtained which crystallizes rapidly and is left for 1 hour at 30 m inutes at + 5 ° C. 5.75 g of the expected product are obtained. F = 106-108 ° C. [aD] = -11 ° 5 (c = 1% CH3OH) Stage 6: hydrogenolysis a) desaiification (return to free aia) 4 (S) [4a (S *), 5a] -dlhydro-5-ethoxy -4 - [(1-phenylethyl) amino] -2 (3H) -furanone. At a temperature of 0-5 ° C, 5.55 g of the mono-oroacetic salt obtained in the stage are mixed under an inert atmosphere. above, 60 mL of dichloromethane and 55 mL of sodium bicarbonate, stirred for 10 minutes, washed, extracted, dried and evaporated under reduced pressure until 3.95 g of the desalted product was obtained, in the form of an oil. b) Formation of the hydrochloride hydrochloride of 4 (S) [4 a (S *), 5 a] - dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 (3H) -furanone are added, drop by drop, at a temperature of 0-5 ° C, 6.6 mL of 2N trichloroacetic acid, in isopropyl ether, to 3.36 g of the product obtained above, in 66 mL of isopropyl ether and kept for 1 hour at this temperature. The crystallization is observed. 3.77 g of the expected hydrochloride are obtained. c) Hydrogenolysis hydrochloride (4 (S) - cis) -4-amino-5-ethoxy-dihydro-2 (3H) -furanone To a suspension of 4 g of the hydrochloride obtained above, in 60 mL of tetrahydrofuran, 1.8 are added. m L of water to obtain a solution, then, 400 mg of palladium on carbon at 10%. It is stirred under a hydrogen atmosphere at 1.5 bar for 18 hours, at a temperature of 27-28 ° C. After filtering and rinsing with the mixture, the mixture is evaporated under reduced pressure. 2.54 g of the expected product are obtained. [aD] = -96 ° (c = 1% CH3OH) 1.22 (t) CH2Cj ± 3 2.58 (dd, 3 = 8 and 17.5); 2.70 (dd, 3 = 8 and 17.5); CH? in 3 of the furanone 4.14 (dt, 3 = 5.5 and 8); CJhL in 4 of the furanone 3.61; 3.90 (m) h CHs 5.71 (d, 3 = 5.5) C] ± in 5 of the furanone 8.69 (if) 3H mobile Step 7: Formation of the carbamate of a I i I (2 R-cis) (2-ethoxy-tetrahydro-5-oxo-3-furanyl) -carbamate of 2-propeni lo are added, at a temperature of + 5 ° C, in an inert atmosphere, 3 mL of pyridine to the mixture constituted by 2.4 g of the product obtained in the previous step, 50 mL of dichloromethane and 1.55 mL of allyl orioxide; stir for one hour at this temperature, then add 0.56 mL of allyl C o or r of allyl and 1 mL of pyridine. It is stirred for 6 hours at room temperature, poured into water, extracted with dichloromethane, washed, dried, evaporated under reduced pressure to obtain 2.66 g of the crude product, which is recrystallized from isopropyl ether. 1.95 g of the expected pure product are obtained. [aD] = -56 ° (c = 1% CH2Cl2) 1.26 (t) CHzCtb 2.47 (dd, 3 = 10 and 17.5); 2.84 (dd, 3 = 8.5 and 17.5); - Ctb in 3 of the furanone 3.67 (dq) and 3.92 (dq) ChüCHs 4.55 (m) CJH in 4 of the furanone 4.59 (dl) CH_2-CH = CH2 5.45 (d, 3 = 5.5) Cj ± in 5 of the furanone .25 (dq) and 5.33 (dq) CH2-CH = Ci_h 5.30 hidden N-H. 5.93 (m) CH2-CH = CH2 EXAMPLE 2: (2 R-cis) (2-ethoxy-tetrahydro-5-oxo-3-furani I) - 2-propenyl ba ba Stage 1: Addition of Michael 4 (S *) dihydro-5-ethoxy -4 [(1-phenylethyl) amino] -2 (3H) -furanone 30 mL of 98% S (-) phenylethylamine are added in 30 minutes at 23 to 25 ° C. under an inert atmosphere. 15 g of non-racemic ethanol, in 75 mL of dimethyl formamide, is stirred 24 hours, the solution obtained is then poured into the water / ice mixture. After extraction with cyclohexane, it is washed and dried, evaporated under reduced pressure to obtain 26.6 g of an oil corresponding to the mixture of trans isomers 45/55, expected. NMR (CDCl3, 250 MHzl 1.12 (t), 1.22 (t) CH2Chb 1.37 (dd) Cth (-NH-CH (CH3) (Ph)) 2.13 (dd, 3 = 3.5 and 17.5); 2.35 (dd, 3 = 3 and 127.5); CH? in 3 of the furanone 2.70 (dd, 3 = 7.5 and 17.5); 2.80 (dd, 3 = 7 and 17.5) 3.26 (m) CU in 4 of the furanone 3.30 to 3.90 (m) CH_2CH3 3.82 (m) CH. (-NH-CÍ ± (CH3) (Ph)) .00 (d, 3 = 1.5) and 5.32 (d, 3 = 1.5) Cü in 5 of the furanone 7.2 to 7.4 (m) 5H aromatic Top 2: Splitting of two trans diastereoisomers a) Obtaining the trans diastereomer (4R, 5R) trichloroacetate from 4 (R) [4 a (S *), 5 b] -dihydro-5-ethoxy-4 - [(1) phenylethyl) amino] -2 (3H) -furanone A solution of 10.24 g of trichloroacetic acid (99.5%) in 50 ml of tert.butyl ether is added to 30 g of the mixture from the previous stage in 30 minutes. , in 155 mL of terbutyl ether. The solution obtained is stirred for 2 hours at a temperature of 20-25 ° C, then 2 hours at 5 ° C. 12.63 g of the isomer (4R, 5R) are obtained in the form of a trichloroacetic acid salt. [a D] = -72 ° 5 (c = 1% CH 3 OH) NMR (CDCl 3: 250 MHz) 1.15 (t) CH 2 CH 3 1.75 (d, 3 = 7) CH 3 (-NH-CH (Chb) ( Ph)) 2.78 (dd, 3 = 8.5 and 18.5); 3.05 (dd, 3 = 4 and 18.5); CH? in 3 of the furanone 3.43 (ddd, 3 = 2-4 and 8.5) CfcL in 4 of the furanone 3.59 (dq 1H) 3.79 (dq 1H) CH_2CH3 4.29 (q, 3 = 7) (-NH-CH (CH3) (Ph)) 5.77 (d, 3 = 1.5) Cü in 5 of the furanone 7.42 to 7.57 5H aromatic 9.80 (large m) H mobile b) Obtaining the trans diastereomer (45.58) chloroacetate from 4 (S) [4 a (R *), 5 [beta]] - dihydro-5-ethoxy-4 - [(1-phenylethyl) amtno] -2 ( 3H) -furanone The mother liquors from the previous stage are washed with a saturated solution of sodium bicarbonate, then extracted again with tert-butyl ether. After drying, evaporate under reduced pressure to obtain 17.43 g of the expected product, in the form of an oil. 130 mL of isopropanol are added, then 5 g of monochloroacetic acid and heated to 40 ° C. A solution is observed, then a crystallization, then it is stirred for 1 hour at room temperature, then 2 hours at a temperature of 0-5 ° C. 12.48 g of the expected (4S, 5S) isomer are obtained in the form of a monochloroacetic acid salt. [aD] = + 1 ° (C = 1% CH3OH) NMR (CPCI3; 250 MHz) 1 12 (t, 3 = 7.5) CH2Ctb 1.26 (d, 3 = 6.5) Ctb (-NH- CH (Ctb) (Ph)) 2.18 (dd, 3 = 2.5 and 17.5); 2.66 (dd, 3 = 7.5 and 17.5); CH? in 3 of the furanone 2.95 (ddd, 3 = 1-2 and 7.5) CH. in 4 of the furanone 3.66 (m) CjHbCH3 3.87 (q, 3 = 6.5) CH (-NH-CH_ (CH3) (Ph)) 5.42 (d, 3 = 1) CH. in 5 of the furanone 7.42 (m) 1H, 7.33 (m) 4H H aromatic 4.26 (s) X-CH2 Stage 3: Obtaining the desalted compound (4 S, 5 S) 4 (S) [4a (R *), 5β] -dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 (3H) -furanone are mixed, at a temperature of 0-5 ° C, 12.35 g of the salt obtained in step 2B, and 130 mL of dichloromethane, then add 100 mL of a saturated solution of sodium bicarbonate. After 10 minutes of stirring, it is extracted, washed, dried and evaporated under reduced pressure, until obtaining 8.9 g of the desalted product. [or D] = -6.6 ° (c = 1% CH3OH) Step 4: epimerization: obtaining the diastereoisomer (4S, 5R) 4 (S) [4a (R *), 5a] -dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 (3H) -franone. In an inert atmosphere, in 37 minutes, at a temperature of 0-5 ° C, 37 mL of 1 M tin tetrachloride, in dichloromethane, are added to 8.8 g of the compound (4S, 5S), Desalted, obtained in step 3, in 175 mL of dichloromethane and stirred for 1 hour at this temperature. Then add 14.1 mL of acetic acid, stir 1 hour at a temperature of 0-5 ° C, pour into the water / ice mixture, wash, add cyclohexane, bring to a pH of 7-8, by the addition of sodium bicarbonate, it is extracted with cyclohexane, dried and evaporated under reduced pressure, until obtaining 3.96 g of the expected product, in the form of an oil corresponding to a cis / trans ratio of 90 / 10. NMR f CDCI3: 250 MHz) 1.29 (t) CH2CH 1.35 (d) Ctb (-NH-CH (Cíb) (ph)) 2.28 (dd, 3 = 11.5 and 17); 2.43 (dd, 3 = 8 and 17); Ctb in 3 of the furanone 3.36 (ddd, 3 = 4.5 / 8 / 11.5) CH_ in 4 of the furanone 3.67 (dq); 3.92 (dq) CtbCH3 3.81 (q) Cü (-NH-CtL (CH3) (Ph)) .79 (d, 3 = 4.5) C { ± in 5 of the furanone 7.20 to 7.40 (m) aromatic 5H Stage 5: Formation of the trichloroacetic acid salt of the tetras isomeric cis (4S, 5R) Trichloroacetate of 4 (S) [4 a (R *), 5 a] - dihydro-5-ethoxy-4- [(1-fepileti!) amino] -2 (3H) -furanone 2.34 g of ricloroacetic acid (99%) are added. %), in an inert atmosphere, at a temperature of 20-25 ° C, to 3.8 g of the d i a s t e r o s e r e cis obtained in the previous stage, in 40 μL of terbutilmethyl ether. It is left for 1 hour at a temperature of 0-5 ° C, and 5.58 g of the expected product are obtained. [a D 3 = 49 (C 0.9% C H 3 O H) Step 6: Hydrogenolysis a) from sa I ifi ca tion (return to free amine) 4 (S) [4a (R *), 5a] -dihldro-5-ethoxy-4 - [(1-phenylethyl) amino] ] -2 (3H) -furanone Mixture, at a temperature of 0-5 ° C, in an inert atmosphere, 5.41 g of the trichloroacetic salt obtained in the previous step, 50 mL of cyclohexane and 50 mL of saturated sodium bicarbonate solution, stirred until dissolved, washed, extracted, dried and evaporated under reduced pressure until 3.18 g of the desalted product is obtained, in the form of an oil. [aD] = -93 ° (c = 0.62% CH3OH) This product is purified again by mixing, for 10 minutes, 2.85 g of this product with 30 mL of cyclohexane and 2.8 g of silica. After treatment, 2.3 g of the colorless oil are recovered. b) Formation of the hydrochloride hydrochloride of 4 (S) [4 a (R *), 5 to 3-dihydro-5-e tox i-4 - [(1-phenylethyl) amino] -2 (3H) -furanone are added , dropwise, at a temperature of 0-5 ° C, 4 mL of 2N hydrochloric acid, in isopropyl ether, to 2 g of the product obtained above, in 40 mL of isopropyl ether and kept 15 minutes at this temperature. Evaporate under reduced pressure until 2.29 g of the expected hydrochloride are obtained. c) Hydrochloride (4 (S) - cis) - 4 - am - no - 5 - ethoxy - ihydro - 2 (3H) - furanone hydrochloride To a suspension of 2.29 g of the hydrochloride obtained above, in 40 mL of tetrahydrofuran, 1 mL of water is added, then 300 mg of palladium on carbon at 10%. It is stirred under a hydrogen atmosphere at 1.5 bar for 5 hours. After filtering and rinsing with the mixed mixture, it is evaporated at reduced pressure at 45 °. 1.40 g of the expected product are obtained. [aD] = -87 ° 4 (c = 1% CH3OH) 1.22 (t) CH2Ctb 2.58 (dd, 3 = 8 and 17.5); 2.70 (dd, 3 = 8 and 17.5); CH? in 3 of the furanone 4.14 (dt, 3 = 5.5 and 8); Cj ± en 4 of the furanona 3.61 to 3.90 (m) CibCH3 5.71 (d, 3 = 5.5) CH_ in 5 of the furanone 8.69 (if) 3H mobile Step 7: Formation of allyl (2R-cis) (2-ethoxy-tetrahydro-5-oxo-3-furanyl) -carbamic acid 2-propenyl carbamate is added, at a temperature of + 5 ° C, in an atmosphere inert, 1 mL of c 1 orioformate of atiil at 99%, then 2 mL of pyridine to 1.3 g of the product obtained in the previous stage, in 50 mL of dichloromethane, stir for one hour at this temperature, then add 0.3 mL of I or of allyl ormia to 0.6 mL of pyridine. It is stirred for 16 hours at room temperature, poured into water, extracted with dichloromethane, washed, dried, evaporated under reduced pressure to obtain 1.62 g of the crude product, which is recrystallized from isopropyl ether 1.34 g of the product are obtained. expected. [aDJ = -52.4 ° (c = 1% CH2Cl2) 1.26 (t) CHjCt 2.47 (dd, 3 = 10 and 17.5); 2.84 (dd, 3 = 8.5 and 17.5); CH? in 3 of the furanone 3.67 (dq) and 3.92 (dq) CJ ± 2CH3 4.55 (m) CtL in 4 of the furanone 4.59 (dl) Ctb-CH = CH2 5.45 (d, 3 = 5.5) CtL in 5 of the furanone .25 (dq) and 5.33 (dq) CH2-CH = Ctb 5.30 hidden N-H 5.93 (m) CH2-CH_ = CH2 EXAMPLE 3: dic I -acetate of 4 (S) [4 a (S *), 5 a] -dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 (3H) -furanone Step 1 : Addition of Michael 4 (R *) dihydro-5-ethoxy-4 [(1-phenylethyl) amino3-2 (3H) -furanone They are added, in about 1 hour 30 minutes, with stirring and under nitrogen, maintaining the temperature at 0 ± 2 ° C, 20 L of R (+) phenol the mine (19.06 g), to a solution of 20 g of non-racemic toxin, in 156.8 mL of isopropanol and 3.2 L of water, and stir 24 hours at this temperature. Stage 2: Double diastero and trans shallow: obtaining diasteroi, trans (4S, 5S) tr i chloroaceta to 4 (S) [4 a (S *), 5 ß] - dihyd ro - 5 -toxy- 4 - [(1-phenylethyl) amino] -2 (3H) -furanone The solution consisting of 25.55 g of trichloroacetic acid in 39.2 ml of isopropanol and 0.8 ml is added to the previous solution (the product is not isolated). of run-off water, the temperature is allowed to rise to 20-22 ° C, and the crystallization of the salt is observed after introduction. This suspension is maintained for 24 hours at a temperature of 20 ± 2 ° C, then the product is dried and washed with 2% isopropanol water. 18 g of the expected product are obtained. 1.15 (t) 0-CH2Ctb 1.75 (d, 3 = 7) Ph -CH (Ctb) - -N 2.78 (dd, 3 = 8.5 and 18.5); Ctb at 3.05 (dd, 3 = 4 and 18.5); 3.43 (ddd, 3 = 2.4 and 8.5) H4 3.59 (dq) 1H, 3.79 (dq) 1H; 0- CtbCH3 4.29 (q, 3 = 7); Ph-CH (Ctb) -N 5.77 (d, 3 = 1.5) H5 7.42 to 7.57 (5H); H aromatic 9.80 large; H mobile Step 3: epimerization: obtaining the diastereoisomer (4S, 5R) 4 (S) E4a (S *), 5a] -dihydro-5-ethoxy-4 - [(1-phenylethyl) amino] -2 (3 H) - furanone. In a nitrogen atmosphere, maintaining the temperature at 20 ± 2 ° C, 45 mL of methanic acid in a 50 g suspension of the tricarbonate (4S, 5S) are added. obtained in the previous stage, in 150 mL of toluene, maintaining a temperature of 20 ± 2 ° C for 2 hours and then lowering the temperature to 0 + 5 ° C, adding 111 μL of triethylamine in 1 hour 30 minutes. After a series of washing, extraction and drying, 400 mL of a solution containing an 85/15 mixture of the cis / trans isomer is obtained. Stage 4: Formation of the dichloroacetic acid salt of the cis (4S, 5R) diasterisomer diastereoisomer of 4 (S) [4 a (S *), 5 a] -dihydro-5-e tox-4 - [(1-phenylethyl!) amino] -2 (3H) -furanone 10 mL of dichloroacetic acid are added to 400 mL of the above solution, concentrated to 6 volumes, crystallization is observed and maintained under stirring, a temperature of 20 ± 2 ° C, for 2 hours, in a nitrogen atmosphere. After washing with toluene, 32.8 g of the expected product are obtained. 1.21 (t) 0-CH2Ctb 1.72 (d, 3 = 6.5) Ph-CH (Ctb) -N 2.77 (dd, 3 = 8.5 and 17); Ctb in 3. 2.97 (dd, 3 = 11 and 17); 3.76 (m) H4 3.34 (dq), 3.66 (dq); 0-CH2CH3 4.27 (q, 3 = 6.5); Ph-C3 (CH3) -N 4.88 (d, 3 = 5) H5 5.95 (s); CHCl2 7.42 (m) 3H, 7.51 (m) 2H; H aromatic 9.79 (if) 2H mobile It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. Compounds of the following formulas (IVa), (IVb), (IVc) or (IVd): (vat) (IVb) (IVc) (IVd) characterized in that R is an alkyl group comprising from 1 to 4 carbon atoms, or a phenylalkyl group comprising from 7 to 11 carbon atoms, as well as their addition salts with the acids.

2. The compound of the formula (IVd), characterized in that it is defined according to claim 1, as well as its addition salts with acids.

3. The compound of the formula (IVd), according to claim 2, characterized in that Rx is an ethyl group, as well as its addition salts with acids.

4. A process for the preparation of the compounds of the formulas (IVa), (IVb), (IVc) or (IVd), according to claim 1, characterized in that it comprises at least one of the following steps: a) the action of an arylamine, of the formula R3R4CHNH2, wherein R3 is a hydrogen atom or an alkyl group comprising 1 to 4 carbon atoms; and R 4 is an aryl and substituted on the racemic alkyloxyfuranone of the formula (II): in which Ri is an alkyl group comprising from 1 to 4 carbon atoms, or phenylalkyl comprising from 7 to 11 carbon atoms; and obtaining the trans isomers (4R, 5R) and (4S, 5S), respectively, of the formulas (Illa) and (Illb): (Illa) ílllb) which, afterwards: - are separated by crystallization, carrying out, if required, one or several salification reactions, or - when R3 is a hydrogen atom, they are split by the action of an optically active acid; b) if required, the epimerization reaction of the compound of the formula (Illa) or (Illb), salified or non-salified, in the presence of an acid, to obtain the cis (4, 5 S) or (4S, 5R), of the formula (lile) or (Illd), which are salified, if required, (Ule) (Ill) c) Hydrogenolysis reaction, either on the trans isomer (4R, 5R) or (4S, 5S), of the formula (Illa) or (Illb), salified or non-salified, to obtain the compound of the formula (IVa) ) or (IVb), in the form of the trans (4R, 5R) or (4S, 5S) isomer, as defined above, which, if required, is salified and / or protected, either on the cis isomer (4R) , 5S) or (4S, 5R), of the formula (lile) or (Illd), salified or non-salified, to obtain the compound of the formula (IVc) or (IVd), in the form of the cis isomer (4R, 5S ) or (4S, 5R) which, if required, is salified and / or protected.

5. The process according to claim 4, characterized in that the protection reaction of the amines of the formula (IVa), (IVb), (IVc) or (IVd), salified or non-salified, is effected by the action of the I or of ormiato, of formula CI-CO-OC H 2- R2, where R2 represents a terbutyl, alkenyl (C2-C4), alkynyl (C2-C4) or phenyl, substituted or unsubstituted radical, to obtain the compounds of the formula (la), ( Ib), (le) or (Id), respectively, in the form of the trans diastereomers (4R, 5R), (4S, 5S) or cis (4R, 5S) or (4S, 5R), which, if required, they are salified, (le) (Id)

6. The process according to claim 4, characterized in that the separation by crystallization of the compounds of the formulas (Illa) and (IHb), is carried out: a) by the action of trichloroacetic acid, to obtain the corresponding salt of the formula (Illa) or (IHb), b) then, by the action of the monochloroacetic acid, on the mother liquors, to obtain the corresponding salt of the other diastereoisomer of the formula (Illa) or (III b).

7. The process for the preparation, according to claim 4, of the compounds of the formula (IVd), according to claim 2, or of the compounds of the formula (Id), according to claim 5, characterized because it comprises at least one of the following steps: a) action of the phenylethylamine R on the compound of the formula (II), to obtain the compounds of the following formulas (Ill'a) and (III 'b): (Ill'a) (Ill'b) b) separation of the trans steroisomers, from the formulas (Ill'a) and (Ill'b), by the action of trichloroacetic acid, to obtain the stereoisomer (Ill'b) ( 4S, 5S), in the form of the trichloroacetic acid salt, then by the action of the monochloroacetic acid, to obtain the stereoisomer (Ill'a) (4R, 5R), in the form of the monochloroacetic acid salt; c) as required, return to the free amine by the action of a base; d) epimerization reaction of the stereoisomer (4S, 5S) of the formula (Ill'b), in the presence of an acid, to obtain a cis (4S, 5R) steroisomer of the formula (IH'd): e) as required, crystallization, after salification, by the action of an acid such as monochloroacetic or dichloroacetic acid; f) if required, return to the free amine by the action of a base; g) if required, recrystallization, after salification, especially in the hydrochloride form; h) Hydrogeoisis of the stream i. shallow cis (4S, 5R), of the formula (Ill'd), to obtain the compound of the formula (IVd) in the form of the cis diastereoisomer (4S, 5R); i) if required, action of the allyl chloroformate on the compound of the formula (IVd) to obtain the compound of the formula (Id) in the form of the cis diastereoisomer (4S, 5R), where R2 represents -CH = CH2.

8. The process for the preparation, according to claim 4, of the compounds of the formula (IVd), according to claim 2, or of the compounds of the formula (Id), according to claim 5, characterized because it comprises at least one of the following steps: a) action of the phenylethylamine S on the compound of the formula (II), to obtain the compounds of the following formulas (III "a) and (III" b): (III "a) (IIT" b) b) splitting of the trans steroisomers, of the formulas (III "a) and (111" b), by the action of trichloroacetic acid, to obtain the stereoisomer (III "a) ( 4R, 5R), in the form of the trichloroacetic acid salt, then by the action of monochloroacetic acid, to obtain the stereoisomer (111"b) (4S, 5S), in the form of the monochloroacetic acid salt; c) as required, of the I i f i c ation by the action of a base; d) epimerization reaction of the stereoisomer (4S, 5S), of the formula (III "b), in the presence of an acid, to obtain a cis (4S, 5R) steroisomer, of the formula (III" d): R «Q e) as required, crystallization, after salification, by the action of an acid such as monochloroacetic or dichloroacetic acid; f) if required, return to the free amine by the action of a base; g) if required, recrystallization, after salification, especially in the hydrochloride form; h) hydrogenolysis of the cis (4S, 5R) steroisomer of the formula (III "d), to obtain the compound of the formula (IVd) in the form of the cis diastereoisomer (4S, 5R): i) if required, action of the allyl chloroformate over the compound of the formula (IVd) to obtain the compound of the formula (Id) in the form of the cis diastereoisomer (4S, 5R), where R2 represents -CH = CH2.

9. The process according to any of claims 4 to 8, characterized in that the addition of the amine on the compound of the formula (II), according to claim 4, is carried out in dimethylformamide or in aqueous isopropanol.

10. The process according to any one of claims 4 to 8, characterized in that the epimerization reaction is carried out with tin tetrachloride or with a non-solid acid.

11. The process according to any of claims 4 to 8, characterized in that Ri is an ethyl radical.

12. The process according to any of claims 8 to 11, characterized in that the cleavage of the trans steroisomers with the trichloroacetic acid (step b) is carried out in aqueous isopropanol.

13. The process according to any of claims 8 to 11, characterized in that the epimerization reaction of the stearose (4S, 5S), of the formula (III "b, step d), is carried out in the presence of methanesulfonic acid in toluene .

14. The process according to any of claims 8 to 11, characterized in that the crystallization (step e) is carried out by the action of dichloroacetic acid in toluene.

15. E I u s either of the compounds of the formulas (IVa), (IVb), (IVc) or (IVd), according to claim 1, or that are obtained according to claim 4; either of the compounds of the formulas (la), (Ib), (le) or (Id), obtained by the process according to the rei indication 5, where the use is characterized because it is in the amidation reactions, to starting from the acid of the formula A -COOH, to obtain a compound of the following formula (V): where A represents an organic radical any

16. The use: either of the compounds of the formulas (IVb) or (IVd), according to claim 1, or that are obtained in accordance with claim 4; either of the compounds of the formulas (Ib) or (Id), obtained by the process according to claim 5, wherein the use is characterized in that it is in the synthesis of the compounds of the formula (V) that they have a inhibitory activity of the interleukin conversion enzyme.

17. The use: either of the compound of the formula (IVd), wherein Rx = ethyl, according to claim 3, or which is obtained from the process according to claim 7 or 8; either the compound of the formula (Id), where Rt = ethyl, obtained by the process according to claim 5, wherein the use is characterized in that it is for the preparation of the compounds of the formula (V) having an activity inhibitor of the interleukin conversion enzyme.

18. The use, according to claim 17, of the compounds of the formulas (IVd) or (Id), according to claim 17, wherein the use is characterized in that it is for the preparation of the compound of the formula ( V) that has the following structure:

19. The compounds of the formulas (Illa), (Illb), (lile), (Illd), as novel intermediate compounds, as well as their addition salts with acids, with the exception of the compounds of the formulas (III "a) and ( III "b), according to claim 8, wherein Ri = methyl.