Title of Invention

"PROCESS FOR THE PREPARATION OF AMINATED ALKYLOXFURANONE COMPOUNDS"

Abstract

The present invention relates to the process for the preparation of aminated alkyloxyfuranone compounds of formula (IVa), (IVb), (IVc) or (IVd), characterized in that the said process includes at least one of the following stages: a) the action of an arylamine of formula R3R4 CHNH2 wherein R3 is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms and R4 is an optionally substituted aryl, on the racemic alkyloxyfuranone of formula (II), and obtaining the trans (4R,5R) and (4S,5S) isomer compounds of formulae (IIIa) and (IIIb) respectively; which are then separated by crystallization by carrying out, if appropriate, one or more salification reactions, -or, when R3 is a hydrogen atom, resolved by the action of an optically active acid, b) if appropriate, an epimerization reaction of the compound of formula (IIIa) or (IIIb), salified or non salified, in the presence an acid, in order to obtain the cis (4R,5S) or (4S, 5R) isomer compounds of formula (IIIc) or (IIId), which if appropriate are salified, e) hydrogenolysis reaction, either on the trans (4R, 5R) or (4S, 5S) isomer of formula (IIIa) or (IIIb), salified or non salified, in order to obtain the compound of formula (IVa) or (IVb) in the form of the trans (4R, 5R) or (4S, 5S) isomer, which if appropriate is salified and/or protected, -or on the cis (4R, 5S) or (4S, 5R) isomer of formula (IIIc) or (IIId), salified or non salified, in order to obtain the compound of formula (IVc) or (IVd) in the from of the cis (4R, 5S) or (4S, 5R) isomer, which if appropriate is salified, and/or protected.

Full Text

The present invention relates to the process for the preparation of aminated alkyloxyfuranone compounds. A subject of the invention is a new preparation process for aminated derivatives of alkyloxyfuranone, the compounds originating from this process and the use of these compounds in the synthesis of inhibitors of the conversion enzyme of interleukin-lbeta. Patent Applications WO9535308, W09722619, W09722618, EP519748, WO9633209 describe compounds which inhibit the conversion enzyme of interleukin-lbeta. The preparation process for some of the compounds described in the Applications mentioned above use the following compounds of formula (I): (Formula Removed) in which R1 represents an ethyl radical and R2 represents a -CH=CH2 radical. The compounds of formula (I) are prepared from protected L-aspartic acid and require 4 synthesis stages: 1) acylation, 2) reduction, 3) oxidation, 4) cyclization, (Chapman K. T. et al Eoorg. Med. Chem. Lett.. 2. (6), 613-8 (1992)). This process has significant disadvantages, in particular in the case where one wishes to obtain the chiral compounds of formula (I). In fact, an expensive chiral starting reagent must be used: L-aspartic acid p-tert-butylester, and above all chromatographic methods must be used to isolate and/or to purify the different dias te reois ome rs . Therefore a subject of the invention is to find another synthesis route for the compounds of formula (I), which avoids starting with this starting product and which does not require separations by chromatography. The Applicant therefore proposes a new synthesis route, starting with the alkyloxyfuranone of formula (II), in racemic form, allowing access to new compounds of formulae (IVa), (IVb), (IVc) or (IVd) as defined below, salified or non salified, which are subsequently, if appropriate protected, in order to obtain in particular the compounds of formula (I). This process has the advantage of being able to be implemented on a large scale, starting from a compound of formula (II), which is easily accessible and inexpensive, with separation and/or purification stages carried out by crystallization and not by chromatography. Each diastereoisomer of formula (III), (IV) or (I) can therefore be isolated. Therefore a subject of the invention is on the one hand the following compounds of formula (IVa), (IVb), (IVc) or (IVd): (Figure Removed) in which R^ is an alkyl group containing 1 to 4 carbon atoms or a phenylalkyl group containing 7 to 11 carbon atoms, as well as their addition salts with acids. The invention naturally extends to the salts of the compounds of formula (IVa), (IVb), (IVc) or (IVd), such as for example the salts formed with mineral or organic acids on the amine. These can then be the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonics such as methane or ethane sulphonics, arylsulphonics, such as benzene or paratoluene sulphonics and arylcarboxylics. They can also be chloroacetic or trichloroacetic acids. Quite particularly it is the salts formed with hydrochloric acid. When % is an alkyl group containing 1 to 4 carbon atoms, it is in particular methyl, ethyl, butyl or propyl, and quite particularly ethyl. B/ phenylalkyl, is preferably meant the benzyl group. A more particular subject of the invention is the compound of formula (IVd) as defined previously, as well as its addition salts with acids. A quite particular subject of the invention is the compound of formula (IVd) in which % is an ethyl group, as well as its addition salts with acids. On the other hand a subject of the invention is a preparation process for the compounds of formula (IVa), (IVb), (IVc) or (IVd) as described above, characterized in that it comprises at least one of the following stages: a) the action of an arylamine of formula R3R4CHNH2 in which R3 is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms and P^ is an optionally substituted aryl, on the racemic alkyloxyfuranone of formula (II): (Figure Removed) in which R^ is an alkyl group containing 1 to 4 carbon atoms, or phenylalkyl containing 7 to 11 carbon atoms, and obtaining the trans (4R/5R) and (4S/5S) isomeric compounds of formulae (Ilia) and (Illb) respectively: (Figure Removed) which then -are separated by crystallization by carrying out, if appropriate, one or more salification reactions, -or, when R3 is a hydrogen atom, resolved by the action of an optically active acid, b) if appropriate, an epime ri zation reaction of the compound of formula (Ilia) or (Illb), salified or non salified, in the presence of an acid, in order to obtain the cis (4R,5S) or (4S,5R) isomeric compounds of formula (IIIc) or (II Id), which if appropriate are salified, (Figure Removed) c) hydrogenolysis reaction, - either on the trans (4 R, 5 R) or (4S,5S) isomer of formula (Ilia) or (Illb), salified or non salified, in order to obtain the compound of formula (IVa) or (IVb) in the form of the trans ( 4 R, 5 R) or ( 4 S, 5 S) isomer as defined previously, which if appropriate is salified and/or protected, - or on the cis (4 R, 5 S) or (4 S, 5 R) isomer of formula (IIIc) or (Ilid), salified or non salified, in order to obtain the compound of formula (IVc) or (IVd) in the form of the cis (4R,5S) or (4S,5R) isomer, as defined previously, which if appropriate is salified, and/or protected. In particular the protection reaction of the amines of formula (IVa), (IVb), (IVc) or (IVd), salified or non salified, is carried out by the action of the chloroformate of formula Cl-CO-0-CH2- &2' % representing a terbutyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl or phenyl radical, substituted or non substituted, in order to obtain the compounds of formula (la), (Ib), (Ic) or (Id), respectively in the form of the trans (4R,5R), (4S,5S) or cis (4R,5S), (4 S, 5 R) diastereoisomers, which if appropriate are salified, (Figure Removed) The action of the arylamine of formula R3R4CHNH2 on the racemic alkyloxyfuranone of formula (II) is carried out according to standard methods required by Michael's reaction, namely, in particular, in a dipolar aprotic solvent such as dimethylformamide at ambient temperature. The operation can also be carried out with R or S phenylethylamine or in aqueous isopropanol. The separation of the two trans (4R,5R) and (4S,5S) isomers, namely the compounds of formulae (Ilia) and (Illb) respectively by crystallization is carried out according to methods known to a person skilled in the art concerning the separation of isomers. B/ way of preferred example the separation is carried out by the action of trichloroacetic acid in a solvent such as terbutylmethylether or aqueous isopropanol. The trans (4R,5R) isomer (Ilia) is crystallized in the form of the salt of t richloroacetic acid, while the trans (4S,5S) isomer (Illb) is recovered in the form of the salt of monochloroacetic acid by treatment of the mother liquors in the presence of monochloroacetic acid. When R3 is a hydrogen atom (non-chiral amine) the separation (resolution) is then carried out by means of a chi ral acid such as tartaric/ camphos ulphoni c, salicylic, dibenzoyltartaric or R+ 2, 4-hyd roxyphenoxyp ropi onic acid. The epimeri zation reaction on one of the (4R, 5 R) or (4S,5S) isomers of formula (Ilia) or (Illb) is carried out in the presence of a Lewis acid such as ferric chloride, titanium tetrachloride optionally complexed with tetrahydrofuran, boron trichloride, the etherate of boron tri fluoride and tin tetrachloride or an organic acid such as methane sulphonic acid, tri f luoroacetic acid and paratoluenesulphonic acid. Preferably it is tin tetrachloride, in the presence of a slightly polar solvent such as dichloromethane, or methanes ulphoni c acid in a solvant such as toluene. The hydrogenolysis reaction on the cis or trans dias tereoisomer of formula (Ilia), (Illb), (IIIc) or (Hid), is carried out according to standard methods known to a person 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 chloroformate is preferably carried out in the presence of a base such as pyridine, in a slightly polar solvent such as dichloromethane. The formation of the base from the corresponding salt, i.e. return to the free amine, as well as salification methods with acids as defined previously is carried out according to methods known to a person skilled in the art. As regards the compounds of formula (III) when R^ is an alkyl group containing 1 to 4 carbon atoms, it is preferably methyl or ethyl and when R^ is an aryl group, it is preferably phenyl or naphthyl. As regards the compounds of formula (I), when R> is a (C2-C4) alkenyl or (C2-C4) alkynyl group, it is preferably -CH=CH2,-OCH, -CH-CH2-CH3' -OC-CH3. The protection reactions of the compounds of formula (I) are carried out according to methods known to a person skilled in the art and in particular with reference to the work of Philip J. Kociensky Protecting Groups Ed. Georg. Thieme Verlog Stuttgart New-York 1994. A more particular subject of the present invention is the process as defined previously, characterized in that the separation by crystallization of the compounds of formulae (Ilia) and (Illb) is carried out: a) by the action of trichloroacetic acid, in order to obtain the corresponding salt of formula (Ilia) or (Illb), b) then by the action of monochloroacetic acid on the mother liquors in order to obtain the salt corresponding to the other dias tereoisomer of formula (Ilia) or (Illb). A quite particular subject of the present invention is a preparation process as described previously for the compounds of formula (IVd) or (Id) as defined previously, characterized in that it comprises at least one of the following stages: a) the action of S phenylethylamine on the compound of formula (II), in order to obtain the following compounds of formulae (III1 a) and (Ill'b): (Figure Removed) separation of the trans stereoisomers of formulae (III1 a) and (Ill'b) by the action of trichloroacetic acid in order to obtain the (4R,5R) stereoisomer (III1 a) in the form of the salt of trichloroacetic acid then by the action of monochloroacetic acid in order to obtain the (4S,5S) stereoisomer (Ill'b) in the form of the salt of monochloroacetic acid, b) if appropriate return to the free amine by the action of a bas e, c) epimeri zation reaction of the (4 S, 5 S) stereoisomer of formula (Ill'b) in the presence of an acid in order to obtain a cis (4S, 5 R) stereoisomer of formula (IlI'd): d) (Figure Removed) e) if appropriate crystallization after salification by the action of an acid such as monochloroacetic or dichloroacetic acid, f) if appropriate return to the free amine by the action of a base, g) if appropriate recrystallization after salification in particular in the form of the hydrochloride, h) hydrogenolysis of the cis (4S/5R) stereoisomer of formula (IlI'd), in order to obtain the compound of formula (IVd) in the form of the cis (4S/5R) diastereoisomer, i) if appropriate to the action of an allyl chloroformate on the compound of formula (IVd) in order to obtain the compound of formula (Id) in the form of the cis (4S/5R) dias tereoisomer, with R-|_ representing -CH=CH2. A quite particular a subject of the present invention is also a preparation process as described previously for the compounds of formula (IVd) or (Id) as defined previously, characterized in that it comprises at least one of the following stages: a) the action of R phenylethylamine on the compound of formula (II), in order to obtain the following compounds of formulae (III"a) and (III"b): ((Figure Removed) resolution of the trans stereoisomers of formulae (III"a) and (III"b) by the action of trichloroacetic acid in order to obtain the (4S,5S) stereoisomer (III"b) in the form of the salt of trichloroacetic acid then by the action of mono- chloroacetic acid in order to obtain the (4 R, 5 R) stereoisomer (III"a) in the form of the salt of monochloroacetic acid, b) if appropriate return to the free amine by the action of a base, c) epimerization reaction of the (4S,5S) stereoisomer of formula (III"b) in the presence of an acid in order to obtain a cis (4S,5R) diastereoisomer of formula (III"d): (Figure Removed) e) if appropriate crystallization after salification by the action of an acid such as monochloroacetic or dichloroacetic acid, f) if appropriate return to the free amine by the action of a has e, g) if appropriate recrys talli zation after salification in particular in the form of the hydrochloride, h) hydrogenolysis of the cis (4S, 5 R) stereoisomer of formula (III"d), in order to obtain the compound of formula (IVd) in the form of cis (4S,5R) stereoisomer, i) if appropriate to the action of an allyl chloroformate on the compound of formula (IVd) in order to obtain the compound of formula (Id) in the form of the cis (4 S, 5 R) dias tereoisomer. A quite particular subject of the invention is the process as defined previously characterized in that the addition of the amine on the compound of formula (II) is carried out in dimethylformamide or in aqueous isopropanol. A quite particular subject of the invention is the process as defined previously characterized in that the epimeri zation reaction is carried out with tin tet rachloride or me thanes ulphonic acid. A quite particular subject of the invention is the process as defined previously characterized in that R^ is an ethyl radical. A quite particular subject of the invention is the process as defined previously characterized in that the separation of the trans s tereoisomers with trichloroacetic acid (stage b) is carried out in aqueous isopropanol. A quite particular subject of the invention is the process using (R) phenylethylamine characterized in that the epimeri zation reaction of the (4S/5S) stereoisomer of formula (III"b) (stage d) is carried out in the presence of methanes ulphonic acid in toluene. A quite particular subject of the invention is the process using ( R) phenylethylamine characterized in that the crystallization (stage e) is carried out by the action of dichloroacetic acid in toluene. A subject of the invention is also the use: either of the compounds of formula (IVa), (IVb), (IVc) or (IVd) as defined previously or originating from the process as described previously, or of the compounds of formula (la), (Ib), (Ic) or (Id) originating from the process as described previously in the amidification reactions starting from the acid of formula A-COOH in order to obtain the following compound of formula (V): (Figure Removed) A representing any organic radical. A subject of the invention is also the use: either of the compounds of formula (IVb) or (IVd) as defined previously or originating from the process as described previously, ox of the compounds of formula (Ib) or (Id) originating from the process as defined previously in the synthesis of the compounds of formula (V) having an inhibitory activity on the conversion enzyme of interleukin. These compounds of formula (V) are in particular described in the Patent Applications W09535308, W09722619, EP0519748 and W09633209. A quite particular subject of the invention is the use: either of the compound of formula (IVd) with Rj_ = ethyl as defined previously or originating from the process as described previously, or of the compound of formula (Id) with Rj_ = ethyl originating from the process as described previously in the preparation of a compound of formula (V) having an inhibitory activity on the conversion enzyme of interleukin. A quite particular subject of the invention is the use: ei ther of the compound of formula (IVd) with % = ethyl as defined previously or originating from the process as described previously, or of the compound of formula (Id) with RQ_ = ethyl originating from the process as described previously in the preparation of the compound of formula (V) having the following structure: O (Figure Removed) This compound being described in Patent Application W09722619 (Pdt 412e). A subject of the invention is also the compounds of formulae (Ilia), (Illb), (IIIc), (Hid) , as well as their addition salts with acids as described above, as new intermediate compounds, with the exception of the compounds of formulae (III"a) and (III"b) with % - methyl. The compounds of formula (II) are known or are easily accessible from methoxyfuranone by the action of PTSA (paratoluene sulphonic acid), in the presence of water then of a reagent of. formula (R10)3CH in the presence of an acidic catalys t. The following examples illustrate the invention without however limiting it. EXAMPLE 1: 2-propenyl (2R-cis) (2-ethoxy-tetrahydro-5-oxo-3- furanyl)-carbamate Stage 1: Michael addition 4(R*) dihydro-5-ethoxy-4[ (1-phenylethyl) amino]-2 (3H) -) furanone 15 ml of 98% R( + ) phenylethylamine is added over 30 minutes at between 23 and 25°C, under an inert atmosphere to 15 g of racemic ethoxy furanone in 75 ml of di methyl fo rmami de, the solution obtained is agitated for 24 hours then poured into a water/ice mixture. Isopropyl ether is added, followed by extraction, washing, drying and evaporating under reduced pressure until 27 g of an oil is obtained corresponding to the expected 50/50 mixture of trans isome rs. i NMR (CDC13; 250 HZ) 1.12; 1.22 (t) CH2CH3 1.37 (dd) CH3 (-NH-CH(CH3) (Ph)) 2. 13 (dd, J=3.5 and 17.5); 2.35 (dd, J=3 and 17.5); CH2 in position 3 of the furanone. 2. 70 (dd, J = 7.5 and 17.5); 2. 80 (dd, J = 7 and 17.5) 3.26 (m) CH in position 4 of the furanone 3. 30 to 3. 90 (m) CH2CH3 3.82 (m) CH (-NH-CH(CH3) (Ph)) 5.00 (d, J=1.5) and 5.32 (d, J=1.5) CH in position 5 of the furanone 7.2 to 7.4 (m) aromatic 5H Stage 2: Resolution of the two trans dias tereoisomers A) obtaining the trans (4S,5S) trichloroacetate diastereoisomer of 4(S)[4p(S*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone A solution of 10. 6 g of trichloroacetic acid (99,5 %) in 50 ml of methylterbutylether is added over 20 minutes to 27 g of the mixture of dias tereoisomers obtained in the preceding stage in 164 ml of methylterbutylether. The solution obtained is agitated for 2 hours at 20-25°C then for 2 hours at 0-5°C. 12 g of the (4S,5S) isomer is obtained in the form of a salt of trichloroacetic acid. I" pD] = + 71° (c = 1 % CH3OH) 250MHz; NMR (CDC1- 1.15 (t) 1.75 (d, J=7) 2. 78 (dd, J=8.5 and 18.5 3. 05 (dd, J=4 and 18.5); CH3 (-NH-CH(CH3) (Ph) CH2 in position 3 of the 3.43 (ddd, J=2-4 and 8.5) 3.59 (dq 1H) 3. 79 (dq 1H) 4.29 (q, J=7)) 5.77 (d, J=1.5) 7. 42 to 7.57 9.80 (wide) furanone. CH in position 4 of the furanone CH2CH3 (-NH-CH(CH3) (Ph)) CH in position 5 of the furanone aromatic 5H mobile H B) Obtaining the trans (4R,5R) chloroacetate diastereoisomer of 4(R) [4p(R*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl) amino]-2(3H)-furanone The mother liquors of the preceding stage are washed with a saturated solution of sodium bicarbonate then with water, then reextracted once with isopropyl ether. After drying, evaporation is carried out under reduced pressure until 15.45 g of the expected product is obtained in the form of an oil. 5 g monochloroacetic acid is added to 15. 45 g of the product in 130 ml of isopropanol, and the reaction medium is heated to 40°C. Dissolution then crystallization is observed, then agitation is carried out for 1 hour at ambient temperature then for 2 hours at 0-5°C. 11.98 g of the expected (4R,5R) isomer is obtained in the form of the salt of monochloroacetic acid. Stage 3: obtaining the desalified (4 S, 5 S) compound 4(S) [4p(S*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]- 2(3H)-furanone 11.8 g of the salt obtained in Stage 2A is mixed at ambient temperature with 120 ml of dichloromethane then 100 ml of a saturated solution of sodium bicarbonate is added. Agitation is carried out for 10 minutes, followed by extraction, washing, drying and evaporation under reduced pressure until 7.1 g of desalified product is obtained. [ pD] = +114° (c = 1 % CH3OH) Stage 4: epimeri zation: obtaining the (4S/5R) dias tereoisomer 4 (S) [4p(S*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone 28.6 ml of 1M tin tetrachloride in di chloromethane is added under an inert atmosphere over 1 hour at 4 ± 1°C to 6.8 g of the (4S,5S) desalified compound obtained in Stage 3 in 135 ml of dichloromethane and agitation is carried out for 40 minutes at this temperature. Then 11 ml of acetic acid is added, followed by agitation for 30 minutes at 5°C, pouring into a water/ice mixture, washing, adding cyclohexane, adjusting to pH 7-8 by the addition of sodium bicarbonate, extracting with cyclohexane, drying and evaporating under reduced pressure until 4.39 g of the expected product is obtained in the form of an oil corresponding to a 90/10 cis/trans ratio. [ pD] = -1°5 (c = 1% CH3OH) NMR (CDC13; 250 MHz) 1.23 (t) CH2CH3 1.40 (d, J=6.5) CH3 (-NH-CH(CH3) (Ph)) 2. 39 (dd, J=ll and 17); 2.61 (dd, J=Q and 17); CH2 in position 3 of the furanone. 3.32 (m) CH in position 4 of the furanone 3.77 (m) CH (-NH-CH(CH3) (Ph)) 4.96 (d, J=5) CH in position 5 of the furanone 7.20 to 7.40 (m) aromatic 5H Stage 5: formation of the salt of monochloroacetic acid of the cis (4S,5R) dias tereoisomer 4 (S) [4b(S*> ,5p]-dihydro-5-ethoxy-4-[ (1 -pheny 1 ethyl) ami no] -2(3H)-furanone chloroacetate 1.82 g of monochloroacetic acid (96%), is added under an inert atmosphere, at 20-25°C to 5 g of the cis diastereoisomer obtained in the preceding stage in 50 ml of terbutylmethylether. A solution is obtained which crystallizes rapidly and is left for 1 hour 30 minutes at +5°C. 5.75 g of the expected product is obtained. M.p. = 106-108°C [ pD] - -11 °5 (c = 1% CH3OH) Stage 6: hydrogenolysis a) Desalification (return to the free amine) 4 (S) [4p(S*) ,5b]-dihydro-5-ethoxy-4-[ (1-phenylethyl)amino]-2(3H)-furanone 5.55 g of the monochloroacetic salt obtained in the preceding stage, 60 ml of dichioromethane and 55 ml of sodium bicarbonate are mixed together at 0-5°C, under an inert atmosphere, followed by agitation for 10 minutes, washing, extracting, drying and evaporating under reduced pressure until 3.95 g of desalified product is obtained in the form of an oil. b) Formation of the hydrochloride 4 (S) [4b(S*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone hydrochloride 6. 6 ml of 2N hydrochloric acid in isopropyl ether is added dropwise at 0-5°C to 3.36 g of the product obtained previously in 66 ml of isopropyl ether and the reaction medium is maintained at this temperature for one hour. Crystallization is observed. 3.77 g of expected hydrochloride is obtained. c) Hydrogenolysis (4(S)-cis)-4-amino-5-ethoxy-dihydro-2(3H)-furanone hydrochloride 1.8 ml of water is added to a suspension of 4 g of the hydrochloride obtained previously in 60 ml of tetrahydrofuran in order to obtain a solution then 400 mg of palladium on carbon at 10% is added. Agitation is carried out under 1.5 bar of hydrogen for 18 hours at 27-28°C. After filtration and rinsing with a tet rahydrofuran/wate r mixture, evaporation is carried out under reduced pressure. 2.54 g of expected product is obtained. [ pD] = -96° (c = 1% CH3OH) 1.22 (t) CH2CH3 2.58 (dd, J=8 and 17.5); 2.70 (dd, J=8 and 17.5); CH2 in position 3 of the furanone. 4.14 (dt, J=5.5 and 8) CH in position 4 of the furanone 3.61; 3.90 (m) CH2CH3 5.71 (d, J=5.5) CH in position 5 of the furanone 8. 69 (ws ) mobile 3H' s Stage 7: Formation of allyl carbamate 2-propenyl (2R-cis) (2-ethoxy-tetrahydro-5-oxo-3-furanyl)-carbamate 3 ml of pyridine is added at +5°C, under inert atmosphere to a mixture constituted by 2.4 g of the product obtained in the preceding stage, 50 ml of dichloromethane and 1.55 ml of allyl chloroformate, agitation is carried out for one hour at this temperature then 0.56 ml of allyl chloroformate and 1 ml of pyridine are added. Agitation is carried out for 6 hours at ambient temperature and the reaction medium is poured into water, followed by extraction with dichloromethane, washing, drying, evaporating under reduced pressure until 2.66 g of crude product is obtained which is recrys talli zed from isopropyl ether. 1.95 g of pure expected product is obtained. [ pD] = -56° (c = 1% CH2C12) 1.26 (t) CH2 CH3 2. 47 (dd, J=10 and 17.5); 2.84 (dd, J=8.5 and 17.5); CH2 in position 3 of the furanone 3.67 (dq) and 3.92 (dq) CH2CH3 4.55 (m) CH in position 4 of the furanone 4.59 (wd) CH2-CH=CH2 5.45 (d, J=5.5) CH in position 5 of the furanone 5.25 (dq) and 5. 33 (dq) CH2-CH=CH2 5. 30 masked N-H 5.93 (m) CH2-CH=CH2 EXAMPLE 2: 2-propenyl (2R-cis) (2-ethoxy-tetrahydro-5-oxo-3-furanyl)-carbamate Stage 1: Michael addition 4(S*) dihydro-5-ethoxy-4 [(1-phenylethyl)amino]-2(3H)-furanone 15 ml of 98% S(-)phenylethylamine is added over 30 minutes at between 23 and 25 °C, under inert atmosphere to 15 g of racemic ethoxyfuranone in 75 ml of dimethylformamide, the solution obtained is agitated for 24 hours then poured into a water/ice mixture. After extraction with cyclohexane, washing and drying, evaporation is carried out under reduced pressure until 26. 6 g of an oil is obtained corresponding to the expected 45/55 mixture of trans isomers. NMR (CDC13; 250 MHZ) 1.12 (t); 1.22 (t) CH2CH3 1.37 (dd) CH3 (-NH-CH(CH3) (Ph) ) 2. 13 (dd, J=3.5 and 17.5); 2.35 (dd, J=3 and 127.5); CH2 in position 3 of the furanone 2. 70 (dd, J = 7.5 and 17.5); 2. 80 (dd, J - 7 and 17.5) 3.26 (m) 3. 30 to 3. 90 (m) 3. 82 (m) CH in position 4 of the furanone CH2CH3 CH (-NH-CH (CH3) (Ph)) 5.00 (d, J=1.5) and 5.32 (d, J=1.5) CH in position 5 of the furanone 7.2 to 7.4 (m) aromatic 5H Stage 2: Resolution of the two trans diastereoisomers a) obtaining the trans (4R,5R) diastereoisomer trichloroacetate of 4(R)[4b(S*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone A solution of 10.24 g of t richloroacetic acid (99.5%) in 50 ml of terbutylether is added over 30 minutes to 26 g of the mixture of the preceding stage in 155 ml of terbutylether. The solution obtained is agitated for 2 hours at 20-25°C then for 2 hours at 5°C. 12.63 g of the (4R,5R) isomer is obtained in the form of the salt of trichloroacetic acid. [pD] = -72°5 (c - 1% CH3OH) NMR (CDC13; 250 MHZ) 1.15 (t) 1.75 (d, J=7) 2. 78 (dd, J=8.5 and 18.5); 3. 05 (dd, J=4 and 18.5); 3.43 (ddd, J=2-4 and 8.5) 3.59 (dq 1H) 3. 79 (dq 1H) 4.29 (q, J=7) 5.77 (d, J=1.5) 7. 42 to 7.57 9. 80 (m wide) CH2 CH3 CH3) CH3 (-NH- CH CH2 in position 3 of the furanone CH in position 4 of the furanone CH2 CH3 (-NH-CH(CH3) (Ph)) CH in position 5 of the furanone aromatic 5H mobile H b) obtaining the trans (4S,5S) diastereoisomer chloroacetate of 4(S)[4p(R*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone CH2CH3 CH3 (-NH- CH ( CH3 i !Ph) The mother liquors of the preceding stage are washed with a saturated solution of sodium bicarbonate, then reextracted with terbutylether. After drying, evaporation is carried out under reduced pressure until 17.43 g of expected product is obtained in the form of an oil. 130 ml of isopropanol then 5 g monochloroacetic acid are added and the reaction medium is heated to 40°C. Dissolution then crystallization is observed, then agitation is carried out for 1 hour at ambient temperature then for 2 hours at 0-5 °C. 12.48 g of the expected (4S,5S) isomer is obtained in the form of the salt of monochloroacetic acid. [ pD] = +1° (c - 1% CH3OH) NMR (CDC13; 250 MHZ) 1.12 (t, J=7.5) 1.26 (d, J=6.5) 2. 18 (dd, J=2.5 and 17.5); 2. 66 (dd, J=7. 5 and 17.5); CH2 in position 3 of the furanone 2.95 (ddd, J=l-2.5 and 7.5) 3. 66 (m) 3.87 (q, J=6.5) 5.42 (d, J=l) 7.24 (m) 1H, 7.33 (m) 4H 4.26 (s) CH in position 4 of the furanone CH2 CH3 CH (-NH-CH(CH3) (Ph) ) CH in position 5 of the furanone aromatic H X-CH2 Stage 3: obtaining the desalified (4S,5S) compound 4(S)[4p(R*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone 12.35 g of the salt obtained in Stage 2B and 130 ml of dichloromethane are mixed together at 0-5°C, then 100 ml of a saturated solution of sodium bicarbonate is added. Agitation is carried out for 10 minutes, followed by extraction, washing, drying and evaporating under reduced pressure until 8.9 g of the desalified product is obtained. [ pD] = -6. 6° (c = 1 % CH3OH) Stage 4: epimeri zation: obtaining the (4S,5R) dias tereoisomer 4 (S) [4b(R*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]- 2(3H)-furanone 31 ml of 1M tin tet rachloride in di chlo romethane is added under an inert atmosphere over 45 minutes at 0-5°C to 8.8 g of the desalified (4S,5S) compound obtained in Stage 3 in 175 ml of dichloromethane and agitation is carried out for 1 hour at this temperature. Then 14.1 ml of acetic acid is added, the reaction medium is agitated for 1 hour at 0-5°C and poured into a water/ice mixture, followed by washing, cyclohexane is added, the pH is adjusted to 7-8 by the addition of sodium bicarbonate, extraction is carried out with cyclohexane, followed by drying and evaporating under reduced pressure until 3.96 g of expected product is obtained in the form of an oil corresponding to a 90/10 cis/trans ratio. NMR (CDC13 250 MHZ) 1.29 (t) CH2CH3 1.35 (d) CH3 (-NH-CH(CH3) (Ph) ) 2.28 (dd, J=11.5 and 17); 2.43 (dd, J=8 and 17); CH2 in position 3 of the furanone. 3.36 (ddd, J=4.5/8/11.5) CH in position 4 of the furanone 3.67 (dq); 3.92 (dq) CH2CH3 3.81 (q) CH (-NH-CH(CH3) (Ph)) 5. 79 (d, J=4. 5 ) CH in position 5 of the furanone 7.20 to 7.40 (m) aromatic 5H Stage 5: formation of the trichloroacetic acid salt of the cis (4 S, 5 R) dias tereoisomer Trichloroacetate of 4 (S) [4p (R*) ,5p] -dihydro-5-ethoxy-4- [ (1-phenyl ethyl) ami no] -2 (3H) -furanone 2.34 g of trichloroacetic acid (99%) is added under an inert atmosphere, at 20-25°C to 3. 8 g of the cis diastereoisomer obtained in the preceding stage in 40 ml of terbutylmethylether. The reaction medium is left for 1 hour at 0-5°C and 5.58 g of the expected product is obtained. [ pD] = -49° (c - 0. 9% CH3OH) Stage 6: hydrogenolysis a) desalification (return to the free amine) 4 (S) [4p(R*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2 (3H)-furanone 5.41 g of the trichloroacetic salt obtained in the preceding stage, 50 ml of cyclohexane and 50 ml of a saturated solution of sodium bicarbonate are mixed together, under an inert atmosphere at 0-5 °C, the reaction medium is agitated until dissolution, followed by washing, extracting, drying and evaporating under reduced pressure until 3.18 g of desalified product is obtained in the form of an oil. [pD] = -93° (c = 0.62% CH3OH) This product is repurified 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 a colourless oil is collected. b) formation of the hydrochloride 4 (S) [4p(R*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2 (3H)-furanone hydrochloride 4 ml of 2N hydrochloric acid in isopropyl ether is added dropwise at 0-5°C to 2 g of the product obtained previously in 40 ml of isopropyl ether and the reaction medium is maintained for 15 minutes at this temperature. Evaporation under reduced pressure is carried out until 2.29 g of the expected hydrochloride is obtained. c) hydrogenolysis (4(S)-cis)-4-amino-5-ethoxy-dihydro-2(3H)-furanone hydrochloride 1 ml of water, then 300 mg of 10% palladium on carbon are added to a suspension of 2.29 g of the hydrochloride obtained previously in 40 ml of tetrahydrofuran. Agitation is carried out for 5 hours under 1.5 bar of hydrogen. After filtration and rinsing with a tetrahydrofuran/water mixture, evaporation is carried out under reduced pressure at 45°C. 1. 40 g of expected product is obtained. [ bD] = -87°4 (c=l% CH3OH) 1.22 (t) CH2CH3 2.58 (dd, J=8 and 17.5); 2.70 (dd, J=8 and 17.5); CH2 in position 3 of the furanone 4.14 (dt, J=5.5 and 8) CH in position 4 of the furanone 3. 61 to 3. 9 (m) CH2CH3 5.71 (d, J=5.5) CH in position 5 of the furanone 8. 69 (si) mobile 3H1 s Stage 7: Formation of the allyl carbamate 2-propenyl (2R-cis) (2-ethoxy-tetrahydro-5-oxo-3-furanyl)-carbamate 1 ml of 99% allyl chloroformate then 2 ml of pyridine are added at +5°C, under an inert atmosphere to 1.3 g of the product obtained in the preceding stage in 50 ml of dichloromethane, agitation is carried out for one hour 40 minutes at this temperature then 0.3 ml of allyl chloroformate and 0.6 ml of pyridine are added. Agitation is carried out for 16 hours at ambient temperature, the reaction medium is poured into water, followed by extracting with dichloromethane, washing, drying, evaporating under reduced pressure until 1.62 g of crude product is obtained which is recrys tallis ed from isopropyl ether. 1.34 g of expected product is obtained. [pD] - -52. 4° (c=l% CH2C12) 1.26 (t) CH2CH3 2. 47 (dd, J=10 and 17.5); 2.84 (dd, J=8.5 and 17.5); CH2 in position 3 of the furanone 3. 67 (dq) and 3. 92 (dq) CH2CH3 4.55 (m) CH in position 4 of the furanone 4.59 (dl) CH2-CH=CH2 5.45 (d, J=5.5) CH in position 5 of the furanone 5.25 (dq) and (5.33 (dq) CH2-CH=CH2 5.30 masked N-H 5.93 (m) CH2-CH=CH2 EXAMPLE 3: 4(S)[4p(S*),5b]-dihydro-5-ethoxy-4-[(1-phenylethyl) amino]-2(3H)-furanone dichloroacetate Stage 1: Michael addition 4(R*) dihydro-5~ethoxy-4 [ (1-phenylethyl) amino] -2 (3H) -furanone 20 ml of R( + ) -1-phenylethylamine (19.06 g) is added over about 1 hour 30 minutes under agitation and a nitrogen atmosphere while maintaining a temperature of 0±2°C to a solution of 20 g of racemic ethoxyfuranone in 156.8 ml of isopropanol and 3.2 ml of water and the reaction is agitated for 24 hours at this temperature. Stage 2: Resolution of the two trans diastereoisomers: obtaining the trans (4S/5S) diastereoisomer 4(S)[4p(S*),5b]-dihydro-5-ethoxy-4-C(1-phenylethyl)amino]-2(3H)-furanone trichloroacetate A solution composed of 25.55 g of trichloroacetic acid in 39.2 ml of isopropanol and 0.8 ml of demineralized water is added to the preceding solution (the product is not isolated), the temperature is allowed to rise to 20-22°C, and crystallization of the salt is observed after introduction is completed. This suspension is maintained at 20±2°C for 24 hours, then the product is separated and washed with isopropanol with 2% water. 18 g of expected product is obtained. 1. 15 (t) 0-CH2-CH3 1.75 (d, J=7) Ph-CH(CH3)-N 2.78 (dd, J=8.5 and 18.5); CH2 in position 3 3. 05 (dd, J=4 and 18.5); 3.43 (ddd, J=2. 4 and 8.5); H4 3.59 (dq) 1H, 3.79 (dq) 1H; 0-CH2-CH3 4.29 (q, J=7); Ph-CH(CH3)-N 5.77 (d, J=1.5); H5 7.42 to 7.57 (5H); aromatic H's 9. 80 wide; mobile H. Stage 3: epime ri zation: obtaining the ( 4 S, 5 R) di as tereoisomer 4 (S) [4p(S*),5b]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]- 2(3H)-furanone 45 ml of methanesulphonic acid is added, under a nitrogen atmosphere, while maintaining the temperature at 20±2°C, to a suspension of 50 g of the (4S,5S) trichloroacetate obtained in the previous stage in 150 ml of toluene, the reaction medium is maintained at 20±2°C for 2 hours arid, after having lowered the temperature to 0+5 °C, 111 ml of t riethylamine is added over 1 hour 30 minutes. After a series of washings, 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 ( 4 S, 5 R) di as te reoisomer 4 (S) [4p(S*),5p]-dihydro-5-ethoxy-4-[(1-phenylethyl)amino]-2(3H)-furanone dichloroacetate 10 ml of dichloroacetic acid is added to 400 ml of the preceding solution, followed by concentration to 6 volumes and, having observed crystallization, is maintained at 20±2°C under agitation for 2 hours under nitrogen. After washing with toluene, 32. 8 g of expected product is obtained. 1.21 (t) 0-CH2-CH3 1.72 (d, J=6.5) Ph-CH(CH3)-N 2.77 (dd, J=8.5 and 17); CH2 in position 3 2. 97 (dd, J=ll and 17); 3.76 (m); H4 WE CLAIM: 1. Process for the preparation of aminated alkyloxyfuranone compounds of formula (IVa), (IVb), (IVc) or (IVd): (Formula Removed) in which R1 is an alkyl group containing 1 to 4 carbon atoms or a phenylalkyl group containing 7 to 11 carbon atoms, as well as their addition salts with acids. characterized in that the said process includes at least one of the following stages: a) the action of an arylamine of formula R3R4 CHNH2 wherein R3 is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms and R4 is an optionally substituted aryl, on the racemic alkyloxyfuranone of formula (II): (Formula Removed) in which R1 is an alkyl group containing 1 to 4 carbon atoms, or phenylalkyl containing 7 to 11 carbon atoms, and obtaining the trans (4R,5R) and (4S,5S) isomer compounds of formulae (IIIa) and (IIIb) respectively: (Formula Removed) which are then separated by crystallization by carrying out, if appropriate, one or more salification reactions, or, when R3 is a hydrogen atom, resolved by the action of an optically active acid, b) if appropriate, an epimerization reaction of the compound of formula (IIIa) or (IIIb), salified or non salified, in the presence an acid, in order to obtain the cis (4R,5S) or (4S, 5R) isomer compounds of formula (IIIc) or (IIId), which if appropriate are salified, (Formula Removed) c) hydrogenolysis reaction, either on the trans (4R, 5R) or (4S, 5S) isomer of formula (IIIa) or (IIIb), salified or non salified, in order to obtain the compound of formula (IVa) or (IVb) in the form of the trans (4R, 5R) or (4S, 5S) isomer, which if appropriate is salified and/or protected, or on the cis (4R, 5S) or (4S, 5R) isomer of formula (IIIc) or (IId), salified or non salified, in order to obtain the compound of formula (IVc) or (IVd) in the from of the cis (4R, 5S) or (4S, 5R) isomer, which if appropriate is salified, and/or protected. 2. The process as claimed in claim 1, wherein the protection reaction of the amines of formula (IVa), (IVb), (IVc) or (IVd), salified or non salified, is carried out by the action of the chloroformate of formula C1-CO-0-CH2-R2, R2 representing a substituted or non substituted terbutyl, (C2-C4)- alkenyl, (C2-C4)-alkynyl or phenyl radical, in order to obtain the compounds of formula (la), (lb), (Ic) or (Id), respectively in the form of the trans (4R,5R), (4S,5S) or cis (4R,5S), (4S,5R) diastereoisomers, which if appropriate are salified, (Formula Removed) 3. The process as claimed in claim 1, wherein the separation by crystallization of the compounds of formulae (IIIa) and (IIIb) as defined in claim 1, is carried out: a) by the action of trichloroacetic acid, in order to obtain the corresponding salt of formula (IIIa) or (IIIb), b) then by the action of monochloroacetic acid on the mother liquors in order to obtain the salt corresponding to the other diastereoisomer of formula (IIIa) or (IIIb). 4. The process as claimed in claim 1, for the compounds of formula (IVd) as defined in claim 1 or for the compounds of formula (Id) as defined in claim 2, wherein it includes at least one of the following stages: a) the action of the phenylethylamine R on the compound of formula (II), in order to obtain the following compounds of formulae (III'a) and (Ill'b): (Formula Removed) b) resolution of the trans stereoisomers of formulae (III'a)- and (Ill'b) by the action of trichloroacetic acid in order to obtain the (4S,5S) stereoisomer (Ill'b) in the form of the trichloroacetic acid salt then by the action of monochloroacetic acid in order to obtain the (4R,5R) stereoisomer (III'a) in the form of the monochloroacetic acid salt, c) if appropriate returning to the free amine by the action of a base, d) epimerization reaction of the (4S,5S) stereoisomer of formula (III'D) in the presence of an acid in order to obtain a cis (4S,5R) stereoisomer of formula (IlI'd): (Formula Removed) e) if appropriate crystallization after salification by the action of monochloroacetic or dichloroacetic acid, f) if appropriate return to the free amine by the action of a base, g) if appropriate recrystallization after salification in particular in the form of the hydrochloride, h) hydrogenolysis of the cis (4S,5R) stereoisomer of formula (IlI'd), in order to obtain the compound of formula (IVd) in the form of the cis (4S,5R) diastereoisomer, i) if appropriate to the action of an allyl chloroformate on the compound of formula (IVd) in order to obtain the compound of formula (Id) in the form of the cis (4S,5R) diastereoisomer, with R2 representing -CH=CH2. 5. The process as claimed in claim 1 for the compounds of formula (IVd) as defined in claim 1 or for the compounds of formula (Id) as defined in claim 2, wherein it includes at least one of the following stages: a) the action of phenylethylamine S on the compound of formula (II), in order to obtain the following compounds of formulae (III"a) and (III"b): (Formula Removed) b) resolution of the trans stereoisomers of formulae (III"a) and (III"b) by the action of trichloroacetic acid in order to obtain the (4R,5R) stereoisomer (III"a) in the form of the trichloroacetic acid salt then by the action of monochloroacetic acid in order to obtain the (4S,5S) stereoisomer (III"b) in the form of the monochloroacetic acid salt, c) if appropriate desalification by the action of a base, d) epimerization reaction of the (4S,5S) stereoisomer of formula (III"b) in the presence of an acid in order to obtain a cis (4S,5R) diastereoisomer of formula (III"d): (Formula Removed) e) if appropriate crystallization after salification by the action of an acid such as monochloroacetic or dichloroacetic acid, f) if appropriate return to the free amine by the action of a base, g) if appropriate recrystallization after salification in particular in the form of the hydrochloride, h) hydrogenolysis of the cis (4S,5R) stereoisomer of formula (III"d), in order to obtain the compound of formula (IVd) in the form of the cis (4S,5R) diastereoisomer, i) if appropriate to the action of an allyl chloroformate on the compound of formula (IVd) in order to obtain the compound of formula (Id) in the form of the cis (4S,5R) diastereoisomer, R2 representing a -CH=CH2 radical.

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1982-DEL-1998-Abstract (28-12-2007).pdf

1982-del-1998-abstract-(06-08-2008).pdf

1982-del-1998-abstract.pdf

1982-DEL-1998-Claims (28-12-2007).pdf

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1982-del-1998-form-2.pdf

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1982-DEL-1998-GPA (28-12-2007).pdf

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1982-DEL-1998-Petition-137 (28-12-2007).pdf

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