PROCESS FOR THE PREPARATION OF 1,3-DIAZA-SPIRO (4.4) NON-1-EN-4-ONE DERIVATIVES AND 1-CYANO-1-ACYLAMINO-CYCLOPENTANE INTERMEDIATES

Abstract: Process for the preparation of compounds of formula (I) wherein R means hydrogen atom, or C1-6 alkyl group, or C7-12 aralkyl group or phenyl group, characterised in that: a) the compound of formula (III) is reacted with a compound of formula (IV) wherein X means halogen atom or C1-5 alkoxy group or hydroxyl group and the resulting compound of formula (II) is transformed in the presence of an oxidising agent in a reaction medium with pH above 7, into the compound of formula (I), or b) the compound of formula (III) is reacted with an anhydride of general formula (V) and the resulting compound of formula (II) transformed in the presence of an oxidising agent, in a reaction medium with pH above 7, into the compound of formula (I), or c) a compound of formula (II) is transformed in the presence of an oxidising agent, in a reaction medium with pH above 7, into the compound of formula (I), and if desired, the resulting compounds of formula (I), before or after isolation, are transformed into acid addition salts, or the compounds of formula (I) are liberated from their acid addition salts. Thus a process for the preparation of intermediates useful in synthesis of angiotensin II antagonists is disclosed.

Description: Proces s for the preparati on of 1 , 3-Di aza-Spi ro (4.4 ) non-l-en-4-one deri vati ves and 1-Cyano-l-Acyl ami no-Cycl opentane i ntermedi ates This invention relates to the new process for the preparation of compounds of general formula (I) -wherein R means hydrogen atom, d -6 alkyl group, phenyl group or C 7- ι 2 aralkyl group -, and to the intermediates of general formula (II) - wherein the meaning of R is the same as above. Compounds of general formula (I) are important intermediates used in the course of preparation of active components of pharmaceuticals. They are e.g. applied in the synthesis of angiotensine II antagonists (PCT application, publication number WO-91/14679A). Synthesis of 4-irnidazolinones and their 2-substituted derivatives, constituting the main skeleton of compounds of general formula (I) is known from the literature (Bruckner: Szerves kemia Band III-l page 296. Edition: Tankόnyvkiadό, Budapest 1964). Takenaka and his co-workers described the preparation of 2-phenyl-4,4'- dialJcyl-5-oxo-2-imidazorines in tetrahydrofuran-water heterogeneous system by a 5- 12 hours reflux /Heterocycles 29 (6) p 1185 (1989)/. The above method is, however, difficult to implement since preparation of the appropriate carboxamides is problematic. The appropriate carboxamides are in general synthetised by partial hydrolysis of α-aminonitriles, thus, by that of the α-aminonitrile (III). Taking into account the sensitivity of the aminonitriles against alkalines and oxidants, from the known methods only the partial hydrolysis performed in concentrated acidic medium is considered as feasible. The transformation of nitriles into carboxamides in strongly acidic medium, preferably in concentrated sulfuric acid, raises, however, a number of problems. To be able to stir the reaction mixture, sulfuric acid has to be applied in large excess. As a consequence, heating up the reaction mixture to 70 °C and cooling it down takes considerable time and keeping the reaction product for longer time in a concentrated sulfuric acidic medium will cause partial decomposition. This will cause the necessity of further purification steps. Since the aminocarboxamides are obtained in the form of sulfate salts, the amides have to be liberated. Neutralization of the large excess of acid means the addition of large amounts of base and also that of water, in order to keep the resulting salt in solution. The amino-carboxamide obtained is well solvated, its extraction from the reaction mixture requires a minimum 40-fold excess of the extracting solvent, even if the best - but from the aspect of health very unfavourable - chlorinated hydrocarbones are applied. These solvents, at that, can be recovered only with high losses. Our aim was to work out a novel process for the preparation of the compounds of general formula (I) eliminating the above problems. We have found that if a) the compound of formula (III) is reacted with a compound of general formula (IV) - wherein R means hydrogen atom, C 1-6 alkyl group, phenyl group or C 7-12 aralkyl group, X means halogen atom, C 1-5 alkoxy group or hydroxyl group - and the resulting compound of general formula (II) - wherein the meaning of R is the same as given above - is transformed, in the presence of an oxidising agent in a reaction medium with pH above 7, into the compound of general formula (I) - wherein the meaning of R is as defined above -, or b) the compound of formula (III) is reacted with an anhydride of general formula (V) - wherein the meaning of R is the same as defined above -, and the resulting compound of general formula (II) - wherein the meaning of R is as given above - is transformed in the presence of an oxidising agent, in a reaction medium with pH above 7, into the compound of general formula (I), or c) a compound of general formula (II) - wherein the meaning of R is the same as defined above - is transformed in the presence of an oxidising agent, in a reaction medium with pH above 7, into the compound of general formula (I), and, if desired, the resulting compounds of general formula (I), before or after isolation, are transformed into acid addition salts, or the compounds of general formula (I) are liberated from their acid addition salts, then the disadvantages of the known methods are avoided and the new method is also suitable for the "one-pot" synthesis of the compounds of general formula (I). In the first, acylation step the use of acid chlorides is the most advantageous, in the presence of an organic solvent and an acid binding agent. As for organic solvents for example ethers (methyl tert.-butyl ether), aromatic hydrocarbones e.g. toluene, xylene or chlorinated hydrocarbones e.g. dichloroethane can be applied, as for acid binding agents inorganic bases, for example alkali metal carbonates, alkali-earth metal oxides, organic bases e.g. trialkylamines may be employed. The resulting, if desired isolated, compounds of general formula (II) are new, they are not known from the literature. Transformation of the compounds of general formula (II) was carried out in the presence of the above solvents or of alcohols, preferably by use of hydrogen peroxide, but other oxidising agents can also facilitate the reaction. Reactions performed in water-organic solvent mixtures may be accelerated by use of dissolution transfer, phase transfer catalyst or by intensive stirring. As phase transfer catalyst preferably substituted ammonium salts, as for example tetrabutyl ammonium hydroxides, hydrogen halogenides, hydrogen sulfates, as well as other ammonium derivatives containing equal or different subsituents can also be applied. The reaction is carried out in basic medium, above pH=7, for instance in the presence of sodium hydroxide, but other alkali metal hydroxides, as well as alkali metal carbonates, alkali-earth metal hydroxides, alkali-earth metal carbonates or anion-exchange resins may also be used. Cyclisation may be accomplished in 0,5-2 hours. The cyclisation step is preferably carried out at a temperature between 50-160 °C. The whole process can be carried out in one reaction pot and the resulting compounds of general formula (I) contain, at the highest. 0, 1% amount of contamination. The yield of the process is over 70%, calculated on the starting compound of formula (III). The compounds of general formula (I) are preferably isolated in the form of their organic or inorganic acid addition salts. Synthesis of the starting compound of formula (III) is known from the literature /it was synthesised according to the method of the PCT application, publ. number WO-91/14679 and of Org. Synt. 1955 3; (MS: (m/z) JJO, 95, 8_L 68, 54, 41, 28)/. Further details of the invention are illustrated by the following examples, without limiting our claims to the examples. Example 1. 1 -cyano- 1 -n-pentanoylaminocyclopentane To 1 1,0 g (0, 1 mol) of 1-amino-l-cyanocyclopentane dissolved in 100 ml of dichloromethane, 15 ml 10,9 g (0, 1 mol) of triemylamine was added, then dropwise 13 ml, 13 g (0,1 mol) of valeroyl chloride, while keeping the temperature at 25-35 "C. The reaction mixture was stirred at 30-35 °C for 2 hours, then it was washed with water. The phases were separated, the organic phase was evaporated to obtain the pure title compound as an oil. The compound was identified by elementary analysis, IR, NMR and GC-MS spectromerry. 1H-NMR (CDC1 3 ): δ 0,81 (CH 3 ); 1,25 (CH 2 ); 1,51(CH 2 ); 2, 14 (CH 2 ); 1,73 (m, ring, 1,2); 2,21 (ring 3H); 2,05 (ring 4H); 7,39 (1H, NH); 13 C-NMR (CDCI 3 ): δ 13,4(CH 3 ); 21,9(CH 2 ); 27,3(CH 2 ); 35,4(CH 2 ); 22,7[2C(1,2)]; 38,4[2C(3,4)]; 54,6(C quaternary); 121,2(CN); 173,7(NH-CO); IR v max: 2238(CN); 1654 (CO); 3304(NH); MS: (m/z) 194 (M+H), 165, 152, 137, 111, 102, 85, 51, 41, 29. Example 2. 1 -cyano- 1 -n-pentanoylaminocyclopentane 11,0 g (0, lmol) of 1-amino-l-cyanocyclopentane and 20,5 g (0, 11 mol) of valeric anhydride were refluxed for 3 hours. The reaction mixture was evaporated under vacuo to constant weight. The resulting 19,3 g oil (98,5 %) was identical with the product obtained in Example 1. Example 3. 1 -cyano- 1 -n-pentanoylaminocyclopentane l l,0g (0, 1 mol) of 1-amino-l-cyanocyclopentane and 20,4 g (0,2 mol) of valeric acid were placed in an apparatus equipped with water-separatory distillation head and boiled until 1,8 ml of water distilled off. The reaction mixture was then evaporated in fine vacuum to constant weight. 19, 1 g (97,4 %) of oily product was obtained, which was identical with the product obtained in Example 1. Example 4. 1 -cyano- 1 -n-pentanoylaminocyclopentane 11.0 g (0, 1 mol) of 1-arnino-l-cyanocyclopentane, 13,9 g (0, 12 mol) of methyl valerate and 1,0 g sodium methylate were boiled for 16 hours. The volatile products were then distilled off in vacuo. To the residue 50 ml of water was added, the pH was adjusted to neutral by the addition of acetic acid and the mixture was extracted with 70 ml followed by 2x50 ml of dichloroethane. The combined organic phases were dried over sodium sulfate and evaporated in vacuo to constant weight. 13.1 g (66,8 %) of oily product was obtained which was identical with the product obtained in Example 1. Example 5. 1-cyano- 1-formylarninocyclopentane 11,0 g (0, 1 mol) of 1-amino-l-cyanocyclopentane and 10 ml of 85 % formic acid were placed in an apparatus equipped with water-separatory distillation head and boiled for 3 hours. The reaction mixture was then evaporated to constant weight in vacuo. 12,4 g (90 %) of oily product was obtained which on investigation by GC-MS gave the following fragments of the title product M: 138, 137, 123, 111, 110, 109, 93, 81, 68, 66, 54, 46, 41 (R t : 10,7') Example 6. 1 -cyano- 1 -acetylaminocyclopentane l l,0g (0, 1 mol) of 1-amino-l-cyanocyclopentane and 20 ml of acetic anhydride were boiled for 3 hours, then the mixture was evaporated in vacuo to constant weight. 14,4 g (94 %) of oily product was obtained which on investigation by GC-MS gave the following fragments of the title product M: 153, 152, 137, 111, 109, 81, 60, 43 Example 7. 1 -benzoylamido- 1 -cyanocyclopentane To the 10% solution of 11,0 g (0, 1 mol) of 1-amino-l-cyanocyclopentane in dichloroethane were added 16 g of rriethylamine, then at a temperature not exceeding 30 °C 14 g (0, 103 mol) of benzoyl chloride. The reaction mixture was stirred for 30 minutes, then refluxed for 30 minutes. It was then cooled to 20-25 °C, washed with 20 ml of water, the phases were separated, the dichloroethane solution was checked by GC-MS. (m/z: 214, 199, 185, 171, 156, 106, 104, 83, 77, 76, 54, 39, 28). Beside the solvent only traces of the starting material were shown. The product is an oil. Example 8. 1 -phenylacetamido- 1 -cyanocyclopentane To the 10% solution made of 11,0 g (0,1 mol) of 1-amino-l-cyanocyclopentane in dichloroethane were added 16 g of triemylamine, then at a temperature not exceeding 30 °C 16 g (0, 104 mol) of phenylacetyl chloride. The reaction mixture was stirred for 30 minutes, then refluxed for 30 minutes. It was then cooled to 20-25 °C, washed with 20 ml of water, the phases were separated, the dichloroethane solution was checked by GC-MS. (m/z: 228, 201, 200, 137, 118, 111, 91, 65, 39, 28) Beside the solvent only traces of the starting material were shown. The product is an oil. Example 9. 2-butyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride To the solution made of 11,0 g (0, 1 mol) of 1-amino-l-cyanocyclopentane and 12,2 g (0, 12 mol) of triethylamine in 80 ml of toluene, 13,0 g (0, 1 mol) of valeroyl chloride was added at 30 °C. After the addition the mixture was stirred at 60 °C for 1 hour, then it was cooled and washed three times with water. The phases were separated and to the organic phase at first 25 g of 20 w/v % sodium hydroxide solution and 7 g of tetrabutyl ammonium hydrogen sulfate, then at 10-15 °C 40 g of 30-35 w/v % hydrogen peroxide solution were added. The reaction mixture was heated to 25-30 °C and was stirred at that temperature for 2 hours. The mixture was then heated to 60 °C and the phases were separated again. To the toluene phase the solution of 3 g of sodium in 30 ml methanol was added and the mixture was heated to reflux temperature to distille out the solvent and the volatile components. The concentration was continued until the mixture was stirrable. To the resulting product 100 ml of acetone was added, the mixture was filtered and the pH of the filtrate was adjusted to 1-2 with cone, hydrochloric acid. The precipitated product was filtered off and dried to obtain 14 g of the title compound, yield 60,8%. IR: 3600-2200 : vibr, NH; 1779 : γ c = o; 1642 γ c, 1517 : δ NH (IRFT Perkin Elmer) 1H NMR: 0,9 ppm T (CH 3 ); 1,34 ppm S (CH 2 ); 1,73 ppm Q (CH 2 ); 1,78-2,01 ppm M cyclopentane (CH 2 ); 2,78 ppm T (CH 2 ); 9-15 ppm (NH, N) MS: 194, 179, 166, 165, 152, 124, 84, 83, 54, 41 VRK: Eluent: chloroform: methanol = 6: 1, TLC plate: Kieselgel GF254 Detection: I 2 vapor Rf = 0,64 Example 10. 2-buyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride The procedure as described in Example 9 was followed, but 5 g of cetyltrimethylammonium hydroxide was applied. 17 g of the title compound was obtained (yield 74 %). Physical characteristics of the product are identical with those of the product obtained in Example 9. Example 11. 2-butyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride The procedure as described in Example 9 was followed, but to promote the heterogen phase reaction the mixture was stirred with sonicator. 14 g of the title compound was obtained (yield 61 %). Physical characteristics of the product are identical with those of the product obtained in Example 9. Example 12. 2-butyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride The procedure as described in Example 9. was followed, but the amino-1- cyanocyclopentane was dissolved in methyl terc.-butyl ether, instead of toluene and the separation of the aqueous layer was performed at 50 - 55°C. 14 g of the title compound was obtained (yield 61 %). Physical characteristics of the product are identical with those of the product obtained in Example 9. Example 13. 2-butyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohidrochloride To the solution of 11,0 g (0, 1 mol) of 1-amino-l-cyanocyclopentane in 110 g of toluene 12,2 g (0, 12 mol) of triemylamine was added and to this solution 13,0 g (0, 1 mol) of valeroyl chloride was added dropwise, under cooling, at 25-30 °C. After 10 minutes the temperature was raised to 60 °C and the mixture was stirred at that temperature for 1 hour. The reaction mixture was then cooled to 20 °C and it was extracted consecutively with: 50 ml of water, 50 ml of 2% hyrochloric acid solution and 30 ml of water. The toluene solution was evaporated to constant weight in vacuo, to the residue were added at first the solution of 3 g (0,056 mol) of potassium hydroxide in 50 ml of methanol, then under cooling, at a temperature between 20-30°C 30 ml of 30 % hydrogenperoxide solution. External cooling was then discontinued and the temperature was allowed to raise 50-60 °C. After approximately 30 minutes the temperature began to decrease. At that point the solution of 17 g (0,314 mol) of potassium hydroxide in 17 ml of water was added to it, and the mixture was heated under reflux conditions for 1 hour. The reaction was then freezed by the addition of 20 g of ammonium chloride and methanol was distilled out by raising the inner temperature to 85 °C. The reaction mixture was extracted with 50 and 2x30 ml of toluene, the combined organic phases were evaporated in vacuo, the residue was dissolved in 5-fold amount of acetone, the resulting solution was filtered, its pH was adjusted to 1-2 by the addition of cone, hydrochloric acid solution. The suspension thus obtained was stirred for 30 minutes, cooled to 0 °C, the crystals were filtered off, washed with cold acetone and dried to obtain 18 g of the title compound (yield 78,3 %). Physical characteristics of the product were identical with those of the product obtained in Example 9. Example 14. 2-butyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride The mixture of 19,6 g of 1 -ammo- 1 -n-pentanoylaminocyclopentane, 200 ml of water, 300 ml of acetone and 36,9 g of sodium perkarbonate (0,3 equivalent hydrogenperoxide) was stirred for 3 hours at 50 °C. Acetone was removed in vacuo, to the residue 50 ml of methanol and 15,0 g (0,28 mol) of potassium hydroxide was added and the solution thus obtained was refluxed for 2 hours. To the reaction mixture 15 g of ammonium chloride was added and after 10 minutes of stirring methanol was distilled off in vacuo. The residue was extracted with 70ml and 2x50 ml of toluene, the combined organic phases were evaporated, the residue was dissolved in 100 ml of acetone, after filtration the pH of the solution was adjusted to 1-2 with concentrated hydrochloric acid and the resulting suspension was cooled, filtered, the crystals were washed with cold acetone and dried. 16, 1 g of title compound was obtained, yield 70 %. Physical characteristics of the product were identical with those of the product obtained in Example 9. Example 15. 2-methyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride The mixture of 15,3 g (0, 1 mol) of 1 -cyano- 1-acetylaminocyclopentane, 38,6 g (0,25 mol) of sodium perborate, 300 ml of water and 100 ml of methanol were refluxed under stirring for 30 hours. Then 16 g (0,4 mol) of sodium hydroxide was added to the mixture and reflux was continued for an addition al 2 hours. After the addition of 16 g of ammonium chloride methanol was distilled off and the residue was extracted with 70 ml and 2x50 ml of dichloromethane. From the combined lower phases solvent was removed, the residue was dissolved in 100 ml of acetone, the solution was filtered, the pH was adjusted to 1-2 with concentrated hydrochloric acid. The resulting suspension was cooled to 0 °C, the solid material was filtered off, washed with cold acetone and dried. 13.5 g of the title compound was obtained, yield: 66,8 %. Mp: 204-212 °C (decomp.) Example 16. 2-butyl-l,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride 19.6 g (0, 1 mol) of 1 -cyano- 1 -n-pentanoylaminocyclopentane was dissolved in 70 ml of ethanol, to the solution 3,7 g (0,05 mol) of calcium hydroxide, and then, dropwise, under cooling 25 ml of 30 % hydrogenperoxide solution. The temperature was allowed to raise to 50-60 °C, without external cooling. After 1 hour of stirring the reaction mixture was filtered, to the filtrate solution 10 g of freshly activated VARION AD ion-exchange resin was added, after 2 hours of reflux the resin was filtered off. The filtrate was evaporated to constant weight in vacuo, to the residue 100 ml of acetone was added. The pH of the resulting solution was adjusted to 1-2 with dry hydrogen chloride gas, the suspension thus obtained was cooled to 0 °C, the crystals were filtered off, washed with cold acetone and dried. 15.7 g of title compound was obtained,, yield: 68,3 %. Physical characteristics of the product were identical with those of the product obtained in Example 9. Example 17. 1,3-diaza-spiro [4.4] non-l-en-4-one monohydrochloride To the suspension of 13,8 g (0, 1 mol) of 1 -cyano- 1-formylaminocyclopentane 70ml of n-butanol and 5,0 g (0,05 mol) of calcium carbonate was added, dropwise 20 ml of 30 % hydrogenperoxide solution, in a pace that the temperature of the mixture slowly enhances and does not exceed 50 °C. After 1 hour of stirring the reaction mixture was filtered. To the filtrate solution 12,0 g (0,3 mol) of sodium hydroxide was added and after 30 minutes of reflux the reaction was freezed by the addition of 12 g of ammonium chloride. To the reaction mixture water was added, in an amount that the precipitated salt dissolves The solution was then extracted with 70 ml and 2x50 ml of methyl terc.butyl ether. After drying over sodium sulfate the solution was saturated with dry hydrogen chloride gas, the resulting suspension was cooled, the crystals were filtered off, washed with dry acetone and dried. 9,0 g of title compound was obtained, yield: 52 %. Mp: 219-221 °C (decomp.) IR: 1663 cm "1 C = N 1739 cm "1 C = O 3197 cm '1 H(NH) MH + : 139 Example 18. 2-phenyl-l,3-diaza-spiro[4,4]non-l-en-4-one monohydrochloride The dichloroethane solution obtained in example 7 was evaporated in vacuo, to the residue (-0, 1 mol benzoylamidocyclopentylcyanide) the solution made of 4 g of NaOH in 50 ml of metanolban was added, and to this mixture under stirring, at a temperature below 30 °C, in a period of 30 minutes 25 ml of hydrogenperoxide (30- 35 %) was added. After 30 minutes of stirring at that temperature the mixture was cooled back to 30 °C, the pH was adjusted with acetic acid, the solvent was distilled off, the residue was taken up in acetone, filtered, acified with hydrochloric acid to pH 1-2 cooled to -5 °C filtered and dried. Yield: 12 g, (48 %) of title compound, which is pure as shown by TLC, Rf = 0,68, eluent: chloroform-methanol = 6: 1, TLC plate: Kieselgel GF 254, visualiser: J? vapors. MS: (m/z) 214, 199, 185, 171, 106, 83, 77, 54, 39, 28. Example 19. 2-benzyl- 1 , 3 -diaza-spiro [4,4]non- 1 -en-4-one monohydrochloride 2,28 g (0,01 mol) of 1-phenylacetylamido-l -cyanocyclopentane (Example 8) in 10 %-os dichloroethane solution was reacted in the presence of 1 g of tetrabutylammonium hydrogensulfate phase transfer catalyst and 5 g of 20 % sodium hydroxide solution with 5 ml of 30 % hydrogenperoxide under vigorous stirring at room temperature, for 120 minutes. The precipitated product was collected and to the wet solid material 1 g of sodium hydroxide and 20 ml of toluene was added, the mixture was heated to reflux temperature,. The3 n the solvent was distilled off, the residue was dissolved in 25 ml of acetone, the mixture was filtered, acified with hydrochloric acid, the resulting hydrochloride salt was filtered at -5 °C and dried. Yield: 2,3 g (87 %) of the title compound, which is pure as shown by TLC, Rf = 0,7, eluent: chloroform-methanol = 6: 1, TLC plate: Kieselgel GF 254, visualiser: J 2 vapors. MS: (m/z) 228, 213, 200, 185, 172, 144, 130, 118, 109, 91, 67, 54, 41, 28.

Claims: Claims 1. Compounds of general formula (II) - wherein R means hydrogen atom, C ]-6 alkyl group, C7- 12 aralkyl group or phenyl group. 2. 1 -Cyano- l-«-pentanoylaminocyclopentane and its acid addition salts. 3. 1 -Cyano- l-«-pentanoylaminocyclopentane, characterised in that its Η-NMR spektrum taken in deutero chloroform solution is the following: δ 0,81 (CH 3 ); 1,25 (CH 2 ); 1,51(CH 2 ); 2, 14 (CH 2 ); 1,73 (m, ring, 1,2); 2,21 (ring 3H); 2,05 (ring 4H); 7,39 (1H, NH). 4. 1 -Cyano- l-«-pentanoylaminocyclopentane, characterised in that its retention factor in chloroform-methanol 6: 1 mixture on Kieselgel GF 254 TLC plate is 0,85. 5. Process for the preparation of compounds of general formula (I) - wherein R means hydrogen atom, or C 1-6 alkyl group,or C 7-12 aralkyl group or phenyl group - characterised in that a) the compound of general formula (III) is reacted with a compound of general formula (IV) - wherein the meaning of R is the same as defined in Claim 1, and X means halogen atom or C 1-5 alkoxy group or hydroxyl group - and the resulting compound of general formula (II) - wherein the meaning of R is the same as given in Claim 1 - is transformed in the presence of an oxidising agent in a reaction medium with pH above 7, into the compound of general formula (I) - wherein the meaning of R is as defined above -, or b) the compound of formula (III) is reacted with an anhydride of general formula (V) - wherein the meaning of R is the same as defined above -, and the resulting compound of general formula (II) - wherein the meaning of R is as given above - is transformed in the presence of an oxidising agent, in a reaction medium with pH above 7, into the compound of general formula (I), or c) a compound of general formula (II) - wherein the meaning of R is the same as defined above - is transformed in the presence of an oxidising agent, in a reaction medium with pH above 7, into the compound of general formula (I), and if desired, the resulting compounds of general formula (I), before or after isolation, are transformed into acid addition salts, or the compounds of general formula (I) are liberated from their acid addition salts. 6. The process according to Claim 5 a) or b) or c), characterised in that the reaction is carried out in homogenous phase. 7. The process according to Claim 5 a) or b) or c), characterised in that the reaction is carried out in heterogeneous phase. 8. The process according to Claim 5 a) or b) or c), characterised in that as for oxidising agents hydrogen peroxide or organic or inorganic peroxi-compounds are applied. 9. The process according to Claim 7 a) or b) or c), characterised in that as for oxidising agents peroxo-carbonates, peroxo-borates, peroxo-disulfates are employed. 10. The process according to Claim 5 a) or b) or c), characterised in that the compounds of general formula (II) are transformed into the compounds of general formula (I) in the presence of an oxidising agent and base. 11. The process according to Claim 9 a) or b) or c), characterised in that as for base, alkali alcoholates, alkali metal hydroxides, alkali metal carbonates or ion-exchange resins are used. 12. The process according to Claim 5 a) or b) or c), characterised in that in the reaction taking place between the compound of formula (III) and a compound of general formula (IV) or (V) an acid binding agent is used. 13. The process according to Claim 11, characterised in that as for acid binding agent amines, alkali-earth metal carbonates, alkali-earth metal carbonates or alkali- earth metal oxides are applied. 14. The process according to Claim 5, characterised in that as for solvents aromatic hydrocarbones, halogenated aliphatic hydrocarbones, aliphatic ethers, alcohols, as well as homogenous or heterogenous aqueous solvent systems formed between the above solvents and water, are applied. 15. The process according to Claim 7, characterised in that phase transfer catalyst and/or d ssolution transfer is used. 16. The process according to Claim 14, characterised in that as for phase transfer alkyl ammonium hydrogen sulfates, hydrogen halogenides or hydroxides, and as for dissolution transfer longer chain alcohols are used. 17. The process according to Claim 5 a) or b) or c), characterised in that the reaction is carried out without isolating the compounds of general formula (II).

Inventors: ARANYOSI PETER, BOGNAR ERZSEBET, CASTRO BERTRAND, CSETRINE HARI ZSUZSANNA, DERVALICSNE ZRINYI ILONA, DUBOVSZKI KATALIN, GAJARI ANTAL, GYUERE KAROLY, HUSZAR CSABA, KIS-TAMAS ATTILA, KOLLAR ENDRE, KUNSZTNE KARASZ AGNES, MAKOVI ZOLTAN, MESZAROS ISTVAN, NAD ZSUZSANNA, NEMETH ATTILA, PALI LAJOSNE, SUPIC ATTILA, ARANYOSI, PETER, BOGNAR, ERZSEBET, CASTRO, BERTRAND, CSETRINE HARI, ZSUZSANNA, DERVALICSNE ZRINYI, ILONA, DUBOVSZKI, KATALIN, GAJARI, ANTAL, GYUERE, KAROLY, HUSZAR, CSABA, KIS-TAMAS, ATTILA, KOLLAR, ENDRE, KUNSZTNE KARASZ, AGNES, MAKOVI, ZOLTAN, MESZAROS, ISTVAN, NAD, ZSUZSANNA, NEMETH, ATTILA, PALI, LAJOSNE, SUPIC, ATTILA
Applicants: ARANYOSI PETER, BOGNAR ERZSEBET, CASTRO BERTRAND, CSETRINE HARI ZSUZSANNA, DERVALICSNE ZRINYI ILONA, DUBOVSZKI KATALIN, GAJARI ANTAL, GYUERE KAROLY, HUSZAR CSABA, KIS TAMAS ATTILA, KOLLAR ENDRE, KUNSZTNE KARASZ AGNES, MAKOVI ZOLTAN, MESZAROS ISTVAN, NAD ZSUZSANNA, NEMETH ATTILA, PALI LAJOSNE, SANOFI SA, SUPIC ATTILA, ARANYOSI, PETER, BOGNAR, ERZSEBET, CASTRO, BERTRAND, CSETRINE HARI, ZSUZSANNA, DERVALICSNE ZRINYI, ILONA, DUBOVSZKI, KATALIN, GAJARI, ANTAL, GYUERE, KAROLY, HUSZAR, CSABA, KIS-TAMAS, ATTILA, KOLLAR, ENDRE, KUNSZTNE KARASZ, AGNES, MAKOVI, ZOLTAN, MESZAROS, ISTVAN, NAD, ZSUZSANNA, NEMETH, ATTILA, PALI, LAJOSNE, SANOFI, SUPIC, ATTILA
Application year: 1998
Main classification: C07D235
IPC codes: C07C255, C07D235