MXPA00000858A - Process for the preparation of 1,3-diaza-spiro (4.4) non-1-en-4-one derivatives and 1-cyano-1-acylaminocyclopentane intermediates - Google Patents

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 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 a reaction medium with pH above 7, into the compound of formula (I), or c) a compound of formula (II) is transformed, 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

PROCESS FOR THE PREPARATION OF DERIVATIVES OF 1,3-DIAZA- ESPIRO- [4,4] -NON-1-EN-4-ONA AND INTERMEDIATE COMPOUNDS OF 1-CYANO-L-ACILAMINOCICLOPENTANO This invention relates to a new process for the preparation of compounds of the general formula (I), wherein R means hydrogen atom or alkyl group of 2 to 6 carbon atoms and intermediates of the general formula (II), wherein the meaning of R is the same as before. The compounds of the general formula (I) are important intermediates used in the course of the preparation of the active components of pharmaceutical compounds. For example, they are applied in the synthesis of angiotensin II antagonists (PCT application, publication number WO-91 / 14679A). The synthesis of the 4-imidazolinones and their 2-substituted derivatives, which constitute the main structure of the compounds of the general formula (I) is known from the literature (Bruc ner: Szerves kémia Band III-I page 296. Edition : Tankónyvkiadó, Budapest 1964). Takenada and his colleagues described the preparation of 2-phenyl-4,4'-dialkyl-5-oxo-2-imidazolines in a heterogeneous system of tetrahydrofuran and water for a reflux of 5 to 12 hours (Heterocycles 29 (6) p 1185 (1989)). The above method, however, is difficult to implement since the preparation of the appropriate carboxamides is problematic. The appropriate carboxamides are synthesized in general by partial hydrolysis of the a-aminonitriles, in this way, by that of the α-aminonitriles (III) - taking into account the sensitivity of the aminonitriles against the alkaline and oxidizing products, of the known methods only partial hydrolysis performed in the concentrated acid medium is considered feasible. However, the transformation of nitriles into carboxamides in strongly acidic medium, preferably in concentrated sulfuric acid, causes a number of problems. In order to be able to stir the reaction mixture, the sulfuric acid has to be applied in large excess. As a result, heating the reaction mixture to 70 ° C and cooling takes considerable time and maintaining the reaction product for longer in a concentrated sulfuric acid medium will cause partial decomposition. This will cause the need for additional purification steps. Since the aminocarboxamides are obtained in the form of sulfate salts, the amines have to be released.

The neutralization of the large excess of acid means the addition of large amounts of base and also that of water, in order to maintain the resulting salt in solution. The amino-carboxamide obtained is well solvated, its extraction from the reaction mixture requires a minimum of 40 times excess of the extraction solvent, even if at best, but from the very unfavorable health aspect, chlorinated hydrocarbons are applied. These solvents, like those, can be recovered only with high losses. Our purpose was to work on a new process for the preparation of the compounds of the general formula (I), eliminating the previous problems. It has been found that: a) the compound of the formula (III) is reacted with a compound of the general formula (IV), wherein R means hydrogen atom or alkyl group of 2 to 6 carbon atoms, X means atom of halogen, alkoxy group of 1 to 5 carbon atoms or hydroxyl group, and the resulting compound of the general formula (II), wherein the meaning of R is the same as above, is transformed, into a reaction medium with pH above 7, in the compound of the general formula (I), wherein the meaning of R is as defined above, or b) the compound of the formula (III) is reacted with an anhydride of the general formula (V) ), where the meaning of R is the same as defined above, and the compound resulting from general formula (II), where the meaning of R is as given above, is transformed, in a reaction medium with pH above 7, into a compound of the general formula (I), or c) a compound of the general formula (II), wherein the meaning of R is the same as defined above, it is transformed, in a reaction medium with pH above 7, into the compound of the general formula (I), and if desired, the resulting compounds of the general formula (I), before or after the isolation, they are transformed into acid addition salts, or the compounds of the general formula (I) are released from their acid addition salts, then the disadvantages of the known methods are avoided and the new method is also suitable for the synthesis in "a pot" of the compounds of the general formula (I). In the first acylation step, the use of acid chlorides is most advantageous, in the presence of an organic solvent and an acid binding agent. With respect to organic solvents, for example ethers (methyl tert-butyl ether), aromatic hydrocarbons, for example toluene, xylene or chlorinated hydrocarbons, for example, dichloroethanes, are applied as far as the acidic binding agents are concerned. they can employ inorganic bases, for example, alkali metal carbonates, alkaline earth metal oxides, organic bases, for example, trialkylamines. The resulting compounds, if desired, isolated, of the general formula (II) are new, are not known from the literature. The conversion of the compounds of the general formula (II) is carried out in a homogeneous phase, in mixtures of water and organic solvent, preferably in aqueous alcohols, and more preferably in aqueous methanol. The reaction is carried out in basic medium, above pH = 7, for example the presence of sodium hydroxide, but other alkali metal hydroxides can also be used, as well as alkali metal carbonates, alkaline earth metal hydroxides, carbonates of alkaline earth metals or anion exchange resins. Cyclization can be achieved in 0.5-2 hours. The cyclization step is preferably carried out at a temperature between 50-160 ° C. The entire process can be carried out in a reaction kettle and the resulting compounds of the general formula (I) contain, at most, 0.1% of the amount of contamination. The yield of the process is more than 70%, calculated in the starting compound of the formula (III). The compounds of the general formula (I) are preferably isolated in the form of their acid addition salts, organic or inorganic. The synthesis of the starting compound of the formula (III) is known from the literature (this was synthesized according to the method of the PCT application, publication number O-91/14679 and Org. Synt. 1955 3; (MS: (m / z) 110, 95, 81, 68, 54, 41, 28)). Further details of the invention are illustrated by the following examples.

EXAMPLE 1 1-cyano-l-n-pentanoylaminocyclopentane A 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane dissolved in 100 ml of dichloromethane, ml 10. g (0.1 mol) of triethylamine was added, then dropwise 13 ml, 13 g (0.1 mol) of valeroyl chloride, while the temperature was maintained at 25-35 ° C. The reaction mixture was stirred at 30-35 ° C for 2 hours, then washed with water. The phases were separated, the organic phase was evaporated to obtain the pure title compound with an oil. The compound was identified by elemental analysis, IR, NMR, GC-MS spectrometry. 1 H NMR (CDC13): d 0.81 (CH3); 1-25 (CH2); 1.51 (CH2); 2.14 (CH2); 1.73 (, ring, 1.2); 2.21 (ring 3H); 2.05 (ring 4H); 7.39 (1H, NH); 13 C NMR CDCl 3): d 13.4 CH 3); 21.9 CH2); 27.3 (CH2); 35.4 (CH2); 22.7 [2C (1.2)]; 38.4 [2C (3,4]; 54.6 (quaternary C); 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-l-n-pentanoylaminocyclopentane 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane and 20.5 g (0.11 mol) of valeric anhydride were refluxed for 3 hours. The reaction mixture was evaporated under vacuum to constant weight. The resulting 19.3 g of oil (98.5%) was identical with the product obtained in Example 1.

EXAMPLE 3 1-cyano-ln-pentanoylaminocyclopentane 11.0 (0.1 mol) of 1-amino-1-cyanocyclopentane and 20.4 g (0.2 mol) of valeric acid were placed in an apparatus equipped with a distillation head with water separation and boiled until that 1.8 ml of water was distilled. The reaction mixture was then evaporated in a vacuum to constant weight. 19.1 g (97.4%) of the oily product was obtained, which was identical with the product obtained in Example 1.

EXAMPLE 4 1-cyano-l-n-pentanoylaminocyclopentane 11.0 g (0. mol) of 1-amino-1-cyanocyclopentane, 13.9 g (0.12 mol) of methyl valerate and 1.0 g of sodium methylate were boiled for 16 hours. The volatile products were then distilled completely in vacuo. To the residue 50 ml of water were added, the pH was adjusted to neutral by the addition of acetic acid and the mixture was extracted with 70 ml followed by 2 x 50 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated in vacuo to constant weight. 13.1 g (66.8%) of the oily product was obtained which was identical with the product obtained in Example 1.

EXAMPLE 5 1-cyano-l-formylaminocyclopentane 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane and 10 ml of 85% formic acid were placed in an apparatus equipped with a distillation head with water separation and boiled for 3 hours. The reaction mixture was then evaporated to constant weight in vacuo. We obtained 12.4 g (90%) of oily product that in the investigation by GC-MS gave the following fragments of the product of the title M: 138, 137, 123, 111, 110, 109, 93, 81, 68, 66, 54 ., 4_6, 41 (R3: 10.7 ') EXAMPLE 6 2-Butyl-1, 3-diaza-spiro [4.4] -non-1-en-4-one momochlorhydrate A 19.6 g (0.1 mol) of 1-cyano-ln-pentanoylaminocyclopentane dissolved in 70 ml of methanol, 25 g (0.46 mol) of potassium hydroxide dissolved in 50 ml of water were added. The resulting solution was stirred and heated to 50-60 ° C, then under reflux conditions for 2.5 hours. The pH was decreased by the addition of 25 g of ammonium chloride, then the methanol was distilled. The residue was extracted with 50 ml and 2 x 30 ml of toluene, the combined organic phases were evaporated to constant weight. The residual 16 g of the title compound was dissolved in 100 ml of acetone, the resulting solution was adjusted to pH 1-2 with hydrochloric acid solution, the mixture was crystallized, the crystals were collected by filtration to obtain 14 g of the compound of the title compound. Title, performance 60.8%.

IR: 3600-2200: vibr, NH; 1779:? c = o; 1642? c, 1517: d NH (IRFT Perkin Elmer) XH NMR: 0.9 ppm T (CH3); 1.34 ppm S (CH2); 1.73 ppm Q (CH2); 1.78-2.01 ppm M cyclopentane (CH2); 2.78 ppm T (CH2); 9-15 ppm (NH, N) MS: 194, 179, 166, 165, 152, 124, 84, 83, 54, 41 TLC: eluent: chloroform: methanol = 6: 1, TLC plate: Kieselgel GF254 Detection by: Vapors of I2; RF = 0.64 EXAMPLE 7 2-butyl-l, 3-diaza-spiro [4.4] non-l-en-4-one A 19.6 g (0.1 mol) of 1-cyano-ln-pentanoylaminocyclopentane dissolved in 70 ml of methanol, 5 g of Varion AD resin were added, the reaction mixture was heated under reflux conditions for 3 hours. After filtration and evaporation, 16.5 g (71.7%) of the title compound was obtained, assay by GC: 92%.

EXAMPLE 8 1-Phenylacetamido-1-cyanocyclopentane To the 10% solution made up of 11.0 g (0. mol) of 1-amino-1-cyanocyclopentane in dichloroethane was added 16 g of triethylamine, then at a temperature not of 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 verified by GC-MS. (m / z: 228, 201, 200, 137, 118, 111, 91, 65, 39, 28). In addition to the solvent, only the traces and 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 19.6 g (0.1 mol) of 1-cyano-ln-pentanoylaminocyclopentane dissolved in 70 ml of methanol , 25 g (0.46 mol) of potassium hydroxide dissolved in 50 ml of water were added. The resulting solution was stirred and heated to 50-60 ° C, then under reflux conditions for 2.5 hours. The pH was decreased by the addition of 25 g of ammonium chloride, then the methanol was distilled. The residue was extracted with 50 ml and 2 x 30 ml of toluene, the combined organic phases were evaporated to constant weight. The residual 16 g of the title compound was dissolved in 100 ml of acetone, the pH of the resulting solution was adjusted to 1-2 with hydrochloric acid solution, the mixture was crystallized, the crystals were placed by filtration to obtain 14 g of the composed of the title, yield 60.8%.

IR: 3600-2200: vibr, NH; 1779:? c = o; 1642? c, 1517: NH d (IRFT Perkin Elmer) XH NMR: 0.9 ppm T (CH3); 1.34 ppm S (CH2); 1.73 ppm Q (CH2); 1.78-2.01 ppm M cyclopentane (CH2); 2.78 ppm T (CH2); 9-15 ppm (NH, N) MS: 194, 179, 166, 165, 152, 124, 84, 83, 54, 41 TLC: eluent: chloroform methanol = 6: 1, TLC plate: Kieselgel GF254 Detection by: Vapors of I2; RF = 0.64 EXAMPLE 10 2-Butyl-1,3-diaza-spiro [4.4] -non-1-en-4-one A 19.6 g (0.1 mol) of 1-cyano-ln-pentanoylaminocyclopentane dissolved in 70 ml of methanol were added 5 g of Varion AD resin, the reaction mixture was heated under reflux conditions for 3 hours. After filtration and evaporation, 16.5 g (71.7%) of the title compound was obtained, assay by GC: 92%.

EXAMPLE 11 2-Methyl-l, 3-diaza-spiro [4.4] -non-1-en-4-one monohydrochloride The mixture of 15.4 g (0.1 mol) of 1-cyano-l-acetylaminociclopentane, 12 g (0.3 mol) of sodium hydroxide, 30 ml of water and 50 ml of ethanol was stirred at room temperature overnight and under reflux conditions for 30 minutes. The mixture was neutralized with acetic acid, the ethanol was distilled off, the residue was extracted with ethyl acetate and the organic phase was evaporated. The residue was dissolved in 80 ml of toluene and saturated with dry hydrogen chloride gas. The resulting suspension was cooled, filtered and the crystals were washed with cold acetone and dried. 14.0 g of the title compound were obtained, yield: 74.5%. P.f .: 204-212 ° C (decomposition).

Claims (14)

1. CLAIMS: 1. Compounds of the general formula (II), wherein R means hydrogen atoms, or alkyl group of 2 to 6 carbon atoms. 2. 1-Cyano-l-n-pentanoylaminocyclopentane. 3. 1-Cyano-l-n-pentanoylaminocyclopentane, characterized in that the 1 H NMR spectrum taken from the deutero-chloroform solution is as follows: d 0.81 (CH 3); 1.25 (CH2); 1.51 (CH2); 2.14 (CH2); 1.73 (m, ring, 1.2); 2.21 (ring 3H); 2.05 (ring 4H); 7.39 (1H, NH). 4. 1-Cyano-l-n-pentanoylaminocyclopentane, characterized in that its retention factor in chloroform-methanol, 6: 1 mixture in Kieselgel GF 254 plate of TLC is 0.5. 5. Process for the preparation of compounds of the general formula (I), wherein R means hydrogen atom or alkyl group of 2 to 6 carbon atoms, characterized in that: a) the compound of the formula (III) is reacting with a compound of the general formula (IV), wherein the meaning of R is the same as defined in claim 1, and X means halogen atom, alkoxy group of 1 to 5 carbon atoms or hydroxyl group, and the resulting compound of the general formula (II), wherein the meaning of R is the same as given in claim 1, is transformed, in a reaction medium with pH above 7, into the compound of the 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 the general formula (V), wherein the meaning of R is the same as is defined above, the compound resulting from the general formula (II), in where the meaning of R is as given above, it is converted, in a reaction medium with pH above 7, into the compound of the general formula (I), or c) a compound of the general formula (II), in where the meaning of R is the same as defined above, it is transformed, in a reaction medium with pH above 7, into the compound of the general formula (I), and if desired, the resulting compounds of the general formula (I), before or after isolation, are transformed into acid addition salts, or the compounds of the general formula (I) are released from their acid addition salts. 6. The process according to claim 5, a) or b) or c), characterized in that the reaction is carried out in a homogeneous phase. 7. The process according to claim 5, a) or b) or c), characterized in that the reaction is carried out in a heterogeneous phase. The process according to claim 5, a) or b) or c), characterized in that alkali alcoholates, alkali metal hydroxides, alkali metal carbonates or ion exchange resins are used as the base. 9. The process according to claim 5, a) or b) or c), characterized in that the reaction takes place between the compound of the formula (III) and a compound of the general formula (IV) or (V), a acid binding agent. The process according to claim 9, characterized in that, as regards the acid binding agent, amines, alkaline earth metal carbonates, alkaline earth metal carbonates or alkaline earth metal oxides are applied. The process according to claim 5, characterized in that aromatic hydrocarbons, halogenated aliphatic hydrocarbons, aliphatic ethers, alcohols, as well as homogeneous or heterogeneous aqueous solvent systems formed between the above solvents and water are applied to the solvents. 12. The process according to claim 7, characterized in that the phase transfer and / or solution transfer catalyst is used. The process according to claim 11, characterized in that, in terms of phase transfer, alkyl ammonium acid sulphates, halogens or hydrogen hydroxides are used, and in terms of solution transfer, longer chain alcohols are used. . The process according to claim 5, a) or b) or c), characterized in that the reaction is carried out without the isolation of the compounds of the general formula (II).