GB2135996A

GB2135996A - New isoxazoles and process for the preparation thereof

Info

Publication number: GB2135996A
Application number: GB08405001A
Authority: GB
Inventors: Karoly Lempert; Gabor Doleschall; Jozsef Fetter; Gyula Hornyak; Jozsef Nyitrai; Gyula Simig; Karoly Zauer
Original assignee: Richter Gedeon Vegyeszeti Gyar RT; Biogal Gyogyszergyar Rt
Current assignee: Teva Pharmaceutical Works PLC; Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1983-02-28
Filing date: 1984-02-27
Publication date: 1984-09-12
Also published as: BE899007A; ES544192A0; ES8601935A1; NL8400575A; ES544191A0; FR2541678A1; CH658655A5; HU189236B; PT78157B; SE8401064D0; DE3405422A1; GB8405001D0; ES8604174A1; ES8604175A1; PT78157A; IT1174498B; IT8419806A0; JPS59164784A; ES530121A0; SE8401064L

Abstract

The invention relates to new isoxazole derivatives of the general formula <IMAGE> wherein X and Y which are the same or different, stand for a nitrile group, an optionally activated carboxylic group, a -CO2Z or -CONRR' group wherein Z represents a C1-6 alkyl group, R and R' represent a hydrogen atom, a phenyl or benzyl group or R and R' together with the nitrogen atom may form a heterocyclic ring, or X and Y together stand for an anhydride group of the formula <IMAGE> By catalytic hydrogenation, the compounds of the formula (I) can be transformed to intermediates for the preparation of thienamycin, a known broad-spectrum antibiotic.

Description

SPECIFICATION New isoxaloes and process for the preparation thereof The invention relates to new isoxazole derivatives of the general formula

wherein X and Y which are the same or different, stand for a nitrile group, an optionally activated carboxylic group, a -CO2Z or CONRR' group wherein Z represents a C16 alkyl group, R and R' represent a hydrogen atom, a phenyl or benzyl group or R and R' together with the nitrogen atom may form a heterocyclic ring, or X and Y together stand for an an hydroxide group of the formula

The compounds of the general formula (I), after transforming them by catalytic hydrogenation to the appropriate compounds of the general formula

wherein X and Y are as defined in the formula (I), can primarily be used as intermediates of thienamycin, a known broad-spectrum antibiotic.

The compounds of the general formula (iX) then are reduced, then condensed with benzaldehyde and the condensation product is, again, reduced to yield the lactone of the formula

which may be transformed to thienamycin according to the European Patent Application No. 32 400.

It has been found thqt the compounds of the general formulae (I) and (IX), respectively can be prepared from easily available starting materials, via an original, double ring-transformation method, which is easy to carry out. The compound of the formula (X) can then be obtained from the compound of the general formula (IX).

According to the process, the acetoacetate ester derivative of the formula

is cyclized with hydroxylamine hydrochloride to an isoxazole derivative of the formula

which is then hydrolyzed to yield the isoxazole-carboxylic acid of the formula

the carboxyl group of which is then activated by e.g. a phosphorus halide, thionyl chloride or a chloroformate ester to give a compound of the formula

wherein Q stands for a halogen or a C15 alkoxy-carbonyloxy group.

The compound of the formula (V) is brought into reaction- with a dialkyl malonate in the presence of magnesium, potassium tertiary-butylate or an alkali metal alkoholate to yield a compound of the general formula

and/or

wherein Z stands for a C16 alkyl group.

The tautomer pair so obtained is reacted with hydroxylamine hydrochloride to give compound(s) of the formula

and/or

which is converted into the compound(s) of the formula

by using acetic acid in the presence of sulphuric acid or an other strong acid. In the formulae (Ill), (ill), (li) and (lea) Z stands for a C, 6 alkyl group.

According to the invention compounds of the formulae (II) and (ill) are reacted with a strong base to yield a compound of the general formula (I) wherein Y stands for a carboxyl group and X stands for a nitrile group while other compounds covered by the general formula (I) are built up via further reaction steps.

All the compounds of the formulae (V), (IV), (IVa), (III), (Illa), (Ila) and (I) are new. Under the reaction conditions described in the examples the compounds are present in the tautomeric forms shown by formulae (IV), (III) and (II), respectively.

The invention relates to a process for the preparation of compounds of the general formula (I) wherein X and Y which are the same or different, stand for nitrile group, an optionally activated carboxylic group, a -CQ2Z or a CONRR' group wherein Z represents a C16 alkyl group, R and R' represent a hydrogen atom, phenyl of benzyl group or R and R' together with the nitrogen atom may form a heterocyclic ring, or X and Y together stand for an anhydride group of the formula

in such a way that a compound of the formula (II) and (ill) is reacted with a strong base to yield a compound of the general formula (I) wherein Y is a carboxyl and X is a nitrile group and the product so obtained a) is isolated, or b) optionally is subjected to hydrolysis to yield to compound of the general formula (I) wherein Y and X each represents a carboxyl group, or c) optionally the product of process variant a) is reacted with an activator for the carboxylic group to yield a compound of the general formula (I) wherein Y is an activated carboxylic and X is nitrile group, said product is isolated or optionally is reacted with an amine capable of providing an -NRR' group wherein R and R' have the same meaning as defined above, and the resulting compound of the general formula (I) wherein Y stands for a -CONRRC, and X for a nitrile group is isolated, or d) optionally the product of process variant a) or b) is reacted with a Cut 6 alkanol in the presence of a catalyst to yield a compound of the general formula (I) wherein X and Y each represents a COOZ group, or e) optionally the product of process variant b) is reacted with a dehydrating agent and the resulting compound of the general formula (I) wherein X and Y form together an anhydride group of the formula

is isolated, or f) optionally the product of process variant d) is reacted with an amine capable of providing an -NRR' group, wherein R and R' have the same meaning as defined above, and the resulting product of the general formula (I) in which Y is a -CONRR' group and X is a -COOZ group wherein Z has the same meaning as defined above, is isolated. The products are optionally converted to salts.

According to the process variant a) the reaction of the compound of the formula (ill) and/or (ill) with a strong base provides a compound of the general formula (I) wherein Y is a carboxylic group and X is a nitrile group. As a strong base an alkali metal hydroxide, an alkali metal alcoholate, diazabicyclo-/5.4.Q/undec-5-ene/DBU/ or like are used.

According to process variant b) of the invention, the product of the process variant a) is subjected to hydrolysis preferably in the presence of an acid, although alkaline hydrolysis is also applicable. A compound of the formula (I) wherein X and Y each represents a carboxylic group, is obtained.

According to process variant c) of the invention the product of process variant a) is first treated with an activator for the carboxyl group. Such activating agents are the phosphorus halides, thionyl chloride, carboxylic acid anhydrides or mixed anhydrides.

The activated compound is then brought into reaction with a substance capable of providing a Z esterifying group or a -NRR' group. Preferably, C16 alkanols, aniline, benzylamine and morpholine are used as reactants. When this reactant is a C1 6 alkanol, a tertiary amine is employed as an acid binding agent. When the reactant is an amine, the excess of this amine is used for binding the acid. When a C, 5 alkyl chloroformate is used as activator for the carboxylic group, a compound of the formula (I) is obtained wherein Y represents a -CO2Z group. In process variant c), compounds of the formula (I) can be prepared wherein X stands for a nitrile group and Y represents a -CO2Z or -CONRR' group.

According to process variant d) of the invention, the product of the process variant a) or b) is esterified. Preferred esterifying agents are C1 6 alkanols, in the presence of an acid catalyst. This reaction results in a compound of the general formula (I) wherein X and Y each represents a -CO2Z group.

According to the process variant e) of the invention, the product of the process variant b) is treated with a dehydrating agent. Preferably, an alkanecarboxylic acid anhydride is used and the reaction is carried out at elevated temperature, suitably at the boiling point of the reaction mixture. This reaction results in a compound of the general formula (I) wherein Y and X together represents a

group.

According to the process variant f) of the invention, the product of the process variant d) is reacted with an amine affording a -NRR' group at an elevated temperature to give a compound of the general formula (I) wherein Y represents a CONRR' group and X stands for a -CO2Z group.

The compounds prepared according to any process of the invention can be converted into the compounds of the formula (IX) by reduction.

The invention is elucidated in detail by the non-limiting Examples 1 to 16, while the preparation of the compounds of the general formula (IX) is demonstrated by the Examples 1 7 to 22, and that of the compound of the formula (X) by Example 23.

Example 1 Ethyl 5-methyl-4-isoxazolecarboxylate To a solution of 350 g (1.88 moles) of ethyl a-ethoxymethyleneacetoacetate in 400 ml of ethanol, a mixture containing 154 g (2.2 moles) of hydroxylamine hydrochloride, 180 g (2.2 moles) of sodium acetate and 500 ml of water is added and the solution is boiled for 30 minutes. The reaction mixture is poured into 2 litres of water, the phases are separated and the aqueous layer is extracted three times with 250 ml of dichloromethane, each. The dichloromethane solutions are combined with the organic phase and washed twice with 300 ml of water, each. After separation the phases the dichloromethane is evaporated under reduced pressure to obtain 281 g (96%) of the title compound; b.p.: 58-60 C (0.3 Hgmm). The product can be used for the next steps without purification.

1H-NMR (CDCl3): 8 1.4 t (3H); 2.7 s(3H); 4.25 g (2H); 8.5 s(1 H).

Example 2 5-Methyl-4-isoxazolecarboxylic acid A mixture containing 281 g (1.81 moles) of the product prepared according to Example 1, 200 ml of acetic acid, 200 ml of water and 200 ml of aqueous concentrated hydrochlorid acid is boiled for 8 hours, then evaporated to dryness. To the residue 400 mls of acetone are added and the solutions again, evaporated, and dried, to obtain 201 g (87%) of the title compound; m.p.: 146-147"C (toluene).

This compound is identical with that described by Kochetkov et al. (C.A. 1959, 9187i) on the basis of melting point and IR spectrum.

Example 3 5-Methyl-4-isoxazolecarboxylic acid chloride 350 ml of thionyl chloride are added within 10 minutes to 201 g (1.58 moles) of the product prepared according to Example 2 under stirring, then the reaction mixture is refluxed over oil bath of the temperature 1 20 C for one hour. The excess of thionyl chloride is distilled off under reduced pressure, then the residue is purified by fractional distillation in vacuo to give 191 g (83 %) of the title compound; b.p.: 100-102 C (18 Hgmm).

Analysis: for C5H4CINO2 (145.55) Calculated: C 41.26; H 2.77; N 9.68; Cl 24.36 % Found: C 41.19; H 2.92; N 9.57; Cl 24.22 % Example 4 Ethyl 1 -ethoxycarbonyl-2-hydrnxy-2-(5-methyl-4-isoxazolyl)-acrylate A mixture containing 66.5 g (2.73 atoms) of magnesium chips, 175 ml of benzene, 20 ml of ethanol and 1 ml of carbon tetrachloride is refluxed and within an hour a solution of 436 ml (2.73 moles) of diethyl malonate in 600 ml of benzene and 140 ml of ethanol is added to it under continuous boiling, then the reaction mixture is boiled for additional 3 hours. About 500 ml of solvent are distilled off from the reaction mixture, then 191 g (.31 moles) of the product prepared according to Example 3 dissolved in 200 ml of benzene are added to the residue under vigorous stirring at 35-40 C.The reaction mixture is stirred for additional 10 minutes, then cooled and is admixed with 230 ml of acetic acid and 1 800 ml of water. The benzene layer is separated, then is shaken once with aqueous concentrated hydrochlorid acid and twice with 300 ml of benzene, each. The combined benzene solution is washed with the mixture of 40 ml of concentrated hydrochlorid acid and 350 ml of water and then again with 400 ml of water and is filtered off.

From the organic phase the benzene is distilled off under reduced pressure. To the residue 600 mls of dichloromethane are added and after evaporation 600 ml of n-heptane are added to the residue, and after repeated evaporation the excess of the diethyl malonate is also distilled off over an oil bath of 135-140"C temperature (b.p.: 70-80" C/0.4 Hgmm, about 230 ml) From the residue under cooling 292 g (83 %) of crystalline title compound was obtained; b.p.: 140-144" C/0.4 Hgmm; m.p.: 56"C (1:1 ether-n-hexane) 'H-NMR (CDCl3): 6 1.3 t (3H), 2.7 s (3H), 4.25 q (2H), 4.9 s(1H), 8.5 s(lH).

Example 5 Ethyl 3-(5-methyl-4-isoxazolyl)-5-hydroxy-4-isoxazole-carboxylate A solution containing 292 g (1.08 moles) of the product prepared according to Example 4 and 100 g (1.45 moles) of hydroxylamine hydrochloride in 1 litre of ethanol is boiled for 5 hours and then evaporated under reduced pressure. The residue is dissolved in 1.2 litres of hot dichloromethane and is filtered off. The precipitate is washed twice with 200 ml of hot dichloromethane, each. The washings are combined with the filtrate. This solution is washed twice with 300 ml of water, each. Then the organic phase is evaporated under reduced pressure. To the residue 750 ml of dichloromethane are added, and is repeatedly evaporated.

The residue obtained is mixed thoroughly with 1 20 ml of ethyl acetate and is left to stand at 0 C. The crystalline precipitate is filtered, washed twice with 25 ml of cold ethyl acetate, each, then twice with 200 ml of n-hexane, each to obtain 1 54 g (62 %) of the title compound; m.p.: 153-154"C (ethyl acetate).

1H-NMR (DMSO-d6) 8 1.1 t (3H), 2.4 s (3H), 4.0 q (2H), 8.6 s (1H), 11.0 s (1H).

Example 6 3-(5-Methyl-4-isoxazolyl)-4,5-dihydro-5-isoxazolone A solution containing 1 54 g (0.646 mole) of the product prepared according to Example 5, 14 ml of concentrated sulphuric acid and 650 ml of acetic acid is boiled for 1 5 minutes. After ceasing of the vigorous evolution of carbon dioxide, 40 g of sodium acetate are added and the mixture is evaporated under reduced pressure. To the residue 300 ml of water are added and extracted first with 500 ml and then twice with 300 ml of dichloromethane, each. The organic phases are combined, washed twice with 250 ml of water each and the organic layer is evaporated. First, 500 ml of dichloromethane and then 300 ml of n-heptane are distilled off from the residue.The remained material is recrystallized from 1 30 ml of 2-propanol, filtered, washed, twice with 1 5 ml of ice-cold 2-propanol each, then twice with 75 ml of n-hexane each and was dried in the air yield 93.4 g (87 %) of the title compound; m.p.: 94-95"C.

1H-NMR (CDCl3): 6 2.7 s (3H), 3.8 s (2H), 9.4 s (1 H).

Example 7 4-Cyano-5-methyl-3-isoxazoleacetic acid To the solution of 57 g (1.42 moles) of sodium hydroxide in 350 ml of water, 93.4 g (0.563 mole) of the product prepared according to Example 6 are added at once under stirring at 25 C, then the mixture is stirred for 2 minutes, wherupon the temperature raises to about 70"C.

The reaction mixture is cooled by ice-water and then 145 ml of concentrated hydrochloric acid are added to it. After repeated cooling it is extracted with 350 ml, then twice with 1 50 ml of dichloromethane, each. After combination, the organic solution is washed twice with 80 ml of saturated aqueous sodium chloride solution each, then the organic phase is evaporated under reduced pressure. From the residue 250 ml of dichloromethane and then 150 ml of n-hexane are distilled off. The residue crystals upon standing to give 91.5 g (98 %) of the title compound; m.p.: 90-91 'C (benzene).

1H-NMR (CDCl3): 6 2.6 s (3H), 4.0 s (2H).

Example 8 4-Carboxy-5-methyl-3-isoxazoleacetic acid A solution containing 91.5 g (0.55 mole) of the product prepared according to Example 7, 100 ml of water and 100 ml concentrated hydrochloric acid is boiled for 3 hours, and then is cooled. The product precipitated is filtered off, washed twice with 40 ml of ice-cold water, each and dried in the air to yield 95.7 g (92 %) of the title compound; m.p.: 230-231 "C.

1H-NMR (DMSO-d6): 8 2.4 s(3H), 3.55 s (2H).

Example 9 Ethyl 4-ethoxycarbonyl-5-methyl-3-isoxazoleacetate a) A solution containing 95.7 g (0.517 mole) of the product prepared according to Example 8, 550 ml of ethanol and 1 60 ml of concentrated sulphuric acid is boiled for 8 hours, then poured into the mixture of 1 500 ml of water and 500 g of ice. The resulting solution is extracted with 500 ml, then twice with 250 ml of dichloromethane, each. After combination the organic phase is washed twice with 400 ml of water each and the organic solution is evaporated under reduced pressure. First 500 ml of dichloromethane and then 250 ml of n-hexane are distilled off from the residue, which is then purified by distillation in vacuoto afford 91.3 g (73 %) of the title compound; b.p.: 113-115 C/ 0.2 Hgmm; m.p.: 21" C.

1H-NMR (CDCl3): 6 1.22 t (3H), 1.30 t (3H), 2.6 s (3H), 3.85 s (2H, 41 5 q (2H), 4.25 q (2H).

b) A solution containing 32 g (193 moles) of the product prepared according to Example 7, 150 ml of ethanol and 75 ml of concentrated sulphuric acid is refluxed for 1 6 hours. The solution obtained is poured into the mixture of 250 ml of water and 250 g of ice and extracted with 1 50 ml and then twice with 100 ml of dichloromethane each. The combined organic phase is washed with 200 ml, and then with 100 ml of water. After distilling off the dichloromethane from the organic solution, 200 ml of dichloromethane are added again to, and then distilled off from the residue to give 22 g (47 %) of the title product having the same physical characteristics as given in Example 9a).

Example 10 n-Butyl 4-(n-butoxycarbonyl)-5-methyl-3-isoxazoleacetate The procedure described in Example 8 is followed, except that the mixture of n-butanol with benzene is used as reactant instead of ethanol and the water formed during the reaction is continuously removed. The title compound is obtained in yield of 74 %; b.p.: 130-132 C/0.1 Hgmm.

1H-NMR /CDCI3/: 8 0.90-1.05 m (6H), 1.15-1.90 m (8H), 2.65 s (3H), 3.85 s (2H) and 4.15 q (4H).

Example ii Ethyl 4-cyano-5-methyl-3-isoxazoleacetate A solution of 1 2.7 ml (130 mmoles) of ethyl chloroformate in 20 ml of anhydrous dioxane is added dropwise during 5 minutes to a mixture containing 20 g (120 mmoles) of the product prepared according to to Example 7, 100 ml of dioxane and 1 8 ml (130 mmoles) of triethylamine under cooling and stirring. After stirring for 10 minutes, the precipitated triethylamine hydrochloride is filtered off, the filrate is boiled for 30 minutes and then evaporated under reduced pressure. The distillation residue is mixed thoroughly with 50 ml of water and extracted three times with 80 ml dichloromethane, each. The combined dichloromethane solution is washed twice with each 30 ml of water, and is then evaporated.After distilling off 150 ml of dichloromethane and then 75 ml of n-hexane from the residue, 21.5 g (92 %) of the title compound are obtained. b.p.: 112-114" C/0.4 Hgmm.

IR spectrum: 2300, 1740cm-1.

1H-NMR/CDCl3/: 8 1.25 t (3H), 2.60 s (3H), 3.75 s (2H), 4.25 q (2H).

Example 12 N-(4-Cyano-5-methyl-3-isoxazo leacetyl)-benzyla mine A mixture containing 2 g (12 mmoles) of the product prepared according to Example 7, 20 ml of dry benzene and 2.7 g (13 mmoles) of phosphorus pentachlororide is boiled, and is then evaporated under reduced pressure. To the residue 20 ml of n-heptane preheated to 60"C are added, the oil (2.1 g) formed is separated and is dissolved in 10 ml of dra dioxane and to thie solution 2.3 ml (20 mmoles) of benzylamine are added. After 10 minutes, the solution containing a precipitate in diluted with 60 ml of water, the precipitate is filtered off, washed with water, dried and recrystallized from 20 ml of 2-propanol to give 2.3 g (90 %) of the title compound; m.p.: 143 "C.

IR spectrum: 3300, 2310, 1645 cm - ' .

'H-NMR /CDCI3/: 8 2.50 s (3H), 3.60 s(2H), 4.35 d (2H), 6.40 m (1 H), 7.15 s (5H).

Example 13 N-(4-Cyano-5-methyl-3-isoxazoleacetyl)-amine 10 g (60 mmoles) of the product prepared according to the Example 7 are reacted with 1 3.5 g (65 mmoles) of phosphorus pentachloride in the same way as described in Example 1 2. The oily, crude acid chloride is dissolved in 20 ml of dry dioxane and to the solution 11 ml (120 mmoles) of freshly distilled aniline dissolved in 30 ml of dry dioxane are added dropwise under cooling by ice-water within 5 minutes. The reaction mixture is stirred at room temperature for 1 5 minutes, then diluted with 100 ml of water. After filtration the precipitate is washed twice with 20 ml of water, each, then is dried and recrystallized from 80 ml ethanol to give 8.5 g (60 %) of the title compound; m.p.: 175 C.

IR spectrum: 3250, 2300, 1660 cm-'.

'H-NMR /DMSO-dF/: 8 2.60 s (3H), 3.95 s (2H), 7.00-7.65 m (5H).

N-(4-Cyano-5-methyl-3-isoxazoleacetyl)-morpholine 10 g (60 mmoles) of the product prepared according to Example 7 are reacted with 1 3.5 g (65 mmoles) of phosphorus pentachloride in the same way as described in Example 1 2. The obtained oily, crude acid chloride is dissolved in 25 ml of dry dioxane and is added dropwise to a solution of 10 ml (115 mmoles) morpholine in 25 ml of dry dioxane within 2 minutes. The mixture is stirred for 10 minutes, then the dioxane is distilled off under reduced pressure and the residue is mixed with 30 ml of water. The mixture is extracted three times with 30 ml of chloroform, each, the organic phase is separated, combined, wahed with 50 ml of water and evaporated under reduced pressure.After distilling off 100 ml of dichlormethane from the residue, the latter is recrystallized from 60 ml of 2-propanol to give 7.1 g (50 %) of the title compound; m.p.: 130-131 C.

IR spectrum: 2280, 640 cm-1.

'H-NMR /CDCI3/: 8 2.55 s (3H), 3.60 s (8H, 3.75 s (2H).

Example 15 N-(4-ethoxycarbonyl-5-methyl-3-isoxazoleacetyl)-benzylamine A mixture containing 50 g (207 mmoles) of the product prepared according to Example 9 and 23 ml (209 mmoles) of benzylamine is stirred over an oil bath af 185-195"C for 90 minutes and then is cooled. The product formed is triturated with 100 ml of n-hexane and is filtered off to give 5.4 9 (91 %) of the title compound; m.p.: 124-125"C after recrystallization from 2-propanol.

'H-NMR /CDCI3/: 8 1.30 t (3H), 2.60 s (3H), 3.75 s (2H), 4.20 q (2H), 4.35 d (2H), 7.15s (5H).

Example 16 6,7-Dihydro-4H-pyrano(3,4-c)isoxazole-4,6-dione The solution of 37 g (200 mmoles) of the product prepared according to Example 8 in 100 ml of acetic anhydride is boiled for 2 minutes and then the excess of the acetic anhydride is distilled off on a water bath of 80 C temperature. The residue in 100 ml of dry toluene and kept overnight in the refrigerator. The precipitate is filtered off, washed twice 1 5 ml of toluene each cooled to 0 C, then twice with of 30 ml of n-hexane each, and dried to yield 22.5 g (67 %) of the title compound; m.p.: 170-172" C (with decomposition).

IR spectrum: 1780,1750cm-1 'H-NMR /DMSO-d6/: S 2.40 s (3H), 3.55 s (2H).

Example 17 (E) Diethyl 2-acetyl-3-amino-2-pentenedioate A solution of 91.3 g (0.379 mole) of the product prepared according to Example 9a) or to Example 9b) in 800 ml of ethanol is hydrogenated in the presence of 4 g of palladium-charcoal under normal pressure at room temperature for about 1 50 to 180 minutes. After filtering off the catalyst, the filtrate is evaporated under reduced pessure and 100 ml of n-hexane are also distilled off from the residue which solidifies at 0 C to yield 91.2 g (98 %) of the title compound; b.p.: 147-149" C/0.4 Hgmm; m.p.: 41-42" C (ether-n-hexane).

Analysis: C1lHl7NO5 (243.26) Calculated: C 54.31; H 7.05; N 5.76 % Found: C 54.45; H 7.10; N 5.59 % 1H-NMR /CDCl3/: 8 1.25 t (3H), 1.30 t (3H), 2.28 s (3H), 3.55 s (2H), 4.12 q (2H), 4.18 q (2H).

Example 18 (Z) N-(3-Amino-4cyano-5-oxohexanonyl)-benzylamine A solution of 9 g (35.2 mmoles) of the product prepared according to Example 12 in 200 ml of methanol is hydrogenated in the presence of 1 g of 10 % palladium-charcoal catalyst under normal pressure at room temperature until the absorption of hydrogen ceases. After filtering the catalyst and distilling off the methanol, the residue is crystallized from 100 ml of 2-propanol to afford 7.5 q (83 %) of the title comoound; m.p.: 163 C.

'H-NMR /CDCI3): 8 2.15 s (3H), 3.40 s (2H), 4.30 d (2H), 7.15s (5H). 8.55 H).

Example 19 (Z) N-(3-Amino-4-cyano-5-oxo-3-hexenoil)-aniline A solution of 7.2 g (29.8 mmoles) of the product prepared according to Example 1 3 in 120 ml of dioxane is hydrogenated as described in Example 18, at 60 "C to Yield the title compound of 5.6 g (77 %); m.p.: 226 C (ethanol).

XH-NMR /DMSO-d6/: 8 2.15 s (3H), 3.60 s (2H), 7.00 -7.65 m (5H), 9.10 m (1H).

Example 20 (Z) N-(3-Amino-4-cyano-5-oxo-3-hexenoyl)-morpholine A solution of 7 g (30 mmoles) of the product prepared according to Example 1 4 in 75 ml of methanol is hydrogenated as described in Example 1 8 to give 4.5 g (64 %) of the title product; m.p.: 171 "C (2-propanol).

'H-NMR /DMSO-d6/: 8 1.95 s (3H), 3.30 s (10H), 8.80 H).

Example 21 (E) Ethyl 2-acetyl-3-amino-4-(N-benzylcarbamoyl)-2-butenoate 50 g (1 65 mmoles) of the product prepared according to Example 1 5 is hydrogenated as described in Example 18 to give 50 g (99 %) of the title compound; m.p.: 126-126 C (1:2 2propanol-n-hexane).

IR spectrum: 3250-3050; 1650 cm-l.

'H-NMR /CDCI3/: 8 1.20 t (3H), 2.20 s (3H), 3.30 s (2H), 4.15 q (2H), 4.30 d (2H), 7.10 s (5H), 7.65 m (9H).

Example 22 (Z) Ethyl 3-amino-4-cyano-5-oxo-3-hexenoate 11 g (56.6 mmoles) of the product prepared according to Example 11 are hydrogenated and worked up as described in Example 1 8 to yield 11 g (99 %) of the title compound; m.p.

70-71 C (diethyl ether).

IR spectrum: 3280, 3100, 2260, 1730 cm-l.

'H-NMR /CDCI3/: 8 1.25 t (3H), 2.30 s (3H), 3.55 s (3H), 4.15 q (2H), 7.95 m (1 H), 11.0 m (1 H).

Example 23 Preparation of (2 R S,3 R S,4S R)-2-methyl-4-banzylam ino-6-oxo-tetrahydropyrane-3-carboxylic acid hydrochloride 9 g (about 1 20 mmoles) of sodium cyanoboro-hydride (purity of about 90 %) are portionwise added to the solution of 16 g (53 mmoles) of the product prepared according to Example 21 in 1 50 ml of glacial acetic acid at room temperature under stirring within 30 minutes, then the mixture is stirred at room temperature for additional 3 hours and finally over a water bath of 80 C for 10 minutes. The reaction mixture was cooled to room temperature, 6.5 ml (60 mmoles) of benzaldehyde were added and was left to stand for 12 hours at room temperature.Then 5.5 g (about 75 mmoles) of sodium cyanoborohydride (purity of about 90 %) are, again, added in little portions under stirring within 30 minutes. After stirring for 3 hours at room temperature, the reaction mixture is evaporated under reduced pressure, then 300 ml of n-heptane are distilled off from the residue. To the residue first 300 ml of ethyl acetate then 300 ml of 10 % aqueous potassium hydrogen carbonate solution are added drop-wise and finally 30 g of solid potassium hydrogen carbonate are added. The ethyl acetate layer is separated, the aqueous phase is extracted twice with 200 ml of ethyl acetate each, and the combined ethyl acetate solution is washed first with 200 ml and then with 100 ml 10 % aqueous potassium hydrogen carbonate solution.The organic phase is evaporated under reduced pressure and the residue is boiled with 1 50 ml of aqueous concentrated hydrochloric acid for 3 hours. After evaporating in vacuo the solid residue is triturated with 100 ml of acetone, filtered after standing for 5 minutes and washed twice with each 25 ml of acetone. The product is triturated twice with 30 ml of water each, and is filtered off and dried in the air at 80 C to give 6.7 g (42 %) of the title compound; m.p. 163-164"C (decomposition).

'H-NMR /DMSO-d6 + CDCl3/: a 1.31 d (3H), J 5.6 Hz; 3.08 dd + 3.28 dd (2H, J = 15.5 Hz and 8.0 Hz; and 1 5.5 Hz and 9 Hz, respectively); 3.38 dd (1H, J = 3 Hz and 3.5 Hz); 4.04 dt (1H, J = 3 Hz and 8 Hz); 4.21 s (2H); 5.24 dq (1 H, J = 3.5 Hz and 6 Hz); 7.32-7.73 m (5H).

Claims

1. A process for the preparation of new isoxazole derivatives of the general formula

wherein X and Y which are the same or different, stand for a nitrile group, an optionally activated carboxylic group, a -CO2Z or CONRR' group wherein Z represents a C16 alkyl group, R and R' represent a hydrogen atom, a phenyl or benzyl group or R and R' together with the nitrogen atom may form a heterocyclic ring, or X and Y together stand for an anhydride group of the formula

or a salt thereof, which comprises reacting a compound of the formula

and/or

with a strong base and a) separating the obtained compound of the general formula (I) wherein Y stands for a carboxyl and X for a nitrile group, or b) optionally subjecting it to hydrolysis to yield a compound of the general formula (I) wherein Y and X each represents a carboxyl group, or c) optionally reacting the product of process variant a) with an activator for the carboxylic group to yield a compound of the general formula (I) wherein Y is an activated carboxylic and X is a nitrile group, isolating said product or optionally reacting it with an amine capable of providing an -NRR' group wherein R and R' have the same meaning as defined above, and isolating the resulting compound of the general formula (I) wherein Y stands for à -C0NRR', and X for a nitrile group, or d) optionally reacting the product of process variant a) or b) with a C16 alkanol in the presence of a catalyst to yield a compound of the general formula (I) wherein X and Y each represents a COOZ group, or e) optionally reacting the product of process variant b) with a dehydrating agent and isolating the resulting compound of the general formula (I) wherein X and Y form together an anhydride group of the formula

or f) optionally reacting the product of process variant d) with an amine capable of providing an -NRR' group, wherein R and R' have the same meaning as defined above, and isolating the resulting product of the general formula (I) in which Y is a -CONRR' group and X is a -COOZ group wherein Z has the same meaning as defined above.

2. The process a) as claimed in claim 1, which comprises using an alkaline metal hydroxide or an alcoholate as a strong base.

3. The process d) as claimed in claim 1, which comprises using an acid for promoting the hydrolysis.

4. The process c) as claimed in claim 1, which comprises using a phosphorus halide for activating the carboxyl group.

5. The process c) or f) as claimed in claim 1, which comprises using aniline, benzylamine or morpholine as amines affording a -NRR' group.

6. The process c) as claimed in claim 1, or a process as claimed in claim 4, which comprises using ethyl chloroformate for activating the carboxyl group and separating the compound of the formula (I) wherein X stands for the nitrile group and Y stands for the -CO2C2H5 group.

7. The process d) as claimed in claim 1, which comprises using a mineral acid as catalyst.

8. The process e) as claimed in claim 1, which comprises an acid anhydride as dehydrating agent.

9. A compound of the general formula

wherein X and Y which are the same or different, stand for a nitrile group, an optionally activated carboxylic group, a -CO2Z or -CONRR' group wherein Z represents an alkyl group containing 1 to 6 carbon atoms, R and R' represent a hydrogen atom, a phenyl or benzyl group or R and R' together with the nitrogen atom may also form a heterocyclic ring, or X and Y together stand for an anhydride group of the formula

or a salt thereof.

10. 4-Cyano-5-methyl-3-isoxazoleacetic acid.

11. 4-Carboxy-5-methyl-3-isocazoleacetic acid.

1 2. Ethyl 4-ethoxycarbonyl-5-methyl-3-isoxazoleacetate.

1 3. n-Butyl 4-(n-butoxycarbonyl)-5-methyl-3-isoxazoleacetate.

14. N-(4-cyano-5-methyl-3-isoxazoleeacetyl)-benzylamine.

1 5. N-(4-cyano-S-methyl-3-isoxazoleacetyl)-aniline.

1 6. Ethyl 4-cyano-5-methyl-3-isoxazoleacetate.

1 7. N-(14-cyano-5-methyl-3-isoxazoleacetyl)-morpholine.

18. N-(4-ethoxycarbonyl-5-methyl-3-isoxazole-acetyl)-benzylami ne.

1 9. 6, 7-Dihydro-4H-pyrano(3,4-c)-isoxazole-4,6-dione.

20. A process according to claim 1, substantially as hereinbefore described with reference to any of the Examples.

21. An isoxazole derivative according to claim 9, substantially as hereinbefore described with reference to any of the Examples.

21. An isoxazole derivative of the formula (I), when prepared by a process according to any of claim 1 to 8 and 20.