HU189236B - Process for producing new type isoxazoles - Google Patents

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

This invention relates to novel isoxazole derivatives of general formula (I).

In Formula 1, X and Y may be the same or different and X is a nitrile group, while Y may be a carboxyl group, -COOZ or -CONRR ', wherein Z is C 1 -C 6 alkyl, R is hydrogen, and R' is phenyl or benzyl, either R and R 'together with the nitrogen atom represent a morpholine ring, or X and Y are the same carboxyl or -COOZ group, where Z has the meaning given above, or X represents -COOZ group, where Z has the meaning and Y-CONRR' group. wherein R and R 'are as defined above or X and Y together are an anhydride of the formula O = C-O-C = O.

The compounds of formula I can be used primarily as an in-process product of Thienamycin, known as a broad spectrum antibiotic, when converted to the corresponding compounds of formula IX by catalytic hydrogenation. In Formula IX, X and Y have the same meaning as in Formula I. ^F

The compound of formula IX thus obtained can be converted into the lactone X by reduction and subsequent reduction of benzaldehyde condensation. European patent application can be further transformed into Thienamycin.

In our experiments, we have found that the compounds of formula I and IX can be prepared from the readily available starting materials by simple process steps and then transported to the compound of formula X.

The process involves firstly converting an acetoxyacetate derivative of formula VII in the presence of an acid scavenger with hydroxylamine hydrochloride to an isoxazole derivative of formula VII and then converting it to the isoxazole carboxylic acid of formula VI by hydrolysis. The resulting compound is then activated on its carboxyl group. As the carboxyl group activator, e.g. phosphorus halide, thionyl chloride or chloroformate. The compound of formula V thus obtained, wherein Q is halogen or C1-C5 alkoxycarbonyloxy, is reacted with a dialkyl malonate in the presence of magnesium, potassium tert-butylate or alkali metal alcoholate to form IV and / or IVa (Z = 1-6). C 1 alkyl). The tautomer (s) thus obtained is then converted to the compound of formula III and / or IIa with hydroxylamine hydrochloride and then to the compound of formula II and / or IIa in acetic acid in the presence of sulfuric acid or other strong acid. In the formulas III, IIIa, II, IIa, Z is a C 1-6 alkyl group. Compounds of formula II and IIa are starting materials for the process of the present invention, from which Y is -COOH and X is nitrile to a strong base, and the other compounds of formula I are formed by equine reaction.

The compounds of formulas V, IV, IVa, III, IIIa, IIa and I are all new.

Under the reaction conditions used, the possible tautomeric pairs are present in the tautomeric form of formulas IV, III and II.

The present invention therefore relates to a process for the preparation of isoxazole derivatives of formula I

in which X and Y may be the same or different and X may be a nitrile group, wherein Y is a carboxyl group, -COOZ or -CONRR ', wherein Z is C 1-6 alkyl, R is hydrogen, and R' is phenyl or benzyl, or R and R 'together with the nitrogen atom form a morpholine ring, or X and Y are the same carboxyl or -COOZ, wherein Z is as defined above, or X is -COOZ, wherein Z is the above and Y is a -CONRR' group, wherein R and R 'is as defined above, or X and Y together represent an O = C = O = C = O acid anhydride group by reacting a compound of Formula II and / or IIa with a strong base and yielding Y a carboxylic acid. and X is nitrile

(a) retrieved, or

b) if desired, hydrolyzing it preferably in the presence of an acid to recover the resulting compound of formula I having Y and X as carboxyl groups and optionally

i) converting the product of step a) into an acid halide and further reacting the resulting acid halide with an amine providing a -NRR 'group, wherein R and R' are as defined above, wherein X is a nitrile group and Y is a CONRR 'group. or (ii) reacting the product of step (a) with a (C1-C6) alkyl chloroformate and heating the resulting intermediate to give a compound of formula I wherein X is a nitrile group and Y is a -COOZ group. or (iii) reacting the product of (a) or (b) with a C 1-6 alkanol in the presence of a catalyst to give a compound of formula I wherein X and Y are -COOZ, wherein Z is above, recovering, or if desired, a product thus obtained, a -NRR 'group with a reaction amine wherein R and R 'are as defined above, recovering the resulting compound of formula I wherein Y is -CONRR' and X is -COOZ; or iv) reacting the product of step b) with a dehydrating agent. and recovering the product of formula I, wherein X and Y together form an acid anhydride.

According to process (a) of the present invention, the compound of formula II and / or IIa is reacted with a strong base to give a compound of formula I wherein Y is carboxyl and X is nitrile. Strong bases include alkali metal hydroxide, alkali metal alcoholate, or diazabicyclo [5.4.0] undec-5-ene (DBU), or the like.

According to process b) of the present invention, the product of process a) is hydrolyzed. The hydrolysis is preferably carried out in the presence of an acid, but is alkaline hydrolyzed

189,236 may also be used, e.g. In the presence of 20% aqueous sodium hydroxide. Y = X = COOH in the product obtained.

According to the subsequent step i) or ii) according to the invention, the product of process a) is first treated with a carboxyl group activator. Suitable activators for the subsequent step i) are in particular phosphorus halides, thionyl chloride, acid anhydrides or alkyl chloroformates (C16) for the subsequent step ii). The carboxyl-activated compound, the acid chloride, is then reacted with a compound providing a -NRR 'group. Preferably, aniline, benzylamine, morpholine is used as the reagent which is used in the excess to bind the resulting acid. If the activating agent used is C 1 -C 6 alkyl (chloroformate), it is heated in the presence of an acid acceptor directly to a Y-COZO group. Subsequent step (i) provides compounds of formula (1) wherein X is nitrile and Y is -CONRR ', and subsequent step (ii) is X which is nitrile and Y is -COOZ.

In step iii) of the present invention, the product of process a) or b) is esterified. The esterifying agent is preferably a C 1-6 alkanol in the presence of an acid catalyst. The product obtained is X = Y = -COOZ. If desired, the resulting compound is reacted with an amine providing a NRR 'group to give a product containing Y from -CONRR' to X from COOZ.

The product of process b) is treated with a dehydrating agent in step ar). Alkane carboxylic anhydride is preferably used and the reaction is carried out at elevated temperature, preferably at the reflux temperature of the reaction mixture. The reaction produces a compound in which Y and X together are O = C-O-C = O.

Any product of the present invention may be reductively converted to compounds of formula IX.

The procedure is described in more detail in Figures 1-16. Examples 17-22 of Examples 17-22. and the preparation of the compound of Formula X is illustrated by Example 23, but is not limited to the Examples.

/. example

Ethyl (5-methyl4-i: oxa: ol-carhoxyl)

350 g (1.88 mol) of α-ethoxymethylene acetacetate are dissolved in 400 ml of ethanol. 154 g (2.2 mol) of hydroxylamine hydrochloride and 180 g (2.2 mol) of sodium acetate in 500 ml of water are added and the solution is refluxed for 30 minutes. The reaction mixture was poured into water (2 L), the layers were separated, the aqueous layer was extracted with dichloromethane (3 x 250 mL), and the dichloromethane was combined with the organic phase and washed with water (2 x 300 mL). The phases were separated and dichloromethane was evaporated in vacuo. The residue can be used without further purification for further reaction steps.

Yield: 281 g (96,) of the title compound Fp .: 58-60 ° C (0.3 mmHg) @ 1 H-NMR (CDCl3): .delta., 4t (3H); 2.7 s (3H); 4.25 q (2H); 8.5 s (1H).

Example 2

5-methylpyridin-4-isoxazole carboxylic acid

281 g (1.81 mol) of the compound prepared in Example 1 are heated to reflux for 8 hours in 200 ml of glacial acetic acid, 200 ml of water and 200 ml of concentrated aqueous hydrochloric acid. Acetone (400 mL) was added to the residue and then distilled. The residue was air dried.

Yield: 201 g (87%) of the title compound

146-147 'C (toluene)

Op. And IR, the compound is identical to that described by Kochetkov et al. (CA / 959 9187i).

Example 3

5-Methyl-4-isoxazole-caronic acid chloride

To the compound prepared in Example 2 (201 g, 1.58 mol) was added thionyl chloride (350 mL) under stirring over 10 rpm and the reaction mixture was refluxed for one hour in a 120 ° C oil bath. The thionyl chloride residue is then distilled off in vacuo and the residue is purified by vacuum distillation.

Yield: 191 g (83%) of the title compound

Fp: 100-102 'C (18 mm Hg)

Elemental analysis for C ₅ H ₄ ClNO ₂ (M: 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 N-ethoxycarbonyl-2-hydroxy-2- (5-methylisoxazol-4-yl)] acrylate

66.5 g (2.73 atoms) of magnesium turnings are refluxed in a mixture of 175 ml of benzene, 20 ml of methanol and 1 ml of carbon tetrachloride and a mixture of 436 ml (2.73 mol) of diethyl malonate, 600 ml of benzene and 140 ml of ethanol is added over 1 hour. at reflux and reflux for an additional three hours. The reaction mixture was then cooled to ca. 500 ml of solvent were distilled off and 191 g (1.31 mol) of the compound prepared in Example 3 dissolved in 200 ml of benzene were added with vigorous stirring at 35-40 ° C. After stirring for ten minutes, 230 ml of glacial acetic acid and 1800 ml of water were added to the precipitated reaction mixture. The benzene layer was separated, and the aqueous layer was concentrated with concentrated hydrochloric acid, followed by 2 x 300 mL of benzene. After extraction, the combined benzene phase was washed with a mixture of 40 ml of concentrated hydrochloric acid and 350 ml of water, twice with 400 ml of water, filtered, and the organic phase was distilled off under reduced pressure. Dichloromethane (600 mL) was added to the residue and then distilled, then 600 mL of n-heptane was added and then distilled and finally the excess diethyl malonate was distilled using a 135-140 ° C oil bath (Fp: 70-80 ° C). , 0.4 mmHg, ~ 230 mL).

The residue was cooled and allowed to crystallize. Yield: 292 g (83%) of the title compound Mp: 140-144 ° C (0.4 mm Hg)

M.p. 56 'C (ether-n-hexane = 1: 1)

1 H-NMR (CDCl ₃ ): δ 1.3 t (3H), 2.7 s (3H).

4.25 q (2H), 4.9 s (1H), 8.5 s (1H).

Example 5

Ethyl [3- (5-methylisoxazol-4-yl) -5-hydroxy-4-isoxazolecarboxylate]

292 g (1.08 mol) of the compound prepared in Example 4 are heated to reflux for 5 hours with 100 g (1.45 mol) of hydroxy xylamine hydrochloride in 1 liter of ethanol. Then subject. the reaction mixture was concentrated in vacuo and the residue was dissolved in hot CH 2 Cl 2 (1.2 L) and filtered. The filtered precipitate was washed twice with 200 mL of warm dichloromethane and the wash was combined with the filtrate. The combined solution washed twice with 300 ml of water and the organic phase: concentrated in vacuo. Dichloromethane (750 ml) was added to the residue, which was distilled off and the residue was triturated with ethyl acetate (120 ml) and left to stand at 0 ° C. The crystals were filtered, washed with cold ethyl acetate (2 x 25 mL), n-hexane (2 x 200 mL) and air-dried.

Yield: 154 g (62%) of the title compound.

153-154 ° C (ethyl acetate) * 1 H-NMR (DMSO-d ₆ ): δ 1.1 t (3H), 2.4 s (3H), 4.0 q (2H), 8.6 s (1H), U, 0s (1H).

Example 6

3- (5-methylisoxazol-4-yl) -4,5-dihydroisoxazol-5-one

154 g (0.646 mol) of the compound prepared in Example 5 are heated in 650 ml of acetic acid in the presence of 14 ml of concentrated sulfuric acid for 15 minutes. After the vigorous evolution of carbon dioxide ceased, 40 g of sodium acetate were added to the solution and the mixture was concentrated in vacuo. To the residue was added water (300 mL) and extracted with dichloromethane (500 mL, 2 x 300 mL). The dichloromethane layers were combined, washed with water (2 x 250 mL) and the organic layer was evaporated. 500 ml of dichloromethane and then 300 ml of n-heptane are distilled off from the residue. The residue was recrystallized from 130 ml of 2-propanol, filtered, washed twice with 15 ml of ice-cold 2-propanol and twice with 75 ml of n-hexane and air dried.

Yield: 93.4 g (87%) of the title compound

94-95 ° C 1 H-NMR (CDCl ₃ ): δ 2.7 s (3H), 3.8 s (2H), 8.4 s (1H).

Example 7 To a solution of (5-Methyl-4-cyano-3-isoxazolyl) -acetic acid in g (1.42 mol) of sodium hydroxide in 350 ml of water at 25 'C with stirring,

In 236 portions, 93.4 g (0.563 mol) of the compound prepared in Example 6 are added and the mixture is stirred for 2 minutes while maintaining the temperature at ca. Rises to 70 'C. The reaction mixture was cooled with ice water and ⁵¹⁴⁵ mL of concentrated hydrochloric acid was added. After cooling again, it was extracted with dichloromethane (350 ml, then 150 ml twice). The organic layer was washed twice with 80 mL of saturated brine, and the organic layer was concentrated in vacuo. The residue is distilled off first with 250 ml of dichloromethane and then 150 ml of n-hexane. The rest crystallizes on standing.

Yield: 91.5 g (98%) of the title compound. 90-91 ° C (benzene) ' ⁵ ' H-NMR (CDCl ₃ ): δ 2.6 s (3H), 4.0 s (2H).

Example 8 _2Q (5-Methyl-4-carboxy-3-isoxazolyl) -acetic acid

91.5 g (0.55 mol) of the compound prepared in Example 7 are refluxed for 3 hours in a mixture of 100 ml of water and 1 ml of conc. Hydrochloric acid. After cooling, the precipitated product is filtered, washed twice with 40 ml of ²⁵ ice-cold water and air dried.

Yield: 95.7 g (92%) of the title compound.

230-231 C (water)

1 H-NMR (DMSO-d ₆ ): δ 2.4 s (3H), 3.55 s

Example 9

Ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetate ³⁵ a) The compound prepared in Example 8 (95.7 g, 0.517 mol) was heated to reflux for 8 hours in 550 ml of ethanol and 160 ml of concentrated sulfuric acid. The reaction mixture was poured into 500 g of ice and 1500 ml of water, the resulting solution was extracted first with 250 ml ⁴⁰ dichloromethane 500 mL and then twice. The organic layer was washed with water (2 x 400 mL) and the organic layer was concentrated in vacuo. 500 ml of dichloromethane and then 250 ml of n-hexane are distilled off from the residue and the residue obtained is purified by vacuum distillation.

Yield: 91.3 g (73%) of the title compound. Mp: 113-115 'C (0.2 mm Hg)

Mp: 21 'C

1 H-NMR (CDCl ₃ ): δ 1.22 t (3H), 1.30 t (3H),

2.6 s (3H), 3.85 s (2H), 4.15 q (2H), 4.25 q (2H). b) (5-Methyl-4-cyano-3-isoxazolyl) -acetic acid (32 g, 193 mmol) prepared in Example 7 was heated under reflux for 150 hours with 150 ml of ethanol and 75 ml of concentrated sulfuric acid. The reaction mixture was poured into a mixture of water (250 mL) and ice (250 g) and extracted with dichloromethane (150 mL, then 100 mL x 2). The dichloromethane phase was washed with water (200 ml) and then with water (100 ml). Dichloromethane is then distilled off. To the residue was added 200 ml of di60 chloromethane and distilled off.

Yield: 22 g (47%) of the title compound having the same physical constants as in Example 9a).

Example 10 n-Butyl [5-methyl-4- (n-butoxycarbonyl) -3-isoxazole] acetate.

The procedure was analogous to that described in Example 8 except that the reagent was replaced with n-butanol-benzene instead of ethanol and the resulting water was continuously removed.

mining; 74%

Mp .: 130-132 'C (0.1 mm Hg)

1 H-NMR (CDCl ₃ ): δ 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 11

Ethyl (5-methyl-4-cyano-3-isoxazolyl) acetate (g, 120 mmol) (5-methyl-4-cyano-3-isoxazolyl) acetic acid prepared in Example 7 under water-cooling in 100 ml dioxane 18 Stir in the presence of triethylamine (130 mL) and add a solution of ethyl chloroformate (12.7 mL, 130 mmol) in dry dioxane (20 mL) over five minutes. After stirring for 10 minutes, the precipitated triethylamine hydrochloride was filtered and the filtrate was refluxed for 30 minutes and then concentrated in vacuo. The residue was triturated with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The dichloromethane layer was washed with water (2 x 30 mL) and evaporated. To the residue was added dichloromethane (150 ml) and distilled off, followed by addition of n-hexane (75 ml) and distillation.

Yield: 21.5 g (92%) of the title compound.

Mp: 112-114'C (0.4 mm Hg)

IR: 2300, 1740 cm ^-1 .

1 H-NMR (CDCl 3): δ 1.25 t (3H), 2.60 s (3H),

3.75 s (2H), 4.25 q (2H).

Example 12

N-Benzyl (5-methyl-4-cyano-3-isoxazolyl) -acetamide (5-methyl-4-cyano-3-isoxazolyl) -acetic acid ( ² g, 12 mmol) in anhydrous 20 ml of anhydrous boiling in benzene with phosphorus pentachloride (2.7 g, 13 mmol) and evaporating the solution in vacuo. To the residue was added 20 ml of n-heptane at 60 ° C and the separated oil (2.1 g) was separated. It is then dissolved in 10 ml of anhydrous dioxane and 2.3 ml (20 mmol) of benzylamine are added. After 10 minutes, the precipitated solution was diluted with water (60 mL), filtered, washed with water, dried and recrystallized from 2-propanol (20 mL).

Yield: 2.3 g (90%) of the title compound.

Mp 143 ° C.

IR: 3300, 2310, 1645 cm -1 ¹ H-NMR (CDCl 3): δ 2.50 s (3H), 3.60 s (2H), 4.35 d (2H), 6.40 m (1H), 7.15 s (5H).

Example 13 (5-Methyl-4-cyano-3-isoxazolyl) acetanilide g (60 mmol), (5-Methyl-4-cyano-3-isoxazolyl) acetic acid prepared in Example 7 and 13.5 g Phosphorus pentachloride (65 mmol) was reacted as described in Example 12. The oily consistency of the crude acid chloride was dissolved in 20 ml of anhydrous dioxane and a solution of 11 ml (120 mmol) of freshly distilled aniline in 30 ml of anhydrous dioxane was added dropwise over 5 minutes under ice-water cooling. The reaction mixture was stirred for 15 minutes at room temperature and then diluted with 100 ml of water. The precipitated product was filtered off, washed with water (2 x 20 ml), dried and then recrystallized from ethanol (80 µl).

Yield: 8.5 g (60%) of the title compound

M.p. 175 'C

IR: 3250, 2300, 1660 cm '

1 H-NMR (DMSO-d ₆ ): δ 2.60 s (3H), 3.95 s (2H), 7.00-7.65 m (5H).

Example 14

N - [(5-Methyl-4-cyano-3-isoxazolyl) methylcarbonyl] morpholine g (60 mmol), (5-Methyl-4-cyano-3-isoxazolyl) acetic acid prepared in Example 7 Phosphorus pentachloride (13.5 g, 65 mmol) was reacted as described in Example 12. The resulting oily consistency of the crude acid chloride crude product was dissolved in 25 mL of anhydrous dioxane and added dropwise over 2 minutes to a solution of 10 mL (115 mmol) of morpholine in 25 mL of anhydrous dioxane. After stirring for 10 minutes, the dioxane was distilled off in vacuo and the residue was stirred with water (30 mL). The aqueous mixture was extracted with chloroform (3 x 30 mL), the chloroform layer was separated, washed with water (2 x 50 mL) and evaporated in vacuo. Dichloromethane (100 mL) was added to the residue, which was distilled off. The residue was recrystallized from 60 ml of 2-propanol.

Yield: 7.1 g (50%) of the title compound

M.p. 130-131 ° C

IR: 2280, 1640 ^cm-1

1 H-NMR (CDCl 3): δ 2.55 s (3H), 3.60 s (8H),

3.75 s (2H).

Example 15

N-Benzyl (5-methyl-4-ethoxycarbonyl-3-isoxazolyl) -acetamide g (207 mmol), ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazole) acetate prepared in Example 9 (23 mL). Stir with benzylamine (209 mmol) in an oil bath at 185-195 ° C for 90 minutes and cool the reaction mixture. The precipitated product was triturated with 100 mL of nhexane and filtered.

Yield: 5.4 g (91%) of the title compound.

124-125 ° C (2-propanol).

1 H-NMR (CDCl 3): δ 1.30 t (3H), 2.60 s (3H),

3.75 s (2H), 4.20 q (2H), 4.35 d (2H), 7.15 s (5H).

189,236

Example 16

6,7-Dihydro-4H-pyrano [4,3-c] isoxazole-4,6-dione (200 mmol) (5-methyl-4-carboxy-3-isoxazole) acetic acid prepared in Example 8 (100 mL) After boiling for 2 minutes in acetic anhydride, the excess acetic anhydride was distilled off in a water bath at 80 ° C. Dissolve the residue in 100 ml of anhydrous pond and leave to stand overnight in a refrigerator. The precipitate was filtered and washed twice with 15 ml of toluene at 0 ° C and twice with 30 ml of n-hexane and dried.

Yield: 22.5 (67%) of the title compound

170-172 ° C (dec.).

IR: 1780, 1750 ^cm-1

1 H-NMR (DMSO-d ₆ ): δ 2.40 s (3H), 3.55 s (2H).

Example 17

Diethyl (E) -2-acetyl-3-amino-2-pentene-1,5-dioate

91.3 g (0.379 mol) of the compound prepared in Example 9a or b are hydrogenated in 800 ml of ethanol in the presence of 4 g of palladium on charcoal at atmospheric pressure at room temperature (150-180 minutes). The catalyst was filtered off, the filtrate was concentrated in vacuo, and 100 ml of n-hexane was distilled off. The residue thus obtained solidifies at 0 ° C.

Yield: 91.2 g (98%) of the title compound.

MP: 147-149 'C (0.4 mm Hg)

41-42 'C (ether / n-hexane)

Elemental analysis for C _n H ₁₇ NO ₅ (M = 243.26):

Found: C, 54.31; H, 7.05; N, 5.76; Found: C, 54.45; H, 7.10; N, 5.59.

1 H-NMR (CDCl ₃ ): δ 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) -3-Amino-4-cyano-5-oxo-3-hexenoic acid benzylamide (35.2 mmol), N-benzyl- (5-methyl-4-cyano) prepared in Example 12 -3-isoxazolyl) acetamide in methanol (200 mL) in the presence of 1 g of 10% palladium on carbon at room temperature was 1 atm. hydrogenation under pressure until hydrogen consumption stops. The catalyst is filtered off, the methanol is removed from the filtrate and the residue is recrystallized from 100 ml of 2-propanol.

Yield: 7.5 g (83%) of the title compound.

M.p .: 163 'C 1 H-NMR (CDCl ₃ ): δ 2.15 s (3H), 3.40 s (2H),

4.30 d (2H), 7.15 s (5H), 8.55 m (1H).

Example 19 (Z) -3-Amino-4-cyano-5-oxo-3-hexenoic anilide

(5-Methyl-4-cyano-3-isoxazolyl) -acetanilide (7.2 g, 29.8 mmol) prepared in Example 13 was hydrogenated in 120 mL of dioxane at 60 ° C as described in Example 18.

Yield: 5.6 g (77%) of the title compound. M.p .: 226 'C (ethanol).

1 H-NMR (DMSO-d ₆ ): δ 2.15 s (3H), 3.60 s (2H), 7.00-7.65 m (5H), 9.10 m (1H).

Example 20

N - [(Z) -3-Amino-4-cyano-5-oxo-3-hexenoyl] -morpholine.

g (30 mmol) of N - [(5-methyl-4-cyano-3-isoxazolyl) methylcarbonyl] morpholine prepared in Example 14 was hydrogenated in 75 mL of methanol as described in Example 18.

Yield: 4.5 g (64%) of the title compound.

M.p .: 171 C (2-propanol) 1 H-NMR (DMSO-d ₆ ): δ 1.95 s (3H), 3.30 s (10H), 8.80 s (1H).

Example 21

Ethyl [2-acetyl-3-amino-4- (N-benzylcarbamoyl) -2- (E) -butenoate] g (165 mmol), prepared as in Example 15, was treated with N-benzyl- (5-methyl- 4-Ethoxycarbonyl-3-isoxazolyl) -acetamide is hydrogenated as described in Example 18 and the product is isolated as described there.

Yield: 50 g (99%) of the title compound, m.p. 126-127 ° C (1: 2 mixture of 2-propanol and n-hexane)

IR: 3250-3050; 1690; 1650 cm -1 ¹ H-NMR (CDCl ₃ ): δ 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

Ethyl [3-amino-4-cyano-3 (Z) -hexenoate] g (56.6 mmol), all. The ethyl (5-methyl-4-cyano-3-isoxazole) acetate prepared according to Example 1b was hydrogenated and recovered as described in Example 18.

Yield: 11 g (99%) of the title compound.

M.p. 70-71 ° C (diethyl ether).

IR: 3280, 3100, 2260, 1730 cm -1 1 H-NMR (CDCl 3): δ 1.25 t (3H), 2.30 s (3H),

3.55 s (3H), 4.15 q (2H), 7.95 m (1H), 11.0 m (1H).

Example 23 (2RS, 3RS,

4SR) -4- (Benzylamino) -2-methyl-6-oxo-tetrahydropyran-3-carboxylic acid hydrochloride g (53 mmol), Example 21 Ethyl [2-acetyl-3-amino-4- (N- benzylcarbamoyl) -2- (E) -butenoate] To 150 ml of glacial acetic acid was added 9 g (~ 120 mmol) of ~ 90% sodium tri-cyano trihydroborate in small portions at room temperature for 30 minutes, followed by stirring for 3 hours at room temperature and and finally for 10 minutes in a water bath at 80 ° C. The reaction mixture was cooled to room temperature and this was 61

After 189,236, benzaldehyde (6.5 mL, 60 mmol) was added and the mixture was allowed to stand at room temperature for 12 hours, and a further portion of sodium cyanohydroborate (5.5 g, ~ 75 mmol) ~ 90% was added over 30 minutes with stirring. installments. The reaction mixture was stirred at room temperature for 3 hours, evaporated in vacuo and 300 ml of n-heptane was distilled off. Ethyl acetate (300 mL) was added to the residue and carefully added (10 mL) with 10% aqueous potassium bicarbonate solution (30 mL) and solid potassium bicarbonate (30 g). The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL), and the combined ethyl acetate was washed with 10% aqueous potassium bicarbonate (200 mL, then 100 mL). The organic phase is concentrated in vacuo and the residue is refluxed with 150 ml of concentrated aqueous hydrochloric acid for 3 hours. The reaction mixture was concentrated in vacuo and the residual solid was triturated with acetone (100 mL), filtered after standing for 5 min, washed with acetone (2 x 25 mL). The reaction mixture was then triturated with water (2 x 30 ml), filtered and air-dried at 80 ° C.

Yield: 6.7 g (42%) of the title compound. 163-164 'C (dec.).

1 H-NMR (DMSO-d ₆ + CDCl ₃ ): δ 1.31 d (3H,

J = 5.6 Hz); 3.08 dd + 3.28 dd (2H, J = 15.5 Hz and 8.0 Hz; respectively 15.5 Hz and 9 Hz); 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 (1H, J = 3.5 Hz and 6 Hz); 7.32-7.73 m (5H).

Claims (7)

Claims A process for the preparation of novel isoxazole derivatives of formula I in which X and Y may be the same or different and X may be a nitrile group, wherein Y is a carboxyl group, -COOZ or - CONRR ', wherein Z is a C 1-6 alkyl group, R is a hydrogen atom, and R' is a phenyl or benzyl group, or and R 'together with the nitrogen atom form a morpholino ring, or X and Y are the same carboxyl or -COOZ, wherein Z is as defined above, or X is -COOZ, wherein Z is as defined above, and Y is -CONRR', wherein R and R ', as defined above, desire X and Y together represent an O = C = O = C = O acid anhydride - characterized in that a compound of formula II and / or Ha is reacted with a strong base and the resulting Y is carboxylic acid. and X is nitrile (a) retrieved, or b) optionally hydrolyzed preferably in the presence of acid and I is the received Y and X is karboxilcsor ports compound of formula ⁵ is recovered and, if desired, i) converting the product of step a) into an acid halide and further reacting the resulting acid halide with an amine providing a -NRR 'group, wherein R and R' are as defined above, wherein X is a nitrile group and Y is a CONRR 'group recovering, or ii) the product of process a) is reacted with a (1-6C) alkyl chloroformate (chloroformate), then heating the resulting intermediate ^15, and X is a nitrile group, and Y is obtained although alkaline hydrolysis moiety having formula I wherein Z is as defined in the scope, 9n ^or iii) reacting the product of process a) or b) with a C 1 -C 6 alkanol in the presence of a catalyst to recover the resulting compound of formula I wherein X and Y are -COOZ, wherein Z is as defined in the present invention, 25 or optionally the product obtained is a -NRR' provider amine group - where R and R 'are as defined above - is further processed and the resulting Y is CONRR' group and X is - COOZ group containing I ^{to 30} it or (iv) reacting the product of method (b) with a dehydrating agent and recovering the product of formula (I) wherein X and Y together form an anhydride. ³⁵ Process (a) according to claim 1, characterized in that the strong base is an alkali metal hydroxide or an alcoholate. Subsequent step i) according to claim 1, characterized in that phosphorus halide ^{40 is} used for the acid halide conversion. The subsequent step (i) or (iii) of claim 1, wherein the amine providing the -NRR 'group is aniline, benzylamine, or morpholine. 45 Subsequent step ii) of claim 1, wherein the reagent is ethyl chloroformate and the compound of formula I is obtained after heating, wherein X is nitrile and Y is -COOZ. 50 6. The subsequent step iii) of claim 1, wherein the catalyst is a mineral acid. Subsequent step iv) according to claim 1, characterized in that it is a dehydrating agent 55 anhydrides are used.