HU188431B - Process for producing new alkene-diacid derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of novel alkenic acid derivatives of the formula I, wherein X is a nitrile group or a (C 14) alkoxycarbonyl group, and Y is -COOZ or -CONRR ', wherein Z is C 1-4 alkyl. , R and R 'are phenyl or benzyl. or R and R ', together with the nitrogen atom, represent a morphine ring. by reducing a new compound of formula II wherein X and Y are as defined above. The novel compounds produced are intermediates of thienamycin and related compounds. y-ch2 y-CH2 X • ch3

Description

The present invention relates to novel alkenedioic acid derivatives of the general formula (I).

In the general formula I

X is a nitrile group or a (C 1 -C 4) alkoxycarbonyl group, and

Y is -COOZ or CONRR ', wherein Z is C1-C4 alkyl, R and R' are phenyl or benzyl, or R and R 'together with the nitrogen atom are morpholino ring.

The compounds of formula I are primarily useful as in-process products of Thienamycin, known as a broad spectrum antibiotic.

The compound of formula (1) can be converted into the lactone of formula X by reduction followed by further reduction of benzaldehyde condensation. can be further converted to thienamycin.

In our experiments, we have found that readily available starting materials can be used to prepare compounds of Formula I in an easy, two-step procedure using the original double-ring transformation process to yield the compound of Formula X.

First, an acetyl acetate derivative of formula IX in the presence of an acid acceptor is converted to the isoxazole derivative of formula VIII by hydroxylamine hydrochloride, followed by hydrolysis to the isoxazole carboxylic acid of formula VII. The resulting compound is then activated on its carboxyl group. As a carboxyl group activator, e.g. phosphorus halide, thionyl chloride or chloroformate. The compound of formula VI thus obtained, wherein Q represents a halogen atom or a C 1 -C 5 alkoxycarbonyloxy group, is reacted with a dialkyl malonate in the presence of magnesium, potassium tert-butylate or an alkali metal alcoholate (Z = 1-). C 6 alkyl). The tautomer (s) thus obtained is then converted to compounds of formula IV and / or IVa with hydroxylamine hydrochloride and then to acetic acid in the presence of sulfuric acid or other strong acid to give compounds of formula III and / or IIIa.

In the formulas III, IIIa, IV, IVa, Z is a C 1-6 alkyl group.

From the compounds of the formulas III and / or IIIa the isoxazole derivatives of the formula II are prepared.

In the general formula II

X and Y may be the same or different and represent a nitrile group, an optionally activated carboxyl group, -COOZ or -CONRR 'group, wherein Z is (C 1 -C 6) alkyl, R and R' are hydrogen, phenyl or benzyl, or R and R 'are a heterocyclic group containing a nitrogen atom, or

X and Y together represent an acid anhydride of the formula O = C-O-C = O.

Compounds of formula II are prepared by reacting a compound of formula III and / or IIa with a strong base to give the product of formula II, wherein Y is carboxyl and X is nitrile

(a) retrieved, or

b) if desired hydrolyzing and yielding Y and

Recovering a compound of formula II wherein X is carboxyl; or

c) optionally reacting the product of step a) with a carboxyl activator, optionally recovering a compound of formula II containing a carboxyl group activated by Y, or reacting a carboxyl group of a compound of formula II with an amine providing -NRR ', wherein R and R 'is as defined above, and is reacted to give the resultant compound II wherein X is nitrile and Y is -CONRR'. recovering a compound of the formula: or

d) if desired, reacting the product of process a) or b) with a C 1-6 alkanol in the presence of a catalyst to recover the resulting compound of formula II wherein X and Y are -COOZ; or

e) optionally reacting the product of process b) with a dehydrating agent and recovering the product of formula II in which X and Y together form an acid anhydride; or

f) optionally reacting the product of method d) with an amine providing a -NRR 'group, wherein R and R' have the meanings given above, to give the resulting compound of formula II wherein Y is -CONRR 'and X is -COOZ compound.

The isoxazole derivatives of formula 11 are starting materials for the process of the present invention. From these, the novel alkene diacid derivative of formula I of the present invention can be obtained by reduction, preferably by catalytic hydrogenation.

The compounds of formulas VI, V, Va, IV, IVa, III, IIIa, II and I are all new. The preparation of the compounds of formula II is protected by a separate application. The tautomeric pairs of formulas V-Va, IV-IVa, IIIIIa are present under the reaction conditions used in the tautomeric forms of formulas IV, 111 and II.

The present invention therefore relates to a process for the preparation of the novel alkenedioic acid derivatives of the general formula (1) in this formula

X is a nitrile group or a (1-4C) alkylcarbonyl group, and

Y is -COOZ or -CONRR ', where Z is C 1 -C 4 alkyl, R and R' are phenyl or benzyl, or R and R 'are taken together with the nitrogen atom to form a morpholino ring, such that a new compound wherein X and 5 'are as defined above is reduced.

In the process of the invention, compounds of formula II are reduced. The reduction is conveniently carried out by catalytic hydrogenation.

The catalyst used is a platinum metal, especially palladium on carbon, but Raney nickel can also be used.

The catalytic hydrogenation may be carried out in C1-C5 alkanol or alkane carboxylic acid or in a cyclic ether. Preferred representations of the solvent types listed are methanol, ethanol, glacial acetic acid and dioxane.

The catalytic hydrogenation is suitably room temperature2

188 431 at atmospheric pressure and after filtering off the catalyst, the product is isolated by evaporation and / or extraction.

17-22. Examples 1 to 16 are the starting materials for the preparation of starting materials. Examples 1 to 6 and Examples 23 further illustrate the manner in which the compounds of Formula I may be further transformed, but are not limited to the Examples.

1. péhlct

Enl- (5-Melheim-4-i t> x t> yl) -kurboxilál

Dissolve 350 g (1.88 mol-ethoxymethylene-acetyl acetate) in 400 ml of ethanol, add 154 g (2.2 mol) of hydroxylamine hydrochloride and 180 g (2.2 mol) of sodium acetate in 500 ml of water, and add The mixture is poured into 2 L of water, the phases are separated, the aqueous phase is extracted three times with 250 ml of dichloromethane each time, the dichloromethane is combined with the organic phase and washed twice with 300 ml of water each time. The methane is removed in vacuo and the residue can be used without further purification for further reaction steps.

Yield: 281 g (96%) of the title compound.

Mp: 58-60 ° C (0.3 mmHg)

1 H-NMR (CDCl 3): 51.4 t (3H); 2.7 s (3H); 4.25 q (2H); 8.5 s (1H).

Example 2 (5-Inctil-4-i: i) X (i: (ylcarboxylic acid)

The compound prepared in Example 1 (281 g, 1.81 mol) was heated to reflux for 8 hours in glacial acetic acid (200 ml), water (200 ml) and concentrated hydrochloric acid (200 ml). Acetone (400 mL) was added to the residue and then distilled. The residue was air dried. Yield: 201 g (87%) of the title compound m.p. 146-147'C (toluene)

Op. And IR, the compound is identical to that described by Kochetkov et al., CA 1959 9187i.

Example 3 (5-inelyl-4-i: t) .alpha.-olyl i-carboxylic acid chloride

To the compound prepared in Example 2 (201 g, 1.58 mol) was added thionyl chloride (350 mL) over 10 minutes with stirring, and the reaction mixture was refluxed for one hour in a 120 'Cos oil bath. The excess thionyl chloride 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 ₊ C ₁ NO 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 [1-ethoxycarbonyl-2-hydroxy-2- (5-methylisoxazol-4-yl)] acrylate

A mixture of magnesium turnings (66.5 g, 2.73 atoms) was heated to reflux in benzene (175 ml), ethanol (20 ml) and carbon tetrachloride (1 ml) and diethyl malonate (436 ml, 2.73 mol), benzene (600 ml) and ethanol (140 ml). and the reaction mixture is refluxed 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 elimination, the combined Bezolic 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 benzene in the organic phase was distilled off in vacuo. Dichloromethane (600 mL) was added to the residue and distilled off, followed by addition and distillation of n-heptane (600 mL) and finally distilling off excess diethyl malonate using a 135-140 ° C oil bath (Fp: 70-80 ° C). .4 mmHg, ~ 230 mL). The residue was cooled and allowed to crystallize.

Yield: 292 g (83%) of the title compound Fp: 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-methyl-i-Oxa: ol-4-yl) -5-hydroxy-4-isoxazole: ol-carboxylate]

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 hydroxylamine hydrochloride in 1 L of ethanol. The reaction mixture was concentrated in vacuo and the residue was dissolved in hot 1.2 L dichloromethane and filtered. The filtered precipitate was washed twice with 200 mL of warm dichloromethane and the washings were combined with the filtrate. The combined solution was washed with water (2 x 300 mL) and the organic phase was concentrated in vacuo. Dichloromethane (750 mL) was added to the evaporation residue and the resulting residue was triturated with ethyl acetate (120 mL) and allowed to stand at 0 ° C. The crystals were filtered and 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), 11.0 s (1H).

188,431

Example 6

3- (5-methylisoxazol-4-11) -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 has ceased, 40 g of sodium acetate are added and the mixture is 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 of the title compound (87%) mp: 94-95 ° C NMR _(CDCl3)?: 2.7 s (3H), 3.8 s (2H), 8.4 s (2 H).

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, was added in one portion 93.4 g (0.563 mol). the compound prepared in Example 6 was added and the mixture was stirred for 2 minutes while maintaining the temperature at ca. Rises to 70'C. The reaction mixture was cooled with ice water and 145 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 aqueous sodium chloride solution 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 Mp: 90-91 'C (benzene)

1 H-NMR (CDCl 3) δ: 2.6 s (3H), 4.0 s (2H).

Example 8 (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 100 ml of water and 100 ml of concentrated hydrochloric acid. The reaction mixture is cooled, the precipitated product is filtered off, washed twice with 40 ml of 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 (2H).

Example 9

Ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazolyl) acetate

a) 95.7 g (0.517 mol) of the compound prepared in Example 8 are heated in a mixture of 550 ml of ethanol and 160 ml of concentrated sulfuric acid for 8 hours. The reaction mixture was then poured into a mixture of 500 g of ice and 1500 ml of water, and the resulting solution was extracted with 500 ml of dichloromethane and twice 250 ml of dichloromethane. 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.

Fo: 113-115'C (0.2 mm Hg)

M.p. 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 g (2H).

b) (5-Methyl-4-cyano-3-isoxazolyl) -acetic acid (32 g, 193 mmol) was heated under reflux for 16 hours with a mixture of 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. Dichloromethane (200 mL) was added to the residue 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-isoxazolyl facerate

The procedure was analogous to that described in Example 8, except that the reagent was replaced with n-butanol-benzene and the effluent was continuously removed.

Yield: 74%

Fp: 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-ylanil-3-i: oxa: (> lyl) -acetate g (120 mmol) of the (5-methyl-4-cyano-3-isoxazolyl) acetic acid prepared in Example 7 while cooling with water, stirred in dioxane (100 mL) in the presence of triethylamine (18 mL, 130 mmol) and a solution of ethyl chloroformate (12.7 mL, 130 mmol) in dry dioxane (20 mL) was added dropwise over 5 minutes. After filtration, the filtrate was refluxed for 30 minutes, evaporated in vacuo, the residue was triturated with water (50 mL) and extracted with dichloromethane (3 x 80 mL), washed with water (2 x 30 mL), methane was added and distilled off, then 75 ml of n-hexane was added and then distilled,

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

Fp: 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).

188,431

Example 12

N-Benzyl- (5-methyl-4-cyano-3-isoxazolyl) -acetamide (12 mmol) (5-methyl-4-cyano-3-isoxazolyl) -acetic acid prepared in Example 7 in 20 ml of anhydrous benzene. After boiling with 7 g (13 mmol) of phosphorus pentachloride, the solution was concentrated in vacuo. To the residue was added n-heptane (60 mL, 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 standing for 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).

Mp: 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 75

N-Benzyl (5-methyl-4-ethoxycarbonyl-3-isoxazolyl) acetamide g (207 mmol) of ethyl (5-methyl-4-ethoxycarbonyl-3-isoxazolyl) acetate prepared in Example 9 (23 mL) The reaction mixture was cooled. The precipitated product was triturated with 100 ml of n-hexane and filtered.

Yield: 54 g (91%) of the title compound

Mp: 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).

Example 13 (5-Methyl-4-cyano-3-isoxazolyl) -acetanilide g (60 mmol) in (7-methyl-4-cyano-3-isoxazolyl) -acetic acid prepared in Example 7 and 13.5 g (65 mmol) Phosphorus pentachloride was reacted as described in Example 12. The oily consistency 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 ml).

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

Mp: 175 'C

IR: 3250, 2300, 1660 cm -1

Ή NMR (d DMS _O) 8: 2.60 s (3H). 3.95 s (2H), 7.00-7.65 m (5H).

Example 14

N - ((5-Methyl-4-cyano-3-isoxazole) -acetyl) -morpholine g (60 mmol) The (5-methyl-4-cyano-3-isoxazolyl) -acetic acid prepared in Example 7 was treated with 13.5 g (65%). Phosphorus pentachloride (mmol) was reacted as described in Example 12. The resulting oily crude acid chloride was dissolved in 25 mL of anhydrous dioxane and added dropwise to a solution of 10 mL (115 mmol) of morpholine in 25 mL of anhydrous dioxane. The dioxane was distilled off in vacuo and the residue was stirred with water (30 mL), extracted with chloroform (3 x 30 mL), the chloroform layer was separated, washed with water (2 x 50 mL), and the residue was treated with dichloromethane (100 mL). The residue was recrystallized from 60 ml of 2-propanol.

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

Example 76

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

Yield: 22.5 g (67%) of the title compound

Mp: 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 7

Dielyl [(E) -2-acetyl-3-amino-2-pentenedioate]

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

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

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

Mp: 4M2 ° 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).

188,431

Example 18 (Z) -3-Amino-4-cyano-5-oxo-3-hexenoic acid benzylamide g (35.2 mmol) was prepared as described in Example 12 for N-benzyl- (5-methyl-4- cyano-3-isoxazole) acetamide

200 ml of methanol in the presence of 1 g of 10% palladium on carbon at room temperature and 1 atm. hydrogenation under pressure until hydrogen consumption stops. The catalyst was filtered off, the methanol was removed from the filtrate and the residue was recrystallized from 100 ml of 2-propanol.

Yield: 7.5 g (83%) of the title compound. Mp: 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-hexenoic anilide

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

Yield: 5.6 g (77%) of the title compound.

Mp: 226 'C (ethanol)

Ή NMR (DMSO-d _O): δ 2.15 s (3Ή), 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-isoxazole) -acetyl] -morpholine prepared in Example 14 were hydrogenated in 75 ml of methanol as described in Example 18.

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

Mp: 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 (165 mmol) was prepared in accordance with the procedure described in Example 15 for N-benzyl-5-methyl-4-ethoxycarbonyl. -3-isoxazole) acetamide was hydrogenated as described in Example 18 and the product was isolated as described there.

Yield: 50 g (99%) of the title compound Mp: 126-127 ° C. (From 2: propanol-n-hexane = 1: 2)

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 (1H).

Example 22

Ethyl [3-amino-4-cyano-5-oxo-3 (Z) -hexenoát].

g (56.6 mmol). Example 5a Ethyl (5-methyl-4-cyano-3-isoxazole) acetate was hydrogenated and recovered as described in Example 18.

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

Mp: 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 (2 RS, 3RS, 4SR) - 4- (Benzylamino) -2-methyl-6-oxo-tetrahydro-pyran-3-carboxylic acid hydrochloride g (53 mmol) Example 21 Ethyl [2-acetyl] To a solution of -3-amino-4- (N-benzylcarbamoyl) -2-E-butenoate] in 150 ml of glacial acetic acid was added 9 g (~ 120 mmol) of ~ 90% sodium cyanohydroborate in small portions over 30 minutes at room temperature, followed by stirring. stir for a further 3 hours at room temperature and finally for 10 minutes in a water bath at 80 ° C. To the reaction mixture, cooled to room temperature, was added benzaldehyde (6.5 mL, 60 mmol) and allowed to stand at room temperature for 12 hours, followed by the additional stirring of ~ 90% sodium cyanohydroborate (5.5 g, ~ 75 mmol) over 30 min. added in small details. The reaction mixture was stirred at room temperature for 3 hours, evaporated in vacuo and 300 ml of n-heptane was distilled off. To the residue was added ethyl acetate (300 mL) and carefully added dropwise with 300 mL of 10% aqueous potassium bicarbonate solution, followed by the addition of 30 g of solid potassium bicarbonate. 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). It is then triturated with water (2 x 30 mL), filtered and air dried at 80 ° C.

Yield: 6.7 g (42%) of the title compound

Mp: 163-164'C (decomposes)

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 (2)

Patent claims A process for the preparation of new alkenedioic acid derivatives of the formula I - in this formula X is a nitrile group or a (C 1 -C 4) alkoxycarbonyl group, and Y is -COOZ, or -CONRR ', wherein Z is a C 1 -C 4 alkyl group, R and R' are phenyl or benzyl, or R and R 'are taken together with the nitrogen atom to form a morpholine ring, characterized in that , wherein X and Y are as defined above, are reduced. 2. A process according to claim 1 wherein the reduction of the compound of formula 11 is carried out by catalytic hydrogenation.