HU187186B - Process for producing esters of azetidinone-caeboxylic acids - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds of formula IV wherein R1 is hydrogen or benzhydryl, or benzyl or phenyl optionally substituted with one or more C1-C4 alkoxy groups, and Z is C1-C4 alkyl. means a compound of formula I wherein R is a benzhydryl group or a phenyl or benzyl group optionally substituted with one or more C 1 -C 4 alkoxy groups, for the temporary protection of amides R and Z is as defined above for haloacetic acid. the compound of formula II wherein R and Z are as defined above and X is halogen in the presence of an acid acceptor, preferably in the presence of a tertiary amine, is converted to the compound of formula III in the formula III: the compound of formula III is reacted with an alkali metal halide in pyridine or aqueous dimethylsulfoxide and the resulting compound of formula IV wherein Z is as defined above is recovered or, if desired, an amide protecting group; and the resulting compound of formula IV, wherein R1 = H, is recovered. R-NH-CH · COOO 'COOZ -COOZ N. -1-

Description

The present invention relates to a process for the preparation of compounds of formula IV.

In formula IV

R 'is hydrogen, or benzhydryl as a temporary protecting group for amides, or phenyl or benzyl optionally substituted with one or more C 1 -C 4 alkoxy groups, and Z is C 1 -C 4 alkyl.

The compounds produced are thienamycin and its derivatives as intermediates in the preparation of thienamycin in a simpler and more economical manner than hitherto known.

Thienamycin is a broad-spectrum antibiotic, the microbiological preparation of which is disclosed in U.S. Patent No. 3,950,357 and the synthesis of which is disclosed in U.S. Patent No. 2,751,597.

The initial step of the above synthesis is carried out with a yield of less than 10%, which makes production extremely uneconomic.

In our experiments, we have found that compounds of formula IV can be prepared easily and in good yield from compounds of formula III. In formula III, Z is as defined for formula IV and R is an amide protecting group as defined for R '.

The compounds defined by formulas III and IV are, with one exception, novel. Specifically, compounds containing Z at the ethyl group and R and R ¹ at the phenyl group have already been prepared by Sheehan et al., J. Am. Chem. Soc., 72, 5158 (1950), under reaction conditions other than our process.

The present invention therefore relates to a process for the preparation of compounds of formula IV in this formula

R ^{1 is} hydrogen, or benzhydryl as a temporary protecting group for amides, or benzyl or phenyl optionally substituted with one or more C 1 -C 4 alkoxy groups, and Z is C 1 -C 4 alkyl, such that j is a compound of formula I wherein R is a phenyl, benzhydryl, or phenyl or benzyl optionally substituted with one or more C 1 -C 4 alkoxy groups for the temporary protection of amides R, and Z is as defined above for the acylation of a haloacetic acid, and wherein R and Z are as defined above and X is halogen atoms in the presence of an acid acceptor, preferably a tertiary amine, to give compound of formula III; in formula III, R and Z are as above followed by pyridine din, or aqueous dimethylsulfoxide, to recover the resulting compound of formula IV, wherein Z is as defined above and R '= R, or, if desired, cleave the amide protecting group and yield the compound of formula IV, wherein R = H, or ₂ ) a compound of formula II wherein R,

X and Z are converted into the compound of formula III in the presence of an acid scavenger, preferably a tertiary amine, and the resulting compound of formula III, wherein R and Z are as defined above, is reacted with pyridine or aqueous dimethyl sulfoxide, and recovering the resulting compound of formula IV wherein Z is as defined above and R * = R, or, if desired, removing the amide protecting group, and recovering the resulting compound of formula IV, wherein R '= H, or ₃ ) reacting a compound of formula III wherein R and Z are as defined above with an alkali metal halide in pyridine or aqueous dimethylsulfoxide to give a compound of formula IV wherein Z is as defined above and R '= R, or, if desired, cleaving the amide protecting group to give the resulting compound of formula IV t where R '= H is recovered.

The process of the present invention is based on a dialkyl (substituted amino) malonate of formula I which is acylated with a haloacetic acid derivative, e.g. with the halide, anhydride or active ester of the acid.

The compound of formula (II) thus obtained is then cyclized to the compound of formula (III) using an acid-binding agent, preferably a tertiary amine.

The compound of formula III is then reacted with an alkali metal halide, preferably sodium or lithium chloride. The reaction is carried out in the presence of pyridine, quinoline, homologues or mixtures thereof, or in the presence of water and dimethylsulfoxide.

The product of formula IV is obtained by extraction and / or evaporation.

If desired, the amide protecting group is cleaved from the resulting product of formula IV.

The methoxy substituted benzyl groups or oxidatively, preferably a compound of the peroxydisulfate type, especially potassium or sodium peroxidiszulfáttal (Na 2 S ₂ O _8, K ₂ S ₂ O ₈₎ can be removed by one, a buffer of about pH 7, and water and in the presence of an organic solvent.

The phenyl group may be removed as follows: first by nitration, the nitrophenyl protecting group is formed and then converted to the aminophenyl protecting group by reduction, preferably by catalytic hydrogenation. The latter is removed by an oxidation method such as a mixture of a cerium (IV) salt and a mineral acid, or preferably glacial acetic chromium (VI) oxide.

The invention is further illustrated by the following non-limiting examples.

Example 7

Ethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidinecarboxylate]

Diethyl [1- (2,4-dimethoxybenzyl) 4-oxo-2,2-azetidinedicarboxylate] (66.2 g, 0.18 mol) in dimethyl sulfoxide (70 ml) was treated with sodium (12.7 g, 0.22 mol). chloride and 6.5 mL (0.36 mol) of water for 6 hours at 170-180

187 186 C oil bath. The mixture was poured into saturated aqueous sodium chloride solution (500 mL), extracted with ethyl acetate (5 x 100 mL), and the organic phase was dried over magnesium sulfate, filtered, and the ethyl acetate was distilled off from the filtrate. ⁵

Yield: 47.6 g (90%) of the title compound.

MP: 170-176 / 0.15 mmHg. ?

Elemental analysis for C ₅ Hien ₅ (293.32): Calcd

Calculated:% 61.42; H, 6.53; N, 4.77; ^10% Found: C, 61.25; H, 6.87; N, 4.58.

IR (film): 2900; 1750-1725 cm ' ¹ .

The starting material of Example 1 was prepared as follows:

a) 50 g (0.30 mol) of 2,4-dimethoxybenzaldehyde, 34.4 ml of ¹⁵ (33.6 g; 0.31 mol) benzylamine in 300 ml of dry toluene, 1 g of p-toluenesulfonic acid for 8 hours. while the resulting water is continuously removed with a water separator. The toluene is then distilled off. The resulting oil was dissolved in dioxane (120 mL) and treated with 3.2 g of sodium [tetrahydroborate (III)] under cooling with external ice-water and stirring for 2 hours. ₂₅

After standing for 3 days, the reaction mixture was diluted with water (400 mL), the resulting oil was extracted with ether, dried over magnesium sulfate, filtered and the filtrate was concentrated to half. Then, while cooling with ice-water, hydrochloric ethanol was added dropwise to the _3Q ethereal solution.

Yield: 59 g (67%) of benzyl (2,4-dimethoxybenzyl) amine hydrochloride.

156-157 ° C (ethyl acetate)

Analysis calculated for C ₁₆ H ₂₀ ClNO ₂ (293.78): ³⁵ %:

C, 65.41; H, 6.86; Cl, 12.07; N, 4.77; tslált

C 65 * 63; H, 7.30; Cl, 11.69; N, 4.72.

b) The base of the product obtained in Example 1a) is liberated and the resulting benzyl (2,4-dimethoxybenzyl) amine (175 g, 0.68 mol) is 89.6 g (0.38 mol; 64). ml) with diethyl bromo malonate at room temperature until the reaction mixture solidifies. The resulting mixture was triturated with about 1 liter of ⁴⁵ ether and the precipitated crystalline material was filtered. (The excess amine starting material can be recovered in about 95% yield as hydrobromide.) The filtrate is evaporated and the residual oil is triturated with ethanol. ⁵⁰

Yield: 114.5 g (81%) of diethyl [N-benzyl-N- (2,4-dimethoxybenzyl) amino-malonate).

Mp 62-63 'C (ethanol).

Analysis calculated for C ₂₃ H ₂₉ NO ₆ (415.47): ⁵⁵ %: C, 66.49; H, 7.04; N, 3.37.

Found: C, 66.58; H, 7.09; N, 3.43.

IR (KBr): 1750/1725 cm -1, d.

c) 61.7 g (0.149 mol) of diethyl [N-benzyl-N- (2,4-dimethoxybenzyl) ^-60- amino malonate] prepared in Example 1b) in the presence of about 20 g of palladium on charcoal. Hydrogenated in 500 ml of ethanol at atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated.

Yield: 47.1 g (97%) of dielyl- [N- (2,4-dimethoxybenzyl) amino-malonate]; optionally converting it to the acid addition salt with hydrochloric acid.

HCl salt: mp 122-124 ° C (EtOAc).

Elemental analysis for C ₆ H ₂₄ ClNO ₆ (361.82):

calculated%:

C, 53.11; H, 6.69; Cl, 9.80; N, 3.87. found *

C 52.51; H, 6.77; Cl, 10.30; N, 4.09.

IR (film): 3250, 2900, 2850, 1730, 1720 cm Ή NMR (CDC1 _3): δ 1.3 t (6H); 3.78 s (3H); 3.82 s (3H); 4.21 q (4H); 6.20 s (2H); 6.4 6.6 m (2H) + 7.3-7.55 m (1H); 7.7 s (1H).

d) 47 g (0.144 mol) of diethyl [N- (2,4-dimethoxybenzyl) amino-malonate] prepared in Example le) in 200 ml of anhydrous benzene, 13.8 ml (19.6 g; 0.173 mol). ) with chloroacetyl chloride was refluxed for 3.5 hours. The benzene was distilled off and the residual oil was recrystallized from about 100 ml of ethanol.

Yield: 66% diethyl [N- (2,4-dimethoxybenzyl) -N- (cpr-acetyl) amino-malonate].

M.p. 83-84'C (ethanol).

Elemental analysis for C ₁₈ H ₂₄ ClNO ₇ (401.84):

calculated%:

C, 53.80; H, 6.02; Cl, 8.82; N, 3.49; found %:

C, 53.63; H, 6.26; Cl, 8.79; N, 3.56.

IR (KBr): 2920; 1755, 1680 ^cm-first

1 H-NMR (CDCl 3): δ 1.2 t (6H); 3.72 s (6H); 4.08 q (4H); 4.17 s (2H); 4.56 s (2H); 4.95 s (1H); 6.2 6.6 m (2H) F 6.95-7.25 m (1H).

e) 35 g (0.087 mol) of diethyl [N- (2,4-dimethoxybenzyl) -N- (chloroacetyl) amino malonate] prepared in Example 1d (15.9 ml). Triethylamine (4 g, 0.113 mol) in anhydrous benzene (200 ml) was refluxed for 8 hours. The mixture was partitioned between water (100 ml), dilute hydrochloric acid (100 ml) and water (100 ml) again, and the benzene layer was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 28.4 g (89%) of diethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate].

MP: 175-180 'C / 0.1 mmHg.

Anal calcd for C ₈ H ₂₁ NO ₇ (365.38): Calculated% C, 59.17; H, 6.34; N, 3.83;

Found: C, 59.24; H, 6.24; N, 3.54.

IR (KBr): 2900; 1760-1720 cm -1 ¹ H-NMR (CDCl ₃ ): δ 1.15 t (3H); 1.25 t (3H); 3.25 s * (2H); 3.7 s (6H); 3.8-4.25 m (4H); 4.50 s (2H); 6.3 m (2H) + 7.0 d (1H).

Example 2

Ethyl (4-oxo-2-a: ethidine carboxylate) g (20.5 mmol), prepared as in Example 1, ethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2- azetidine carboxylate], 11 g (41 mmol) of potassium peroxydisulfate and 14.5 g (82 mmol) of disodium hydrogen phosphate · 2H ₂ O are refluxed for 6 hours in 60 mL of water and 90 mL of acetonitrile. The biphasic mixture was separated, the aqueous phase was extracted with 100 mL of benzene, and the combined organic layer was washed with three 30 mL portions of

The extract was extracted with aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated. The resulting oil was subjected to column chromatography. (Adsorbent: Kiesel gel 60, 0.063-0200 mm; running mixture: benzene, then benzene: acetone = 99: 1)

Yield: 1.21 g (41%) of the title compound.

IR (film): 3250; 2930; 1740 cm ^-1 .

1 H-NMR (CDCl 3): δ 1.3 t (3H); 3.15 m (2H); 4.15 m (1 H); 4.22 q (2H); 6.6 s (1H).

example

Ethyl (1-benzyl-4-oxo-2-azetidine carboxylate) g (0.065 mol) of diethyl (1-benzyl-4-oxo-2,2-azetidine dicarboxylate) in 30 ml of dimethyl sulfoxide 4, In the presence of 95 g (0.084 mol) of sodium chloride and 2.35 ml (0.13 mol) of water, ca. Stir for 6 hours in an oil bath at 170-180 ° C. The reaction mixture was poured into saturated aqueous sodium chloride solution (200 mL), extracted with ether (2 x 30 mL), dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 11.4 g (75%) of the title compound.

MP: 156-160 ° C / 0.2 mm Hg.

Elemental analysis for C ₁₃ H ₁₅ NO ₃ (233.26): calculated: Ν 6.00;

Found: Ν 6.01.

1 H-NMR (CDCl ₃ ): δ 1.25 t (3H); 3.1 m (2H); 3.9 m (1 H); 4.18 q (2H); 4.20 d (1H); 4.65 d (1H); 7.3 s (5H).

The starting material of Example 3 was prepared as follows:

a) To a mixture of 59.2 g (41.2 ml; 0.199 mol) of diethyl bromobromate and 22.5 g (31.5 ml; 0.225 mol) of triethylamine was added 24 g of vigorous external ice-water cooling and vigorous stirring. Benzylamine (24.3 mL, 0.207 mol) was added dropwise. A thick, immiscible mixture is formed which is stirred for 1.5 hours, triturated with 100 ml of ether, the crystalline solid is filtered off, and hydrochloric acid ethanol is added dropwise to the filtrate. The crystalline material from the filtrate was filtered and washed with ether.

Yield: 23 g (31%) of diethyl N-benzylaminomalonate hydrochloride, m.p. 146-148 ° C (dec.).

b) 30 g (0.1 mol) of diethyl benzylaminomalonate hydrochloride prepared in Example 3a) with 9.6 ml (13.6 g; 0.12 mol) of chloroacetyl chloride. Boil for 1 hour. The benzene is distilled off. The residual oil was crystallized by trituration with petroleum ether. Yield: 32.5 g (95%) of diethyl [N-benzyl-N- (chloroacetyl) amino malonate].

M.p. 53-54 ° C (petroleum ether).

Elemental analysis for C ₁₆ H ₂₀ ClNO ₅ (341.85):

calculated%:

C, 56.21; H, 5.89; N, 4.10; Cl, 10.37; tucked away *

C 56 ° -13; H, 5.94; N, 3.94; Cl, 10.20.

IR (KBr): 2950; 1760, 1740, 1685 cm ^-1 .

1 H-NMR (CDCl ₃ ): δ 1.21 (6H); 4.05 s (2H); 4.15 q (4H); 4.75 s (2H); 5.35 s (1 H); 7.28 s (5H).

c) 34.1 g (0.1 mol) of diethyl [N-benzyl-N- (chloroacetyl) amino-malonate] prepared in Example 3b) in 18.2 ml (13.2 g; Triethylamine (0.13 mol) in benzene (100 ml) was stirred at room temperature for 8 hours. The mixture was partitioned between water (100 ml), 10% aqueous hydrochloric acid (50 ml) and water (100 ml) again. The organic phase was dried over magnesium sulfate, filtered, and the benzene was distilled off from the filtrate. The residual oil was distilled at 0.1 mmHg at 149-150 ° C

Yield: 23 g (75%) of diethyl (1-benzyl-4-oxo-2,2,2-azetidine dicarboxylate).

Elemental analysis for C ₁₆ H ₁₉ NO ₅ (305.33):

Found: C, 62.94; H, 6.27; N, 4.59; Found: C, 63.29; H, 6.75; N, 4.83.

IR (film): 2950; 1760-1730 cm ^- '.

1 H-NMR (CDCl ₃ ): δ 1.151 (6H); 3.38 s (2H); 4.0 q (4H); 4.6 s (2H); 7.25 s (5H).

Example 4

Ethyl (1-phenyl-4-oxo-2-azetidine carboxylate)

151 g (0.52 mol) of diethyl (1-phenyl-4-oxo-2,2-azetidine dicarboxylate) (JC Sheehan, AK Bosese: 1 Am. Chem. Soc. 72, 5158 [1950]). In 150 ml of dimethyl sulfoxide was stirred in 36.5 g of sodium chloride and 18.7 ml (1.04 mol) of water in a 170-180 ° C oil bath for 4-5 hours. The reaction mixture was poured into 1350 mL of water, extracted three times with 200 mL of diethyl ether, and the layers were separated. The aqueous phase is saturated with sodium chloride and extracted three times with 100 ml of ether each time. The combined ethereal solution was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 106.5 g (94%) of the title compound. Mp: 34-36 ° C.

IR (KBr): 2900; 1750-1720 cm -1.

1 H-NMR (CDCl ₃ ): δ 1.25 t (3H); 3.25 m (2H); 4.25 q (2H); 4.5 m (1 H), 7.3 s (5 H),

Example 5

Ethyl (1-benzhydryl-4-oxo-2-azetidine carboxylate)

Diethyl (1-benzhydryl-4-oxo-2,2-azetidine dicarboxylate) (2.5 g, 6.6 mmol) in dimethylsulfoxide (5 mL) was treated with sodium chloride (0.46 g, 7.9 mmol) and sodium hydroxide (0.24 mL). (2 mmol) in water in a 180 ° C oil bath for 6 hours. The mixture was poured into a saturated aqueous solution of sodium chloride (20 mL), extracted with ether (3 x 20 mL), dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 1.8 g (89%) of the title compound. 1 H-NMR (CDCl 3): δ 1.10 t (3H); 3.07 m (2H); 3.73-4.09 m (3H); 5.93 s (1 H); 7.26 s (10H).

The starting material of the example is prepared as follows:

a) Benzhydrylamine (40 g, 0.218 mol) in diethyl bromobromate (26.2 g, 18.7 ml, 0.109 mol) was allowed to stand at room temperature for one week with stirring. The solidified mixture was triturated with ether and the resulting crystalline material was collected by filtration.

The excess benzhydrylamine was recovered as the hydrobromide. The ethereal mother liquor was evaporated and the residual oil was dissolved in ethanol (100 mL) and allowed to freeze. A small amount of crystalline material precipitates and is filtered off. The ethanolic solution was evaporated.

Yield: 24.2 g of diethyl (N-benzhydrylaminomalonate) which can be used without purification.

b) 23.8 g (69.7 mmol) of diethyl (N-benzhydrylaminyl malonate) obtained in Example 5a) are treated with 11.8 g (8.3 ml, 104.6 mmol) of chloroacetyl chloride in 120 ml of anhydrous benzene is refluxed for 15 hours. The mixture was partitioned between 5% aqueous sodium bicarbonate and water. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residual oil was crystallized by trituration with ether / petroleum ether.

Yield: 12.2 g (42%) of diethyl [N-benzhydryl-N- (chloroacetyl) amino malonate].

98-100 ° C.

IR (KBr): 3050, 2950; 1740s, 1680cm ' ¹ . 1 H-NMR (CDCl 3): δ 1.20 t (6H); 4.05 s (2H); 4.06 q (2H); 4.38 s (1H); 6.5 s (1H); 7.38 s (5H).

c) Diethyl [N-benzhydryl-N- (chloroacetyl) amino-malonate] (4.2 g, 10 mmol) prepared in Example 5b) in anhydrous benzene (30 mL) was treated with 1.82 mL (1.31 mL). g (13 mmol) with triethylamine for 1 day at room temperature. The mixture was partitioned between dilute aqueous hydrochloric acid and water. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residual oil was triturated with petroleum ether. Yield: 3 g (79%) of diethyl (1-benzhydryl-4-oxo-2,2-azetidine dicarboxylate).

Mp: 65 'C.

1 H-NMR (CDCl ₃ ): δ 1.11 t (6H); 3.35 s (2H); 3.96 q (4H); 5.68 s (1H); 7.2 s (10H).

Example 6

Diethyl [4-oxo-2,2-azetidinedicarboxylate] g (3 mmol) diethyl [1- (4-methoxybenzyl) -4-oxo-2,2-azetidinedicarboxylate], 3.25 g (12 mmol) potassium peroxide sulfate, 8.6 g (24 mmol) of disodium hydrogen phosphate 12 H ₂ O in a mixture of 12 mL of acetonitrile and 2.8 mL of water at 100-110 ° C. (TLC monitoring; adsorbent: Kieselgel G according to Stahl; eluent: benzolacetone = 8: 2). After cooling, the precipitated inorganic material is filtered off and the aqueous phase is extracted three times with 10 ml of ethyl acetate each time. The combined organic layers were evaporated and the residue was dissolved in dichloromethane (20 mL) and extracted with saturated brine (20 mL). The dichloromethane solution was dried over magnesium sulfate and concentrated by filtration. The residual oil was purified by chromatography (adsorbent: Kieselgel 60; PF _{254 + 366} ; eluent: benzene-acetone = 8: 2). Yield: 0.3 g (47%) of the title compound. 1 H-NMR (CDCl ₃ ): δ 1.3 t (6H), 3.3 d (2H), 4.2 q (4H), 7.0-7.2 s (1H).

The starting material of the example is prepared as follows:

a) 41 g (0.3 mol) of anisaldehyde is dissolved in 150 ml of 96% ethyl alcohol. To the page is added a solution of 23 g (0.3 mol) of hydroxylamine hydrochloride in 25 ml of water and 12 g (0.3 mol) of sodium hydroxide in water (20 mL) and the reaction mixture was stirred at room temperature for 4 hours. The precipitated sodium chloride is filtered off and the mother liquor is evaporated. The residue was dissolved in benzene (100 mL) and extracted with water (25 mL). The benzene solution was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residual oil crystallizes. Yield: 34 g (76%) of 4-methoxybenzaldehyde oxime. 65 DEG C. (benzene).

b) 25 g (0.165 mol) of 4-methoxybenzaldoxime prepared in Example 6a) in 100 ml of abs. dissolved in ethyl alcohol. While boiling, 31.6 g (1.38 g atom) of sodium metal and 150 ml of abs. ethanol. After complete dissolution of the sodium, 50 ml of water were added to the side and evaporated in vacuo. The residue is dissolved in 150 ml of ether and extracted with 50 ml of water. The ethereal solution was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residual oil was fractionated in vacuo.

Yield: 11.2 g (50%) of 4-meloxybenzylamine.

MP: 118-119 'C / 10 mm Hg.

c) 22.7 g (0.095 mol) of diethyl bromobromate and

To a mixture of triethylamine (9.6 g, 0.095 mol) was added 4-meloxybenzylamine (13b, 0.095 mol) prepared in Example 6b under vigorous stirring and external cooling with ice water. The resulting thick mixture was stirred for 1 hour so that the internal temperature did not rise above 40-50 ° C. The resulting material was triturated with ether (50 mL) and filtered. The mother liquor was evaporated. The residual oil was dissolved in ether (100 mL) and hydrochloric ethanol was added dropwise until the solution was strongly acidic. The precipitate was filtered off and recrystallized from ethyl acetate.

Yield: 10 g (32%) of diethyl [N- (4-methoxybenzyl) amino malonate hydrochloride.

87-90 'C (EtOAc)

Analysis calculated for C ₁₅ H ₂₂ ClNO ₅ :%:

C, 54.35; H, 6.68; Cl, 10.68; N, 4.22; found %:

C, 52.85; H, 6.15; Cl, 11.10; N, 4.27.

IR (KBr): 3400-2500, 1720 cm @ -1.

d) 1.2 g (3.6 mmol) of diethyl [N- (4-methoxybenzyl) amino-malonate] hydrochloride prepared in Example 6c and 0.42 g (3.7 mmol) of chlorine. acetyl chloride in 5 ml of abs. boil in benzene for 1.5 hours. The solution was evaporated. Filter the resulting residue. Yield: 1.2 g (90%) of diethyl [N- (4-methoxybenzyl) -N- (chloroacetyl) amino] malonate.

Elemental analysis for C ₁₇ H ₂₂ ClNO ₆ calculated:%:

C, 54.92; H, 5.96; Cl, 9.53; N, 3.77; tcilá It *

C 54 ° 45; H, 5.61; Cl, 10.03; N, 3.89.

IR (film): 1720 and 1640, 1220 cm H-NMR (CDC1 _3): δ 1.2 t (6H), 3.8 s (3H), 4.2 q (4H), 4.7 s ( 2H), 5.2 s (1H), 6.7-7.2 m (4H).

e) 4.1 g (0.011 mol) of diethyl [N- (4-methoxybenzyl) -N- (chloroacetyl) aminomalonate] obtained in Example 6d) and 1.21 g (0.012 mol). triethylamine 10 ml

187 186 abs. with stirring in benzene for 5 hours. (TLC monitoring; adsorbent: Kieselgel G, Stahl; eluent: hexane dioxane triethylamine = 4: 2: 1). The mixture was extracted with water (15 ml), dilute hydrochloric acid (15 ml), water (15 ml) again, .

Yield: 3.6 g (95% of diethyl [1- (4-methoxybenzyl) 4-oxo-2,2-azetidine dicarboxylate).

Analysis calculated for C ₁₇ H ₂₁ NO ₆ :% C, 60.87; H, 6.31; N, 4.18; Found: C, 60.98; H, 6.38; N, 4.48.

IR (film) 1770 and 1740, 1240 and 1120 ^cm-first 1 H-NMR (CDCl ₃ ): δ 1.2 t (6H), 3.3 s (2H), 3.75 s (3H), 4.0 q (4H), 4.5 s (2H) , 6.6-7.2 q (4H).

Example 7

Ethyl [1- (3,4-dimethoxybenzyl) -4-oxo-2-azetidine carboxylate] g (0.011 mol) in diethyl [1- (3,4-dimethoxybenzyl) -4-oxo-2,2 azetidine dicarboxylate] in 6 mL of dimethyl sulfoxide in the presence of 0.84 g (0.0143 mole) of sodium chloride and 0.4 mL (0.022 mole) of water in a 175 ° C oil bath for 6 hours. (TLC monitoring; adsorbent: Kieselgel G, Stahl; eluent: benzene-acetone = 7: 3). The mixture was poured into 30 ml of a saturated aqueous sodium chloride solution and extracted 3 times with 20 ml of ether. The combined ethereal phases were dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 2.6 g (81%) of ethyl [1- (3,4-dimethoxybenzyl) -4-oxo-2-azetidine carboxylate].

Analysis for C ₁₅ H ₁₉ NO ₅ Calcd: Calculated%: H, 6.53; N, 4.77;

Found: H, 6.47; N, 4.75.

1 H-NMR (CDCl ₃ ): δ 1.3 t (3H), 3.1 m (2H), 3.98 s (6H), 4.2 q (2H), 4.25 m (1H), 4.55 s (2H), 6.8 s (3H).

The starting material of the example is prepared as follows:

a) 66.5 g (0.4 mol) of veratrumaldehyde and 43 g (0.4 mol) of benzylamine in 300 ml of abs. in methanol for 20 minutes at room temperature. The solution is then cooled to 0 ° C using external ice-water cooling and 15.2 g (0.4 mol) of sodium tetrahydroborate (III) are added in small portions and stirred at this temperature for another hour. (TLC monitoring; adsorbent: Kieselgel G, Stahl; eluent: hexane-dioxane-triethylamine = = 4: 2: 1). . The combined ethereal phases were dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 97.5 g (95%) of benzyl- (3,4-dimethoxybenzyl) -amine.

Formation of the hydrochloride salt: 1 g of the product is dissolved in 10 ml of ether and the solution is acidified to pH 1 with hydrochloric acid ethanol.

The precipitated white crystalline material is filtered off. HCl salt: mp 188-190 ° C (ethanol).

Analysis calculated for C ₁₆ H ₂₀ ClNo ₂ :%:

C, 65.39; H, 6.86; Cl, 12.06; N, 4.77; found *

C, 6546; H, 6.81; Cl, 12.22; N, 4.80.

b) 92.5 g (0.36 mol) of benzyl (3,4-dimethoxybenzyl) amine prepared in Example 7a, 86 g (0.36 mol) of diethyl bromobromate. and triethylamine (36.3 g, 0.36 mol) were dissolved in ether (200 ml) and the solution was stirred at room temperature for 34 hours. The precipitated triethylamine hydrobromide salt was filtered off and the mother liquor was evaporated.

Yield: 115 g (77%) of diethyl [N-benzyl-N- (3,4-dimethoxybenzyl) amino-malonate] (oil).

g of oil was subjected to column chromatography: adsorbent: 300 g of Kieselgel 60, 0.02-0.0063 mm; eluent: benzene-acetone 100: 1 and 100: 4.

Analysis calculated for C ₂₃ H ₂₀ NO ₆ :% C, 66.49; H, 7.04; N, 3.74; % C, 66.65; H, 7.02; N, 3.40.

IR (film): J730, 1240 and 1130 cm ^-1 . 1 H-NMR (CDCl ₃ ): δ 1.3 t (6H), 3.8 s (1H), 3.9 s (6H), 4.2 s (4H), 4.3 q (4H), 6.8-7.5 m (8H).

c) 7.7 g (0.0186 mol) of diethyl [N-benzyl-N- (3,4-dimethoxybenzyl) amino malonate] prepared in Example 7b) are treated with 1.5 g of palladium on charcoal. in the presence of 100 ml of abs. hydrogenation in ethanol at atmospheric pressure. The catalyst is filtered off and the mother liquor is evaporated. Yield: 6 g (96%) of diethyl [N- (3,4-dimethoxybenzyl) amino-malonate].

HCl salt: mp 148-150 ° C (ethyl acetate).

Elemental analysis for C ₆ H ₂₄ ClNO ₆ calculated:%:

C, 53.11; H, 6.68; Cl, 9.80; N, 3.87. found '

C 52 ° 90; H, 6.23; Cl, 11.0; N, 3.84.

IR (KBr): 3000-2400, 1740 cm @ -1.

d) 10 g (0.0318 mol) of diethyl N- (3,4-dimethoxybenzyl) aminomalonate prepared in Example 7c) in 40 ml of abs. in benzene was refluxed for 2 hours with 3.8 g (0.0325 mol) of chloroacetyl chloride. The benzene is distilled off and the residual oil is crystallized by trituration with petroleum ether.

Yield: 8.8 g (70%) of diethyl [N- (3,4-dimethoxybenzyl) -N- (chloroacetyl) amino malonate].

M.p. 68-70 ° C (ethanol).

Analysis calculated for C ₁₈ H ₂₄ ClNO ₇ :% C, 53.80; H, 6.02; N, 3.48;

Found: C, 52.83; H, 5.74; N, 3.43.

IR (KBr): 1720 and 1660, 1130 and 1240 cm @ -1. 1 H NMR (CDCl ₃ ): δ 1.2 t (6H), 3.8 s (6 (), 4.0 s (2H), 4.1 q (4H), 4.6 s (2H), 5.2 s (1H), 6.7 s (3H).

e) 6.4 g (0.016 mol) of diethyl [N- (3,4-dimethoxybenzyl) -N- (chloroacetyl) amino] malonate prepared according to Example 7d) are 1.8 g (0.0176 mol). ) with triethylamine in 15 ml of abs. boil in benzene for 8 hours. After cooling, the solution is partitioned between 15 ml of dilute hydrochloric acid and 15 ml of water. The organic phase is dried over magnesium sulfate and then concentrated by filtration. Yield: 5 g (86%) of diethyl [1- (3,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate].

Analysis calculated for C ₁₈ H ₂₃ NO ₇ :% C, 59.17; H, 6.34; N, 3.83; Found: C, 58.95; H, 6.27; N, 3.85.

187 186

IR (film): 1780 and 1740, 1120 and 1240 cm -1, 1 H NMR (CDCl ₃ ): δ 1.15 t (6H), 3.3 s (2H), 3.8 s (6H), 4.0 q (4H), 4.5 s (2H), 6.7 s (3H).

Example 8

Ethyl (4-oxo-2-azetidine carboxylate)

Ethyl [1- (3,4-dimethoxybenzyl) -4-oxo-2-azetidinecarboxylate] prepared in Example 7 (1.5 g, 0.005 praol), 5.4 g (0.02 mol) potassium peroxydisulfate, 14.3 g (0.04 mol) of disodium hydrogen phosphate · 12H ₂ O in 20 mL of acetonitrile and 4.7 mL of water is heated to reflux at 110 ° C. The reaction was monitored by thin layer chromatography. (Adsorbent: silica gel G, Stahl; developing mixture: benzoacetone = 7: 3) After cooling, the precipitated salts are filtered off and the two phases are separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were evaporated. The resulting oil was dissolved in dichloromethane (30 mL) and extracted with saturated brine (20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated. The resulting oil was subjected to column chromatography. (Adsorbent: silica gel 60; 0.02-0.0063; eluent: benzene → benzene-acetone = 7: 3).

Yield: 0.34 g (45%) of ethyl (4-oxo-2-azetidine carboxylate).

1 H-NMR (CDCl ₃ ): δ 1.30 t (3H), 3.2 m (2H), 4.15 m (1H), 4.25 q (2H), 6.5-6.9 s . s (1H).

Example 9

Diethyl [4-oxo-1,2-azetidine dicarboxylate]

0.7 g (0.0018 mol) of diethyl [1- (3,4,5-trimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate], 1.94 g (0.0072 mol) Potassium peroxydisulfate, 5.15 g (0.0144 mole) of Na ₂ HPO ₄ · 12H ₂ O was dissolved in a mixture of 7.2 ml of acetonitrile and 1.7 ml of water and the solution was stirred at 100 ° C for 6 hours. After cooling, the precipitated salts are filtered off and the biphasic filtrate is separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL), combined with the acetonitrile phase and evaporated. The resulting oil is chromatographed. (Adsorbent: silica gel 60, PF _{254 + 36} ; eluent: benzene-acetone = 8: 2).

Yield: 0.2 g (52%) of the title compound. 1 H-NMR (CDCl 3):? Δ 1.3 t (6H), 3.4 d (2H), 4.3 q (4H), 6.3-6.6. s (1H).

The starting material of Example 9 can be stated as follows:

a) 3,4,8-Trimethoxybenzaldehyde (11.8 g, 0.06 mol) and benzylamine (6.4 g, 0.06 mol) in 80 ml of abs. methanol and 20 mL of dioxane. The solution is further stirred in an external ice-water bath and 2.25 g (0.06 mol) of sodium tetrahydroborate (III) are added in small portions, and the reaction mixture is kept at this temperature for a further 20 minutes and then concentrated. The residue was dissolved in 40 ml of ether and extracted with 30 ml of water. The ether layer was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 17 g (98%) of benzyl- (3,4,5-trimethoxybenzyl) -amine.

HCl salt: m.p. 157-159 ° C.

Elemental Analysis for: C ₁₇ H ₂₂ CINO ₃ : Calculated%:

C, 63.06; H, 6.85; Cl, 10.95; N, 4.33; found *

C, 62θ38; H, 7.04; Cl, 10.44; N, 4.60.

IR (KBr): 3100-2600, 1240 and 1110 cm

b) 16.5 g (0.0575 mol) of benzyl- (3,4,5-trimethoxybenzyl) amine prepared in Example 9a, 13.8 g (0.0575 mol) of diethyl bromobromate. and 5.8 g (0.0575 mol) of triethylamine in 40 ml of ether at room temperature for 30 hours. The precipitated salt is filtered off, washed with ether and the mother liquor is concentrated in vacuo.

Yield: 22 g (86%) of diethyl [N-benzyl-N- (3,4,5-trimethoxybenzyl) amino] malonate.

Analysis for C ₂₄ H ₇ NO _3I calcd Calculated% N 3.14;

Found: N, 2.88.

IR (film): 1760, 1240-1120 cm @ -1.

1 H NMR (CDCl ₃ ): δ 1.3 t (6H), 3.78 s (1H), 3.8 s (9H), 4.15 q (4H), 4.25 s (4H), δ 6 s (2H), 7.2 7.5 ni (5H).

c) Diethyl [N-benzyl-N- (3,4,5-trimethoxybenzyl) amino] malonate (5.2 g, 0.0117 mol) prepared in Example 9b was treated with 150 ml of abs. dissolved in ethanol and hydrogenated at room temperature in the presence of 0.5 g of palladium on charcoal. The catalyst is filtered off and the mother liquor is evaporated in vacuo. The evaporation residue crystallizes. Yield: 2.4 g (60%) of diethyl [N- (3,4,5-trimethoxybenzyl) amino] malonate.

156-157 ° C (ethanol).

Elemental Analysis for: C _{t 7} H ₂₅ NO ₇ : Calculated: N, 3.94;

Found: N, 3.63.

IR (KBr): 3400, 1780, 1250-1130 cm -1. > H-NMR (CDC1 _3): δ 1.3 t (6H), 3.78 s (IH), 3.8 s (9H), 4.25 q (4H), 4.4 s (2H); 6.9 s (2H).

d) 1.4 g (0.004 mol) of diethyl [N- (3,4,5-trimethoxybenzyl) amino] malonate prepared in Example 9c) with 0.55 g (0.0048 mol) of chloroacetyl chloride. Reflux in 10 ml of benzene for 2 hours. The solution was concentrated in vacuo and the residual oil was triturated with petroleum ether. The crystals were filtered.

Yield: 1.6 g (92%) of diethyl [N- (3,4,5-trimethoxybenzyl) -N- (chloroacetyl) amino] malonate.

903) 2 'C (ethanol).

Elemental analysis for C ₉ H ₂₆ ClNO ₈ calculated:%:

C, 52.84; H, 6.07; Cl, 8.21; N, 3.24; found *

C 51 ° 24; H, 5.46; Cl, 8.79; N, 3.40.

IR (KBr): 1740 and 1680, 1240 and 1120 cm -1 H-NMR (CDCl ₃ ): δ 1.3 t (6H), 3.8 s (9H), 4.2 q (4H), 4.3 s (2H), 4.7 s (2H), 5.2 s (1H), 6.5 s (2H).

e) 1.6 g (0.0037 mol) of diethyl [N- (3,4,5-trimethoxybenzyl) -N- (chloroacetyl) amino] malonate prepared in Example 9d and 0.415 g Triethylamine (0.004 mol) in benzene (10 ml) was heated under reflux for 4 hours. The precipitated salt is filtered off and washed with benzene. The mother liquor is diluted with 15 ml of dilute aqueous hydrochloric acid solution7

187 186 bowls, then shake with 15 ml of water. The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated. The residue crystallizes. Yield: 1.2 g (85%) of diethyl [1- (3,4,5-trimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate].

76-77 ° C (ether).

Analysis calculated for C ₁₉ H ₂₅ NO ₈ :% C, 57.71; H, 6.37; N, 3.54;

Found: C, 57.35; H, 6.90; N, 3.66.

IR (KBr): 1770 and 1760, 1250 and 1110 ^cm-first 1 H NMR (CDCl 3): δ 1.2 t (6H), 3.4 s (2H), 3.8 s (9H), 4.1 q (4H), 4.55 s (2H), 6.5 s (2H).

Claims (2)

l. A process for the preparation of compounds of formula IV in this formula R ^{1 is} hydrogen, or benzhydryl as a temporary protecting group for amides, or benzyl or phenyl optionally substituted with one or more C 1 -C 4 alkoxy groups, and Z is C 1 -C 4 alkyl, wherein a,) is a compound of formula I wherein R is a benzhydryl group or a phenyl or benzyl group optionally substituted with one or more C 1 -C 4 alkoxy groups and Z is reacted with an acylating derivative of the above haloacetic acid to provide a compound of formula II wherein R and Z are as defined above and X is a halogen atom - converted to a compound of formula III in the presence of an acid scavenger, preferably a tertiary amine - R and Z are as defined above - and a compound of formula III with an alkali metal halide in pyridine; reacting the brain with aqueous dimethylsulfoxide to recover the resulting compound of formula IV wherein Z is as defined above and R ¹ = R, or, if desired, cleaving the amide protecting group and yielding a compound of formula IV wherein R ¹ = H) recovering, or ₂ ) converting a compound of formula II wherein R, X and Z are as defined above, into the compound of formula III in the presence of an acid acceptor, preferably a tertiary amine, and the resulting compound of formula III wherein R and Z is reacted with an alkali metal halide, as defined above, in pyridine or aqueous dimethylsulfoxide, and the resulting compound of formula IV, wherein Z is as defined above and R ¹ = R, is recovered or, if desired, the amide protecting group is cleaved, and recovering the resulting compound of formula IV wherein R ¹ = H, or »3) a compound of formula III Ű compound - wherein R and Z are as defined above - an alkali metal halide in pyridine or in aqueous dimethyl sulfoxide is reacted and a compound of formula IV obtained, in which Z is as defined above and R ¹ = R meaning - is recovered, or if desired, the amide the protecting group is cleaved and the resulting compound of formula IV where R ¹ = H is recovered. 2. a0 according to claim 1, embodiment of the method ₂₎ or _3), characterized in that sodium chloride is used an alkali metal halide.