HU182840B - Process for producing new acyl-derivatives of bracket-substituted amino-bracket closed-malonates - Google Patents

Abstract

The present invention relates to a novel (Ha) and / or (IIb) to form a protecting group for the temporary protection of amines and amides of R, optionally substituted with one or more methoxy groups, and Z is C1-4 alkyl. - preferably methyl or ethyl by reacting a compound of formula I in the formula wherein R and Z are as defined above with diketene and the resulting compound of formula (IIa) and / or IIb is removed from the reaction mixture. The new compounds produced are intermediates of thienamycin. R-NH-CH (COO 2) 2 1 H 3 C-C-CH 2 CH (C 100 Z) 2 Tb -N. -1-

Description

Their inventors): (72) dr. Charles Lempert, okay. chemist, 10.5%, dr. Kálmán Harsányi, okay. chemical engineer, 10.5%, dr. Gábor Doleschall, okay. chemical engineer, 10.5%, dr. Gyula Hornyák, okay. Chemical Engineer, 10.5%, Budapest, dr. József Nyitrai, okay. chemical engineer, 10.5%, dr. József Fetter, okay. chemical engineer, 10.5%, dr. Gyula Símig, okay. chemical engineer, 10.5%, Visky Györgyné dr., oki. chemical engineer, 8%, Budapest. Dr.Károly Zauer, oki.chemical engineer, 10.5%, Szentendre, Gizella Bartáné Szalai, oki. Chemical Engineer, 8.0%, Vecsés

Patented: (73)

Gedeon Richter Chemical Co., Budapest (54) PROCESS FOR THE PRODUCTION OF NEW ACYLED DERIVATIVES OF SUBSTITUTED-AMINO MALONATES (57)

The present invention relates to a process for the preparation of novel compounds of formula (IIa) and / or (IIb)

Phenyl or benzyl optionally substituted with one or more methoxy groups as protecting groups for the temporary protection of amines and amides R, and

Z is C 1-4 alkyl, preferably methyl or ethyl, by reacting a compound of formula (I) wherein R and Z are as defined above with diketene and the resulting compound (IIa) and / or The compound of formula (III) is recovered from the reaction mixture.

The novel compounds prepared are thienamycin intermediates.

R-NH-CH (COO ₂ ) ₂ L

fiction

H3C-CH2-C

-CH (C00Z) 2

tb

-N.

182,840

The present invention relates to a process for the preparation of novel acylated derivatives of the (substituted-amino) -malonates of the formula (IIa) and / or (IIb).

In the formulas (IIa) and (IIb), phenyl or benzyl optionally substituted with one or more methoxy groups as protecting groups for the temporary protection of amines and amides R and

Z is C 1 -C 4 alkyl, preferably methyl or ethyl.

The novel compounds are thienamycin intermediates that are more readily available and in better yields than previously known.

Thienamycin is a broad-spectrum antibiotic, first produced microbiologically (U.S. Patent No. 3,950,357), and then synthetically (U.S. Patent No. 2,751,597).

The aim of our experiments was to develop a synthesis pathway that solves the formation of an azetidinone backbone and an α-hydroxyethyl side chain (or one which can be easily converted to it).

In our experiments, it has been found that when a dialkyl [(substituentamino) malonate] of formula (I) is acylated with diketene to a compound of formula (Ha) and / or (IIb), then the acylated product is directly cyclized. the desired α-acetyl- (N-substituent) azetidinone derivatives are obtained.

The present invention therefore relates to a process for the preparation of novel compounds of formula (IIa) and / or (IIb)

Phenyl or benzyl optionally substituted with one or more methoxy groups as protecting groups for the temporary protection of amines and amides R, and

Z is C 1 -C 4 alkyl, preferably methyl or ethyl, characterized in that a compound of formula I, in which R and Z are as defined above, is reacted with diketene and the resulting compound (IIa) and / or The compound of formula (IIb) is recovered from the reaction mixture.

In formula (I), the substituent R is a protecting group for the temporary blocking of an amino and amido group, in particular benzyl or substituted benzyl, preferably 4-methoxy, 3,4-dimethoxy or 2,4-dimethoxybenzyl, or phenyl or 4-methoxyphenyl. The most preferred starting material is the novel diethyl [(2,4-dimethoxybenzylamino) malonate] of formula (I) as prepared in Example 1 and the novel diethyl [(4-methoxyphenylamino) - malonate], the preparation of which is given in Example 5. A compound of formula (I) wherein R is benzyl is known [P.J.Li: J.Org. Chem. 40 (23) 3414 (1975)] and R.Blank, Bér. 31, 1815 (1895)].

The compound of formula (I) is reacted with diketene in the presence of an organic solvent. As an organic solvent, an indifferent solvent such as tetrahydrofuran or dioxane or saturated aliphatic carboxylic acids which are liquid at room temperature, such as formic acid, acetic acid, propionic acid and the like. It can be used.

The reaction is conveniently carried out at temperatures above 60 ° C, sometimes at the spinning temperature of the reaction mixture.

The reaction gives compound (IIa) and / or (IIb). In the examples provided herein, under the conditions of Ή-NMR (CDCl ₃ ), a form corresponding to formula 2 (IIa) can be detected. However, the tautomeric form of formula (IIb) is also present in an amount of less than 5% in the case of the compound having the 2,4-dimethoxybenzyl group R.

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

Example 1

a) 50 g (0.30 mole) of 2,4-dimethoxybenzaldehyde in 34.4 ml (33.6 g; 0.31 mole) of benzylamine in 300 ml of anhydrous toluene in the presence of 1 g of p-toluenesulfonic acid are refluxed for 8 hours. 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 3.2 g of sodium tetrahydroborate (III) were added under ice-cooling with stirring under ice-cold water, followed by stirring for another 2 hours.

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. Ethanol containing hydrogen chloride is slowly added dropwise to the ethereal solution while cooling with ice-water.

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

156-157 ° C (ethyl acetate)

Analysis for C ₁₆ H ₂ oClN0 ₂ (293.78) Calcd: Calculated% C, 65.41; H6,86; Cl, 12.07; N4,77; Found: 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 thickens. The solidified mixture is then cooled for approx. Triturate with 1 L of ether and filter the precipitated crystals. (The excess amine starting material can be recovered in about 95% yield as the hydrobromide) The filtrate is evaporated and the residual oil is triturated with ethanol.

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

Mp 62-63 ° C (ethanol)

Analysis calculated for C23H29NO6 (415.47):%. 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) -aminomalonate] prepared in Example 1b) was ca. Hydrogenation is carried out under atmospheric pressure in the presence of 20 g of palladium on charcoal in 500 ml of ethanol. The catalyst was filtered off and the filtrate was evaporated.

Yield: 47.1 g (97%) of diethyl [(2,4-dimethoxybenzylamino) malonate of formula (I); optionally converting it to the acid addition salt with hydrochloric acid.

HCl salt: mp 122-124 ° C (EtOAc)

Elemental analysis for C ₆ H ₂ 4C1N0 ₆ (361.82) Calcd: Calculated% ·. C, 53.11; H6,69; Cl, 9.80; N3,87;

Found: C, 52.51; H6,77; Cl, 10.30; N4,09.

182,840

IR (film): 3250. 2900, 2850, 1730, 1720 cm -1 1 H-NMR (d DCM): 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 (211) t 7.3-7.55 m (1H); 7.7 ss (1H)

d) 39.6 g (0.122 mol) of diethyl [(2,4-dimethoxybenzylamino) malonate] prepared in Example le) in 80 ml glacial acetic acid with 12.3 g (11.2 ml, 0.146 mol) of diketene boil for half an hour. Glacial acetic acid is distilled off from a water bath under vacuum. The residual oil was crystallized by trituration with 150 ml of water, then dissolved in 60 ml of ethyl acetate and recrystallized by addition of petroleum ether. Yield: 29.6 g (60%) of diethyl ester (6a) N- (2,4-Dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate] cs / or Form IIIb.

Mp 106-107 ° C.

Elemental Analysis for (?)? -? (409.43): Calcd: C 58.67: 116.65; N: 3.42%;

Found: C, 58.79; (16.33; N, 3.34 7+)

IR (KBr): 3400; 2950, 2850; 1730 (1740 v), 1710 cm @ -1 (cm- ¹⁾ -NMR (C DC1.-,): δ]. I t (3 Η); 1. 17 t (3H); 1.52 s (~ 3H); 2.08 K0.1H); 2.65 s (211); 3.75 s (6H); 3.8-4.15 m (4H1; 6.7 s (2H); 6.25 6.45 ni + 7.0 -7.25 m (3H).

Example 2

a) To a mixture of 59.2 g (41.2 ml; 0.199 mol) of diethyl (bromo malonate) and 22.5 g (31.5 ml: 0.225 mol) of triethylamine was added vigorous external ice-water cooling with vigorous stirring to 24 g (24.3 ml; 0.207 mol) of benzylamine are added dropwise. Dense. After stirring for 1.5 hours, the mixture was triturated with ether (100 mL), the precipitated crystalline material was filtered off, and ethanol containing hydrogen chloride was added dropwise to the filtrate. The precipitated crystalline material is filtered off and washed with ether.

Yield: 23 g (31,7) of diethylbenzylaminomalonate -HCl of formula (I).

146 DEG-8 DEG C. (decomposition).

bt 2.52 g (9.5 mmol) of Jietild benzylamino malonate obtained in Example 2a) are heated in 10 ml of glacial acetic acid for 2 hours with 0.8 g (0.73 ml; 9.5 mmol) of diketene. Glacial acetic acid is distilled off in vacuo. The product is a residual oil.

Yield: 3.06 g (92) of diethyl (3-hydroxy-3-hydroxy-3-ethyl-5-oxo-2,2-pyrrolidinedicarboxylate) of formula (IIa) and / or (IIb) N-aetoacetyl-N-benzyl-aminonnalonate.

IR (film): 3350; 2950 1750-1670 cm cm ¹ .

¹ H-NMR 1 ( ¹ DCl ₃ ): 61.12 t (6H); 1.51 (3H); 2.68 s (211);

3.65 4.25 m (5H); 4.8 s (2H); 7.2 s (5H).

Example J (10,152 moles) of diethyl lanyl aminomalonate of formula (1) [R. Blank: Yeah. 31, 1815 (18898 µl) in glacial acetic acid (158 g, 13.9 mL, 0.182 mole) was refluxed for half an hour with diketene. The residue was distilled off from a water bath in vacuo.

Yield: 36.5 g (72%) of diethyl [N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinecarboxylate of formula (Ha)] and / or (IIb). ).

M.p. 98-99 ° C (ethyl acetate-petroleum ether).

Elemental Analysis for: C ₁₇ H ₂ NO ₆ (335.35): Calculated: C 60.88; H6,31; N4.18;

Found: C, 60.83; H, 6.15; N, 4.43.

IR (KBr): 3350; 2950 1760 + 1750 d, 1700 cm ' ¹ . 1 H-NMR (CDCl ₃ ): δ 1.02 t (3H); 1.3 t (3H); 1.6 s (3H);

2.8 s (2H); 3.6 s (1H); 4-4.45m (4H): 7.2s (5H).

Example 4

The reaction steps described in Examples 1a) and lb) may be carried out together without the preparation of the product of Example 1a) as follows:

109.7 g (0.66 mole) of 2,4-dimethoxybenzaldehyde and 72 ml (0.66 mole) of benzylamine in 660 ml of methanol are stirred for 20 minutes at room temperature (initially as a suspension) and then under external ice-water cooling. 2 g (0.33 mol) of sodium) tetrahydroborate (III)] are added in small portions.

After completion of the reaction, which was monitored by thin layer chromatography (layer: Kieselgel G; Stahl, developing solvent: benzene: acetone = 9: 1), the mixture was evaporated to dryness in vacuo, water (300 mL) was added and the residue was extracted with 500 mL ether. The aqueous phase is extracted twice more with 200 ml of ether. The combined ether layer was dried over magnesium sulfate, filtered, and then ether (112 mL, 0.66 ntol) and triethylamine (93 mL, 0.66 ntol) were added to the ether solution. The reaction mixture was stirred for 2 to 3 days at room temperature. The precipitated triethylammonium bromide was filtered off and washed with ether. The mother liquor was evaporated and the residue was crystallized from 1 50 ml of ethanol. 210 g of crude product are obtained, which is recrystallized from 400 ml of ethanol.

Yield: 197 g (72 +) of diethyl [N-benzyl-N- (2,4-dimethoxybenzyl) amino] malonate.

The physical constants are the same as in Example lb).

Example 5

a) 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) of diethyl bromo malonate are stirred for 2 days at room temperature. The resulting material was triturated with diethyl ether (100 mL) and the precipitated 4-methoxy anisidine hydrobromide was filtered off and washed on the filter with a little diethyl ether. The mother liquor was evaporated and the residue crystallized by the addition of dilute acetic acid.

Yield: 13.2 g (47%) of diethyl (4-methoxyanilino) malonate. Mp 64-65 ° C (ethanol).

Elemental Analysis for C14H19NO5 (281.31): Calculated,%: € 59.77; H6.81; N, 4.99;

found 74 C, 59.99; Η ó'97; N, 5.25.

IR (KBr): 3300. 1775, 1725 cm @ -1.

1 H-NMR (CDCl 3): 51.23 (t, 6H, J = 7.2 Hz), 3.67 (s.3H),

4.2 (q. 4H, .1 = 7.2 Hz), 4.62 (s, 1H), 4.1 -4.5 (s, 1H), 6.55 (2H) + 6.73 (2H), (AA BB'.J = 9 Hz).

182,840

b) Diethyl (4-methoxyanilmo) malonate (11.2 g, 0.04 mol) in glacial acetic acid (15 ml) was heated to reflux with 4 g (3.7 ml, 0.048 mol) of diketene for half an hour. The solution was evaporated in vacuo and the oily residue was triturated with diethyl ether and filtered.

Yield: 10.5 g (72%) of diethyl [1- (4-methylphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate] and / or its tautomer.

Mp 137 ° C (ethyl acetate).

Analysis calculated for C ₁₈ H ₂₃ NO ₇ (365.38):% C, 59.17; H, 6.39; N, 3.83;

Found: C, 58.98. H, 6.90; N, 4.04.

IR (KBr): 3600-3000, 1760, 1740, 1685 cm @ -1. 1 H NMR (CDCl 3): 51.07 (t, 3H, J = 7.2 Hz), 1.28 (t, 3H,

J = 7.2 Hz), 1.58 (s, 3H), 2.76 (s, 2H), 3.64 (s, 1H), 3.76 (s, 3H), 4.1 (q, 2H, J = 7.2Hz), 4.27 (q, 2H, J = 7.2Hz), 6.7 (2H) +7.0 (2H), (AA'BB ', J = 9Hz) ).

Claims (6)

Patent claims A process for the preparation of new compounds of the formula (Hair and / or IIb) - in this formula Phenyl or benzyl optionally substituted with one or more methoxy groups as protecting groups for the temporary protection of amines and amides R, and Z is C 1 -C 4 alkyl, preferably methyl or ethyl, characterized in that a compound of formula (I): wherein R and Z are reacted with the above diketone and the capotl, (Ha) and / or ( The compound of general formula IIb) is recovered from the reaction mixture. 5 Process according to Claim 1, characterized in that the reaction is preferably carried out in an organic solvent in liquid saturated aliphatic carboxylic acid. The method of claim 1, wherein said method is an embodiment 10, characterized in that the reaction is 60 ° C and the reaction ^; at a reflux temperature. The tautomer of the process according to claim 1 having the formula ηκ djadiethyl- [N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-15-2-pyrrolidinedicarboxylate] and / or IIb. characterized in that diethyl [(2,4-dimethoxybenzylamino) malonate] is reacted with diketene. The process of claim 1 for preparing diethyl [N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate] and / or its tautomer according to formula (IIb), characterized in that diethyl-aniline-malonate) is reacted with diketene. The process according to claim 1, wherein the tautomer is of diethyl [1- (4-methoxyphenyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate] and / or formula (Ib). characterized in that diethyl (4-methoxyanilino) malonate is reacted with diketene.