HU183488B - Process for producing new azetidinone derivatives containing protected c-acetyl-group - Google Patents

Abstract

The present invention relates to a process for the preparation of the novel compounds of formula IV wherein benzyl groups substituted with one or more methoxy groups are useful as temporary protecting groups for R amides. Z is a C 1-4 alkyl group and Y 1 and Y 2 together represent a suitable substituent for protecting the ketone group with an ethylene ketal group or a thioanalogon thereof. by reacting a compound of formula III wherein R and Z have the same ethylene glycol or thioanalogon as defined in formula IV and recovering the resulting product. -1-

Description

This invention relates to novel compounds of formula IV.

AIV in the general formula

Benzyl substituted with one or more methoxy groups as a temporary protecting group for R amides,

Z is C 1-4 alkyl and

Y ¹ and Y ² together represent an ethylene ketal group or a thioanalogone as a temporary protecting group for a keto group.

Compounds of formula AIV are novel intermediates for the production of thienamycin and related compounds which can be prepared in a simpler and better manner 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 synthetic pathway which, at the beginning of the synthesis, solves the co-formation of the azetidinone backbone and the α-hydroxyethyl side chain (or an easily convertable side chain) and the resulting key compound into thienamycin. processing.

It has been found that when a dialkyl [(substituted amino) malonate] of the formula I is acylated with diketene, the benzyl group substituted with one or more methoxy groups in the formula I and a C 1 -C 4 alkyl group preferably as a protecting group for R amides then reacting the resulting compound of formula IIa and / or Ilb with an alkali metal alcoholate and iodine of the formula Ra and Zb as defined above, to form a C-acetyl compound of formula III. yielding a side chain azetidinone suitable as a key intermediate. In Formula AIII, R and Z are as defined for Formulas I, IIa and IIb.

The preparation of the key intermediates of Formula AIII is protected by a separate application. In the present application, the process for preparing the novel diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dikerboxylate] as the most preferred representative of the compounds of the formula III ). The other compounds of formula III may be prepared in an analogous manner to that described in Examples 1a-le.

The present application relates to the conversion of compounds of formula III into new thienamycin intermediates of formula IV.

In our experiments, it has been found convenient to protect the keto group in the C-acetyl solution of the compound of formula III before converting it to thienamycin with a protecting group which can be subsequently cleaved, preferably ethylene ketal or thioanalagon. In particular, ethylene glycol or a thio analogue such as mercaptoethanol is used to form the ethylene ketal or hemithioketal protecting group and the resulting compound of formula IV, wherein Y ¹ and Y ² together are an ethylene ketone or thioanalone, R and Z are as defined in formulas I-III.

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

Benzyl substituted with one or more methoxy groups as a temporary protecting group for amides R,

Z is a C1-C4 alkyl group

Y ¹ and Y ² together is keto ethylene ketal or a tioanalogonját is suitable for temporary protection of the group - characterized in that a compound of the formula III - is reacted with ethylene glycol or tioanalogonjával, and the resulting product - wherein Z and R are as defined in formula IV recovered.

According to the process of the present invention, compounds of formula III are converted to compounds of formula IV. The reagent used is an ethylene ketal forming compound suitable for the temporary protection of the keto group, or its thioanalogone, in particular ethylene glycol, or its thioanalogone. The reaction is conveniently promoted with a suitably selected compound such as boron trifluoride diethyl etherate or an arenesulfonic acid such as p-toluenesulfonic acid, naphthalenesulfonic acid, and the like.

The reaction is carried out in the presence of an organic solvent, preferably benzene, toluene, dioxane, tetrahydrofuran or the like. The reaction is carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the examples.

Example 1

Diethyl 1.1 - (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2-azetidine dicarboxylate] (Compound IV) wherein R-2,4-dimethoxybenzyl, Y * and Y ² 'are ethylene ketal and Z-ethyl.

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 treated with 3.2 g of sodium tetrahydroborate (III) under ice-cooling and stirring for 2 hours.

After standing for 3 days, the reaction mixture was diluted with water (400 mL), the resulting oil was partitioned between 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).

Elemental analysis of C | ₆ H ₂₀ ClNCh (293.78):

Found: C, 65.41; H, 6.86; Cl, 12.07; N, 4.77; 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 is settled. The solidified mixture is triturated with about 1 liter of ether and the precipitated crystalline material is filtered off. (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) amino-malonate] prepared in Example 1b in the presence of about 20 g of palladium on charcoal, 500 g. Hydrogenate under atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated.

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

HCl salt: mp 122-124 ° C (EtoAc).

Elemental analysis for CuHmCINOí (361.82):

Found: 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-first

1 H-NMR (CDCl 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) 39.6 g (0.122 mol) of diethyl [(2,4-dimethoxybenzylamino) malonate] prepared in Example le) in 80 ml glacial acetic acid 12.3 g (11.2 ml 0.146 mol) ) with diketene and reflux for half an hour. Glacial acetic acid was distilled off from a water bath in vacuo, 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 [N- (2,4-dimethoxybenzyl) -3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate] and / or Formula IIb. its corresponding tautomer. 50

Mp 106-107 ° C.

Analysis calculated for C 20 H 27 NO 8 (409.43):% C, 58.67; H, 6.65; N, 3.42; Found: C, 58.79; H, 6.33; N, 3.34.

IR (KBr): 3400, 2950, 2850, 1730 (1740v), 1710 cm ^-1 . ₁ H-NMR (CDCl 3): δ 1.1 t (3H); 1.17 t (3H); 1.52 s (~ 3H);

2.08 (<0.1H); 2.65 s (2H);

3.75 s (6H);

3.8-4.15 m (4H); 6.7 s (2H); _δ0 6.25-6.45 m + 7.0-7.25 m (3H).

e) 20.5 g (50 mmol) of the product prepared according to Example 1d) are suspended in 50 ml of anhydrous ether and, under vigorous stirring and cooling with external ice-water, simultaneously 3.45 g (150 mmol) of two beakers are added simultaneously. 100 ml of anhydrous ethanol solution of sodium metal and a solution of 12.7 g (50 mmol) of iodine in 150 ml of anhydrous ethereal solution are added with stirring, 5 g of sodium bisulfite dissolved in 200 ml of a saturated aqueous solution of brine. The organic layer was separated and extracted with ether (2.times.100 mL), the organic phase was dried over magnesium sulfate (10 mL), filtered and the filtrate was evaporated to give an oil (18.5 g). It was crystallized from 30 ml of 2-propanol.

Yield: 10.99 (54%) of diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate].

84-85 ° C (2-propanol).

Analysis calculated for C20 H25 NO8 (407.41): C, 58.96; H, 6.19; N, 3.44; Found: C, 58.99; H, 6.04; N, 3.57.

IR (KBr): 2900, 1780, 1740, 1710 ^cm-first

1 H-NMR (CDCl 3): δ 1.12 t (3H); 1.21 t (3H); 2.31 s (3H);

3.76 s (6H); 3.8-4.2 m (4H); 4.53 d (1H);

4.63 d (1H); 4.69 s (1H); 6.3-6.4 2: 5 m (2H) + 7.07d (1H).

fi) Diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate] (25.5 g, 0.063 mol) obtained in Example le) (0.126 mol; 7.8 g) in ethylene glycol and 15.8 ml (0.126 mol; 17.9 g) in 30 ml of boron trifluoride diethyl etherate in 100 ml of anhydrous dioxane were allowed to stand at room temperature for 3 days followed by 150 ml of water and 150 ml of dichloromethane. is added to the reaction mixture. The organic phase was then separated and extracted with 50 ml of 5% aqueous sodium bicarbonate solution and then with 35 ml of water. The organic layer was separated again, dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 23.6 g (84%) of diethyl [1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2,2 -aze40 thidine dicarboxylate].

IR (film): 2900, 1770-1730 cm ^-1 .

1 H-NMR (CDCl 3): δ 1.5 t (3H); 1.31 t (3H); 1.50 s (3H);

3.8 s (6H); 3.85-4.75 m (11H);

6.4 m (2H) + 7.1 d (1H).

₂ ) 0.5 g (1.2 mmol) of diethyl [3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate] prepared in Example le) 0.2 ml of ethylene glycol in 5 ml of anhydrous toluene in the presence of p-toluenesulfonic acid is refluxed for 25 hours while the reaction water is continuously removed.

Subsequently, the product of the reaction is isolated by preparative thin layer chromatography (layer: Kieselgel 60 PFj54 + J66 developing solvent: toluene: acetone - 8: 2).

Yield: 0.11 g (20%) of the product of Example 1f).

Example 2

Diethyl [1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-oxathiolan-2-yl) -4-oxo-2,2-azetidine dicarboxylate] (IV

a compound of the general formula wherein R is 2,4-dimethoxybenzyl, Y ¹ and Y ² -ethylenemithiocetal and Z-ethyl) ____

Diethyl {3-acetyl-1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine dicarboxylate] (0.5 g, 1.2 mmol) was prepared as described in Example 3). A solution of boron trifluoride diethyl etherate (0.53 g, 3.6 mmol) and mercaptoethanol (0.29 g, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added and water (10 mL) and chloroform (10 mL) were added. The organic layer was separated, partitioned between 5% aqueous sodium bicarbonate solution, the organic layer was separated again, dried over magnesium sulfate, filtered and the filtrate was subjected to preparative thin layer chromatography (layer: Silica gel 60; PF _2j 4x3x3);

toluene: acetone 8: 2) the product is isolated. Yield: 0.30 g (53%) of the title compound. 1 H-NMR (CDCl 3): δ 0.8-1.55 m (6H), 1.72+ 1.77 d (3H),

2.9-3.4 m (2H), 3.75 s (6H), 4.0-5.0 m (9H),

6.4m (2H) + 7.1 d (1H).

Example 3

The reaction steps described in Examples 1a) and 1b) may be carried out in the same manner 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 with external ice-water cooling). Sodium tetrahydroborate (III) J (13.2 g, 0.33 mol) was added in small portions.

After completion of the reaction, which was monitored by thin layer chromatography (layer: silica gel G; Stahl, developing solvent: benzene: acetone = 9: 1), the mixture was evaporated to dryness in vacuo to a residue.

Water (300 mL) was added and the mixture was extracted with ether (500 mL). The aqueous phase was further extracted with ether (2 x 200 mL). The combined ethereal phase was dried over anhydrous magnesium sulfate, filtered, and diethyl bromoformate (112 mL, 0.66 mol) and triethylamine (93 mL, 0.66 mol) were added to the ether solution. The reaction mixture was stirred for 2-3 days at room temperature. The precipitated triethylammonium bromide was filtered off and washed with ether. The mother liquor is evaporated and the residue is crystallized from 150 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].

Its physical constants are the same as in Table lb).

Claims (3)

A process for the preparation of a novel azetidinone derivative of the Formula IV in the following formula Benzyl substituted with one or more methoxy groups as a temporary protecting group for R amides, Ζ C 1-4 alkyl and " Y * and Y ² together represent an ethylene ketal group or a thioanalogone thereof as a substituent for the temporary protection of a keto group, characterized in that a compound of formula III wherein R and Z are as defined in formula IV is reacted with ethylene glycol or thioanalogone recovered. The process of claim 1, wherein the reaction is carried out in the presence of boron trifluoride diethyl etherate. 3. A process according to claim 1 or 2, wherein the reaction is carried out in the presence of an organic solvent.