HU193323B - Process for preparing azetidinone derivatives - Google Patents

Abstract

Azetidinone derivatives of the formulae (Ia) <IMAGE> and/or (Ib) <IMAGE> are prepared by a1) treating a compound of the formula (IV) <IMAGE> (R is a protecting group), with an acid and reducing the compound of the formula (III) <IMAGE> obtained and eliminating the R protecting group from the diastereomeric pair of the formula (II) <IMAGE> obtained, by oxidation, or a2) reducing a compound of the formula (III), and eliminating the R protecting group from the diastereomeric pair of the formula (II), or a3) splitting off the R protecting group from the diastereomeric pair of the formula (II) and, in each of a1, a2 and a3, isolating the diastereomeric mixture of the compounds of the formulae (Ia) and (Ib) obtained, or if desired, separating the component of the formula (Ia) from the component of the formula (Ib) by selective crystallization.

Description

The present invention relates to a novel process for the preparation of azetidinone derivatives of formula Ia and / or Ib.

The trans configuration compounds of formulas Ia and Ib are diastereomers of each other which differ in the position of the hydroxyl group. Diastereoisomers are herein and hereinafter referred to as racemic modifications of the diastereomers in question.

The diastereomer Ia is prepared from pyranone derivatives which already have the appropriate hydrogen atoms in space, and the diastereomer Ib is prepared by the isomerization of the diastereomer Ia and then converted to thienamycin (EP 62840), a known broad-spectrum antibiotic.

Compounds of the structure (azetidinone acetic acid benzhydryl esters) analogous to the diastereomers of formulas Ia and Ib were prepared as a diastereomeric mixture from trans-configured azetidinone backbone precursors (Hungarian Patent No. 2218/83 = BE 899,936).

In our experiments, it has been found that the azisidinone derivative of the general formula IV, which is a mixture of trans isomers of the cis, where R is an benzyl or phenyl substituted by one or more methoxy groups as an oxidatively removable protecting group, is subjected to acid treatment followed by reduction only of formula II. It has further been found that if the protecting group R is subsequently removed, the resulting diastereomeric mixture (Ia and Ib) can be selectively crystallized.

No. 62,840 of this solution. Compared to the process described in European Patent Application, the advantage is that the azetidinone precursors do not have to be converted to a pyranone derivative having the appropriate substituents in the synthesis and then to the corresponding azetidinone because the present process derive the appropriate configuration.

No. 2218/83. In the case of the analogous compounds described in the Hungarian application, the same separation by selective crystallization does not take place, whereby the components of the diastereomeric mixture can be separated only by chromatography.

The present invention therefore relates to a process for the preparation of azetidinone derivatives of formula Ia and / or Ib, wherein a, a) is a compound of formula IV which is a mixture of cis and trans isomers, in which R is oxidatively removable by one or more methoxy groups. benzyl or phenyl substituted with an acid, and the resulting compound of Formula III is reduced and the resulting diastereomeric pair of Formula II, wherein R is the same as in Formula IV, is R the protecting group is cleaved by oxidation and the resulting mixture of diastereomers of formula Ia and Ib is recovered or, if desired, component Ia is separated from component Ib by selective crystallization or ₂ ) a compound of formula III is reduced and the resulting diastereomer II is obtained a pair of compounds of formula (III) and (II), R is as defined for formula (IV), and the resulting mixture of diastereomers of formula (Ia) and (Ib) is recovered or optionally separated from component (Ib) by selective crystallization; ₃ ) deprotecting a pair of diastereomeric compounds of formula II and recovering the resulting mixture of diastereomers of formula Ia and Ib, or, if desired, separating component Ia from component Ib by selective crystallization.

The process according to the invention is based on a mixture of cis-trans isomers of formula IV, which may be prepared as follows:

A mixture of cis-trans isomers of formula VII, which is described in Hungarian Patent No. 180,608 (= US 4,434,099), is hydrolyzed. The resulting azetidinone carboxylic acid isomeric mixture (VI) is then reacted with a carboxyl group activator followed by diazomethane. The resulting diazo ketone isomeric mixture of general formula V is then subjected to diazoketone rearrangement in the presence of water and the resulting azetidinone acetic acid derivatives are converted to the cis-trans isomer mixture of formula IV with diazomethane. In the general formulas VII, VI and V, R is an oxidatively removable protecting group. The conversion of VII to VI => V to IV is described in more detail in the examples.

From the compounds of formula IV, the ethylene ketal group is cleaved with an acid. The acid may be a sulfonic acid, e.g. p-toluenesulfonic acid, can be a silyl halide formed from a mixture of a silyl halide such as sodium iodide and silicon tetrachloride or a mixture of sodium iodide and trimethylsilicon chloride, or a mineral acid, preferably perchloric acid. The decantation is carried out with a suitable organic solvent, preferably a ketone, e.g. acetone, or a mixture of chlorinated hydrocarbon and acetonitrile.

The reaction mixture is then neutralized and the resulting compound of formula III is recovered if desired.

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The compound of formula III is then reduced. The reduction is conveniently carried out with a complex metal hydride, preferably an alkali metal [tetrahydroborate III]. The resulting compound of formula II is trans-configurated during the IV-to-II conversion, so that the cis isomer is also reversed.

The compound of formula II is then deprotected by oxidation. R may be substantially benzyl or phenyl substituted with one or more methoxy groups. The dimethoxybenzyl group can be removed by the use of a peroxydisulfate oxidant, the methoxyphenyl group being combined with a cerium (IV) salt and an acid.

After oxidation, a mixture of diastereomers of formula Ia and Ib is obtained which is recovered or preferably the bulk of the diastereomer of formula Ia is isolated by selective crystallization. The crystallization is preferably carried out in dichloromethane. The crystallization mother liquor retains a mixture of diastereomers la and Ib, which may be separated by chromatography. The compounds of formula Ia and Ib are racemates.

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

example

34.8 g (0.0918 mol) of cis and trans ethyl [1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azetidinecarboxylate) is dissolved in 50 ml of pyridine and a solution of 3.67 g (0.0918 mol) of sodium hydroxide in 100 ml of water is added. After stirring for 12 hours at room temperature, water (500 mL) was added and the mixture was extracted with diethyl ether (3 x 100 mL). The phases are separated, the aqueous phase is acidified to pH 1 with concentrated aqueous hydrochloric acid and extracted three times with 100 ml of dichloromethane each time. The dichloromethane phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. Yield: 28.7 g (89%) of trans- and cis-1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4-oxo-2 a mixture of azetidine carboxylic acid.

Example 2

a) 28.7 g (0.816 mol) of cis and trans -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxalan-2-yl) prepared according to Example 1 ) -4-ΟΧΟ-2-Azetidine carboxylic acid mixture was dissolved in 290 ml of anhydrous tetrahydrofuran and 13.6 ml (0.097 mol) of triethylamine were added followed by 9.5 ml (0.097 mol) of ethyl chloroformate under ice-cooling. to the solution. The reaction mixture was cooled to -15 ° C, stirred for 20 minutes, and the precipitated triethylamine salt was filtered off under an argon atmosphere. To the filtrate was added diazomethane (370 mL) in cold diethyl ether, prepared from 36.75 g (0.245 mole) of N-methyl-N-nitrosourea. The reaction mixture was allowed to warm to room temperature with stirring and after two hours evaporated to dryness in vacuo. The residue was subjected to column chromatography. (Adsorbent: 400 g Kieselgel G, eluent: dichloromethane: acetone = 10: 1).

Yield: 16.3 g (53.3%) of cis and trans -4- (diazoacetyl) -1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolane). 2-yl) -2-azetidinone.

IR (film): 2900, 2110, 1760 ^cm-1

b) The product of Example 2a) was dissolved in a mixture of 800 mL of peroxide-free tetrahydrofuran and 320 mL of water and irradiated in 8 portions in a pyrex apparatus under high pressure mercury submersible lamp (HPK 125) under argon until the starting material was consumed. The combined reaction mixture was concentrated to a volume of 300 mL, diluted to 1200 mL with water and ca. It is made basic with 20 ml of 10% aqueous sodium hydroxide solution and extracted three times with 200 ml of dichloromethane each time. The aqueous phase was acidified to pH 2 with concentrated aqueous hydrochloric acid and extracted with dichloromethane (3 x 160 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to 50 mL.

To the concentrated solution was added 6.0 g of diazomethane liberated from N-nitroso-N-methylurea in 60 ml of ether while cooling with external ice-water. After the nitrogen evolution ceased, the excess diazomethane was decomposed with acetic acid and the reaction mixture was evaporated.

Yield: 11.2 g (68%) of cis and trans-methyl- [1- (2,4-dimethoxybenzyl) -3- (2-methyl-1,3-dioxolan-2-yl) -4- oxo-2-azetidineacetate].

IR (film): 3000-2840, 1750, 1720 (shoulder) cm ^-1

c) The product of Example 2b) is dissolved in 250 ml of acetone and 5 ml (0.056 mol) of 70% aqueous perchloric acid is added under ice-water external cooling. After stirring for 1 hour under ice-cooling, 5.22 g (0.062 mol) of sodium bicarbonate are added and the mixture is stirred for a further 5 minutes. The reaction mixture was evaporated to dryness in vacuo. 150 ml of abs. methanol was added followed by stirring and cooling with ice-water (0.92 g, 24.5 moles) of sodium tetrahydroborate (III). The mixture was stirred for 1 hour under ice-water cooling, then acidified to pH 7 with acetic acid and finally concentrated. The residue was slurried in 200 mL dichloromethane and extracted with water (2 x 25 mL) and brine (25 mL). The organic phase is dried over anhydrous magnesium sulfate and concentrated by filtration. The residue was subjected to column chromatography. (Adsorbent: Kieselgel G, eluent: dichloromethane: acetone 10: 1; 200 kPa.)

Yield: 6.1 g (54%) of methyl {1- (2,4-dimethoxybenzyl) -3 (SR) - [1 (RS and SR) 3

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-hydroxyethyl] -4-oxo-2 (RS) -azetidine acetate).

IR (film): 3430, 1750, 1720 ^cm-first

Example 3 ⁵

2.7 g (8 mmol) of methyl {1- (2,4-dimethoxybenzyl) -3 (SR) - [1 (RS and SR) -hydroxyethyl] -4-oxo-2 (RS) - azetidine acetate) was dissolved in a mixture of 40 mL of acetonitrile and 10 mL of water.

While stirring and boiling, add a solution of 8.65 g (32 mmol) of dipotassium persulphate (K ₂ S ₂ O ₈ ) and 11.4 g (64 mmol) of disodium hydrogen phosphate in 40 ml of water in four equal portions, argon gas atmosphere. The reaction mixture was refluxed for another hour and then concentrated in vacuo using a bath at 50 ° C.

The residue was decanted three times with 50 ml of _n _ with dichloromethane, and the dichloromethane solution was dried (MgSO ₄₎ and subjected to column chromatography (adsorbent: 50 g of Kieselgel G, eluting solvent: dichloromethane-acetone, 7: 2 mixture; 200 kPa).

Yield: 1.06 g (80.2%) of a mixture of methyl] (2RS, 3SR1-3- [1 (RS and SR-hydroxyethyl] -2-azetidine acetate).

The resulting diastereomeric mixture was dissolved in 2-3 ml of dichloromethane and the precipitated crystalline 1R diastereomer was isolated from the solution.

Yield: 0.29 g (21%) of methyl] (2RS, 3SR) -3- [1 (SR) -hydroxyethyl] -2-azetidine acetate).

M.p. 87 ° C. ^{as AI>}

IR (KBr): 3300, 3200, 1720 cm -1 ¹ H-NMR (CDCl ₃ ): 1.32 d (3H, J = 6.5 Hz);

2.69 d (2H, J = 7.0 Hz);

2.82 s (1H, diffuse);

2.94 dd (1H, J = 2.5 Hz and 6.0 Hz); 3.71 s (3H);

3.85 dt (1H, J = 2.5 Hz and 7.0 Hz); 4.11 quintuplet (1H, J = 6.5 Hz);

6.5 s (1H, diffuse).

By evaporation of the mother liquor obtained by isolation of the crystalline 1SR diastereomer, a mixture of diastereomers la and Ib can be isolated.

IR (film): 3500-3100 (diffuse), 1760-

1720 ^cm-4 NMR _(CDCl3): 1.29 d and 1.33 d (3H, J = 6.5Hz), 2.60 to 3.78 m (2H), 2.7 and diffuse (1H);

2.88 dd and 2.94 dd (1H, J = 2.5 Hz and J = 6.5 Hz),

3.71 s (3H), 3.75-4.00 m (1H), 4.11 quintuplet and 4.14 quintuplet (1H, J = 6.5 Hz), 6.5 diffuse s (1H).

If desired, the above diastereomeric mixture is separated by chromatography on its components.

Claims (4)

PATENT CLAIMS A process for the preparation of azetidinone derivatives of the formula Ia and / or Ib, characterized in that a) a compound of the general formula IV, which is a mixture of cis and trans isomers, in which R can be oxidatively removed with one or more methoxy groups. is a substituted benzyl or phenyl group - treated with an acid and the resulting compound of formula III is reduced and the resulting diastereomeric pair of compounds of formula II - in the formulas III and II - R is the same as in formula IV - cleaving and recovering the resulting mixture of diastereomers of formula Ia and Ib, or, if desired, separating component Ia from component Ib by selective crystallization, or ₂ ) reducing a compound of formula II and the resulting pair of diastereomers of formula II R in formula represents III and II as defined above for formula IV - R protecting group, by oxidation, and isolating the a and diastereoisomers of formula Ib resulting mixture, or, if desired, component of the formula Ia is separated Ib component selective crystallization or ₃₎ removing a protecting group R from a pair of diastereomeric compounds of formula II and recovering the resulting mixture of diastereomers of formula Ia and Ib or, if desired, separating component Ia from component Ib by selective crystallization. Process (a) ( ₅ ) according to claim 1, characterized in that the acid treatment of the compound of formula IV is carried out with perchloric acid. 3 according to claim 1,), or ₂₎ a process wherein the reduction of compound III, generally "well performed a complex metal hydride. Process a,), ₂ ) or ₃ ) according to claim 1, characterized in that the diastereomer Ia is crystallized from dichloromethane.