SU847921A3 - Method of preparing derivatives of oxazolinoazetidinylpentenic acid - Google Patents

Abstract

PURPOSE:To prepare the title cpds. easily, useful as intermediates for 1-oxadithia-3cephem-4-carboxylic acid having an optional substituent at the 3-methyl gp. as antibacterials, by halogenation or substituent interchange of the corresponding methyl cpds.

Description

tetrabutylammonium halide. Typical nucleophilic reagents include free acid or acid salt, which is selected from alkali metal salts (for example, lithium salt, sodium salt, potassium salt), heavy metal salts (for example, silver salt, mercury salt, lead salt, copper salt), organic salts bases (ia example of triethylamine, salt of 1,1 3,3-tetramethylguanidine) and quaternary ammonium salts (for example, tetraethylammonium salt, trimethylbenzylammonium salt, methyltriphenylphosphoric salt), carboxylic acids (for example, formic acid, acetic acids, propionic acid, pivalic acid, benzoic acid), mercapt anans (for example, phenylmercaptan, 1-methyltetrazol-5-mercaptan, 1-substituted alkyl 1 tetraaol-5-mercaptan, 2-methyl-1,3,4 | -thiadiazole-5 mercaptan, 1,3,4-thiadiazole-5-mercaptan, 1,2,3-triazole-4-mercaptan, 1-methyl-4-hydroxy-5-oxo-1, b-dihydro-1,3,4 triazin-2-yl-mecaptan), sulfenic acids (for example, phenylsulfonic acid), halo .ido-hydrogens, or the theme of similar acids.

Polar solvents that accelerate ionic reactions (e.g. alcohol, amide sulfoxy, ketone, nitrile, or nitro-hydrocarbon solvents or various aqueous solvents) can be used to carry out the reaction.

The reaction can be performed in the temperature range, for example, from -30 to + 70 ° C (for - hydroxide introduction), at room ambient temperature for a quarter of an hour (replacing chlorine with iodine) up to 20 hours (replacing chlorine with formyloxy) , and if necessary, in an inert gas atmosphere or with stirring.

The reaction can be accelerated by crown ether (e.g., dibenzo-1e-crown-6-ether, cyclohexyl-18-crown-b-ether or by a phase transfer catalyst (e.g., tetrabutylammonium bromide) or by an increase in anion strength. In some cases, light illumination also can speed up the reaction.

If necessary, the products can be converted to other compounds by various modification reactions, for example, hydrolysis with an acid or a base, oxidation with an oxidizing agent, for example sodium borohydride or triphenylphosphine, or rearrangement upon exposure to heat, acid or base, or claylike similar reactions.

For example, the product (X is acetoxy) -CAPABLY to hydrolyze, in order to obtain a compound, where X is hydroxy, the product (X is phenylsulphenyl) can be treated with an oxidizing reagent.

for example, with peracid to obtain the compound, where X is phenylsulfyl yl, then rearrange ocFioBaHHeM to obtain the compound, where X phenylsulphenyloxy, which when hydrolyzed, results in the compound having X as hydroxy / product (X is chlorine or bromine) sodium to form a compound where X is iodine, then a heavy metal salt (for example, silver nitrate, silver trifluoroacetate, copper acetate, lead acetate, copper nitrate) or alkali metal perchlorate to obtain the compound where X is hydroxy or acetyloxy. Acylates can be hydrolyzed, for example, by base.

Compounds prepared by reaction.

Compounds prepared by these reactions can be obtained by, for example, concentration, extraction, washing or other suitable methods for removing solvents, unreacted starting materials, by-products and other impurities, and then can be purified by reprecipitation, recrystallization, chromatography, processing adsorbent or other appropriate methods.

During the reaction or treatment, intermittent double bond migration or isomerization may occur.

The products obtained can be used as starting materials for the preparation of useful bactericidal substances 1-dithia-1-oxacephalosporins.

PRI me R 1. to a solution of 437 m of diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2, b-diazebicyclo-3,2,0-hept-2-en- 6-yl) -4-bromo-3-exomethylene butyrane in 10 ml of a mixture (3: 1) of acetone and methanol was added 250 ml of phenylmercaptan and 250 mg of sodium phenylmercaptide, and the mixture was stirred at room temperature for 1 hour and at 3-5 seconds 1 h, poured into water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulphate and evaporated.

The residue is chromatographed on a column of silica gel deactivated with 10% water. Elution with a mixture (from 0: 1 to 1:10) of ethyl acetate and benzene gives 400 mg (yield 80%) of diphenylmethyl (2K) -2- (3-phenyl-7-oxo-4-oxa-2, 6-diazabicyclo 3 , 2, O hept-2-en-6-yl) -3-phenylthiomethyl-3-butenoate.

IR-spectr-jf CH "Ce 1787, 1755, 1636.

Example 2. To a solution of 703 mg of Compound obtained in Example 1 in 14 ml of chloroform, a solution of 220 mg of m / chloroperbenzoic acid in 7 ml of chloroform is added dropwise, the mixture is stirred for 10 minutes, mixed with 700 mg of triphenylphosphine and 70 μl of methanol and heated with reverse HfcJM refrigerator at 75 ° C. After completion of the reaction, the mixture is evaporated under reduced pressure. The residue is chromatographed on 30 g of silica gel deactivated with 10% water. Elution with benzene containing 20–30% ethyl acetate and concentration of the eluate containing the desired product by evaporation gives 401 mg (yield 68%) of diphenylmethyl - (2R) -2- (3-phenyl-7-oxo-4-oxo- 2, b-diazabicyclo-p, 2.0-hept-2-en-6-yl) -3-hydroxymethyl-3-butenoate.

Example Z. To a solution of 240 mg of diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2, 6-diazabicyclo-3, 2.0-hept-2-en-6-yl) - 3-trifluoroacetyloxymethyl-3-butenoate in 10 ml of a mixture of {4: 1) methanol and methylene chloride was added 4.8 g of silica gel containing 10% water, the mixture was stirred for 30 minutes and filtered. The filter cake, silica gel, is washed several times with a mixture of methanol and methylene chloride. The filtrate and wash solution are pooled together and the solution is evaporated under reduced pressure. The oily residue is chromatographed on 12 g of silica gel. Elution with a mixture (2: 1) of benzene and ethyl acetate gives 106 mg (yield 53%) of diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2, b-diazabicyclo 3,2,0 - hept-2-en-6-yl) -3-hydroxymethyl-3-butanoate and 90 mg (yield 35%) of the starting material.

Example 4. Diphenyl (2R) -2-- (3-phenyl-7-oxo-4-oxa-2, b-diazabicyclo-3,2,0 -hept-2-en-b-yl) -3-iodomethyl -3-butenoate reacts with calcium carbonate and silver nitrate to give a mixture (1: 3) of diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2, b-diazabicyclo, 2. , 0 -hept-2-en-6-yl) -3-hydroxymethyl-3-butenoate and diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2, b-diazabicyclo-1 3 , 2,0-hept-2-en-b-yl) -3-nitroxymethyl-3-butenoate, which is dissolved in

4.5 ml of methylene chloride. 0.5 ml of acetic acid is added dropwise to the solution prepared in this way, the mixture is mixed with 300 mg of zinc, stirred for 15 minutes, dispersed with methylene chloride, washed with water, dried and evaporated. The residue is purified by thin-layer chromatography to obtain diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2, b-diazabicyclo-chr, 2, Oj 0 -hept-2-en-b-yl) -3-hydroxymethyl-Zbutenoate.

Example 5. (Application of Laser Transition Reagent (We, NJ).

In a solution of 450 mg of diphenylmethyl-25 - (3-phenyl-7-oxo-2,6-diaza-4-oxadicyclo-C3, 2.0-hept-2-en-b-yl) -3-chloromethyl-3- a solution of 300 mg of sodium iodide, 100 mg of sodium thiosulfate pentahydrate and 150 mg of tetra-butylammonium iodide in 2 ml of water at room temperature is added to butenoate in 27 ml of acetone. This solution is concentrated to remove ethyl L-acetate, diluted with water (125 ml) and added by adding 3 ml of 5% sodium hyposulfite solution, washed with water, saturated with brine and dried over sodium sulfate. Next, the solution is evaporated to obtain 376 mg of diphenylmethyl-2- (3-phenyl-70-oxo-2, b-diaza-4-oxadicyclo-3, 2.0) -hept-2-en-b-yl) -3- iodomethyl-3-butenoate with the achievement of 65% product yield from the theoretically possible.

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The abbreviations in the tables below are indicated:

Ac - acetyl.

An - acetone,

A - water

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C H - phenylene,

OMSO - dimethyl sulfoxide,

Et - ethyl,

i - iso-,

on - left overnight

Ph is phenyl,

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refl. - heating temperature

reflux condenser, rt - room temperature, t - tertiary, Ts - p-CH CftH / iSOi.

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v0opMyna invention

The method of obtaining oxazolinoazetidinylpentene acid derivatives of general formula I

A-Z-UHjX

ABOUT

R z

hydrogen, alkyl, aryloxyalkyl, aralkyl or aryl, two} (vale1 {tn group

or

r "v,

where СОВ is tert-butyl, benzyl or diphenylmethyl esters of the carboxyl group,

I

X is a halogen atom, hydroxyl, formyloxy-, acetyloxy-, trifluoroacetyloxy-, nitroxy-, phenylthio-.

or 1-methyl-5-tetrazolylthio, characterized in that the compound of general formula II

1g

I i

„-K-Z-CH.Y, О.

where R and -Z have the indicated Y values — halogen or nitroxy, treat the nucleophilic 1 m reagent replacing Y with X, in an inert organic solvent, mainly acetone, methyl isopropylketone, methanol, acetonitrile and water, at a boiling temperature of the reaction medium, preferably the presence of ether or tetrabutylammonium halide.

Sources of information taken into account in the examination

1. Weigand-Hilgetag. Experimental methods in organic chemistry. M., Himi, 1968, p. 191, 314.

Claims (1)

"Claim A method of obtaining derivatives of oxazolinoazetidinylpentenoic acid of General or 1-methyl-5-tetrazolylthio group, characterized in that the compound of General formula I I of formula I -Z-CH ₂ Y where - hydrogen, alkyl, aryloxyalkyl, aralkyl or aryl, - a divalent group where either no or yo-oo owls COB - tert-butyl, benzyl diphenylmethyl ethers of the carboxyl group, X is an atom of formyloxy, acetyloxy, halogen, hydroxyl, acetyloxy, trifluoronitrooxy, phenylthio, where R and 1 have the indicated meanings; Y is halogen or nitrooxy; acetone, methyl isopropyl ketone, methanol, acetonitrile and water, at the boiling point of the reaction medium, preferably in the presence of ether or tetrabutylammonium halide.