JPS6190A - Preparation of hydroxycepham carboxylic acid ester - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for cephalosporins, etc. without causing side reactions, by reducing an aralkyl oxocepham carboxylate, etc. in an anhydrous lower alcohol solvent with an alkali metal boron hydride at a low temperature. CONSTITUTION:An aralkyl 3-oxo-cepham-4-carboxylate or enol derivative thereof is reduced with an alkali metal boron hydride, preferably L, Na or K as the alkali metal in an anhydrous lower alcohol solvent at <=-20 deg.C, preferably -30- -70 deg.C to give the corresponding aralkyl 3-hydroxycepham-4-carboxylate.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides a 3-hydroxycepham-4-carboxylic acid aralkyl ester by reducing a 3-year-old xocepham-4-carboxylic acid aralkyl ester or its enol form with an alkali metal borohydride. This invention relates to an improved method for manufacturing.

This reaction itself is known from JP-A-49-49989, etc. When the present inventor reduced an aralkyl ester under known conditions, the methanol used as a solvent underwent a transesterification reaction with an aralkyl ester of a carboxylic acid. The generated methyl ester was the main product. Therefore, when the reaction was carried out at around -50°C by cooling beyond the range described in the published patent application, it was discovered that the reduction reaction proceeded satisfactorily, but the transesterification reaction, which is a forced side reaction, did not proceed.
completed this invention.

That is, this invention reduces a 3-year-old xocepham-4-carboxylic acid aralkyl ester compound with an alkali metal borohydride in a water-containing lower alcohol solvent at -20°C or lower to obtain the corresponding 3-hydroxycepham-4-carboxylic acid aralkyl ester compound. This is a method for producing 4-carboxylic acid aralkyl ester.

Raw material 3-oxocepham-4. The -carboxylic aralkyl ester or its enol may have an amide side chain at its 7-position.

Here, as the 7-amide side chain, among the amide side chains and their analogs known for penicillins, cephalosporins, and their synthetic intermediates, those that do not cause any unfavorable changes under these reaction conditions are used. Can be adopted.

As the aralkyl ester, methoxybenzyl ester, diphenylmethyl ester, etc. having an ester group with high nucleophilicity are suitable.

As the lower alcohol, methanol, ethanol, butanol, etc. can be used. This reaction does not interfere with the presence of inert solvents such as halohydrocarbons, amides, and ethers.

The alkali metal of the alkali metal borohydride is preferably lithium, sodium, or potassium.

According to the present invention, preferably 7-amido-3-year-old xocepham-4-carboxylic acid aralkyl ester or its enol form is dissolved in 3 to 20 parts by volume of water-containing lower alkanol, optionally with an inert solvent, After cooling to -20℃ or below (especially -309C to -70℃), 1 to 20 equivalents (especially 1 to 5 equivalents) of alkali metal borohydride are added for 10 minutes to 20 hours (especially 30 minutes to 10 hours). time) If the reaction is carried out, the desired 3ξ-hydroxycepham-
4-carboxylic acid aralkyl ester can be produced with a yield of 70-99%.

If necessary, a reaction accelerator such as acetic acid, an inert gas such as nitrogen,
Conventional methods for smoothing the reaction such as stirring can be used.

The desired product can be collected by subjecting the reaction solution to conventional post-treatments such as vacuum distillation of low-boiling substances, extraction, washing, drying, and crystallization.

3ξ-Hydroxycefam which can be produced in this way
Some of the 4-carboxylic acid esters are known as synthetic intermediates for various 3-unsubstituted cephalosporins.

An example is 7-amide-3ξ-hydroxycepham-4
- 3ξ-(alkane or aryl)sulfonyloxycepham-4-carboxylic acid obtained by esterifying a carboxylic acid aralkyl ester with 1 to 3 equivalents of (AJlecane or aryl)sulfonylno-1lide in an aprotic organic solvent. After forming the ester, 1 to 10 tertiary amines were added at -10°C to -60°C in 5 to 20 parts by volume of an inert solvent.
Equivalence and processing time is 5 hours or less (especially 0.5 to 3 hours)
The desired 3-cephem compound can be produced with a yield of 70 to 90%. If the acylkyl ester of this compound is converted into a carboxylic acid by using the method of JP-A-52-106891, which uses a strong acid carboxylic acid, Lewis acid, etc. and a proton scavenger, it is possible to quickly obtain a cephalic acid that competes for antibacterial properties. Can produce sporine agents.

Unless otherwise specified, each reaction is usually carried out at -80°C to 30°C.
℃ (especially -50℃ to -30℃) for 10 minutes to 1
The reaction is often carried out for 0 hours. These are in a solvent,
If necessary, it is carried out under stirring or anhydrous conditions. Any other conventional law may be applied.

Hydrocarbons (pentane, hexane,
octane, hensen, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, hypochlorite tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (diethyl ether, methyl isobutyl ether, anisole, dioxane, tetrahydrofuran, etc.), Esters (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitriles (acetonitrile, hendinitrile, etc.), amides (formamide,
acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), carboxylic acids (chloroacid, acetic acid, propionic acid, etc.), organic bases (
Industrial solvents belonging to the series such as diethylamine, triethylamine, pyridine, picoline, )IJ, quinoline, alcohol, methanol, ethanol, propatool, hexanol, octatool, benzyl alcohol, etc.), water, and other series can be employed. .

Each desired product is produced by extracting impurities such as unreacted raw materials, by-products, and solvents from the reaction solution, evaporating, washing, concentrating, precipitating,
After removal by conventional methods such as filtration and drying, it can be isolated by combining conventional post-treatment methods such as adsorption, elution, distillation, precipitation, precipitation, and chromatography.

The present invention will be described in detail below with reference to Examples.

The physical constants of the products are summarized in a table.

Post-treatment in the examples is usually carried out by adding water, acid, dichloromethane, etc. to the reaction solution as necessary, separating the layers, washing the organic layer with water, drying, and concentrating the resulting residue under reduced pressure. If necessary, after purifying with silica gel chromatography,
Collection methods such as crystallization, precipitation, and filtration are used in combination.

The abbreviations used are as follows.

BOC=t-butoxycarbonyl.

Bz = benzyl.

13u-t = t-butyl.

Cbz = Carbohenzoxy.

ph -phenyl 0 (blank below) Example 1 1) 3-Hydroxy-7β-phenylacetylamino-
2 g (4 mmole) of 3-cephem-4-carboxylic acid diphenylmethyl ester (1) was dissolved in a mixture of dichloromethane 10IIQ and methanol iQd, cooled to -53°C under N2, and dissolved in sodium borohydride 605+
ng (4 mole eq, ) was added over a period of 7 minutes at -53 to -57°C. After reacting at the same temperature for 30 minutes, 2.5 d of glacial acetic acid was slowly added at the same temperature, and then 20'nQ of water was added. The reaction solution was extracted with dichloromethane, washed with 5% sodium hydrogen suboxide and water, dried over sodium sulfate, and evaporated under reduced pressure. The residue was crystallized from a mixture of dichloromethane (5+iQ) and n-hexane (5nQ) to give 1.806 g of diphenylmethyl 3β-hydroxy-7β-phenylacetylamino-cephalomino-4α-carboxylate (2) (89,8 -5%) is obtained.

2) 3β-Hydroxy-7β-phenylacetylamino-cephem-4α-carboxylic acid diphenylmethyl ester (2) 2,01 g (4 mmole) was suspended in 20 ml of methylene chloride and cooled to −10° C. under N2 to form triethylamine 2. , 23d (4 moleq), then 0.62 ml of methanesulfonic acid chloride:
2 mole eq, ) is added over 7 minutes at -7 to -11°C. The methanesulfonic acid ester produced (
After reacting 3) at around -10°C for 30 minutes, methylene chloride 3
Add QnA. After that, the mixture was washed with water, 5% sulfuric acid, water and dried over sodium sulfate, and the high methylene chloride was distilled off under reduced pressure. Adding methanol 1Q + ml to the residue and crystallizing it gives 7β
-Phenylacetylamine-3-cephem-4-carboxylic acid diphenyl ester (4) 1.46 (75,38%
) is obtained.

Example 2 1) 3-hydroxy-7β-phenylacetylamino-
2 g (4 mmole) of 3-cephem-4-carboxylic acid diphenyl methyl ester (1) was dissolved in 20-20% dimethylformamide (dried with molecular sieves) under N2.
Cool to 0°C and add 605 mg of sodium boron hydride.
(4 mol'eq,) was added over a period of 3 minutes at -53 to 48°C. After reacting at the same temperature for 30 minutes, 2.6 nQ of glacial acetic acid was slowly added at the same temperature, and then 2.6 nQ of water was added.
Add Q nQ. Extract the reaction solution with ethyl acetate, 5%
Wash with sodium bicarbonate and water, dry over sodium sulfate and evaporate under reduced pressure. The residue was dichloromethane (5+
Crystallization from a mixture of mQ) and n-hexane (5++Il) yielded 1.501 g (74,66%) of 3β-hydroxy-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester (2). It will be done. The washing solution was distilled off under reduced pressure and crystallized in the same manner to obtain 33 mg (1.65%) of compound (2). , 194.7°C (decomposed).

Elemental analysis: Calculated value as C1a Hz IN * Os S (x>: c, a6.+; +z; u, 5.zt
;N, 5.57;s, 6. ss experimental value <Z>: C,
66,82:)l, 5.19;N,'5.7o:s,
6.352) 3β-hydroxy-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester (2) 2.01 g (4'mmole)
Dimethylformamide (dried molecular sheets)
Dissolved in 20d, cooled to -50 °C under N2, added triethylamine 2,23d (4 mole eq,), then methanesulfonic acid chloride o,62nQ (2 mol eq.
e eq, ) was added dropwise over a period of 3 minutes at -52 to -45°C. The resulting methanesulfonic acid ester (3) was heated at -55 to -45°C for 2.5 hours, then at -15 to -12°C.
After reacting at ℃ for 50 minutes, extraction with -1 ethyl acetate, water,
Wash with 5% HCI and water, dry over sodium sulfate and evaporate under reduced pressure. The residue was crystallized from methanol 10IIQ to give 7β-phenylacetylamino-3-cephem-4-carboxylic acid phenylmethyl ester (4) 1
．． 58 g (81,53%) are obtained. of. 172.5
°c.

Example 3 Compound (4) shown in the table below can be synthesized in the same manner as in Examples 1 and 2 via the corresponding intermediate.

(Margin below) Procedure Nenan Seisho (self-motivated) May 29, 1985

Claims (1)

[Claims] (1) 3-Hydroxycepham-4-carboxylic acid aralkyl ester or its enol form is reduced with an alkali metal borohydride in a water-containing lower alcohol solvent at -20°C or lower to produce the corresponding 3-hydroxycefam-4-carboxylic acid aralkyl ester or its enol form. - A method for producing hydroxycefam carboxylic acid ester, which comprises producing an aralkyl carboxylic acid ester.