JPH0645625B2 - Process for producing hydroxycepham carboxylic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, 3-oxocepham-4-carboxylic acid aralkyl ester or its enol derivative is reduced with an alkali metal borohydride to produce 3-hydroxycepham-4-carboxylic acid aralkyl ester. Regarding the method.

This reaction itself is known from JP-A-49-49989, etc., but when the present inventor reduced the aralkyl ester under known hydrous conditions, the ester portion of the raw material carboxylic acid was separated and eliminated to produce a large amount of aralkyl alcohol. However, the yield of the target product was low. Therefore, when the reaction was carried out in an anhydrous organic solvent at a low temperature exceeding the range described in the patent document, the reduction reaction quantitatively proceeded, but the decomposition reaction as a side reaction did not proceed and the yield was as shown in Table 1. They found that the rate increased and completed the invention.

That is, the present invention reduces 3-oxocepham-4-carboxylic acid aralkyl ester or its enol form with an alkali metal borohydride at -20 ° C or lower in an anhydrous organic solvent to give the corresponding 3-hydroxycepham-4-. It is a method for producing a carboxylic acid aralkyl ester.

The starting material, 3-oxocepham-4-carboxylic acid aralkyl ester or its enol form, may have an amide side chain at the 7-position.

Here, as the 7-amide side chain, an amide side chain and analogs thereof known for penicillin, cefalosporin, and their synthetic intermediates, which do not cause an inconvenient change under the reaction conditions, can be adopted.

As the aralkyl ester, benzyl ester having a highly nucleophilic ester group, methoxybenzyl ester,
Diphenyl methyl ester and the like are suitable.

As the solvent, methanol, ethanol, propanol,
Substantially anhydrous polar organic solvents such as lower alcohols such as butanol and dialkylamides are preferred. For this reaction, an inert solvent such as halohydrocarbon and ether can be used together.

Lithium, sodium and potassium are preferable as the alkali metal in the boron hydride alkyl metal.

According to the invention, preferably 7-amido-3-oxocepham-4-carboxylic acid aralkyl ester or its enol form, preferably a mixture of halohydrocarbons and anhydrous lower alkanols or N, N-dialkylalkanamide 3 To 30 volume parts and cooled to -20 ° C or lower (especially -30 ° C to -80 ° C), and then 1 to 20 equivalents (especially 1 to 5 equivalents) of alkali metal borohydride is added for 10 minutes to 20 minutes. The desired 3ξ-hydroxycepham-4-carboxylic acid aralkyl ester is produced in a yield of 70 to 99% by reacting for a time (particularly 30 minutes to 10 hours).

If necessary, a reaction accelerator such as acetic acid, an inert gas such as nitrogen,
A reaction smoothing method such as stirring may be used.

The target 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.

Unless otherwise specified, each reaction is usually −80 ° C. to +3.
At a temperature of 0 ° C (especially -50 ° C to -30 ° C) for 10 minutes
It is possible to react for 10 hours. These are carried out in a solvent, preferably under stirring or anhydrous conditions. Any other conventional method can be applied.

As the reaction solvent, hydrocarbons (pentane, hexane,
Octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon 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, benzonitrile, etc.), amides (formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), carboxylic acids (formic acid, acetic acid, propionic acid) Etc.), organic bases (diethylamine, triethylamine, pyridine, picoline, collidine, quinoline, etc.), alcohols (methanol, ethanol, ethanol, etc.) Propanol, hexanol, octanol, benzyl alcohol), other industrial solvents belonging to series or adopt the mixture.

Each target product is an unreacted raw material from the reaction solution, by-products, impurities such as solvent are extracted, evaporated, washed, concentrated, precipitated, filtered, removed by a conventional method such as drying, and then adsorbed,
Isolation can be achieved by a combination of conventional post-treatment methods such as elution, distillation, precipitation, precipitation and chromatography.

Hereinafter, embodiments of the present invention will be described with reference to examples.

The amount of the reagent is expressed in parts (parts by weight) and equivalents (molar equivalents) relative to the beta-lactam raw material. Concentration is performed under reduced pressure, and sodium sulfate is used to dry the solution. Upon deacyloxylation, the reaction system was checked with a damp pH test paper before starting the reaction, and triethylamine was added until pH 9 was reached.

The abbreviations used are as follows.

BOC = t-butoxycarbonyl.

Bz = benzyl.

Bu-t = t-butyl.

Cbz = carbobenzoxy.

Ph = phenyl.

Example (reduction reaction) 1) 3-oxo-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (1) or its enol derivative was dissolved in a mixed solution of 6.5 parts of dichloromethane and 4 parts of methanol, and then in a nitrogen atmosphere- Cool to 53 ° C and add 4 equivalents of sodium borohydride at -53 to -57 ° C.
It takes 7 minutes to put in. After reacting for 30 minutes at the same temperature, 1.4 parts of glacial acetic acid was added slowly at the same temperature, and then 10 parts of water was added. The reaction is extracted with dichloromethane, washed with 5% sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated. The residue is crystallized from a mixture of 4 parts of dichloromethane and 1.7 parts of n-hexane to give 3ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-diphenylmethyl carboxylate (2).
Yield: 89.7%. 2) In the above reaction, ethanol-chloroform (yield: 78
%), Ethanol-dichloromethane (yield: 81%) or methanol-ethanol-dichloromethane (yield:
96%) and used at −35 to −80 ° C.
(2) is obtained.

3) 3-hydroxy-7β-phenylacetylamino-
3-Cefem-4-carboxylic acid diphenylmethyl ester (1) was dissolved in 9.5 parts of dimethylformamide (dry product of molecular sieves), cooled to -50 ° C under N ₂ , and 4 equivalents of sodium borohydride were added at -53 to -53. Charge at −48 ° C. for 3 minutes. After reacting for 30 minutes at the same temperature, 1.4 parts of glacial acetic acid was added slowly at the same temperature, and then 10 parts of water was added. The reaction mixture is extracted with ethyl acetate, washed with 5% sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated. The residue was crystallized from a mixture of 4 parts of dichloromethane and 1.7 parts of n-hexane to give 3ξ-hydroxy-7β.
-Phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (2) is obtained. Yield: 76.3%.

mp.196-198 ° C (decomposition). IR (Nujol) ν: 3450, 3300, 1765, 1740, 1645 cm ^-1 . NMR (CD ₃ SOCD ₃ ) δ: 2.8 to 3.2 (m, 2H), 3.37 (s,
1H), 3.57 (s, 2H), 4.13 (m, 1H), 4.77 (d, J
= 6Hz, 1H), 5.13 (d, J = 4.5Hz, 1H), 5.40 (d
d, J ₁ = 4.5Hz, J ₂ = 9Hz, 1H), 6.10 (d, J = 9
Hz, 1H), 6.80 (s, 1H), 7.23 to 7.33 (m, 15H) pp
m. Elemental analysis: C ₂₈ H ₂₆ N ₂ O ₅ S Calculated value (%): C, 66.92; H, 5.21; N, 5.57; S, 6.38 Experimental value (%): C, 66.82; H, 5.19; N, 5.70 ; S, 6.35

Claims (1)

[Claims] Claims: 1. 3-Oxocepham-4-carboxylic acid aralkyl ester or its enol derivative is reduced with an alkali metal borohydride at -20 ° C or lower in an anhydrous organic solvent to give the corresponding 3-hydroxycepham-4-. A method for producing a hydroxycepham carboxylic acid ester, which comprises producing a carboxylic acid aralkyl ester.