JPS6150986A - Preparation of sulfoxide - Google Patents

Abstract

PURPOSE:To sulfoxidate smoothly and rapidly penicillins or cephalosporins, by reacting the penicillins or cephalosporins with hydrogen peroxide in the presence of a phosphoric acid compound. CONSTITUTION:Penicillins or cephalosporins are reacted with hydrogen peroxide in the presence of a phosphoric acid compound, e.g. orthophosphoric acid, metaphosphoric acid, polyphosphoric acid or phosphorus pentoxide, preferably at 0-50 deg.C for 20min-10hr and sulfoxidated. In the process, a reaction promoter, e.g. carboxylic acid or sulfonic acid, is used, as necessary.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for sulfoxidizing penicillins or cephalosporins, which is characterized in that hydrogen peroxide is applied to penicillins or cephalosporins in the presence of a phosphoric acid compound. Regarding the conversion method.

In recent years, a method for producing a cephalosporin core from penicillin sulfoxide has been put into practical use on an industrial scale, but an important step is to produce the penicillin sulfoxide used here from penicillin. Conventionally, there have been methods using dangerous reagents such as peracids, and methods using hydrogen peroxide as an oxidizing agent and rare element catalysts such as tungsten compounds (Japanese Patent Laid-Open No. 4
8-34192) or a method using a lower alkanoic acid catalyst with a low reaction rate (5ynthesis, 1978
Year.

p. 361;) Leterocyclas, Vol. 22, p. 531 (1984)), but all of them have drawbacks for industrial use. The present inventor has searched for a method free of such drawbacks, and has The present invention was completed based on the discovery that sulfoxidation by hydrogen oxide is promoted and smoothed by a phosphoric acid compound.

The penicillins used in this invention include natural penicillins such as penicillin G1 and penicillin V, synthetic penicillins such as 6 (α or β)-amidopenicillanic acid, and various salts and esters of these natural or synthetic penicillins. Cephalosporins include 7(α or β)-amidocephalosporanic acid, various derivatives at the 3-position thereof, and their salts and esters.

The acyl group constituting the amide group of the penicillins and cephalosporins is an aliphatic or aromatic acyl group,
May contain different atoms and unsaturated bonds.

Examples include alkanoyl-substituted alkanoyl, alkenoyl, benzoyl, substituted benzoyl, aralkayl, substituted aralkayl, alkoxycarbonyl-substituted aralkoxycarbonyl, and the like.

As various derivatives at the 3rd position of cephalosporins,
Examples include alkyl, alkenyl, alkynyl, hydroxy, alkoxy, acyloxy, alkylthio, acylthio, arylthio, and halogen. These groups may have various substituents, and the aryl moiety may be a heterocyclic ring containing a heteroatom such as nitrogen, #, or sulfur.

In particular, known lower alkyl, alkenyl, alkoxy,
Important examples include halogen, alkyldimethyl, alkanoyloxymethinocyclic ring thiomethyl, pyridinium methyl, and substituted pyridinium methyl.

Esters include esters known in the field of penicillin and cephalosporin chemistry as those that can be desorbed without causing any unfavorable changes in other parts of the molecule, such as aralkyl esters (benzyl, methylbenzyl, etc.). ,
esters such as dimethylhensyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminohensyl, diphenylmethyl, phthalidyl, phenacyl), alkyl esters (esters such as trichloroethyl, tertiary butyl, allyl), aryl esters (pentachlorophenyl, indanyl) etc.), esters of N-hydroxyamino compounds (esters with acetone oxime, acetophenone oxime, acetaldoxime, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.), and others.

Here, the substituents include R elementary groups (alkyl, alkenyl, alkylidene, alkynyl, aralkyl, aryl,
carboxy, protected carboxy, carbamoylcaryl, aroyl, aminoalkyl, cyano, etc.)
, nitrogen groups (amine, hydrazinyl, azide, diazo, alkylamino, arylamino, acylated amine, alkylidene amino, imino, alkoxyimino, nitroso, nitro, etc.), oxygen groups (hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy, oxo, etc.), sulfur groups (mercapto, alkylthio, arylthio, acylthio, thioxo, sulfinyl, sulfo, protected sulfo, etc.), phosphorus groups (phosphorus, etc.), halogen atoms (
(fluorine, chlorine, bromine, iodo), and other substituents.

Examples of the phosphoric acid compound include orthophosphoric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, pentoxide, and alkali metal salts thereof.

As the hydrogen peroxide, 30% to 60% hydrogen peroxide solution, which is easily available industrially, can also be used, but the present invention is not limited thereto.

The reaction of this invention can also be carried out in inert solvents (industrial solvents belonging to aromatic hydrocarbons, halogenated hydrocarbons, esters, etc., water, etc.). In addition, as reaction accelerators, carboxylic acids and anhydrides such as alkanoic acids (formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, etc.), aromatic carboxylic acids (benzoic acid, substituted benzoic acids, etc.), aliphatic or aromatic Efficiency can also be improved by coexisting sulfonic acid, a phase transfer reagent (such as tetraalkylammonium halide), and a surfactant.

This reaction is usually carried out at -30 to 80°C, preferably 0 to 50°C.
If the reaction is designed to be completed in 5 minutes to 30 hours, preferably 20 minutes to 10 hours, it is advantageous in terms of yield improvement and suppression of side reactions. For example, the raw material penicillin,
Cephalosporins are mixed with an inert solvent (dichloromethane, chloroform, etc. 5 to 20 parts by weight), a reaction accelerator (formic acid, acetic acid, etc. θ to 10 equivalents), and a phosphoric acid compound (phosphoric acid, polyphosphoric acid, metaphosphoric acid, pentachloride, etc.). .1 to 5 equivalents), then add hydrogen peroxide solution (20 to 65%; 1 to 1.5 equivalents) and stir at 0 to 30°C for 10 minutes to 2 hours.The yield is usually 70 to 98%. % range, by-products such as sulfones and lactam cleavage substances are extremely low.

The desired product is extracted from the reaction solution by unreacted raw materials, by-products,
After removing the solvent by conventional methods such as extraction, evaporation, washing, fi-condensation, precipitation, filtration, and drying, adsorption, elution, distillation,
It can be isolated by a combination of commonly used post-treatment methods such as precipitation, precipitation, chromatography, and crystallization.

The steric configuration of the sulfoxide bond in the main product is often in the same direction as the amide side chain.

The products of this invention are useful as raw materials for the synthesis of useful antimicrobial agents and the like.

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

In the examples, the part representing the amount represents the weight relative to 1 part by weight of the starting β-lactam, and the equivalent represents the number of moles relative to 1 mole of the starting β-lactam.

The abbreviations used are as follows.

Me - methyl.

P, h snow phenyl.

Engineering CE! Trichloroethyl.

Example Penicillin or cephalosporin is dissolved in dichloromethane or toluene, and a reaction accelerator, a phosphoric acid compound and aqueous hydrogen peroxide are added thereto. This is stirred at a predetermined temperature for a predetermined time. The reaction solution was washed with water, 5% sodium bicarbonate water, and water, and the organic layer was separated. This is dried and concentrated under reduced pressure. If the residue is crystallized from methanol or inpropatol, the desired sulfoxide is obtained.

The physical constants of the products are shown in Table 1. Table 2 shows the reaction conditions for penicillins, and Table 3 shows the reaction conditions for deacetoxycephalosporins.

(Left below) Table 1 (Part 1) 0 Ding Ren00R' 1 and 11 1111 eny m, -m-Ph
Pb2 CH152Ph
CH2Ph 2 CH129 PhCH2TCE 174P
hCH2PhCH2174 PhCH2H145 PhOCHz Phz CH92
PhOCH2TCE 147
PhOCH2PhCH2128 PhOCHg H167Ma
c6 Ha-p Phz CH178
MaC6H4-pMe
154MQC6H4-p Me
Ce 84 CH2164Mega H4-p
H180CIC6H4-p
Pb2 CH192CICa H4-H160 Table (Part 2) 0 ↑ PhCHz, TCE 19
9PhCHz H187 PhO(Hz rcE 17
4PhOC) I2H196 (margins below)

Claims (1)

[Claims] (1) A method for sulfoxidizing penicillins or cephalosporins, which comprises reacting penicillins or cephalosporins with hydrogen peroxide in the presence of a phosphoric acid compound.