JPH0256489A - Production of cephalosporine derivative - Google Patents

Abstract

PURPOSE: To obtain the subject deriv. having good antibiotic activity against Gram positive and negative bacteria by oral administration and having high stability against β-lactase by reacting a specific compd. with O-methyl-oximizing agent.

CONSTITUTION: A compd. represented by formula I (wherein R is H or a carbamoyl protective group, Z is S or -SO- and a dotted line sets the compd. to a ceph-2-em or ceph-3-em compd.) is reacted with an O-methyl-oximizing agent to obtain a compd. represented by formula II and, succeedingly, if desired, this compd. is converted to a separate compound by one or more processes such as the reduction of a compd. wherein Z is SO to a compd. wherein Z is S, the conversion of a Δ²-isomer to a Δ³-isomer or the removal of a substituent when the substituent is present on carbamoyl. In the oximizing reaction, temp. is set to -20 to 10°C and it is pref. to use a methoxylmine or its salt as the oximizing agent.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to improvements in or relating to cephalosporins. More specifically, the present invention relates to a method for producing the oral antibiotic cefoxime axetil.

Cefuroxime axetil, i.e. (6R,7R)-3
-carbamoyloxymethyl-7-((Z)-2-(fluor-2-yl)-2-methoxyiminoacetamide) 1- of cef-3-em-4-carboxylic acid (cef-oxime)
7 Cetoxyethyl ester is British Patent No. 1,571,6
It is described in No. 83. Cefuroxime axetil is a particularly valuable cephalosporin because it can be administered orally.

This compound has been shown to have good antibiotic activity against a broad spectrum of Gram-positive and Durum-negative bacteria upon oral administration and to have high stability towards β-lactamases.

Cephalosporin esters can be obtained by acylating a suitable 7-aminose 7 allosborin using a preformed compound capable of introducing a 7-substituent, or by acylating a suitable 7-aminose 7 allosborin using a compound capable of introducing a 7-substituent into the cephalosporin ester. They can usually be prepared by introducing the desired ester group by esterifying the 4-carboxyl group of a 4-carboxylic acid, for example by reacting it with a ester.

These general methods are described in British Patent No. 1,571,683 for the preparation of cefuroxime axetil.

A process has now been devised for the preparation of cefuroxime axetyl and its protected derivatives, which consists in introducing an 0-methyloxime group by an oximation reaction as the last major chemical step of the synthesis.

Therefore, according to one aspect of the present invention, - general formula (1) (wherein P is a hydrogen atom or a carbamoyl protecting group,
2 is S or S→0 and the dotted line indicates that the compound is a cef-2-em or cef-3-em compound). R, Z and the dotted line are as defined above).

The oximation reaction may be carried out in an aqueous or non-aqueous medium, conveniently at temperatures between 0°C and +100°C, such as between 0°C and +75°C.

Examples of reaction media that can be used are water; alcohols such as methanol or ethanol; ethers such as cyclic ethers such as tetrahydrofuran or dioxane or acyclic ethers such as diethyl ether or diglyme; amides such as N,N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoramide; nitriles such as acetonitrile; nitroalkanes such as nitromethane; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; halogenated hydrocarbons such as dichloromethane; It is a mixture of the above.

If the oximation is carried out in an anhydrous reaction medium, it is desirable to have a Lewis acid such as Br3, magnesium chloride or zinc chloride, conveniently in the form of a solvate such as an etherate.

This reaction is conveniently performed when aqueous conditions are used.
．． It can be implemented at 0 to 9.0, preferably 6 to 8. The viscosity can be conveniently maintained within said range by adding a suitable acid or base, for example a mineral acid such as hydrochloric acid or sulfuric acid, or an alkali metal carbonate or bicarbonate, such as sodium bicarbonate.

This oximation reaction may be followed, if desired, by the reaction of the initially obtained compound of the formula (11) Conversion of Δ-isomer to Δ-isomer, On)
If a substituent exists on the carbamoyl, it can be removed and converted into another compound of formula (1) by one or more of the following.

This reaction can be carried out in any convenient order by conventional methods.

Therefore, if desired, the method of the present invention can be used to obtain Δ2−
Cephalosporins, for example! -esters can be converted to the corresponding Δ3-derivatives by treatment with bases such as pyridine or triethylamine.

Cef-2-em reaction products may also be used, for example peracetic acid or m
It can also be oxidized to the corresponding cef-3-em-1-oxide by reaction with a peracid such as -chloroperbenzoic acid.

The resulting sulfoxide can then be reduced to the corresponding cef-3-em sulfite as described below.

When a compound of formula (1) in which 2 is 8-0 is obtained,
As desired, this thing can be done on the spot, for example! can be converted into the corresponding sulfite by reducing the corresponding acyloxysulfonium salt (e.g. by reaction with acetyl chloride in the case of an acetoxysulfonium salt) or an alkoxysulfonium salt prepared by
The reduction is then carried out, for example, with sodium dithionite or with iodite ions, such as a solution of potassium iodide in a solvent such as acetic acid, acetone, tetrahydrone, dioxane, dimethylformamide or dimethylacetamide. This reaction takes place between -20°C and +50°C.
It can be carried out with

The carbamoyl protecting group present in the compound of formula (Xia) or its intermediates is advantageously a group that can be easily removed at an appropriate step in the reaction sequence, such as a γ-syl group, especially a lower group such as acetyl. Alkanoyl group, halo-substituted lower alkanoyl group such as mono-di or trichloroacetyl, chlorosulfonium or haplomosulfonyl group, dihalophosphonyl group such as dichlorophosphonyl group, or 2,2.2-trichloroethoxycar; F : Nil (f
) j 57i is a halogenated alkoxycarbonyl group.

Any carbamoyl protecting group present in a compound of formula (1) may be removed as desired by any suitable method known in the art. Labile groups such as chlorosulfonyl, dichlorophosphonyl and trichloroacetyl can generally be cleaved by acid- or base-catalyzed hydrolysis (eg, base-catalyzed hydrolysis with sodium bicarbonate).

2.2.2 Halogenated groups such as 2-trichloroethoxycarbonyl can also be cleaved reductively, and groups such as chloroacetyl can be cleaved by treatment with thioamides such as thiourea.

The reaction products can be extracted, for example, by solvent extraction, recrystallization, iontophoresis, column chromatography, high pressure liquid chromatography, ion exchange chromatography, or macroreticular resin extraction from the reaction mixture, which may contain unchanged cephalosporin starting material and other materials. They can be separated by a variety of methods, including chromatography.

If the compound of formula (I) is obtained as a mixture of exoisomers, the cisine isomer can be obtained by conventional methods such as crystallization or tetramathography. The product may also be recovered in the form of a mixture of the n and S isomers of the esterified group in an approximately 1=1 molar ratio, as described for example in British Patent No. 2,145,409.

A preferred embodiment of the present invention is a cefuroxime axetil or a protected derivative thereof, i.e., a formula ( 1), followed by optionally in situ removal of the protecting group if desired.

A compound of formula (I[) is, for example, a compound of formula (Ill) (wherein R, Z
and dotted lines as above) or salts thereof such as alkali metal salts (e.g. sodium or potassium salts) or haonium salts such as ammonium salts (e.g. quaternary ammonium salts) with suitable haloesters such as 1-acetoxyethyl It can be prepared by esterification with bromide.

The reaction is conveniently carried out in an inert solvent such as N,N-disubstituted amides such as N,N-dimethylformamide, JN-dimethylacetamide; ketones such as acetone; sulfoxides such as dimethylsulfoxide; 710 in a hydrogenated hydrocarbon; or in a nitrile such as acetonitrile. The reaction is carried out between -50°C and +150°C, for example between -10°C and +50°C, conveniently between 0°C and room temperature.

If a free acid is used as a starting material, the esterification is generally carried out in the presence of a base capable of generating a 4-carboxyl function or anion. Examples of suitable bases are inorganic bases such as alkali metal carbonates such as sodium or potassium carbonate.

Compounds of formula (I[) are described, for example, in British Patent No. 1,453,0
49, by conventional acylation methods.

The invention is illustrated below. All temperatures are in degrees Celsius. "
The term "drying" means drying with sodium or magnesium sulfate. Troll is petroleum ether (
(boiling point 40-60°C).

Intermediate 1 diphenylmethyl (6B, 71'l) -3-carbamoyloxymethyl-7-((flu-2-yl)glyoxamide] cef-6-nimu 4-carboxylate diphenylmethyl (6R,7R) -7-amino -6-
Carbamoyloxymethylcef-3-em-4-carboxylate toluene-p-sulfonate (t2ay) was dissolved in ethyl acetate (200d) and sodium bicarbonate solution (2ootnt). The ethyl acetate layer was separated, washed with water, dried and cooled to 0°C. To this solution was added a solution of dicyclohexylcarbodiimide (1,46II:l) and 2-furylglyoxylic acid (991jllF) in ethyl acetate.

The reaction mixture was stirred for 20 minutes at 0°C, filtered and the p-liquid was evaporated under vacuum. The residue was triturated with ethanol to give the title compound (3,531 units).

Melting point: 169-171°C.

Intermediate 2 (611,7R) -3-carbamoyloxymethyl-
7-[(Flu-2-yl)glyoxamide]Sefu 3-
Em-4-carboxylic acid anisole (5,5ml) and the product of intermediate 1 (t
Trifluoroacetic acid (5.5 m) was added to the cooled (0° C.) stirred mixture of a4.9). After 10 minutes, the reaction mixture was poured into aqueous sodium bicarbonate (100 yd) and ethyl acetate (100 mj). The aqueous layer was separated, washed with ethyl acetate (1001Rt) and acidified to 12-12% ethyl acetate. The insoluble material was filtered off and the ethyl acetate layer was combined with the solid obtained after washing, drying and evaporation.

This product was crystallized from methanol to give the title gold product (6
781v) was obtained.

[α]ゎ+64° (C19'88, in aqueous sodium bicarbonate) Intermediate 3 (R and 5)-1-acetoxyethyl-(6R,7R
)=3-carbamoyloxymethyl-7-((fluor
2-yl)-glyoxamide]Sefu 3-M-4-
A solution of the intermediate 2 product (3,00,P) in carboxylate dimethylformamide (3amt) was stirred with potassium carbonate ([1531) for 1 hour at 22°C under nitrogen. The mixture was cooled to about OC and stirred with (R,S)-j-acetoxyethyl bromide (1,394#) for 3 hours. The mixture was partitioned between 2M hydrochloric acid and ethyl acetate.

The aqueous layer was extracted twice with ethyl acetate) and the organic layers were combined and washed with water, saturated sodium bicarbonate solution (twice) and brine.

The solution was dried, concentrated to about 15 mg and added to the 4-yl to give the title compound as a solid (2,4211).
obtained as.

'mhx (CHBr5) 1788 and 1736
an-';J (CDCl2) ao7 (IH, d,
r 4H2), ao 1 (DJ, cl, 78Hz
), 7.75 (IH, a), 7. CJ 9 and 6.97 (1a, q), 6.61 (IH, m),
5.80 (1H, m), 5.03 (11(, d, T
l3Hz), 4.93 (2H,s), 4.81 and 5.08 (2H,m), 56 and 3.44 (2H
, m), 2.02 (3H,s) and 1.52 (3
H, d J 4Hz).

Example (R and 5)-1-acetoxyethyl (6R,7R)
-5-Carbamoyloxymethyl-7-1)-2-(Flu-2-yl)-2-methoxyiminoacetamide]cef-3-em-4-carboxylate The product of intermediate 3 in ethanol (1QmZ) ( SOO
A suspension of .eta.) and methoxylamine hydrochloride (178 .mu.) was stirred with dimethylformamide (3 oz.) at about OC to give a solution. Pyridine (cL56tnt) was added to give a solution of 4.2 mm in volume when shaken with water, and the solution was stirred at 0-4°C for 50 hours. The solution was partitioned between ethyl acetate and 2M hydrochloric acid, and the aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined and washed with water, saturated sodium bicarbonate solution and brine. Dry this solution
Concentration to approx.
It was identified by comparing it with a standard sample of cicefuroxime axetil.

Claims (1)

[Claims] 1) General formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is a hydrogen atom or a carbamoyl protecting group,
Z is B or -SO- and the dotted line indicates that the compound is a cef-2-em or cef-3-em compound. , tables, etc. ▼ (II) A compound having the formula (R, Z and dotted line are as described above) is reacted with an O-methyl-oximating agent and, if desired, the compound having the formula ( The compound of I) is subjected to the following reactions, namely (i) reduction of a compound in which Z is -SO- to a compound in which Z is S, (ii) conversion of a Δ^2-isomer to a Δ^3-isomer. , (iii) removal of substituents, if any, on the carbamoyl. 2) A process according to claim 1, characterized in that the oximation reaction is carried out at a temperature in the range -20C to 100C. 3) The method according to claim 1 or 2, wherein the oximating agent comprises methoxylamine or a salt thereof. 4) Reacting a compound having formula II (wherein R is a hydrogen atom or a carbamoyl protecting group, Z is S and the dotted line indicates a cef-3-em compound) with the O-methyloximating agent. A method according to any of the preceding claims, consisting of: 5) A compound having the general formula (I) according to claim 1, produced by the method according to any of the preceding claims. 6) Cefuroxime axetil produced by the method according to claim 4.