JPS60172988A - Cephalosporin antibiotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to improvements in or relating to cephalosporins. More particularly, the present invention relates to novel cephalosporin compounds and their derivatives with valuable antibiotic activity.

The cephalosporin compounds herein refer to [Journal of the American Chemical Society (J
, Amer, Chem. This refers to the fam structure.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, and especially those caused by bacteria that are resistant to other antibiotics, such as nihilinated compounds. Useful in the treatment of diseases and in the treatment of penicillin-sensitive patients.

In many cases, it is desirable to use cephalosporin antibiotics that exhibit activity against both Durham-positive and Gram-negative microorganisms, and a considerable amount of research has gone into the development of various types of broad-spectrum cephalosporin antibiotics. It's been directed at me.

For example, in British Patent No. 1.399.086, 7β-(α-etherified oximino)-
Acylamide group (oximino group has syn configuration)
A new class of cephalosporin antibiotics has been described.

This class of antibiotic compounds is characterized by a high degree of antibacterial activity against Durham-positive and Gram-negative microorganisms, combined with a particularly high stability against β-lactamases produced by various Gram-negative microorganisms.

The discovery of compounds of this type has stimulated further research in the field, for example to find compounds with improved properties against certain types of bacteria, especially Gram-negative bacteria.

This interest has been highly posed in relation to cephalosporin antibiotics having specific oximinoetherifying groups in combination with 7β-acylamide side chains and specific substituents at the 3-position of the cephalosporin core. This is reflected in numerous patent applications.

In British Patent No. 1.604.971, 7β
The side chain in position - is especially selected from 2-(2-aminothiazol-4-yl)72-(etherified oximino)acetamide and the etherified group is, among a large number of possible meanings. A wide variety of cephalosporin compounds are generally defined, the preferred etherification group being an unsubstituted methyl group, but which can also be a substituted methyl group. When present, methyl group substituents include inter alia cycloalkyl, carboxyl, alkoxycarbonyl, carbamoyl or cyano groups. 3
The group in the - position can also be selected from a number of alternatives.

European Patent Application No. 88320 discloses a wide variety of cephalosporins in which the 7β-side chain may be selected from among <2-(2-aminothiazol-4-yl)-2-(etherified oximino)acetamide groups. Contains general definitions for antibiotics. The group at the 6-position is an optionally substituted pyridinium methyl group.

The definition of an oximinoetherified group includes, among a large number of possibilities, substitution in the 1-position of the cycloalkyl ring by a substituent selected from carboxyl, alkoxycarbonyl, cyano and optionally substituted carbamoyl. cycloargylmethyl, which can be However, there are no detailed illustrations of compounds having such groups (and no mention in particular of cyclopropyl methyl etherification groups carrying such substituents).

Now, (Z)-2-(
Select the etherified oxyimino) acetamido group, which is substituted in its 2-position by a 2-aminothiazol-4-yl group, and as the etherified oximino group carboxy, alkoxycarbonyl, carbamoyl, substituted It has been found that by selecting a cyclopropylmethoxyimino group substituted by a carbamoyl or cyano group, cephalosporin compounds may be obtained with a particularly favorable activity profile against a wide variety of commonly encountered pathogenic bacteria. (described in more detail below).

According to one aspect of the present invention, cephalosporin compounds having the general formula (1):1 and salts thereof are provided.

In the above formula, Q is a cyclopropylmethyl group, and Y
is carboxyl or a protected carboxyl group, carbamoyl, N-(C1-C4 alkyl)carbamoyl or N,N-di(01-C4 alkyl)carbamoyl group or cyano group, and 2 is a hydrogen atom or optionally 01-C4 alkyl or 01 on the nitrogen atom
A carbamoyloxy group optionally substituted by a ~C4 haloalkyl group, an N-protected carbamoyloxy group, or a carbamoyloxy group of the formula-5za (wherein Za is a carbon bond containing at least one nitrogen atom) a 5- or 6-membered unsaturated heterocycle which may also contain one or more sulfur atoms and/or C
(can be substituted by one or more substituents independently selected from 1-C4 alkyl, oxo, hydroxy or carbamoyloxymethyl groups)
or is a pyridinium group optionally substituted by a halogen atom and one or more substituents independently selected from carbazoyl, hydroxymethyl and 01-C4 alkoxy groups or an optionally substituted 02-C5 hydrocarbon chain containing one or two double bonds and optionally intervening heteroatoms; R1 is amino or a protected amino group, R2 is a hydrogen atom or a carboxyl protecting group, B is -S- or 〉S→0 (α- or β-) and 2-16- and 4- The dotted line spanning the positions indicates that the compound is Cef-2-M or Cef-3-M.
Indicates that it is an M compound.

It will be understood that the term "salt" as used herein with respect to compounds of general formula (1) and intermediates used in their preparation includes within its scope external salts and internal salts. External salts can be, for example, basic salts or acid addition salts formed, for example, with mineral or organic acids. Internal salts may take the form of zwitterions or betaines, for example. For pharmaceutical use, the salt may be a non-toxic salt, but other salts may be used, for example in the preparation of compounds for use as drugs.

It will be appreciated that, for example, if 2 is pyridinium or a bicyclic pyri, an Snium group or a group having the formula -8za, the group 2 may carry a positive charge and in that case the positive charge must be balanced by the negative charge. It will be. The compound can thus be a betaine and the negative charge can be provided by 1000 groups. Alternatively, the negative charge can be provided by the anion A. In compounds used in pharmaceuticals, such anions will be non-toxic and may be derived from any of the acids described below to form non-toxic salt derivatives.

The compounds according to the invention are syn isomers. The syn isomeric form is defined by the configuration of the 1○QY group with respect to the carboxamide group. The syn configuration is herein designated structurally as R1N\o,Q,Y. It will be appreciated that since the compounds according to the invention are geometric isomers, some mixtures with the corresponding anti-isomers may occur.

The present invention also includes within its scope solvates (especially hydrates) of compounds of formula (1). The present invention also includes within its scope solvates of the salts of the compound of formula will be recognized.

It will be appreciated that the group Q in the compounds of this invention may be substituted by the group Y on any part of the cyclopropylmethyl backbone. For the avoidance of doubt, the following conventions are used herein to identify substituent positions on cyclopropylmethyl groups.

If a carbon atom in the α-position carries a substituent, that carbon atom may be in the R or S configuration. The invention also encompasses each enantiomeric form as well as mixtures thereof, including racemic mixtures.

When the group Y in the compounds of the invention is a protected carboxyl group, this may be, for example, an esterified carboxyl group as discussed in more detail below.

When group 2 is a group having the formula -8za, the heterocycle represented by Za can contain, for example, 1 to 4 nitrogen atoms and, if desired, a sulfur atom.

Specific examples of these heterocyclic groups include imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl and thiazolidinyl. Heterocycle, if desired, can contain one or more (
(e.g. 1-3) C1-4 alkyl (e.g. methyl)
, oxo, hydroxy or carbamoylmethyl groups. An alkyl or carbamoylmethyl substituent can be attached to a nitrogen heteroatom, for example. In the heterocycle represented by Zl, one nitrogen atom can be quaternized.

When Z is a 02-C5 hydrocarbon chain or a bicyclic pyridinium group interrupted by a heteroatom, the heteroatom can be, for example, an oxygen, nitrogen or sulfur atom. If 2 is a bicyclic pyridinium group, this can be, for example, a 2,6-cyclopentenopyridinium group.

One important group of compounds of formula (1) is excluding compounds in which Z is an optionally substituted quinolinium or isoquinolinium group (as defined above, Z is an optionally substituted pyridinium group). or a bicyclic pyridinium group, and the cyclopropylmethyl group Q is 1
This is a group of compounds carrying a substituent Y at the - position.

In the compound of the present invention, when the group Z IJ is an N-protected carbamoyloxymethyl group, this group Z has the formula -
〇.Co-NHR5 (wherein R5 is a conventional N-protecting group such as a labile group such as an acyl group, especially a lower alkanoyl group such as acetyl, a halo-substituted lower alkanoyl group such as mono-, di- or trichloroacetyl, chloro- or a promose/l/*=k group, or a halogenated alkoxycarbonyl group, such as 2.2.2-trichloroethoxycarbonyl).

If the group R1 in the compound of the invention is a protected amino group, this may be an amino group protected using, for example, a conventional protecting group as discussed in more detail below.

In the compounds of the present invention, when the group R2 is a carboxyl protecting group, or when this group is a protected carboxyl group, the carboxyl protecting group in Y is, for example, an ester-forming aliphatic or araliphatic group. Residues of alcohols or ester-forming phenols, silanols or stannanols (these alcohols, phenols, silanols or stannanols preferably contain from 1 to 20 carbon atoms) or symmetrical anhydrides or mixtures derived from appropriate knowledge. It can be an anhydride protecting group.

If the compound is to be used in a drug, all ester functionalities R2 must be agonistic, metabolically labile ester functionalities, as discussed in more detail below.

Certain cef-6-em compounds of formula (υ) and their non-toxic salts exhibit interesting biological properties (as described in detail below) and are therefore preferred. These compounds have the general formula (υ) Ia) (wherein Q and 2 are as defined above and Yo is carboxy〃, 02-C5 alkoxycarbonyl, carbamoyl, N-(C1-C4 alkyl)'lupamoyl, N, N-di(01-C4 (alkyl) carbamoyl or cyano groups) and their non-toxic salts (including zwitterion and betaine forms) and non-toxic metabolically labile esters. However, the present invention Other compounds according to the invention, such as those in which R1 is a protected amino group, may be useful intermediates for the preparation of the active compounds.

Preferred compounds having the general formula 1a defined above include compounds in which Z is a pyridinium group.

Intermediates such as cef-2-em, sulfoxides and protected intermediates are useful in the preparation of the active compounds of the invention.

It will be appreciated that the compounds according to the invention may exist in tautomeric forms (eg with respect to the 2-aminothiazolyl group) and such tautomeric forms are encompassed within the scope of the invention.

Examples of non-toxic metabolically unstable ester derivatives include acyloxyalkyl esters such as lower alkanoyloxy-methyl or monoethyl esters such as acetoxy-methyl or monoethyl or piparoyloxymethyl esters, and alkoxycarbonyloxyalkyl esters. Esters such as lower alkoxycarbonyloxyethyl esters such as ethoxycarbonyloxyethyl ester are included. In addition to the ester derivatives mentioned above, the invention also includes the active compounds of the invention in any other physiologically acceptable form, i.e. metabolically labile esters as well as the original antibiotics of the invention in vivo. Also included within the scope are physiologically acceptable compounds that are converted into substance compounds.

Non-toxic salt derivatives which may be formed by reaction of any carboxyl groups present in the compound of formula (1) or by reaction of any acidic hydroxyl groups which may be present on group 2 include:
Alkali metal salts (e.g. sodium and potassium salts)
and inorganic base salts such as alkaline earth metal salts (e.g. calcium salts), amino acid salts (e.g. lysine and arginine salts) and other organic base salts (e.g. zolocaine,
phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, jetanolamine and N-methylglucosamine salts). Other non-toxic salt derivatives include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
Included are salts formed using phosphoric acid, formic acid and trifluoroacetic acid. If appropriate, the compounds may also be in zwitterionic or internal salt forms as described above. Salts may also be formed with resin acids such as those formed with polystyrene resins containing amino or quaternary amine groups or sulfonic acid groups or with cross-linked polystyrene-divinylbenzene copolymer resins or with resins containing carboxyl groups such as polyacrylic acid resins. It can also be in the form of a salt.

Soluble base salts (eg, alkali metal salts such as the sodium salt) of compounds of formula (Ia) can be used for therapeutic administration since such salts are rapidly distributed within the body upon administration. However, if an insoluble salt of compound (Ia) is desired for a particular application, such as use in a devo formulation, such a salt can be formed in conventional manner, for example using a suitable organic amine.

The active compounds according to the invention exhibit a wide range of antibiotic activity in vitro and in vivo. These compounds have good activity against both Durham-positive and Gram-negative bacteria, including many β-lactamase producing strains.

These compounds also have high stability towards β-lactamases produced by Gram-negative and Gram-positive bacteria.

The active compounds according to the invention are derived from Staphylococcus aureus (5 taphylococcus aureus).
) and Staphylococcus evidermidis (5t
aphylococcus epidarmidis
) species (including verisilicase-producing strains of these Gram-positive bacteria). This includes various microorganisms of the Enterobacteriaceae family [e.g., Escherichia coli].
), Klebsiel
lapneumoniae), Enteronoζctor.
Enterobacter clcaca
e), Serratia marcescens (5errati
a marcescens), Proteus m1rabilis and Proteus vulgaris.
ris )) Proteus 0 morganii (Proteu
Indole-positive Zorotelas bacteria such as S. morganii and Providence
) 11) and Haemophilus influenzae and Acinetobacter calcoaceticus.
good activity against strains of Tobacter calcoaceticus and Pseudomonas (Ps.
It has been linked to activity against certain strains of the species Eudo-monas. The combination of high activity against Gram-negative bacteria and high activity against Gram-positive bacteria of the compounds of the invention is extraordinary and particularly advantageous.

The active compounds of the invention can be used in the treatment of various diseases caused by pathogenic bacteria in humans and animals, such as respiratory tract infections and urinary tract infections.

According to another aspect of the present invention, there is provided a method for producing a cephalosporin compound of general formula (1) and a salt thereof, which comprises the following. That is, a compound having the formula (H) (in which the 2% B1 dotted line and R2 are as defined above) or (including zwitterion or betaine form) such as an acid addition salt (e.g. salt dispersion, Hydrogen bromide, mineral acids such as sulfuric acid, nitric acid or phosphoric acid or M such as methanesulfonic acid or toluene-4-sulfonic acid
or a 7-N-silyl derivative formed using a total organic acid] or a 7-N-silyl derivative of the formula (2)% (wherein R1 and Q are as defined above and y
b is defined for the above Y other than the carboxyl group)? IB) In the compound of the present invention, when 2 is an optionally substituted carbamoyloxy group T'6, t A compound wJ having the formula IJVI 1 (wherein Q%Y%Rj , R2, B and the dotted line are as defined above) or a salt thereof,
-cm2zb group (wherein zb is optionally substituted on the nitrogen atom by 01-04 alkyl or c1-c4 haloalkyl group) or a carbamoyloxy group which may also be 1-iN- For example, a carbamoyloxy group with the formula -0-Co-fJHl (5 (wherein R5 is N-
A group having a protecting group, for example, an unstable group such as those mentioned above) is reacted with an acylating agent capable of forming the entire group, (C) even if 2 is optionally substituted in the compound of the present invention. In the case of a good pyridinium or binomial pyridinium group or a group having the formula -〇Za (where zFL is as defined above), the formula (■ 1 (wherein Q, Y% R1, R2, E and The dotted line is as defined above, and X is a substitutable residue of a nuclear compound, such as an acetoxy or dichloroacetoxy group, or a halogen atom, such as chlorine, bromine or iodine), or a salt thereof at all 3-positions. is reacted with a desired group-forming nuclear compound having the formula -aH2z, (Dll) In the compound of the present invention, 2 is of the formula -5Za (wherein Za is 01-C4 alkyl-substituted or carbamoylmethyl (containing a substituted nitrogen atom), the group having the formula (Ib) 1 (in the formula, Q%Y%R1, B and the dotted line are the same as defined above, and R2 is a carboxyl-carrying group) 01 (4 alkyl group or carbamoylmethyl group? i [React with an optional 01-C4 alkylating agent or carbamoylmethylating agent.

Any of the above methods fA) to (after toughening, any of the following reactions,
That is, (1) conversion of △2-isomer to △3-isomer, (ff
J Reduction of a compound in which B is 〉S→0 to a compound in which B is -8-, (11υ Conversion of a carboxyl group into a non-toxic metabolically unstable ester function, V Formation of a non-toxic salt , (■ Conversion of one Y group to another Y group, such as amination of a compound vJ in which Y is a carboxyl or esterified carboxyl group to form a compound in which Y is a carbamoyl or substituted carbamoyl group or by dehydrating a compound in which Y is a carbamoyl group to form Y
is a cyano group, or esterification of the carboxyl group Y, and (VLI any carboxyl protecting group and/or N
- removal of the protecting group, in any suitable order to give a compound of formula (1a) or a non-toxic salt or non-toxic metabolically labile ester thereof. +Ill's starting material member is B
Compounds in which .)S and the dotted line are cef-3-M compounds are preferred.

In the formula tn>, the group 2 is charged, for example in a pyridinium group or a group having the formula -8Za (where Za is an N-alkyl pyridinic group), and there is a degenerate in the molecule, for example. If a carboxyl group is not present, the compound includes an associated anion E0 such as a halide such as chloride or bromide or a trifluoroacetate ion.

Acylating agents that may be used in the preparation of compounds of formula (1) include acid halides, particularly acid chlorides or bromides. , can be prepared by reaction with thionyl chloride or oxalyl chloride.

Acylation using an acid halide, if desired in the presence of an acid binder, is advantageously carried out at -50-+50C, preferably at -40C.
It can be carried out in aqueous and non-aqueous reaction systems at temperatures from 0 to +30°C. Suitable reaction media include aqueous lactones such as aqueous acetone, aqueous alcohols such as aqueous ethanol, esters such as intoxicated ethyl, halogenated hydrocarbons such as methylene chloride, amides such as dinotylacetamide, acetonitrile. Nitriles such as, or mixtures of two or more such nitriles are included. Suitable materials and lamination agents include tertiary amines (e.g. triethylamine or dimethylaniline) that bind the aqueous halide systems liberated during the acylation reaction, ice-free groups (e.g. calcium carbonate or sodium bicarbonate), and oxidants such as lower 1,2-alkylene oxides (e.g., ethylene oxide or zolopylene oxide).

The second compound can be used by itself as an acylating agent in the preparation of compounds of formula (1). LJ4t
T decoy? The alkalinity used is preferably an aphrodisiac such as I
J, N'-dicyclohexylpodiimide or N-
Carbodiimide such as ether-N'-r-dimethylaminopropylcarbodiimide, carbonyl compound such as carbonyldiimidazole 17'C is N-ethyl-5
- Performed in the preparation of chlorine glycum salts such as phenyl isochloride chloride.

Acylation can also be used, for example, Seiju Ester Chi vs. Nei Anhydro vlI
or other amide-forming compounds of formula (2) such as mixed anhydrides (formed with 10 formates such as bibal or lower alkyl haloformates)
It is also possible to open all 84 bodies. Mixed waterless exchange also
-BM relatives (e.g. phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. toluene-4-sulfone) (il-) can also be used.

The active ester can be conveniently formed in situ using, for example, Vc1-hydroxybengutriazole in the presence of a condensing agent as described above. Or again,
Activated esters can also be preformed.

Acylation reactions using the free compound or its above-mentioned amide-forming derivatives are carried out in a strained or anhydrous reaction medium such as methylene chloride, tetodihydrofuran, dimethylformamide or acetonitrile.

Another method of activation is to combine a lower acyl hexaamide such as N,N-dimethylformamide with a halogenated hydrocarbon, e.g. By reacting a phosphoryl compound with a bath solution or suspension previously formed by adding a phosphoryl oxychloride, the activated form of the acid of the formula The raw material can be reacted with a 7-amine compound of formula (2) in excess or a mixture of solvents such as a halogenated hydrocarbon system such as dichloromethane. The acylation reaction is conveniently carried out if desired, e.g. Presence of an acid binder (e.g. dimethylaniline) as described above.
You can get 7 shots at a time.

If desired, the acylation reaction can be carried out in the presence of a catalyst such as 4-dimethylaminopyridine.

The formula (1111) and its corresponding acylating agent are:

If desired, they can be prepared and used in the form of their single addition salts. Thus, for example, acid chlorides may advantageously be used as their 1lff salts and acid bromides as their hydrogen bromide salts.

Methods (Acetylation of 6-hydroxymethyl compounds of formula Ovj by B.J.
41,295, by protecting the 4-carboxy group, acetylating the 3-hydroxymethyl group of the protected compound, and then removing the protective group. It can be carried out.

6-Hydroxymethyl compound 9-carba of formula uvJ.

The moylation can be accomplished by the conventional method using an acylating agent (T or carbamoylating agent). The middle R4 is an unstable Yomata group or the 2R4Neo (2) to obtain a compound containing a 6-. The carbamoylation reaction is carried out using L4.
ti group hydrocarbons], halogenated hydrocarbons (e.g. dichloromethane), amides (e.g. formamide or dimethylformamide), esters (e.g. ethyl acetate),
ethers (e.g. cyclic ethers such as tetrahydro7ran2 and dioxane), ketones (e.g. acetone),
VC can be carried out in the presence of a starter or ID media mixture selected from sulfoxides (eg dimethylformoquinide) and mixtures of these 16 media. This reaction is conveniently carried out at a temperature between -800 and the boiling point of the reaction mixture, for example 1
It can be carried out at temperatures up to 00°C, preferably from -20°C to +60°C. The labile group R4 can then be cleaved, for example by hydrolysis, to form a 3-carno-4moyloxymethyl group. An example of an unstable group R4, which is easily cleaved by subsequent processing, is encased with an unstable group which has been preseparated as an example of a group R5. Such labile groups can generally be cleaved by hydrolysis or base-catalyzed hydrolysis (e.g., base-catalyzed hydrolysis using sodium bicarbonate). Halogenated groups such as chlorosulfonyl, dichlorophosphoryl, trichloroacetyl and 2,2.2-)lichloroethoxycarbonyl can also be reductively cleaved, while groups such as chloroacetyl can be cleaved reductively Treatment with thioamides such as

Carbamoylating agents are most likely to be used for 4 stings (
for example at least 1.1 mol relative to the compound of formula ttV+). Carbamoylation can be assisted by the presence of a tertiary wall base such as a tri(lower alkyl)amine (for example triethylamine) or by using the compound av+e in the form of an alkali metal (e.g. sodium) salt. However, such assistance may not be necessary in the case of active incyanates, such as compounds where R4 is a strong electron-withdrawing group such as chlorosulfonyl or trichloroacetyl. Formula (IVI play dυ) d R'
Carbamoylation, which involves reaction with an excess of incyanate, in which the inocyanate is a group such as chlorosulfonyl or trichloroacetyl, is particularly advantageous in practice because of this rapid regulation of reaction conditions. (“J because of cephalosporin 4
There is no reassurance of temporary protection and subsequent deprotection of the carboxyl group in the -position and the electron-withdrawing group R4 in the resulting N-shared 6-carbamoyloxymethyl cephalosporin product is protected by e.g. This is because it is easily removed by hydrolysis.

It may be advantageous to retain or even introduce the N-substituent H42 during the conversion of the intermediate 5-carbamoyloxymethyl compound in order to minimize the undesired side reactions that the carbamoyloxymethyl group may cause. That is WI
should be neglected.

Other useful carbamoylating agents are cyanic acids, which are conveniently generated in situ from cyanogen alkali gold M salts, such as sodium cyanogens; p is promoted by the presence of strong organic acids. Cyanic acid corresponds in practice to said isocyanate compounds in which R4 is hydrogen and therefore converts compounds of formula uvj directly into their 3-carbamoyloxymethyl analogs.

Alternatively, carbamoylation may be accomplished by reacting compound #2 with phosgene or carbonyldiimidazole followed by ammonia or a suitably substituted amine, optionally in an aqueous or non-aqueous reaction medium.

The 6-hydroxymethyl derivative of formula uv) is a vr compound and constitutes another feature of the invention. These are British Patent No. 1,474,519 and U.S. Patent No. 3.976. It can be prepared in a similar manner to that described in No. s 46. Alternatively, they may be prepared, for example, by sylating the corresponding 7-amino-6-hydroxymethyl compound (i-IJ-7) analogously to AJ.

In method (0), the claimed nuclear compound can be used to substitute a wide variety of substituents X from a cephalosporin of formula It is related to the pKa of the avoided acid HX, that is, atoms or groups X derived from oxidative acids are generally more easily encountered than atoms or groups derived from weaker relatives.

The ease of use also relates to some extent to the precise customization of nucleophilic compounds. The sulfur nucleophile for converting the group -8Z can be used, for example, in the form of a suitable thiol or thione.

Xv displacement by a nucleophilic compound can conveniently be accomplished by keeping the reactants in a stratified or suspended liquid.

The reaction is conveniently carried out using 1 to 10 moles of nuclear compound.

For example, the substituent X is a halogen atom, an acyloxy group, and the formula (
VC can be conveniently performed on compounds of vJ.

Compounds of formula (Vj) in which the acyloxy group Starting materials include compounds of the formula tVJ in which X is the residue of a substituted acetic acid such as chloroacetic acid, dichloroacetic acid and trifluoroacetic acid.

Compounds with Xd substituents M (i for VJ,
The reaction is promoted by the presence of iodide or thiocyanate ions in the reaction medium, especially when X is an acetoxy group. For example, this type of reaction using pyridine (bicyclic pyridine δ') compound is described in British Patent Nos. 1.132,621 and 1.171.6052. Recruitment No. 209B2
It is described in detail in No. 16A.

if substituent X can also be used as noro, fa
It can also be derived from acids or carbamines.

Complementation using the compound eI of the formula (VJ) in which X is an acetoquino or an orthogonal acetoxy group, it is generally desirable that the group R2 in the formula tVJ should be a pilot atom and B should be >S. In this case in VC, the reaction is conveniently carried out in an aqueous medium.

When using pyridine nucleophiles, the aqueous medium has a pH of 5 to
It is preferable that it is 5.5 to 7 to 8%.

Under aqueous conditions, the pH value of the reaction solution is conveniently maintained in the range from 6 to 8 when using sulfur nucleophilic compounds, if necessary by addition of a base. The base is conveniently an alkali metal or alkaline earth metal hydroxide or a carbon atom, such as sodium hydroxide or sodium bicarbonate.

A method using a pyridine nucleophilic compound and a compound of formula (v) in which X is a substituted acetic acid residue is described in British Patent No.
No. 241,657.

When using a compound of formula tVJ in which
It is carried out at a temperature of 0°C.

The compounds of the formula (■) in which halogen In this type of compound of formula tV+, R2 is conveniently a carboxyl anchoring group.When using a yellow nucleophilic compound vIJt-, B in a compound of formula tV+ is conveniently On the other hand, when all pyridine nucleophilic compounds are used, B is >B→
Preferably it is 0. This reaction is preferably carried out using a non-aqueous solution consisting of one or more polar organic solvents such as ethers such as dioxane or tetrahydrofuran, esters such as ethyl acetate, amides such as formamide and N,N-dimethylformamide, and ketones such as acetone. Advantageously carried out in a medium. In some cases the nuclear compound itself may be a solvent.

Another i7-organic solvent is British Patent No. 1,326,531
It is described in detail in the No. KJAMfI book. The reaction medium must not be too acidic or too basic.

Formula m where reaction 2H2 is a carboxyl-branching group.

This is carried out on the compound and the obtained Yj16 is the fourth ?
When referring to a family atom, the product is formed as the corresponding halide salt, which is then subjected to one or more ion exchange reactions to form the desired original ion! You can get salt.

When using a compound of the formula (■) in which X is a halogen atom as described above, the reaction is carried out at -20 to +60C, preferably from 0 to
Preferably, it is carried out at m degrees of +50°C.

If the incoming nuclear compound does not produce a compound with few quaternized atoms, the reaction is generally
IJ is carried out in the presence of a base such as triethylamine or calcium carbonate.

In the said method (DJ), the compound of formula (1b) is conveniently 2R5W (wherein R5 is necessarily a 01-4 alkyl or 2H2N0OOH2kM group and W is a halogen atom (e.g. iodine, LA group). Or odor accumulation〕Mari+
1 hydrocarbyl sulfonate (e.g. mesylate or tosylate) group). Alternatively, a di-01-4 alkyl sulfate, such as dimethyl dimethyl, can be used as the alkylating agent. Iodomethane is preferred as the alkylating agent and iodoacetamide is preferred as the carbamoylmethylating agent. The reaction is preferably 0-6
It is carried out at a temperature of 0°C, conveniently 20-60°C. If the alkylating agent is liquid at the reaction conditions, as in the case of iodomethane, it can serve as a solvent in itself. Alternatively, the reaction is conveniently carried out in an inert solvent such as an ether such as tetrahydrofuran, an amide such as methylformamide, a lower alkanol such as ethanol, a lower dialkyl ketone such as acetone, a halogenated hydrocarbon such as dichloromethane or an ester such as ethyl acetate. It can be carried out.

Method (formula (1b) used as starting material in DJ
) are compounds according to the invention and can be used, for example, in the hydronuclear Okimata reaction described in connection with method IC). Compounds of formula (V) (described above) can be prepared by reacting them with a suitable sulfur nucleophilic compound in a conventional manner. If desired, the nucleophilic compounds can be used in the form of metal thiolate salts.

When X is halogen in formula (VJ), the reaction is preferably carried out in the presence of an acid scavenger such as triethylamine or a base such as calcium carbonate.

The reaction products can be synthesized by recrystallization, iontophoresis, force chromatography and the use of ion exchangers (e.g. by chromadog2 chemistry on ion exchange resins) or by proprietary methods involving the use of macroreticular resins. For example, unreacted cephalosporin starting material and other materials can be separated from the reaction mixture, which may contain M.

The Δ2-cephalosporin ester derivatives obtained by the method of the present invention can be obtained by, for example, treating the Δ2-ester with a tether group such as pyridine or triethylamine to suppress the Δ3-spinal pressure. can be converted.

If a compound is obtained in which B is]S→0, this can be achieved by reduction of the corresponding acyloxysulfonium or alkoxysulfonium salt, prepared in situ in the case of an acetoxysulfonium salt, for example by reaction with mapped acetyl. It can be converted to sulfide. Reduction is carried out, for example, by sodium dithionite or by iodide ions, such as in a solution of potassium iodide in a water-miscible solvent such as acetic acid, acetone, tetrahydro-72, dioxane, dimethylformamide or dimethylacetamide. be exposed. This reaction can be carried out at -20C to +50C.

Metabolically unstable ester derivatives of compounds of formula (IJ) are conveniently prepared by preparing compounds of formula (IJ) or salts thereof or hardened derivatives thereof in an inert organic bath medium such as dimethylformamide or acetone. A suitable esterified SJ such as an acyloxyalkyl halide or an alkoxycarbonyloxyalkyl halide (e.g. iodide)
It can be produced by reacting with and then removing any protection fund if safe.

Base salts of compounds of formula (1) may be formed by reacting relatives of formula +IJ with a suitable base. Thus, for example, the sodium or potassium salts can be prepared entirely using the 2-ethylhexanoate salt or the hydrogen uric acid salt, respectively. Acid addition salts may be prepared by reacting a compound of formula (υ) or a metabolically unstable ester derivative thereof with a suitable acid.

The conversion of compounds in which Y is a carboxyl group to compounds in which Y is an esterified carboxyl or carbamoyl or substituted carbamoyl group is conveniently formed using activated intermediates such as alkylhaloforms. This can be accomplished via the formation of a mixed anhydride. Such activated intermediates may conveniently be prepared in situ. Amination to form compounds in which Y is carbamoyl or a substituted carbamoyl group can be carried out analogously to the method described in EP-A-11J-95329.

Dehydration of a compound in which Y is a carbamoyl group to form a compound in which Y is a cyan group can be accomplished in a conventional manner using, for example, pat5i or P2O5.

Such modifications to the group Y will preferably be carried out using the compound vIJ, where R2 is a carboxyl protecting group.

If Inuyama's compound is obtained as a mixture of isomers,
The syn isomer can be obtained by conventional methods such as packing or chromatography.

Enantiomeric mixtures, including racemic mixtures, or intermediates thereof of the compounds according to the invention may be resolved in a conventional manner. For example, ``Stereochemistry of Carbo'' by Mr. E.L.
'nOompound9' (Me()raw H1ll Publishing, 1962) and Niss Etch-Uilen (S,
H, Wilθn)'s FTables of: Re5
See o'lving AgθntsJ f.

For use as starting material for the preparation of the compounds of the general formula (11) according to the invention, the syn-isomer form or the syn-isomer containing at least 90% of the syn-isomer and the corresponding anti-isomer are combined. General formula (2) in the form of a mixture
It is preferred to use compounds of and the corresponding amide-forming derivatives thereof, such as acid halogen atoms and anhydrides.

Acids of the formula tIIri- and their derivatives are themselves novel compounds and constitute another feature of the invention. These have the general formula (chicken T-Q, -Yb(
(in the formula, Q and yb are as defined above, and T
is a halogen atom such as a chlorine, bromine or iodine atom, a sulfate group or a sulfonate group such as P-)luenesulfonate). , R1 is as described above) and R6 represents hydrogen or a carboxyl protecting group.j) Etherification of the compound i or a salt thereof and subsequent removal of any carboxyl protecting group R6, and the desired i reaction. can be prepared by removal of any carboxyl protecting group in Yb.

Separation of isomers may be carried out before or after such etherification. The etherification reaction is conveniently carried out in the presence of a base such as potassium carbonate or sodium hydride and preferably in a solvent such as dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane or an N,N-di-11 substituted amide such as dimethylformamide. It will be carried out in Under these conditions, the configuration of the oximino groups is substantially unchanged by the etherification reaction. The reaction must be carried out in the presence of a base if the first addition salt of the compound in question is used.The base must be used in sufficient quantity to quickly neutralize the compound in question. There must be.

The acid of formula (g) can also be used to convert a compound of the formula Cl1l) 1 (wherein R1 and R6 are as described above) into AnaeiH2kJ.0.Q-Yb(1)D (wherein Q and yb are It may also be prepared by reacting with a compound having a compound (as defined above) and then removing the optional carboxyl protecting group H6r and, if desired, removing the optional carboxyl protecting group in yb. If necessary, the reaction can be followed by separation of the syn and anti isomers.

Acids of formula (1111) may be converted to the corresponding acid halides and anhydrides and acid addition salts by conventional methods, such as those described above.

When X is a halogen atom in the formula +VJ, Cef-
The 3-Em starting compound can be prepared by conventional methods such as halocylation of the 7β-protected amino-3-methylceph-3-Em-4-carbonyl ester 1β-oxide, removal of the 7β-protecting group, e.g. by the method described above (AJ Acylation of the resulting 7β-monoamine compound to form the desired 7β-acylamido group in a similar manner as described above can be followed by reduction of the 1β-oxide group at a later stage in the sequence.

This is described in British Percent Eaves No. 1,326,531.

The corresponding cef-2-em compound was prepared by the method of Dutch Patent Application No. 6902015.
-Em compounds can be prepared by reacting them with N-promosuccinimide to form the corresponding 3-bromomethylcef-2-Em compounds.

When X is an acetoxy group in the formula (VJ), such a starting material can be prepared, for example, by the method described above (7-
It can be prepared by acylating amitusephalosborane relatives. Compounds of formula (V) wherein M can be prepared by hydrolysis of a methyl compound or by acylation of the corresponding 3-hydroxymethyl compound.

Compounds of formula (n) can also be prepared by conventional methods such as British Patent No.
, 012,943 and 1,241,657 and British Patent Application Nos. 2,02 Otsu 691A and 2,0
46,261A and 2.09a216A by nuclear substitution with a suitable nuclear compound.

Other methods of preparing starting materials of formula +IIJ include, for example, p
The equivalent protected 7 in the conventional way using c75k
The process consists of defrosting the β-amine compound.

Another reference to the production of compounds of the formula FA is U.S. Pat. No. 4,145,538.

It should be appreciated that in some of the above transformations it may be necessary to protect all sensitive groups in the molecule of the compound in question to avoid unwanted side reactions. For example, in any of the reaction sequences described above, it may be necessary to protect the NH2 group of the aminothiazolyl moiety, for example by tritylation, acylation (eg chloroacetylation or formylation), protonation or other conventional methods. As a result, the protected group is stable under reaction conditions involving 1βM or more synthetic steps. The protecting group may be protected by any convenient method which does not result in subsequent decomposition of the desired compound, e.g. in the case of trityl groups, preferably in the presence of a protic solvent such as water, optionally with a halogenated carboxylic acid e.g. acetic acid. , Ant M.

It can be removed by using chloroacetic acid or trifluoroacetic acid or by using mineral acids such as hydrochloric acid or mixtures of such acids or in the case of chloroacetyl groups by treatment with thiourea.

Preferably, the carboxyl protecting group used in the preparation of the compound of formula +IJ or the preparation of the necessary starting materials is a group that can be easily removed at the appropriate step in the reaction sequence, conveniently the last step.

However, in some cases, a tetravalent substituent such as an acyloxy-methyl or monoether group (e.g. acetoxy-methyl or monoethyl or piparoyloxymethyl) or an alkoxycarbonyloxyalkyl group (e.g. ethoxycarbonyloxyethyl) may be used. It may be advantageous to use chemically labile carboxyl protecting groups and to retain these groups in the final product to obtain suitable ester derivatives of metal compounds of formula (1).

Suitable carboxyl protecting groups are well known in the art and representative examples of protected carboxyl groups are contained in GB 1.599.086.

Preferred reserved carboxyl groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl, and lower alkoxycarbonyl groups such as t-butoxycarbonyl; 2
．． 2.2-) Lower haloalkoxycarbonyl groups such as dichloroethoxycarbonyl are included. The carboxyl protecting group may be removed by any suitable method described in the literature. Thus, for example, analogous or IA group-catalyzed hydrolysis can be applied in many cases as well as oxygen-catalyzed hydrolysis.

As will be appreciated, the use of amino and carboxyl protecting groups is well known in the art and successful examples of such use include, for example, T.D.

Greene) substitute author “Protective GrOu
pS 1n OrganicSynthθaiθJ (
Wiley (1981 edition) and Liu F. W. McCormie (J.
Mr. F., W., McOmie) 4 “Protective
Groups inOrganic Ohemiet
ryJ (Plenum Press 1973 edition)
K is listed.

The antibiotic compounds of the invention, like other antibiotics, can be formulated for administration in any convenient manner and the invention is therefore adapted for use in humans or animals. Included within its scope are pharmaceutical compositions that include antibiotic compounds according to t. Such compositions may be provided for use in a conventional manner with any necessary pharmaceutical carriers or excipients.

The antibiotic compound according to the present invention can be made into an injectable compound and is a must! If so, the preservative may be fully added and provided in unit dose form in ampoules or in vials. The compositions can also take such forms as suspensions, baths or emulsions in oily or aqueous vehicles and suspensions,
It may contain formulation agents such as stabilizers and/or dispersants. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

If desired, such powder formulations can be prepared by adding water to the active ingredient! In order to improve the pH and/or to maintain the pH of the aqueous aqueous agent used when the powder is reconstituted with water to be within the physiological KII'+ range (IIIi), an appropriate may contain a non-toxic radical.Alternatively,
The base can be present in the water to reconstitute the powder. Group 14 can be prepared with a sterile base such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base such as lysine or lysine acetate.

The antibiotic compound may also be provided, for example, in a form suitable for absorption by both intestinal tracts, such as a tablet or capsule.

Antibiotic compounds can also be formulated as a biotechnique containing conventional agricultural bases such as cocoa butter or other glycerides.

The veterinary mulberry compositions can also be formulated, for example, as long-acting or rapid-release mammary gland preparations.

The compositions may contain from 0.1 to 99% of active material, depending on the method of administration.

If the composition consists of dosage units, each unit preferably contains from 100 to 6000 doses of active ingredient, such as from 200 to 20
Contains 00#. The dosage used in the treatment of adults depends on the route and frequency of administration, but is preferably in the range of 200 to 12,000 W per day, such as 1000 to 9,000 W per day. For example, in the treatment of adults, an intravenous or intramuscular dose of 400 to 4000 ml per day is usually sufficient.

Higher daily doses may be required in the treatment of pseudomonas infections. As will be appreciated, lower dosage units and daily doses may be desirable in certain situations, such as in the treatment of neonates.

The antibiotic compounds according to the invention may be administered in combination with other therapeutic agents, such as antibiotics such as eghenicillin or other cephalosporins.

The invention is illustrated by the following examples. All temperatures are in °C
It is. DMSO is dimethyl sulfoxide.

Preparation 1 1-Hydroxymethyl-1-cyclopropylcarbonitrile 1,methyl 1-cyano-1-cyclopropylcarbonitrile) (5 ml) in 2-dimethoxyethane (40 m)
,0Of) with lithium borohydride (1,74F) and the mixture was heated under reflux with stirring.

After 6 hours, the suspension was allowed to cool to room temperature and filtered. The solid was washed with 1,2-dimethoxyethane, the wash and p-liquid were combined and it was evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture (3:1) of ether and betrol (boiling point 40-60°) to give the title compound as a colorless oil (1,09f). . Further elution with ether gave further product as a colorless oil (1,
14f). νmaz(CHBrs) 35
95 (free OH), 3460 (bound OH) and 2235cIn-' (ON).

Preparation 2 1-Bromomethyl-1-cyclopropylcarbonitrile Phosphorus tribromide (0.70 m) was added dropwise to a stirred solution of the product of Preparation 1 (1,92 F) in ether (50 m) at -78°C under nitrogen. added.

After 5 hours at -78c, the cooling bath was removed and the reactants were
I left it for a while. Water (10d) was added and the mixture was shaken. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue is dissolved in ether and trol (boiling point 40-6o)
0) while eluting with a mixture (1:1) of silica gel (
ioor) to give the title compound as a colorless oil (1,60f). νrnBz(OHBr5) 2230 an-
'(ON).

Preparation 3 1-Bromomethyl-1-cyclopropanecarboxamide The product of Preparation 2 (1,5F) was dissolved in 98% sulfuric acid (6-) and heated to 23:01 lllff50''.

The solution was stirred rapidly and cooled (5°) water (20 m
6) was added dropwise. The solution was extracted with ether (x8) and the extracts were combined, dried over magnesium sulfate and evaporated.

The residue was purified by chromatography on silica gel (1!M), eluting first with ether and then with a mixture of dichloromethane and ether (1:19) to give the title compound as crystals (0,44F). Ta. νmax(OHBrx) 3498 and 3395
(-NH2 people, and 1673 an-' (0-li.

Production 4 (a) 4-Nitrobenzyl (Z)-2-(1-diphenylmethoxycarbonylcyclopropy)Vmethoxyimino)-2-(2-tritylaminothiazol-4-yl)
Acetate 4-nitrobendi/l/ in DMSO (s*)
(Z)-2-(hydroxyimino)-2-(2-)ditylaminothiazol-4-yl)acetate (1,0
Of), potassium carbonate (o,95y) and diphenylmethyl 1-bromomethyl-1-cyclopropylcarboxylate (prepared according to the method described in GB 1.496,757) (0,70F)
) was stirred at ambient temperature under nitrogen. After 3 hours, further diphenylmethyl 1-bromomethyl-1-
Cyclopropyl carboxylate (0.14f) was added and the reaction was stirred for an additional hour. This suspension was added dropwise to rapidly stirred water (75-). The precipitated solid was removed, washed with water, and dried under vacuum. The solid was dissolved in a mixture (1:3) of ethyl acetate and trol (boiling point 40-60°).
) to give the title compound as form (0,91F). νmax(OH
Brs) 3399 (NH), 1730 (a=o),
and 1525 and 1349 return' (N02).

(b) (Z)-2-(1-diphenylmethoxycarbonylcycloprobylmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetic acid tetrahydrone (35rd), saturated sodium bicarbonate solution (11y) ), preparation 4(a) in sodium carbonate (IJ3F), water (23m) and ice (11F)
Sodium dithionite (1,08F) was added to a stirred two-phase solution of the product (0,64F). After 2 hours the mixture was partitioned between water (150 mA) and ethyl acetate (100 mA) and acidified using 2N citric acid. The organic phase was separated, washed with water (2×150 rnl), dried over sodium sulfate and evaporated to give the title arsenic compound as a yellow foam (0,66)). νmax (
Nujol) 3600-6500 (NH, lI20) and 1775 cm-' (G=O, ester), and τ (DMSO-44) 3.42 (thiazolyl), 5
．． 64 (00dan 2) and a65-9.0 (cyclopropyl).

Preparation 5 (a) 4-Nitrobenzyl-2-(1-cyanocyclopropylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate The title compound was prepared according to the method of Preparation 4(a). Therefore, νmax(OHBrg) 3395 (NH), 2
235 (ON), 1740 (a=o), and 152
2 and 1345 cm-' (NO2).

(b) (Z)-2-(1-cyanocyclopropylmethoxyimino)-2-(2-)ditylaminothiazole-
The title compound of 4-yl)acetic acid was prepared according to the method of Preparation 4(b) and was synthesized with νmaw 3360 (NH,H2O
) and 2235cy++-' (0,N), and τ
(DMso-a6) 3.32 (thiazolyl→, 6.
08 (QC!H2) and a68-a93 (cyclopropyl).

Preparation 6 (a) 4-Nitrobenzyl (Z) -2-(1-carbamoylcyclopropylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate The title compound was prepared according to the method of Preparation 4(a). Therefore, νmaX (Nujol) 3475 (NH), 3350
~3.100 (NH2), 1750 (0=O, ester), 1658 (cmo, amide) and 1525 and 1348m (NO2).

(b) to Z)-2-(1-carbamoylcyclozoropylmethoxyimino)-2-()ditylaminothiazol-4-yl)acetic acid The title compound is prepared according to the method of Preparation 4(b), and νm1LX ( Nujol) 1710 (cmo,
acid), 1660 (0=O% amide), and τ (nM
so-a6) 5.8 (ocH2) and a9-9.3
(cyclopropyl).

Manufacture 7 Diphenylmethylcycloprobil! Schiff tetrapropylglyoxylic acid (Eng., Nasnak and J.

C! by Mr. Farkas 011. (!ZeCh,
Ohem, Comma 40°1038 (1975)
(1,a3y) produced according to the method described in
was treated in portions with a solution of diphenyldiazomethane in dichloromethane (0.5M) until a permanent pink color was obtained.

After 1 hour the mixture was allowed to stand overnight and then evaporated to give a round residue which is a mixture of diethyl ether and betrol.
Purification on a column of silica gel (12oy), eluting with , gave the title compound as a liquid (3.38f). νmax (OHBrx) 1728 (cmo, ester) and 1710 cm (0=O, ketone), Oyohi f (ODOjt5) 3.05 (-caphz),
7.2 q and a65-900 (cyclopropyl ring).

Preparation 8 Diphenylmethyl α-hydroxycyclopropyl acetate - 1,2-dimethoxyethane (15-) at 20°
Sodium borohydride (0,22F) was added to a stirred solution of the product of Preparation 7 (1,65F) in the solution. After 7 minutes, the mixture was dichloromethane (10 (W), water (75 d)
and 1M hydrochloric acid (24 m/liter) was poured into the stirred mixture.

After a few minutes the two phases were separated and the aqueous phase was extracted with dichloromethane (2X50Wt). The organic extracts were combined and washed with saturated sodium bicarbonate solution (100m) and water (1007m), dried over sodium sulphate and evaporated. The residue was purified on a column of silica gel (40F) eluting with a mixture of diethyl ether and betrol (1, 1) to give the title compound as a liquid (1,27F). λma engineering (ethanol) 2
5a5nm (ε650) and r (cDcA3)6.
18 (OH-OH), 7.24 (-OH), a88 and 925-9, 75 (cyclopropyl ring).

Preparation 9 Diphenylmethyl α-mesyloxine chloropropyl acetate - Dichloromethane (5 r
Id! A solution of mesyl chloride (0,367 ml) in 15 min was added dropwise over 15 min. After stirring for a further 30 min, the mixture was diluted with dichloromethane (90 d) and
Washed with saturated sodium bicarbonate solution (100m) and saturated sodium bicarbonate solution (100m), dried over sodium sulfate and evaporated to give the title compound as a low melting solid (1,5Of). Sim6z (OHB
r3) 1750(c=o) and 1654□-1(-
0802), and τ((!DC et al) 5.54 (-0
HC! 02-), 7.01 (-0SO20H3), a
30-8.90 and 910-9.50 (cyclopropyl ring).

Production 10 4-nitrobenzyl (Z) -2-(α-Schiff: r,
= A/methoxy7carbonylcyclozorobylmethoxyimino)-2-(2-)ditylaminothiazole-4-
product of Preparation 9 (1oo) in DMSO (2ml)
w), potassium carbonate (237■) and 4-nitrobenzyl (Z) -2-(hydroacimino) = 2-(2-
tritylaminethiazol-4-yl)acetate) (
The mixture of 237■) was stirred under nitrogen for 21.25 hours. The mixture was added to vigorously stirred water (50m) and the precipitated solids were extracted with ethyl acetate (50m and 2x25m). Combine the organic extracts and add it to water (2X50m)
and saturated sodium chloride solution (50d), dried over sodium sulphate and evaporated. The residue was purified on a column of silica gel (15F), eluting with a mixture of ethyl acetate and betrol (1:3) to give the title compound as a form (189W). λm
ax (ethanol) 250nm (g23300)
% and τ(cncA5) 1.94 and 2.46
(-06 and 4NO2), 3.10 (-ctan'ph2),
3.18 (NH), 3.51 (thiazole 5H), 4
．． 60 (octan 2-), 5.66 (QC! macro-cyclopropyl), a60-9.00 and 925-9.60
(cyclopropyl ring).

Preparation 11 (,Z)-2-(α-diphenylmethoxycarbonylcyclozolobylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid tetrahydrofuran (
75 gloss), saturated sodium bicarbonate solution (25nI7!
Sodium L carbonate (1,5F), water (5M) and ice (
Product of Preparation 10 (1,91 g) in about 252)
Sodium dithionite (1,91F) to a stirred mixture of
added.

After 40 minutes the mixture was poured into a stirred mixture of ethyl acetate (150 mA) and water (150 ml) and dilute hydrochloric acid was added until pH1. The two phases were separated and the aqueous phase was extracted with ethyl acetate (50 rnl). The organic extracts were combined and diluted with water (150 mL dilute hydrochloric acid (150 mL)).
d), washed with water (150 m) and saturated IJ chloride solution (1SO-), dried over sodium sulfate and evaporated. The residue was triturated with diethyl ether and the solid was collected by filtration, rinsed with more ether and dried in vacuo to give the title compound as a solid (o, a9
7F). ν+nax (nujol) 174
5 (C=0, ester) and 1715+o++-'
(0=O1 acid) and τ(DMSO-44) 1.14
(NH), 3.13 (-0 degrees ph2) 3.21 (
Thiazole-5H), 5.81 (0OH-cyclozolopi#), a82 and 920-9.70 (cyclopropyl ring).

Production 12 1-Bromomethylcyclopropanecarboxylic acid, methyl ester 1-Bromomethylcyclopropanecarboxylic acid (2,06f) in methanol (10mA) was dissolved in 98% sulfur 1t (0
, 57 and the solution was heated to reflux for 17 hours. The mixture was evaporated to dryness and the residue was dissolved in ether (1
Partitioned between 0M water and water (50d). The organic phase was separated and mixed with saturated aqueous sodium bicarbonate solution (5M), water (50
7) It was then washed successively with salt water (50 m). The solvent was evaporated and the residue was purified with ether/vetrol (1:4).
Purification by chromatography on silica gel (100F) at m.m. gave the title ester as a colorless oil (0.73f).

'Inax (OHBr+!+) 1728 cm-'
(Ester C=0).

Preparation 13 4-Nitrobenzyl (Z)-2-(1-methoxycarbonylcycloprobylmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetate The title compound is prepared from the product of Preparation 12. 4(a), with νmax(OHBr 5)3
400 (NH), 1730 (ester C=0), 1
525.1348 sub-' (NO2) was shown.

Preparation 14 (Z)-2-(1-Methoxycarbonylcycloprobylmethoxyimino)-2-(2-trity”ylaminothiazol-4-yl)acetic acid The title compound was obtained from the product of Preparation 13 by preparing Preparation 4(b). ) and produced according to the method of νmaX (nujol) 1
720 m-' (0-0), and τ(DMEO-4
6) It showed 5.7'6 (oc assistant), eh6~9.2 (cyclopropyl).

Preparation 15 α-Oxocyclopropaneacetic acid methyl ester α-oxocyclopropaneacetic acid potassium salt (toot) and methyl iodide (0
, 82 tnt) was stirred for 1.75 hours. The resulting pale yellow solution was passed into water (100-) and extracted with ether (3Xsornl). Combine the extracts;
It was washed with water (2×50!nl) and brine (50+d) and dried (over magnesium sulphate). Removal of the solvent gave the title compound as a colorless liquid (0,669F).

νmax (OHBr5) 1730 (-1: Ste#
cmo), 1710 cm-' (ketone C=0).

Preparation 16 α-Hydroxycyclopropane acetic acid methyl ester Sodium borohydride (1,08F) was added to a stirred solution of the product of Preparation 15 (3,661) in methanol (35fnl) at -20°. After 5 minutes the mixture was carefully poured into a stirred mixture of dichloromethane (250m), water (85ml) and 1M hydrochloric acid (115d). The two phases were separated and the aqueous phase was dissolved in dichloromethane (3
X100m). The organic extracts were combined and washed with saturated sodium bicarbonate solution (100 mg) and water (1oo*) and dried (over sodium sulfate).

Removal of the solvent gave the title compound as a colorless liquid (2,63F). νmaw(1:!HBr5) 3535 (
OH), 1732□-1 (C=su.

Preparation 17 α-Methylsulfonyloxycyclopropane acetic acid methyl ester - To a stirred solution of the product of Preparation 16 (2,53F) and triethylamine (4,06mj) in dichloromethane (40mj) at 10° dichloromethane (20mj)
m) in methane sulfoelku02ide (1,66
mg) solution was added dropwise over a period of 20 minutes. After 10 minutes, the mixture was diluted with dichloromethane (100-) and diluted with ice-water (100-).
5M), saturated sodium bicarbonate solution (100tnl)
and brine (150 ml) and dried (
sulfuric acid). Removal of the solvent gave the title compound as a white crystalline solid (!t, 68F). Melting point 109
．． 5°, νmax(OHBr3) 1755 (0=O
), 1355z-” (0802).

Preparation 18 4-Nitrobenzyl (Z)-2-(α-methoxycarbonylcycloprobylmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetate nMso (30m) Product of Preparation 17 C2,
43f), potassium carbonate (6,C1) and 4-nitrobendi#(Z)-2-(hydroxyimino)-2-(2
-) dithylaminothiazol-4-yl)acet-)(
The mixture was stirred under nitrogen for 6.36 hours. This mixture was mixed with ethyl acetate (25o-) and water (250m
) was distributed between

The two phases were separated and the aqueous phase was combined with ethyl acetate (2X
100 m). Combine the extracts and add it to water (
25 awll), 2M salt 112 (250rn1.), washed with water (250 m/liter) and brine (250 d) and dried (IJ sulfate). remove the solvent,
The residue was purified by chromatography (150 g silica gel). Elution with ethyl dihatrol in acetic acid (1:3) gave the title compound as a yellow foam (5,38F). λmaz EitOH239nm (t 21
．． 500), νmaz(OiHBr3) 3585
(NH), 1748 (0=S, 1522 and 134
8 cm-' (MO2) and τ (ODc15) 5
．． 37 (thiazole), 5.71 (o-cH) and 92-96 (cyclopropyl).

Preparation 19 (Z) -2-(α-Methoxycarbonylcycloprobylmethoxyimino)-2-(2-)rityl aminoteazo/l/-4-yl)tetrahydronerane(12
Product of Preparation 18 (5,15 m) in saturated sodium bicarbonate solution (4 Of mL sodium carbonate (5, Of), water (75+/l) and ice (about 40 f).
Add sodium dithionite (5,15
') was added. After 90 minutes, the mixture was diluted with ethyl acetate (25
0m) and .

It was poured into a stirred mixture with water (250rn1.) and 2M@fi was added until the aqueous phase was acidic (pHI). Separate these two phases and add the aqueous phase to KtOAQ.
(125 m). The organic extracts were combined and washed with water (250m), 2M salt i* (250rd), water (250m) and brine (250mz) and dried (dihydrium sulfate). The solvent was removed and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried in vacuo to give the title compound as a pale yellow powdered solid (2,89F). λinf
(KtOH) 233 nm (ε20,500), 2
59.5mm (sll, 100), 265mm (C11
,000), νmax (nujol) 3265 (NH
), 1742 (Cj=0 ester → s 1715(a
-Oe>'syohif (pMso46) 3.14 (thiazole), 5.94 (OOH), 9.3-965 (
cyclopropyl).

Example 1 (6at7R) -7-(2-aminothiazol-4-yl)-2-(1-carboxycyclopropylmethoxyimino)acetamide]-3-pyridiniummethylcef-3-em -4-Carboxylate dihydrochloride To a stirred solution of dimethylformamide (0,16 ml) in dichloromethane (4,37 ml) at -20° under nitrogen was added oxalyl chloride (0,16 ml). Stir at 5° for minutes and then again at 120°C.
Cooled to °. This was added to the product of preparation 4(b) (1,19
F) was added and the resulting solution was stirred for 10 minutes at 5° and cooled again to -20°.

Meanwhile, (6R,7R)-7-amino-6-pyridinium methylcef-3-em-4-carboxylate di-salt [
To a rapidly stirred solution of Shiro (0,659) was added triethylamine (1,00 m
1 m) was added. To this was added the solution of the activated side chain acid described above and the mixture was allowed to warm to room temperature for 15 minutes.

The suspension was washed twice with water, in each case back-extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and evaporated to give a foam. This was dissolved in formic acid (4B9-) and concentrated hydrochloric acid (0,3
9m6).

After 1 hour the mixture was filtered and the solids were washed with formic acid.

The wash and P solutions were combined, evaporated and the residue triturated with acetone to give a solid. This was purified by chromatography on silica gel (30F) eluting with a mixture of acetone and water (9:1 to 4:1) to give the title compound as an off-white solid (0,071). Obtained. λm&k (ethanol) 2
36nm (g17935), and νmax (nujol) 2700, and 1700 (002)I) s
1776 (β-lactam), and 1670 and 1540□-' (-0ONH-).

Example 2 (6R,7R) -7-[(Z)-2-(2-aminothiazol-4-y#)-2-(1-cyanocyclopropylmethoxyiminoacetamide]-6-pyridinium methyl cef- 6-Em-4-carboxylate dihydrochloride The title compound was prepared according to the method of Example 1 using the product of Preparation 5(b) as starting material.
w (Nujol), 2238 (ON), 1785 (I-
lactam), 1705 (0=O1 acid) and 1678c
tn-' (a=o, amide), o and r (DMSQ-
46), o, 88.1.6o and 1.75 (pyridinium), 3.07 (thiazolyl), 5.84 (OCH
2) and a6-a9 (cyclopropyl).

Example 3 (a) Diphenylmethy# (6R,7R) -7-(
(Z) -2-(1-diphenylmethoxycarbonylcycloprobylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-6-carpamoyloxymethylcefu 3-M-4-carpoki V
A solution of oxalyl chloride (0,11 mg) in dichloromethane (1,51 nt) was added to a solution of dimethylformamide (0,14 mg) in dichloromethane (-) for 5 minutes at 115'' with stirring under nitrogen. A white precipitate was formed after the solution was stirred at -5°. The mixture was cooled to -10° and
The product of Preparation 4(b) (0,81F) was added to it at -Summer. The resulting clear brown solution was stirred for 30 minutes at -5° and then recooled to -10°.

Meanwhile in another flask diphenylmethyl (6R,7R) in dichloromethane (8-) at -25°
) N,N-dimethylaniline (0.30 ml) was added to a solution of -7-amino-3-carbamoyloxymethylcef-3-em-4-carboxylate (0.51F). To this was poured the solution of the active side chain, and the mixture was allowed to warm to 10'' over a period of 2 hours.
0 m) was added and each layer was shaken. Heat the organic layer for 2N
Hydrochloric acid (2 x 50-), water (50 tNt), saturated charcoal was washed with sodium hydrogen solution (50+d) and saturated sodium chloride solution (50 mA). The organic phase was dried over sodium sulphate and evaporated. The residue was treated with a mixture of ethyl acetate and betrol (boiling point 40-60') (1:
Purification by chromatography on silica gel (50F) eluting with 6) gave the title compound as a pale yellow form (0,59'2). λmax(
ethanol) 263 nm (ε19400), νmax
(OHBr3) 3535 and 64o8 (NH2, N
H), 1790 (β-lactam) and 1687 cm-
'(amide).

(b) (6R,7R) -7-[:@) -2-(2
-aminothiazol-4-yl)-2-(1-carboxycyclopropylmethoxyimino)acetamide]-6
-Carpamoyloxymethylsefu 6-emu 4-carboxylate The product of Example 6←) (0,44F) in anisole (0,89rnl) is treated with trifluoroacetic acid (i2-) and the mixture is Stir for a minute. This solution was added dropwise to rapidly stirred water (300 mJ) and the resulting hazy solution was washed with 3 x 100 m/litre, partially evaporated and finally lyophilized to give the title compound as a white solid ( 0,23r).λma
w (ethanol) 237 nm (g19200) and νma, x (nujol) 2600 and 1720 (
-002H), 1772 (β-lactam) and 168
8 and 1542CnI-' (-〇〇NH-).

Example 4 (a) Diphenylmethyl (6R,7R) -7-C(
z) -2-(1-cyanocyclozorobylmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamide]-6-carpamoyloxymethyl heptafu 6-emu 4-carboxylate Title compound was prepared according to the method of Example 3(a) using the product of Preparation 5(b) as starting material.

This title compound has νmax(OHBr5) 3535
and 3405 (NH2, N1(), 2235 (O
N) and 1788 cm-' (β-lactam), and τ((1!DC!M5) 3.02 (NI()
, 3, 04 (-co2guph2), 3.22 (thiazolyl), 4.96 and 5.22 (-0dan2-QC!
O-), 5.74 (-ooHz-) and 8,6-2
0 (cyclopropyl).

(b) (6R,7R) -7-C(Z)-2-(2-
aminothiazol-4-yl)-2-(1-cyanocuclopropyl methoxyiminone acetamide]-3-carbamoyloxymethylcef-3-em-4-carboxy V-) The title compound is produced in step (a) above. λmax
(Ethanol, +1/) 235 nm (g19600) and νmax (Nujol) 3300 (NH), 224
0 (C!N), 1772 (β-lactam) and 166
5 and 1548 cm-' (-0ONH).

Example 5 (-) diphenylmethyl(6R,7R)-3-carno(moyloxy7methyl-7''C(Z)'-2
-(α-diphenylmethoxycarponylcyclopropylmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamide] Cef-6-M-4-carboxylate - dichloromethane (4- ) to a stirred solution of dimethylformamide (0.18 mg) in dichlorodimethane (2 ml) was added dropwise a solution of oxalyl chloride (67 μ2) in dichlorodimethane (2 ml). The resulting suspension was stirred at -5° for 30 minutes and cooled again to -10°. To this was added the product of Preparation 11 (500111) and the resulting solution was stirred at -5° for 30 minutes. It was then cooled again to -20''.

diphenylmethyl (6R,7R)-7-amino-5-carbamoyloxymethylcef-3-em-4- in dichloromethane (8m) under nitrogen at -25°.
The above solution of activated side chain was added to a stirred solution of carboxylate (308-) and IJ,N-dimethylaniline (0,20-). The solution was allowed to warm for 1 hour, diluted with dichloromethane (50 d) and water (10 d).
0m/). These two phases were separated and the organic phase was washed with dilute salt solution (100+d), water (100-ton), saturated sodium bicarbonate solution (100 rre) and saturated sodium chloride solution (10M) and dried over sodium sulfate. The residue was purified on a column of 7 silica gel (30F) eluting with a mixture of ethyl acetate and dichloromethane (1:9) to give the title compound as the form (440~).νmax( OHBr3)
3535.3415 and 3275 (NH, NH2
), 1790 (a=o, β-lactam), 1729
(C=O, x ster and -ocONH2) and 16
80m (a=o, 7mid), and r (ODc!j
L3) 1.86 and 1,91 (CONH) 3.
22 (thiazole-light), 6.98 and 4.04
(7-H), 4.89.4, 91.5.18 and 5.
26 (OH20CONH2), 5. ol and 5.02
(6-1(), 5.44(00ONH2), 5.52
and 5.62 (OCH-cyclopropyl), 6.52
．． 6,65.6.72 and 6.90 (2-adan2)
, 8,50-a80 and 9.20-9.50 (cyclopropyl ring).

(b) C6R,7R) -7-1) -2-(2-fmi/fazol-4-yl)-2-(α-carboxycyclopropylmethoxyimino)acetamide]-3-carbamoyloxymethyl7 Fu 3-M-4-carboxylic acid trifluoroacetate The product (411~) of Example 5(a) was stirred in trifluoroacetic acid (4Tnl) and anisole (1rnt) for 1 hour. This solution was added dropwise to vigorously stirred water (5M). Add diethyl ether (50+d) to this,
The two layers were separated after a few minutes. The organic phase was washed with water (2X 25 m
l), the aqueous extracts were combined and it was washed with diethyl ether (3X25 mA), in each case backwashing with water (IM). The aqueous solution was concentrated and lyophilized to give the title compound in the form (2
29■). λmaX (ethanol) 236
nm (ε17300), and τ (DMSO-d, 6)
0.55 (-(!0NH-), 3.14 and 3,
16 (thiazole 5-u), 3.41 (-00O
NH2), 4.11 and 4.15 (7-I(), 4
．． 78 and 4.79 (6-III), 5.08 and 5.33 (-0 degrees 200ONH2), 5.99 and 6
．． 03 (00) I-cyclozolovir→, 6.67 and 6.53 (2-OH2) 8.60-8.90 and 9.25-960 (cyclopropyl ring).

Example 6 ←) Diphenylmethyl (6R, 7R) -; 7-
C(Z) -2-(α-Methoxycarbonylcycloprobylmethoxyimino)-2-(2-)lytylaminothiazole)L/-4-yl)acetamide) -3-carbamoyloxymethylcef-3-em -4-carboxylate To a stirred solution of dimethylformamide (0,34yd) in dichloromethane (3-) at -15° under nitrogen was added a solution of oxalyl chloride (0,19'+11) in dichloromethane (2 m/ml). The resulting white suspension was stirred for 60 minutes at -5° and then cooled to -10°. To this was added the product of Preparation 19 (1
,0834,2,0 mmol) was added, washed with a small amount of dichloromethane and the resulting green solution was incubated for 60 min.
Stir at 5° and recool to -20°.

A solution of this activated side chain acid was prepared in dichlorothane (15 m) under nitrogen at -25°. -carboxylate (0
, 879F) and N,N-dimethylaniline (0,
56at) in one portion. The yellow solution was allowed to warm to +10' over 90 minutes, diluted with dichloromethane (50m), water (1007m), 2M hydrochloric acid (
10 (ld), water (10M), saturated sodium bicarbonate solution (100 mg) and brine C (100 mg) and dried (over sodium sulfate). Remove the solvent and evaporate the residue on 50F silica gel.
It was purified by This was eluted with ethyl acetate/I/nidichloromethane (1N) to give the title compound as a pale yellow 7ohm (1,568y).

λ1nf (KtOH) 236 nm (626,20
0) 258mm (ε19.600), 264mm (ε1
8,300), 'maz (OHBr5), 3540.3
415.3280, (Na, Na2), 1792 cm-
'(β-lactam C=0). τ(ODCβg)5.
62.5.72 (oca.

mixture of di, x, and theo isomers) 9.22 to 9.5
(cyclopropyl).

(b) (6m,7un-74(z)-2-(2-aminothiazol-4-yl)-2-(α-methoxycarbonylcyclo7-day pyrmethoxyimino)acetamido-6-carpamoyloxymethyl-7 A stirred solution of the product (1,00f) of step (a) above in 3-M-4-carboxylated trifluoroacetic acid-loaded anisole (2-) was treated with trifluoroacetic acid (8-) for 1 hour. Afterwards, this solution was mixed with vigorously stirred water (1
00m). Add ether (10M) to this,
The two layers were separated after 2.3 minutes. The organic phase was dissolved in water (2 x 50 m
), the aqueous extracts were combined and it was extracted with ether (2-
×50 ml). The aqueous solution was concentrated by rotary evaporation and lyophilized to give the title compound as a white foam (0.70f).

λInaz (FitOH) 235.5Hm (816
, 500), 'max (Nushor) 1782 (/-
lactam a=o), 1725 (esthetic k (j=Q
) and r (DMBO-66) i 12.3.14
(thiazole, mixture of diastereoisomers), 5.
9 i (OCH), 925-96 (cyclopropyl)
.

Example 7 (a) Diphenylmethyl (6R,7R) -7-((
Z) -2-(1-carbamoylcyclopropylmethoxyimino)-2-(2-tritylaminothiazole-4
-yl) acetamido-6-carpamoyloxymethyl 7-7-3-nimo-4-carboxylate Preparation 6(b) product (0,75F), diphenylmethyl (6R,7R) -7-amino-3- Carbamoyl'oxymethylcef-3-em-4-carboxylate (0,75f), 1-hydroxy-1H-benzotriazole hydrate (0,19F), dicyclohexylcarbodiimide (0,291) and tetrahydro7ran (12 rnl) was stirred for 20 hours. The mixture was filtered and the solids were washed with tetrahydrofuran. The door and washing solutions were combined, evaporated and the residue was washed with water (80%
m) and dichloromethane (80mg).

The organic phase was separated and mixed with 2N hydrochloric acid (2xsort) and water (5
The mixture was washed successively with 0 mjL of saturated sodium bicarbonate solution and saturated brine (50 mg). The organic phase was dried and evaporated to give a brown foam.

This was eluted on silica gel C30O9'l, first with ethyl acetate:itrol (4:1) and then with ethyl acetate.
Purification by chromatography above gave the title compound as a yellow-brown foam (0,67F). νusax (OHBr3)3510.5400
(NH,NH2), 1789 (f7-lactam C-
0), 1730 (ester unvpnc=o), 16
7゜cm (amide cmo), and r (aDal
, s) 5.71 (oca2), a6-9.3 (cyclopropyl).

(b) (6R,7R) -7-C)-2-(2-aminothi-azole-4-i/')-2-(1-carbamoylcyclopropylmethoxyimino)acetamidocy3-carbamoyloxymethyl7-fu 3-M-4-
Carboxylic acid trifluoroacetate The title compound is prepared from the product of step (a) above according to the method of Example 3(b) and contains νmax (nujol) 1772LJn-1 (merlactam 0=O) and τ (DMEIO- d6) 5.71 (OCH3),
It showed a88-9.2 (cyclopropyl).

Example 8 (a) Diphenylmethyl (6u+ 7R) -7-(
(z) -2-(1-Methoxycarbonylsifunoloprobilmethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetamido-3-carbamoyloxymethylcef-5-em-4-carboxine The rate title compound is prepared according to the method of Example 7(a) from the product of Preparation 14 and νmax(C!HBrg
) 354 os 3410 (NH+ NH2),
1790 (β-lactam cmo), 1729 (ester, urethane a=O), 1683ctn (amide cmo) oyobi r (c!DcA5) 5.55.
5.66 (OCH3), a6a ~9.0 (cyclopropyl).

(t+) (6R,7R) -7-[(Z)-2-(2
-aminothiazo-AI-4-yl)-2-(1-methoxycarbonylcycloprobylmethoxyimino)acetamide-6-carpamoyloxymethylcef 3-M-4-carboxylic acid trifluoroacetate The title compound is an example 3(b) from the product of step i(a) and νmaX (nujol) 1772 (β-lactam C=0), 1721
(ester C=0), 1678 (amide C=0) and τ(DMSO-d6)5.68 (OCH3), 8
, 7-90 (cyclopropyl).

Example 9 (6R,7R) -7-C(Z) -2-(2-aminothiazo-yv-4-yv)-2-(1-methoxycarbonylcycloprobylmethoxyimino)acetamide)
-3-pyridinium methylcef-3-em-4-carboxylate dihydrochloride The title compound is prepared from the product of Preparation 14 according to the method of Example 1 and has a νmax (nujol) of 178
8 (β-lactam C=0), 1718 (ester C-
0), 1678m-' (7mid a=o)1 and T (
1M30-46) 5.6-5.8 (oca2), a6
5 to clO (cyclopropyl), λmaw (ethanol) 236.5Hm (ε13,400).

Example 1゜(6R,7R)-7-[:(Z)-2-(2-aminothiazol-4-y,7+/)-2-(1-carbamoylcyclopropylmethoxyimino)acetamidocy 5
-Pyridinium methylcef-3-em-4-carboxylate dihydrochloride production 6(b) product (0,84F), 1-hydroxy-1H-benzotriazole hydrate (0,22F),
A mixture of dicyclohexylcarbodiimide (0,36f) and dimethylformamide (11rnt) was stirred at room temperature for 3 hours and then filtered. The p solution was dihydrated (6R,7R)-7-amino-3-pyridinium methylcef-6-em-4-carboxylate dihydrochloride (0,65m) in dimethylformamide and dimethylaniline (0,65m). 70y) was added to the stirred and cooled (-40°) solution and the mixture was left at room temperature overnight. The suspension was filtered and the yellow-brown F liquid was filtered (400m/!
) was added dropwise. The supernatant was decanted and the precipitate was stirred with acetone, filtered, washed with acetone and dried with suction. The crude product was partitioned between water (50mlt) and dichloromethane (50+g).

The organic layer was extracted with water (5 x 50 ig) for min nl#L in each case with a small tray of dichloromethane. The organic solutions were combined and washed with saturated brine and dried. The solvent was removed by evaporation to give a brown foam (1,08F).

This was dissolved in formic acid (4,89d) and concentrated acid (0,3
9-) and the mixture was stirred at room temperature for 1 hour. The suspension was filtered and the solids were washed with a filter.

The furnace liquor and washing liquor were combined and evaporated to obtain a brown gum;
This was triturated with acetone (x2) to obtain a light brown solid.

This was purified by chromatography on silica gel (100V) eluting with acetone-water (9:1 → 6:1 → 7:3). Fractions containing the desired product were combined and the solution was concentrated by evaporation. This solution was freeze-dried to obtain a light brown solid, which was further dried on a quartz to give the title compound (0,2
2f) was obtained. λmax (ethanol) 234n
m(ε13,130), ν1naX (nujol>1
770CI-lactam C-0), 1655 (amide
C=0) and'r(DMso-a6)5.6-6.0
(OCH3), a85-9.35 (cyclopropyl).

Example 11 (6R,7R)-7-C■)-2-(2-aminothiazo-/I/+4-yl)-2-(α-methoxycarbonylcycloprobylmethoxyimino)acetamido-6-pyridinium methyl Heptafu 3-M-4-carboxy7ate dihydrochloride The title compound is prepared according to the method of Example 1 using the product of Preparation 19 and
) 234.5 nm (ε20,400), 2m1L
X (Nujol) 1778 (β-lactam C=0)
, 1745 (ester C=O), 1675on-'' (amide C=0) and τ(DMso-a6) S, 2
4.3.27 (thiazole, mixture of diastereoisomers), 5.98 (-00H), 9.3-9.6 (cyclopropyl).

Patent Applicant Gractu Group Limited Continued from page 1 Priority claim 0198 tsubo December 30th [Sat] United Kingdom (
GB [Co., Ltd.] Inventor: Priyan Edgar, UK: 28 Middle Tou, Greenford, Middlesex, GB 8334600

Claims (1)

[Claims] 1) Cephalosporin compounds having the general formula CI) 1 and salts thereof [wherein, Q is a cyclopropylmethyl group, and Y is a carboxyl or protected carboxyl group, a carboxyl soyl, N-(01-C4 alkyl)carbamoyl or N,N-di(01-C4 alkyl)carbamoyl group or cyano group, and Z is a hydrogen atom or optionally 01-C4 on the nitrogen atom Alkyl or 01~
A carbamoyloxy group optionally substituted by a C4 haloalkyl group, an N-protected carbamoyloxy group, or a carbamoyloxy group of the formula-5za (wherein Za is a carbon-bonded group containing at least one nitrogen atom). a 5- or 6-membered unsaturated heterocycle which may also contain one or more sulfur atoms and/or C1
-C4 alkyl, oxo, hydroxy or carbamoyloxymethyl groups) or optionally a halogen atom and carbamoyl, viridinium or bearing one or two double bonds, which may be substituted by one (1!) or more substituents independently selected from hydroxymethyl and 01-C4 alkoxy groups; an optionally substituted 02-C5 hydrocarbon chain containing and optionally an intervening Peter atom)
R1 is an amine or a protected amino group, R2 is a hydrogen atom or a carboxyl protecting group, and B is -8- or >S→○
(α- or β-), and 2-13- and 4
A dotted line spanning the - position indicates that the compound is a cef-2-em or cef-6-em compound]. 2) General formula (Ia) (wherein Q and Z are as defined in Section 1 above and ya is carboxyl NC2-C5 alkoxycarbonyl, carbamoyl, N-(self-C4 alkyl)carbamoyl, N, N - cephalosporin antibiotics and their non-toxic salts and non-toxic metabolically unstable esters having a di(01-C4 furkyl) carbamoyl or cyano group. 3) Z is a pyridinium group, Q is as defined in item 1 above, and - is carboxyl, 02-
C5 alkoxycarbonyl, carbamoyl, N-(01
~C4 alkyl)carbamoyl, N,N-di(01~C
4 alkyl) carbamoyl or cyan group. 4) In producing the compound described in item 1 above, (a)
A compound or a salt thereof having the formula (N) H (wherein Z, B, dotted line and R2 are as defined in item 1 above) or 7
-N-silyl derivatives have the formula () % formula % (wherein R1 and Q are as defined in the first term above, and yb is Y in the above first term other than the carboxyl group)
(B), Z is an optionally substituted carbamoyloxy group; To prepare a compound, a compound having the formula 1 (wherein Q%Y%R', R2, B and the dotted line are as defined in Section 1 above) or a salt thereof at the 6-position -CHzb group, where zb is a carbamoyloxy group optionally substituted on the nitrogen atom by an 01-C4 alkyl or 01-C4 haloalkyl group, or is an N-protected carbamoyloxy group. (C) Z is an optionally substituted pyridinium or bicyclic pyridinium group or a compound of the formula -8Za, where za is as defined in paragraph 1 above. To prepare a compound having the group Q% Y% R1, R2, B and the dotted line are as defined in Section 1 above and X is a nuclear compound. is a substitutable residue of ) or a salt thereof is reacted with a desired nucleophilic compound or a sulfur nucleophilic compound capable of forming a desired group having the formula -〇HZ at the 3-position, and (D)
Z is the formula -8za (in the formula, di is 01 to C4 in the heterocycle)
To prepare compounds having the formula () (containing an alkyl-substituted or carbamoylmethyl-substituted nitrogen atom), compounds having the formula () (wherein Q%'Y%R', B and the dotted line are as defined in , and R2 is carboxyl
sil-protecting group and zo is a carbon-bonded 5- or 6-membered heterocycle containing a nitrogen atom) as a substituent on the nitrogen atom in the 20 heterocycles c1 to c
A method comprising reacting with a c1-c4 alkylating agent or a carbamoylmethylating agent capable of introducing a 4-alkyl group or a carbamoylmethyl group. 5) Reactions (4), (pt, (C) or (6) followed by any of the following reactions if necessary and/or desired in each case, namely (1) Δ2-isomer Δ 3-Conversion into isomers, (1 Li
Reduction of a compound in which B is >Si2 to a compound in which B is -S-, (1:+) conversion of a carboxyl group into a non-toxic metabolically unstable ester function, (iV) conversion of a non-toxic salt. formation, (X/) conversion of one Y group to another, and (VD optional carboxyl protecting group and/or N-
4. A method according to paragraph 4 for the preparation of a compound according to paragraph 2, which comprises carrying out the removal of the protecting groups in any order. 6) A pharmaceutical composition comprising a compound according to item 2 above as an active ingredient together with one or more pharmaceutical carriers or excipients. 7) General formula ([[l), GVI
and ■) and their salts, esters and reactive derivatives.