FI65258C - FORM OF ANTIBIOTICS VERKANDE 7-ETA-ACYLAMIDOCEF-3-EM-4-CARBOXYLSYRA - Google Patents

Description

RSr ^ l [B] (11) UJ-UTUSJ U UKISU

l J '' UTLÄGGNINGSSKRIFT OD ^ OO

1¾¾ C (45) Γ -. '. I nvl'y 10 74 1004 ^ (51) Kv.iit? / I «.CL3 C 07 D 501/20 FINLAND —FINLAND pi) PK« ttll «k« n «i -.P »ntwB) CNL« | 3713/7 * + (22) Htk * ml * piM— AmBknlngadag 20 12 7 1 (23) Alkupllvi — Glklghrtadig 2q 12 7l (41) Interpreters (external - Btlvlt oflmtllg 22 Qg

Patent-) · register-administered * (44) Nthtivikslpenon ji kuLJullutain pvm. -

Patent · och ragisterstyralsan AmOkan utlagd och utl.skrtften publlcand 30.12. o3 (32) (33) (31) Claim claimed — Begird prlorltet 21.12.73 03.10.7 * + England-England (GB) 59517/73, * + 3005/7 * + (71) Glaxo Laboratories Limited, Greenford, Middlesex , England-England (GB) (72) Janice Bradshaw, Harrow, Middlesex, Martin Christopher Cook, Liverpool, Gordon Ian Gregory, Chalfont St. Peter, Buckinghamshire,

John Derek Cocker, Chalfont St Peter, Buckinghamshire,

Derek Ronald Sutherland, Harrow, Middlesex, England-England (GB) (7 * +) Oy Kolster Ah (5 * +) Method for the preparation of the anthiotically active 7- [3-acylamidocef-3-em - * + - carboxylic acid - Forfarande för The present invention relates to a process for the preparation of an antibiotic β- / 3-acylamidocef-3-em-4-carboxylic acid of the formula

B H

I I

R-C-CO-NH - (= - ^

Il f I6. 3 I

\ 0, T

\ I

O_ (CH 2) -C- (CH 2) -COOH

z m I z n kb where R is thienyl or furyl, 26258

R a and R b, which may be the same or different, are hydrogen atoms or C 1-4 alkyl, C 2-4 alkenyl, C 1-4 cycloalkyl, phenyl, carboxy or C 2-4 alkoxycarbonyl groups, wherein Ra and R b are the same groups only when they represent hydrogen atoms or C 1-4 alkyl groups, or Ra and R * 3 together with the carbon atom to which they are attached form a C 1-6 cycloalkylidene group, m and n are each 0 or 1, so that the sum of m + n is 0 or 1, and P represents a) a hydrogen atom, b) a halogen atom, c) a group of the formula ^ r1

-CH = C

XR2 1 2 wherein R and R, which may be the same or different, are hydrogen atoms or carboxy, cyano or C2-6 alkoxycarbonyl groups, or d) a group of the formula -CH2Y, wherein Y is: (i) a heterocyclic tertiary amine residue, (ii) an azido, (iii) a group of the formula -SR, wherein R is an unsaturated heterocyclic group having a 5- or 6-membered heterocyclic ring having up to 4 heteroaters, which are sulfur, nitrogen or oxygen, however, the ring has not more than 1 sulfur atom and not more than 16 16 1 oxygen atom, (iv) a group of the formula -O-CO-R, wherein R is a C 1-4 alkyl or phenyl group, or ( v) a group of the formula 14 17 17 -O-CO-NHR, wherein R is a hydrogen atom or a C 1-4 alkyl group, or non-toxic salts and esters thereof, wherein said compound is a syn isomer or is present in the syn- and as a mixture of anti-isomers containing at least 90% of the syn-isomer.

Cephalosporin compounds are referred to herein in J. Am. Chem. Soc., 1962, 84, 3400, wherein the term "kefam-mi" refers to the backbone of a cepham having one double bond.

Cephalosporin antibiotics have been widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, e.g. in the treatment of diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, as well as pe- I; 3 65258 nicillin-sensitive patients. In many cases, the use of cephalosporin antibiotics with activity against both gram-positive and gram-negative microorganisms is desired, and a considerable number of studies have been directed to the development of different types of broad-spectrum cephalosporin antibiotics.

Recently, considerable interest has been shown in the development of broad-spectrum cephalosporin antibiotics with high activity against gram-negative organisms. The available β-lactam antibiotics have relatively low activity against certain gram-negative organisms, such as Proteus, which are a growing source of infection in humans, and are also generally substantially ineffective against Pseudomonas organisms. Several Pseudomonas organisms are resistant to available antibiotic compounds, and the therapeutic use of arainoglycoside antibiotics, such as gentamicin, which has Pseudomonas activity, is limited or hampered by the high toxicity of these antibiotics.

It is well known that cephalosporin antibiotics generally have low toxicity. Thus, the development of broad-spectrum cephalosporin antibiotics with high activity against gram-negative organisms such as Proteus and Pseudomonas strains meets a significant need in chemotherapy.

By the term "biologically acceptable esters" is meant esters of an antibiotic active compound of formula I which are metabolically labile, i.e. they are converted in vivo to an antibiotic active compound of formula I.

The process according to the invention is characterized in that A) a compound of formula 90 is condensed

V-1 — f S

J- »γ1-P

COOR19 19 4 65258 wherein R is a hydrogen atom or a carboxyl protecting group, and P is as defined above, or an acid addition salt thereof, is reacted with an acylating agent corresponding to the formula

R-C-COOH

I! \ \ I 20

O- (CEL ·) -C- (CHO) -COOR ^ 0 VI

2 m | 2 n

An acid of formula Rb wherein R, Ra, Rb, m and n are as defined above and R is a carboxyl protecting group, or B) when P in formula I is a group -CHjY »wherein Y is as defined above, a compound is obtained, whose formula is

H H

; i R-C-CO-NH-1-'fS (0) J |

Il I

N 2 -CH 2 Y 'VII

\ Xr- \ f O- (CH-) -C- (CH_) -COOR 2 m I 2 n

Rb vsb wherein q is 0 or 1 and RR, R, m and n are as defined above 19, and each R may independently be a hydrogen atom or a carboxyl protecting group, and Y 'is a chlorine, bromine or iodine atom or an acetoxy group, to regenerate the group Y then, if necessary and / or desired, carrying out any of the following reactions c) in any appropriate order: i 6 5 2 5 8 5 C i) reducing the compound in which q is 1 to the compound in which q is 0, C ii) deacylating the 3-acyloxymethyl compound to the 3-hydroxymethyl compound, C iii) carbamoylating the 3-hydroxymethyl compound to an unsubstituted or substituted 3-carbamoyloxymethyl compound, and / or C v) removing the carboxyl protecting groups and finally D) recovering the desired compound or a non-toxic salt or ester thereof.

The compounds according to the invention have a broad-spectrum antibiotic activity which is characterized by a particularly high activity against gram-negative microorganisms, in particular against organisms which form β-lactamases, and also has a very high stability with β-lactamases, formed by gram-negative organisms. The compounds are characterized by their high in vitro activity against gram-negative organisms such as Enterobacter cloacae, Serratia marcescens and Klebsiella aerogenes. The compounds have a particularly high activity against Escherichia coli, Haemophilus influenzae and Proteus strains, e.g. Proteus morganii and Proteus mirabilis.

Compounds in which at least one of Ra and Rb is other than hydrogen also have exceptionally high activity against Pseudo-monas organisms, e.g. Pseudomonas aeruginosa strains.

Non-toxic salt derivatives which can be formed from the compounds of formula I include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkali metal salts (e.g. calcium salts), salts of organic bases (e.g. procaine, phenylethyl) benzyl dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine salts), and acid addition salts, e.g. The salts may also be in the form of resinates formed, e.g., with a polystyrene resin or a cross-linked polystyrene-divinylbenzene copolymer resin, T-665258 containing amino or quaternary amino groups, or optionally sulfonic acid groups / or optionally with a resin containing carboxyl. with polyacrylic acid resin. The use of highly soluble base salts of the compounds of formula I (e.g. alkali metal salts such as the sodium salt) is generally preferred for therapeutic uses due to the rapid distribution of the salts after administration. However, if insoluble salts of the compounds of formula I are desired for a particular application, e.g. for use in individual preparations, the salts may be formed in a conventional manner, e.g. with the aid of suitable organic amines.

Biologically acceptable, metabolically stable ester derivatives which can be formed from the compounds of the formula I are, for example, acyloxymethyl esters, e.g. lower alkanoyloxymethyl esters, such as acetoxymethyl or pivaloyloxymethyl esters.

When the group R in the above formulas is a furyl group, it may be fur-2-yl or fur-3-yl, and when it is a thienyl group, it may be thien-2-yl or thien-3-yl.

Si J)

When R and R in the above formulas are different, the carbon atom to which they are attached may form a center of α-symmetry; the compounds of the invention in which Ra and R * 5 are different may thus be diastereoisomeric. The invention encompasses the individual diastereoisomers of such compounds as well as mixtures thereof.

Of particular interest are the cephalosporin antibiotics of the invention according to the compounds of formula

P H

i R-C-CO-NH - K Ϊ

Il [

\ III

\ RC ° T

O-C-COOH C00H

7 6 5 2 5 8 where R is a sauna as above, RC is methyl, ethyl, propyl (3.

li, allyl or phenyl and R is hydrogen, carboxy or preferably a cd group R; or R and R together with the carbon atom to which they are attached form a group of cyclobutylidene, cyclopentylidene or cyclohexylidene, and W is i) hydrogen, ii) acetoxymethyl, iii) benzoyloxymethyl, iv) carbamoyloxymethyl, v) N-methylcarbamoyloxymethyl, a group of the formula -CH = CHR wherein R is cyano, carboxy or C 2 -C 4 alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, vii) a group -C 1 -C 3 wherein G is a nitrogen nucleophile residue which is a compound having a formula of hydrogen, carbamoyl, carboxymethyl or sulfo, or pyridazine, ww viii) azidomethyl, and a group -CH 2 SR, wherein R is pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl or substituted by these groups (lower alkyl or phenyl-substituted) derivatives such as N-methylpyrid-2-yl, 1-methyltetrazol-5-yl, 1-phenyltetrazol-5-yl, 5-methyl-1,3 , 4-thiadiazol-2-yl and 5-phenyl-1,3,4-oxadiazol-2-yl and their n non-toxic derivatives.

These compounds have broad-spectrum antibiotic activity (including very high activity against strains of Haemophilus influenzae and Proteus organisms) and high β-lactamase stability and still have particularly high in vitro activity against Pseudomonas organisms such as Pseudomonas aeruginosa. against nosan positions.

Particularly preferred compounds, due to their particularly high activity against Proteus and Pseudomonas organisms 6 5 2 5 8 8, are the following: (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2 - (fur-2-yl) acetamido / -3-pyridiniummethylcef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (2-carboxyprop-2- Yloxyimino) -2- (fur-2-yl) -acetamido-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) cef-3-em-4-carboxylic acid (syn isomer) , (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid (syn isomer) ), (6Rf 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamide] -3- (trans-2-methoxycarbonylvinyl) cef-3- Eem-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -3 -pyrazinium methylcef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetic acid] amido / ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamide] cef-3-em-4 -Carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxyimino) 2- (fur-2-yl) acetamido] -3-pyridiniummethylcef-3-eme -4-Carboxylic acid (syn-isomer) t (6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) -acetamido] -3- (trans- 2-Carboxyvinyl) cef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2 -yl) -acetamide-3- (1-methyltetrazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-carbamoyloxymethyl-7- [2- (1- carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamide-3-ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2 ”(1-carboxycyclopent-1 -Yloxyimino) -2- (fur-2-yl) -acetamido-7-ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxybut -3-enyloxyimino) -2- (fur-2-yl) acetamide o7kef-3-em-4-carboxylic acid (syn-isomer), η 9 65258 (6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxycyclobut-1-yloxyimino) -2- ( fur-2-yl) acetamide-cef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (1-carboxycyclobut-1-yloxyimino) -2- (fur-2 -yl) -acetamido-3-pyridiniummethylcef-3-em-4-carboxylic acid (syn-isomer)> (6R, 7R) -7- [2- (1-carboxycyclobut-1-yloxyimino) -2- (fur 2-yl) -acetamido-3- (1-methyltetrazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-carbamoyloxymethyl-7- [2 - { 1-Carboxycyclobut-1-yloxyimino) -2- (fur-2-yl) acetamide-3-ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -3-acetoxyacetyl-7- [2- (1-Carboxypropoxyimino) -2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-acetoxymethyl-7- [2- (3- Carboxypent-3-yloxyimino) -2- (fur-2-yl) acetamido-3-em-4-carboxylic acid (syn-isomer-Γΐ) '(6R, 7R) -3-acetoxymethyl-7- [2- (2-Carboxyprop-2-yloxyimino) -2- (thien-2-yl) li) acetamide-cef-3-em-4-carboxylic acid (syn isomer), and their non-toxic derivatives, e.g. alkali metal salts f such as sodium or potassium salts.

Another interesting group of cephalosporin antibiotics prepared according to the invention are compounds of formula

S

R-C-CO-NH - S 2

Il '

'I ._N A w IV

N c /

COOH

O— (CH) -COOH 2 P

wherein R and W are as defined above and p is 1 or 2, and their non-toxic derivatives.

τ ~ 10 65258 These compounds have broad-spectrum antibiotic activity and high β-lactamase stability. The compounds are characterized by their high activity against Haemophilus influenzae strains and their particularly high activity against Escherichia coli and Proteus strains.

Particularly preferred compounds of the above, due to their particularly high activity against Escherichia coli and Proteus, are the following: (6R, 7R) -3-acetoxymethyl-7- [2-carboxymethoxyimino-2- (fur-2 -yl) -acetamido-7-ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-azidomethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamide] cef- 3-Eemi-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamide] -3- (1-methyltetrazol-5-ylthiomethyl) Cef-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-carboamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -cef-3-em-4 -carboxylic acid (syn isomer), (6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamide] cef-3-em-4-carboxylic acid (syn isomer).

The compounds of the invention may be prepared by any suitable method, e.g. according to the methods described in BE Patent No. 783,449.

Non-toxic derivatives of the compounds of formula I may be conveniently formed according to methods known per se in the art. For example, base salts can be formed by reacting cephalosophinic acid with sodium 2-ethylhexanoate or potassium 2-ethylhexanoate. Biologically acceptable ester derivatives can be formed using conventional esterification agents.

Acylating agents which can be used for the preparation of the compounds of the formula I are acid halides, in particular acid chlorides or bromides. They can be prepared by reacting an acid of formula 65258 VI or a salt thereof with a halogenating agent, e.g. phosphorus pentachloride, thionyl chloride or oxalyl chloride. Treatment of the sodium, potassium or triethylammonium salt of the acid with oxalyl chloride is preferred because under these conditions the isomerization is kept to a minimum.

The acylation using acid halides can be carried out in an aqueous or non-aqueous reaction medium, suitably at temperatures of -50 to + 50 ° C, preferably -20 to + 30 ° C, if desired in the presence of an acid scavenger. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as diethylacetamide, nitriles such as acetonitrile, or mixtures of two or more such solvents. Suitable acid scavengers include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which released hydrogen halide.

Acids of formula VI can be used as acylating agents in the preparation of compounds of formula I. Acylation using acids of formula VI is preferably carried out with a condensing agent, e.g. a carbodiimide such as N, N * -diethyl-, -dipropyl- or -diisopropylcarbodi. -imidine N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-Ύ-dinethylaminopropylcarbodiimide, a carbonyl compound such as carbonylimidazole, or, or an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium in the presence of perchlorate. Acylation reactions of this type are preferably carried out in an anhydrous reaction medium, e.g. methylene chloride, dimethylformamide or acetonitrile.

The acylation can also be carried out using other amide-forming derivatives of the acids of formula VI, such as, for example, symmetrical anhydride or mixed anhydride (e.g. with pivalic acid or by formation with a haloformate such as lower alkyl haloformate). Mixed and symmetrical anhydrides can be formed in situ; e.g., a mixed anhydride can be formed using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed using phosphoric acids, sulfuric acid 12 65258 or aliphatic or aromatic sulfonic acids (e.g. p-toluenesulfonic acid). In processes for the preparation of compounds of formula I / wherein R or R is carboxy, it is in many cases necessary to protect the carboxy group, e.g. by substituting it with a carboxyl protecting group, e.g. a group as previously defined in connection with substituent R.

Modification of the substituents at the 3-position can be performed by methods described in the literature. For example, compounds substituted at the 3-position with -Cl 2 Y / wherein Y is a nucleophile residue can be prepared by reacting 3-acetoxymethyl-cephalosporin with a nucleophile, e.g., pyridine or other tertiary amine as described in GB Patent 912,541; with a sulfur- or nitrogen-containing or inorganic nucleophile as described in GB Patent 1,012,943; with a sulfur-containing nucleophile as described in GB Patents 1,059,562, 1,101,423 and 1,206,305; or with a nitrogen-containing nucleophile as described in GB Patents 1,030,630, 1,082,943 and 1,082,962. Compounds in which Y is a derivative of a nucleophile residue, e.g. when Y is an amino or acylamido group derived from an azido group, can be prepared as described in GB Patents 1,057,883 and 1,211,694, these patents further describing compounds in which Y is azido, reaction with dipolarophile. Compounds in which Y is a nucleophile residue can also be prepared by reacting 3-halomethylcephalosporin with any of the nucleophiles described in the above publications, such as the method described in GB Patent 1,241,657, or by reacting 3-halomethylcephalosporin sulfoxide according to any of the methods described in the above publications. .

When 3-halomethylcephalosporin sulfide or sulfoxide ester is reacted with a tertiary nitrogen nucleophile such as pyridine according to the method described in GB Patents 1,241,657 or 1,326,531, the reaction product is usually obtained as the corresponding 3-pyridinium methyl halide. De-esterification of such compounds by treatment with trifluoroacetic acid tends to promote isomerization of the oximino moiety in the 7- / 4-acylamido side chain; isomerization is clearly undesirable when a product containing at least 90% of the syn isomer must be obtained without having to perform an isomer separation step. It has also been found that isomerization can be substantially reduced if the 3-pyridinium methyl halide is converted to the 3-pyridinium methyl salt of a non-hydrogen halide acid (e.g., trifluoroacetic, acetic, formic, sulfuric, nitric or phosphoric acid) prior to deesterification. Conversion of the halide salt to the non-hydrogen halide acid salt is conveniently performed using anion exchange. This can be done e.g. using a suitable anion exchange resin, e.g. in trifluoroacetate form. When an anion exchange resin is used, the 3-pyridinium methyl halide can be passed through a resin column before de-esterification. It is preferable to use an inert organic solvent to ensure adequate dissolution of the cephalosporin compound. Suitable organic solvents include lower alkanols such as ethanol, ketones such as acetone, and nitriles such as acetonitrile.

The carbamoylation of the 3-hydroxymethyl compounds can be carried out by known methods. For example, 3-hydroxymethyl-cephalosporin can be reacted with an isocyanate of formula R -NCO (where R is a labile substituent group or an alkyl group) to give a compound containing a substituent of formula -CH-O- in the 3-position. CONHR (where R is as defined above). If R is a labile substituent, the substituent may be subsequently cleaved, if desired, e.g. by hydrolysis to form a 3-carbamoyloxymethyl group. Labile R groups which are then readily cleavable include chlorosulfonyl and bromosulfonyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; halogenated lower alkoxycarbonyls such as 2,2,2-trichloroethoxycarbonyl. These labile Re groups can generally be cleaved by acid or base catalyzed hydrolysis (e.g., base catalyzed hydrolysis using sodium bicarbonate).

Another carbamoylating agent for use in carbamoylating 3-hydroxymethyl-cephalosporans is cyanic acid, which is suitably formed in situ from e.g. an alkali metal cyanate such as sodium cyanate, the reaction being promoted by the presence of an acid, e.g. a strong organic acid such as trifluoroacetic acid. Cyanic acid 14 6 5258 6 6 corresponds to a compound of formula R -NCO, wherein R is hydrogen, and thus can be used to directly convert 3-hydroxymethyl-cephalosporin to the 3-carbamoyloxymethyl analog.

The 3-hydroxymethyl-cephalosporins used in the aforementioned carbamoylation reactions can be prepared, e.g., as described in GB Patent 1,121,308 and BE Patents 783,449 and 841,937.

Cephalosporin compounds having an acyloxymethyl group as a substituent at the 3-position / can be prepared, for example, from a cephalosporin compound having a -CH 2 X group (X is H or an X residue of an acid H having a pKa of up to 4 .0 / preferably not more than 3.5 measured in water at 25 ° C) in the 3-position. Thus, X may be, e.g., chlorine, bromine, iodine, formyloxy, acetoxy having at least one electron-withdrawing substituent (on a λ carbon atom, or a ring-substituted benzoyloxy group (the ring substituent is an electron-attracting substituent, as described in GB Patent 1,241 657), and a nucleophilic displacement reaction to form the desired 3-position acyloxymethyl can be performed as described in the aforementioned GB Patent 1,241,657. as described, i.e. by aralkylation of the 4-carboxy group, acylation of the 3-hydroxymethyl group of the protected compound and subsequent removal of the aralkyl group.

Compounds with a vinyl or substituted vinyl group in the 3-position can be obtained as described in BE Patent 761,897.

The Δ-cephalosporin ester derivatives obtained in the manner according to the invention can be converted into the corresponding derivatives, e.g. by treating the A2 ester with a base.

The cef-2-emem reaction products can also be oxidized to the corresponding cef-3-emem-1-oxide, e.g., by reaction with peracid as described above; the resulting sulfoxide can then, if necessary, be subsequently reduced to the corresponding cef-3-emem sulfide as described later.

When a compound of formula VII wherein q is 1 is obtained, this can be converted to the corresponding sulphide, e.g. by reduction of the corresponding acyloxysulphonium or alkyloxysulphonium salt, prepared in situ by reaction with e.g. acetyl chloride in the case of the acetoxysulphonium salt, whereby the reduction is carried out, for example, with sodium dithionite or iodine ion in a solution of potassium iodide in a water-miscible solvent, e.g. acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature of -20 to + 50 ° C.

When a compound of formula I is obtained as a mixture of isomers, the syn-isomer can be obtained, e.g., by known methods such as crystallization or chromatography. The syn and anti-isomers can be separated in a known manner, e.g. by means of ultraviolet spectra, thin-layer or paper chromatography or by proton-magnetic resonance spectra. For example, the PMR spectra of the DMSO-dg solutions of the syn compounds of formula I have an amide-NH double line lower than the PMR spectra of the corresponding anti-isomers. These factors can be used to control reactions.

The starting materials of formula V in which P is a hydrogen atom can be prepared, for example, as described in BE patent 774,480 and FR patent 2,165,834. The starting materials of the formula V in which P is a halogen atom, such as fluorine, chlorine or bromine, can be prepared, for example, as described in DE-OLS 2 408 686. Acids of formula VI can be obtained by administering a glyoxylic acid of formula

R-CO-COOH VIII

wherein R is as defined above, or its ester is reacted with a hydroxylamine derivative of the formula

Ra I 20

H_N-O- (CHo) -C- (CH_) -COOR υ IX

2 2 m I 2 n

Rb wherein Ra, Rb, R1, m and n are as defined above. The resulting acid or ester can be separated into syn and anti-isomers, e.g., by crystallization, chromatography, or distillation, after which the ester derivatives can be hydrolyzed to the corresponding acid.

Acids of formula VI can also be prepared by etherification of an acid of formula 65258 16

R-C-COOH

II

N X

\

OH

wherein R is as defined above, e.g. by administering a compound of formula

Ra l 20

T- (CH „) -C- (CH_) - <ΧΧΜΤυ XI

2 m I 2 n

Rb wherein Ra, Rb, R1, m and n are as defined above and T is halogen such as chlorine, bromine or iodine, or a sulphate or sulphonate such as tosylate. Separation of isomers can be performed either before or after esterification. The etherification reaction is preferably carried out in the presence of a base, e.g. potassium tert-butoxide or sodium hydride, and is preferably carried out in an organic solvent, e.g. dimethyl sulfoxide, a cyclic ether r such as tetrahydrofuran or dioxane, or N, N-disubstituted amide, such as amide. Under these conditions, the configuration of the oximino group remains essentially unchanged during the etherification reaction.

Acids of formula VI and acylating agents derived therefrom (e.g. acyl halides such as chlorides) are novel compounds.

Derivatives of the compounds of formula I in which the carboxy substituent of the 7β-acylamido side chain is substituted by a carboxyl protecting group are also novel compounds. These monoester derivatives of the formula

H H

'' e j ·. S.

R-C-CO-NH --f N

i .ZZJ—

\ I

\ * COOH

\ R

X 1 20 O- (CH-) -C- (CHO) -COOR υ 2 m | 2 n R »I; 17 65258 wherein R, Ra, Rb, P, m and n are as defined above and R1 is a carboxyl protecting group such as t-butyl or diphenylmethyl are valuable intermediates in the preparation of antibiotic compounds of formula I. The compounds of formula XII may have antibiotic activity, although generally in very small amounts compared to the corresponding compounds of formula I.

20 19

The carboxyl protecting groups R 1 and R used in the preparation of the compounds of formula I or in the preparation of the necessary starting materials are preferably groups which can be easily cleaved off at a suitable stage of the synthesis, preferably in the last stage. However, in some cases it may be appropriate to use a biologically acceptable, metabolically labile protecting group such as acyloxymethyl groups (e.g. pivaloyloxymethyl) and retain these in the final product to give a biologically acceptable ester derivative of the compound of formula I.

Suitable carboxyl protecting groups are well known in the art and a list of preferred protected carboxyl groups is provided in BE Patent 783,449; they include aryl-lower alkoxycarbonyl such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl protecting groups can then be removed as appropriate as described in the literature; thus, e.g., acid- or base-catalyzed hydrolysis can be used in many cases as well as enzymatically catalyzed hydrolysis.

The pharmaceutical compositions contain more than 0.1%, e.g.

0.1 to 99%, preferably 10 to 60% of active ingredient, depending on the mode of administration. Unit doses may contain from 50 to 1500 mg of active substance. The dose for an adult human is preferably 500 to 5000 mg / day, depending on the method and frequency of administration, although higher daily doses are required for the treatment of Pseudomonas infections.

The antibiotics prepared according to the invention can also be administered in combination with other therapeutic agents, such as antibiotics, e.g. penicillins, tetracyclines or other cephalosporins.

18 65258

Results of pharmacological experiments The microorganism-killing effect (lowest antimicrobial concentration) of the compounds prepared by the process of the invention and the resembling compounds known from F1 application 1363/72 was determined by a conventional dilution method.

The compounds tested had the following general formula:

.S

R-C - CONH - S \

l | I I

n 2 -N 2 J-CH 2 OCOCH 3

0Ra T

COOH

wherein the substituents have the following meaning:

Compounds prepared by the process of the invention according to Application 1363/72

Example Example No. R Ra No. No. Ra 1 'CH2COOH 35 ~ CH3 2 \ s / -CH2C00H 8 "CH3 3 -CHjCOOH 29 -CHjPh ._. _-COOH i - 1 f - 1

7 O Ώ - <> <J

20 <\ / _ -CH2CH2COOH 39 ~ CH2CH3 19 65258

The following table shows the results obtained.

Table

Microorganism killing effect of the compounds and reference compounds prepared by the process of the invention (minimum inhibitory concentration, .mu.g / ml) * PS + Pi § o) • H * τΗ Ή ro s s u <-i

Pci Tn #> r * lr1ci r ~ W W 3 - · ζ

£ * simerKKi m H H E Λ «J

• h n} A = this ή ή ή jg h h H H rH 04 ^ ^ O ^ hAkpiniiQ O O O ϊ ^ ι o H ^ ^ najteraus ^ O o -μ to <n B = 1363/72 · ·. uu WH pq en cu cu A 1 0.25 0.5 0.5 0.25 <0.125 <0.125 B 35 4 4 4 4 8 0.13 A 2 2 4 4 2 0.25 0.25 B 8 16 - 125 125 16 0.5 A3 2 4 42 2 <0.125 B 29 31 - 31 31 62 62 A 7 2 2 2 2 0.25 <0.125 B 69 4 4 4 8 4 0.125 A 20 4 4 4 2 0.5 < 0.125 B 39 8 8 8 62.5 0.13 20 6 5 2 5 8

As is clear from the table, the compounds prepared by the process of the invention have better activity than the known compounds resembling them.

The following examples illustrate the invention. All temperatures are in degrees Celsius. The structure of the products has been confirmed by PMR spectroscopy (preparation of starting materials and examples) and IR spectroscopy (examples only).

Preparation of starting materials 1. 2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn-isomer)

A mixture of 4.2 g of fur-2-ylglyoxylic acid, 4.5 g of t-butoxycarbonylmethoxyamine and 50 ml of water was adjusted to pH 5.0 with 2N sodium hydroxide solution. The resulting solution was stirred for 16 hours. The pH of the solution was raised to 7.0 and the solution was washed twice with ether. The aqueous solution was acidified to pH 1.8 with ether and extracted with additional ether. The combined ether extracts were washed (water, brine), dried and concentrated to give 7.62 g of a solid which was crystallized from carbon tetrachloride to give the title compound (3.67 g, 46%) mp 105, 1-106.2 °. C, X niaks 6 phosphate buffer) 277.5 nm (£ 16,300).

2. 2-t-butoxycarbonylmethoxyimino-2- (thien-3-yl) acetic acid (syn isomer)

Thien-3-ylglyoxylic acid and t-butoxycarbonylmethoxyamine were reacted as described in Preparation 1 to give the title compound, m.p. 102.6-104.4 ° C (from carbon tetrachloride), λ. max (pH 6 phosphate buffer) 258 nm (£ 13,700).

3 ♦ 2-RS-Ot-t-butoxycarbonylbenzyloxyimino-2- (fur-2-yl) acetic acid (syn-isomer) a) i) A mixture of 24.5 g of N-hydroxyphthalimide, 16.5 g of anhydrous potassium carbonate, 41 g of t-butyl CX-bromophenyl acetate and 225 ml of dimethyl sulfoxide were stirred for 18 hours and then poured into 1.2 liters of water. The precipitate was filtered off, washed well with water, dried and crystallized from methylated alcohol to give (t-butoxycarbonyl) benzyloxy-7-phthalimide (41 g, 78%), m.p. 120.6-121.5 ° C.

21 65258 ii) To a solution of 40 g of the above oxyphthalimide in 500 ml of dichloromethane was added 11.4 ml of 100% hydrazine hydrate. A precipitate formed immediately. The mixture was stirred for 1.5 hours, after which a sufficient amount of 5N ammonium hydroxide solution was added to dissolve the precipitate. The two layers were separated and the aqueous layer was extracted once with methylene chloride. The combined organic extracts were washed (water, saturated brine), dried and concentrated to give 25.0 g (98%) of t-butyl ethyl- (aminooxy) phenylacetate as colorless crystals, m.p. 48.2-49.6 ° C.

b) Fur-2-ylglyoxylic acid and t-butyl CL- (aminooxy) phenylacetate were reacted as described in Preparation 1 to give the title compound, 42% yield, m.p. 97.9-98.9 ° C (from carbon tetrachloride), λ max (pH 6 phosphate buffer) 278 nm (6,184,400).

4. 2-t-Butoxycarbonylmethoxyimino-2- (thien-2-yl) acetic acid (syn isomer)

To a stirred suspension of sodium hydride (60% in dispersion oil, 0.96 g) in tetrahydrofuran (40 ml) was added 1.71 g of 2-hydroxyimino-2- (thien-2-yl) acetic acid (syn isomer). The mixture was stirred for 30 minutes, after which 25 ml of dimethyl sulfoxide was added and stirring was continued for another 1 hour. To the mixture was added 1.78 g of t-butyl chloroacetate, stirred for 16 hours and then poured into 300 ml of water. After washing twice with ether, the aqueous phase was acidified to pH 1.7. After washing (water, saturated brine) and extracting the dried extracts with ether, 2.71 g of material crystallized from carbon tetrachloride to give the title compound (0.952 g, 33%), m.p. 88.3-91.3 ° C, λ (pH 6 phosphate peak buffer) 270.5 and 288.5 nm (£ 9,200 and 10,800).

5. 2- (2-t-Butoxycarbonyl-prop-2-yloxy-imino) -2- (fur-2-yl) -acetic acid (syn-isomer)

A solution of 14.1 g of 2- (fur-2-yl) -2-hydroxyiminoacetic acid (syn-isomer) in 100 ml of dimethyl sulfoxide was added in one portion to a magnetically stirred solution of 22.4 g of potassium. t-butoxide in 400 ml of dimethyl sulfoxide, keeping the reaction mixture under a dry nitrogen atmosphere. A gel was formed, 22 65258 which, on stirring, turned into a fine yellow substance. Stirring was continued for 1 hour and then a solution of 24.0 g of t-butyl 2-bromo-2-methylpropionate in 50 ml of dimethyl sulfoxide was added over 1 hour at room temperature to the reaction mixture. At the end of the addition, the resulting solution was stirred for another hour. The reaction mixture was poured into 1.5 liters of ice water and acidified with ether (500 ml) to pH 1.8 with concentrated hydrochloric acid. Two layers separated and the aqueous layer was extracted with ether. The combined ether extracts were washed once with water and then extracted with aqueous sodium bicarbonate solution. The combined alkaline extracts were acidified with ether to pH 1.8 with concentrated hydrochloric acid, and the acidic solution was extracted with ether. The combined ether extracts were washed (water, brine), dried and concentrated to a yellow oil which crystallized under high vacuum (22.41 g, 83%), λmax (ethanol) 272.5 nm (8,400 nm).

The obtained material (22.4 g) was crystallized from carbon tetrachloride (25 ml) to give the title compound (16.42 g, 61%), m.p. 72.5-7 4, 2 ° C (73.0 ° C).

The following starting materials are listed in Table I below. They were prepared by forming the dipotassium salt of 2- (fur-2-yl) -2-hydroxyiminoacetic acid (syn-isomer) under a dry nitrogen atmosphere, and alkylating with halogen t-butyl ester as described in 5, after which the products were isolated by pouring the reaction mixture into water. by acidifying the solution and extracting in the usual manner (method A) · the half-esters were prepared using halogen-diphenylmethyl ester (method B).

---- - Ί ^ · ^ t— V W

. ; -1 -—--------- O S g CM „- '' pi oo vo ro r» en m in m vo o o | ^ «N, ^ rH 00 00 00 ro ro I o vo. 5

^ vo o ... M

in CO VO 00 r- -P

,. »CM» r— r— »<0 M tr1 oo n oo» »oo n 'cö - oo σ \ w ·» m »» t— n · »··. n r · »co o t— r- r— o%« · h «. · »^. in oo m oo m σν o o o o o o o o o o

Jjj m r »» - r »* - m ro in cm _ - _“> _ g 8 3 s? S ä | q ^ | ^ »N β .2 r» a v- r »ft m T- χ ', 2 r» r »r» r ~ r »

^ 3 CM CM CM CM CM

O CO

CM tT

OS »e» ti * CM ori ° ° O (5¾4 oU * "r- Y loi li

K Cr * 00 00 CM

CM Oi »» O

Oi O 'vo ΤΟ o __ * _ g_

\ / i I

Jj ^ *** m w o

J =

"of

"~ C0 CM

s S. | P <y Y J® ϋ 2L 1 M w i, s 0 0 !. * CO - 5> I-1 Θ - s

5 n "? F L J S S

1 g? X € θ "ί

/ x Λ Λ I

--— - -f * 9 -μ Λ m O o • H ”vo r» oo σι τ- Β β g___ ΐ ---- U sj £ - sJ u I - (° * I § I § rH O OO ID o

rH t- O O O VO

·· * '* ^ co n oo ro oo I «- ·' Ä -—-—— - -, —'— · ^ CN ^ 1 2 ^ 00 in ...... ij · CN 00 Q 00 Q Ότ— vo 00 Q 3 1 ΐ · II * I ~ oo mipr · '{j1 crv «rivo r-vo r-' σι on -> · vo, ¾ 05 fOTJ T3 rH νηηΌ ϊ> λλ 'w · ~ · ~ · «. o ^ to 00 O CN | tj * lt> Q · ** · ** -ro O r- r— CO (N r * (Ti Q τ— · * 3 «* * - - * · **" - 'CN σ> · * ςΓ GO LO CX> lO <T \ lO 00 _I _________ ^ ooooooo in ° omo

: VjO 0s »I" ^ I CN LD

oo ro m ro ΐ "I in vd I g-5§i s s - a s! s-Bss § ^ g ~ 3! Ig ·; ί ΐ ί i ^ 3 S S S o“ s g.

1 Cl «M CN CN CN

| ________CN_ | s <*> k. o ™ au f "oo v · =, K tr 1 cn o5 id r-

Oi * - r- U O * “\ / 1Ϊ 3 ω m ®« m <<—--

O

C/O

CN ^ SZ co id s § * § ΐ

«V V S

3 e

4J -H

10 --- I

~, «* S

O OV n ___ cn sf * 1 + »5 lf« “i r ^ | -r,? .¾

5 vT vT I J S S S

3 \ / f V B f Ϊ / \ S Λ e | 3 tn 0 3 ”f— CN n tj · in g__

(N f 'VO <Ti ID

ps m tn m in «- <D *» s ··

«H 00 00 00 00 ro CJ

· CTV

O <N

i “--- ά to m

Ό -r- - ..I

O Q VO Q "> 3 · .— * · mm n en ro r- ~ m <o <0 V" * 0V oo p oop oo oo S oo 7j OS f I 3

· - Ό «" VO I · '·' W

m Ό en Ό vo m σν en 6 t— ^ ro «a · m» * - g

^ «Fc». % w ^ CO H

oo oo Γ 'uo oo uo e o o o §

O O O -H

VO ^ °° "* '£ vo uo p * -> i

_J <D

g _ - I

! sl s il il I

Ib “i s. ^ 1 '-g ·' 7

J "-H VO VO Oi oo CU -H

rCj i Γ "γ ~» r ~ ή - (N CN (N £ 1 __ gji

O + J

™ 7. S

®. n - «f j5 8 * ° u“ i T - +, * I T- I + K CT Λ “i <nw CN 0S r- ΤΟ I σν τ- Ο O__ S \ = z, /// 'S% <<<<«O = y ro _ o Zr> sa 9

3 V

$ 5 rfl --- c • ro * <1)

‘Ro * S

M '~ rn "" ö)

K -H

o O1 3 a k10 a Λ M * <n ° n, / \ o "\ / S3! Q v xa; / ^ ϊ / n A“ 1 --- 1- | sn VO Γ "00 en o * r- «-« - (Ν '- * icg 1___ 26 652 5 8 21. 2- (2-t-butoxycarbonylprop-2-yloxyimino) -2- (thien--2-yl) acetic acid (syn isomer)

The title compound was prepared from 2-hydroxyimino-2- (thien-2-yl) acetic acid (syn-isomer) and t-butyl 2-bromo-2-methylpropionate as described in 5 to give a 78% yield of colorless an oil which was the N-benzyl-2-phenylethylammonium salt, m.p. 201.3-201.9.9 ° C (from ethanol).

22. 2- (2-t-butoxycarbonylethoxyimino) -2- (fur-2-yl) acetic acid (syn isomer)

To a mixture of methyl acetohydroxy acid / CH 2 -C (= NOH) -OCH 2 / (8.9 g) and t-butyl acrylate (12.8 g) was added a solution of potassium t-butoxide (0.1 g) in t- in butanol (1 mL). The mixture was kept at 0 ° C for 65 hours, then washed with water, dried and distilled to give 2-t-butoxycarbonylethyl methyl acetohydroximate (2.37 g, 11%), b.p. 85-87 ° C / 1.2 Torr.

To a solution of 1.26 g of fur-2-ylglyoxylic acid in 50 ml of water was added 2.15 g of 2-t-butoxycarbonylethyl methyl acetohydroximate and a sufficient amount of methanol to obtain a homogeneous mixture which was stirred for 30 minutes at pH 1.5. The pH was adjusted to 4.5 using 2N sodium hydroxide solution and the mixture was stirred for a further 16 hours, after which the reaction was almost complete. The ethanol was removed under reduced pressure, the pH of the residue was raised to 7.0 and the mixture was washed twice with ether. Dichloromethane was added to the aqueous phase and acidified (pH 1.7) and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined dichloromethane extracts were washed with water, dried and concentrated to give 1.53 g of a tan solid (mixture of syn and anti-isomers, 85:15) which was crystallized from carbon tetrachloride to give the title compound (0.975 g, 34%). mp. 74.7-77.2 ° C, A. max (PH 6 buffer) 277 nm (£ 16,500).

23 ♦ t-butyl 1-bromocyclopentanecarboxylate To a mixture of 36.99 g of 1-bromocyclopentanecarboxylic acid and 35 ml of anhydrous ether in a 500 ml pressure flask equipped with a magnetic stir bar was added 3.5 ml of concentrated sulfuric acid, followed by 150 ml of ml of precondensed isobutene. The flask was sealed and stirred at ambient temperature at 20 L for 27 hours. The flask was then opened, the excess isobutene evaporated and the residue in ether washed with aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was distilled under reduced pressure to give the title ester (b.p.

66-74 ° C / 0.5-2.0 Torr) (33.6 g, 70%), λ max (CHBr 3) 1702 cm -1, δ (CDCl 3) 7.78, 8.20 (cyclopentane- protons) and 8.54 (CH 2 Cl 2).

24. Diphenylmethyl (X-bromohexanoate) 1.95 g of Ct-bromohexanoic acid in petroleum ether (25 ml, b.p. 40-60 ° C) was treated with a solution of diphenyldiazomethane in lak-benzene (b.p. 40-60 ° C) (ca. 3.8 mmol / l). 10 ml) dropwise with stirring until a purple color persisted, the mixture was stirred for 2 hours at room temperature and the solvent was removed in vacuo, the resulting oil in ethyl acetate was washed with saturated aqueous sodium bicarbonate and then water and dried to give the title ester (3.0 g, 90%). ,? max (ethanol) 252, 258, 263.5, 267.5 and 276 nm (£ 1,650, 1,600, 1,350, 11 and 850) CO-halogen-substituted carboxylic acid esters These starting materials were prepared by treating Ot-halogen. -ni-carboxylic acid with isobutene and concentrated sulfuric acid in a pressure flask at room temperature for 10-40 hours as described in 23 (Method A) or by treating Qt-halocarboxylic acid in a solvent (e.g. ether, petroleum ethers) in ethyl acetate) with a solution of diphenyldiazomethane until a faint permanent color appeared, after which the resulting ester was washed with alkali as described in 24 (Method B). The compounds are listed in Table 2.

28 6 5 2 5 8 κ κ k ac k! u u u υ u • ΓΟ, -Ο VO «TiTf o 2 Q LD LO T- o OO t- £ _ ° 0S 00 oo ro ro roro ro ^

• S I

£ o 3 M___

M _ ~ ~ --- Q

O <n o ro '' O

«- * ω - cq ^ co ro ro« g - oogiT \ -. g

rH CN M Q OO I Q I o OlQ

, ιμ O <NU σι I * - tn r ~ i oo cq r ^ ii ΓJ Όα> Ω »· Q * VO" S - VO - g -cd H ooor'O CTiQ r-T3 ^ .Q η- ό j · *> · ** · «» VO ·· »« o. KO · *> i vo o · ov r- ~ * - t3 o * rs in o oo j

0 Γ '«no co - cn i— o I

v ** ^ V ^ K *. v «». '^ lO LO <T * Γ · "* LO O LO lO <Tj t ------- 1 Ö £

Xi ii tri VO Γ- σ> o ™ 00 "- - * - W C> ~ m 'cm r> * - o ---—---—. —. — __

<N I MO

«<U ε

(N CM

g m cq cq cq D1 (U -----------

X

ro ro cn I <0 _ UJs.Cs s = s -ro ° U 04 O)

w k S

K u u <u

Il Q) s o

__________ CO

* ~ i U - 1 M

^ —R ro -te —r l X CM -

U .—. ; C/O

Lj ^ cm ro i pj 1 rg ES mm—. f K -

n ^ cm ~ o ® K cn U

H 05 UJ ro cm cn cm K VJ> - «ra S U K US U U U UJ« 0 e ioy \ / '- l U. +) Ξ' ^ ajN'ajrr! uj + j

rt ’ouuuu U -H

| M Λ / \ / \ / \ / \ i 5

H i M

------— ——------- 4 (0

M

^ MMM M MM m! U CQ CQ OQ CQ CQ CQ * - ΐ o: Z m vo r ~ oo σν o t- | cm cm cm m (N ro ro i __L__i 29 652 5 8 - - ------

K

0 T— CM 00 0 in m o CM * - "Λ QS 00 00 ro S '

+ J

0 3 Ή _______________

Zl σ> - (Ti 00 U tr '«00" ^ oo oo oo i i ··>. «(Ti

(Tl OI h CM

* ^ ^ ^ r ~ vo r- vo T— e υ • h m ro ° ^.

m M m Γ "Γ" 1 o m n ^ ^ p εκ ^ ^ w rv u- w V> - 0 ---: - cm i: nj

<ί <U E

cT * S 'öi ^ ^ ® 0 S J-> tr «-

X

ro ro cm o X X! ° H ft * - 'v 53

3 05 CJ O

3 I I

M

+ J

(0 -------------- -ro! "Ö 5? I1 E- * * · mm m« mm j

o I

"CM ro rr I

<5 ro ro ro ___i 30 6 5 2 5 8 35. Di-t-butyl 2-bromo-2-methylmalonate To a stirred suspension of sodium hydride (1.7 g, 80% dispersion in oil) in tetrahydrofuran (60 ml) under nitrogen was added 11 .52 g of di-t-butyl methyl malonate. The mixture was stirred at 60-70 ° C for 1.5 hours to give a clear solution. This solution was cooled to -25 ° C and a solution of 2.6 ml of bromine in 30 ml of dichloromethane was added rapidly. The solution was allowed to warm to room temperature and concentrated. The residue in ether was washed with water, dried and partitioned under reduced pressure to give the title compound, (7.56 g, 49%), b.p. 78-86 ° C / 1.0 Torr, A.max (CBr 2) 1730 cm -1 (CCl 2 BuS, δ (CDCl 3): 8.05 (s, C (CH 3) 3) and 8.53 (2 s, CH 3 and C (CH 3) 3).

36. t-Butyl ethyl 2-bromo-2-methylmalonate The title compound was prepared in the same manner as in 35, with dibutyl ester; yield 83%, b.p. 64-68 ° C / 0.03 Torr.

37. 1-Bromomethylcyclopropane-1-carboxylic acid Cyclobutanecarboxylic acid was brominated to give the title compound (about 15% yield), m.p. 83-84 ° C (laccacensin, b.p. 60-80 ° C), (dg-DMSO) values 6.25, 8.65 and 8.90.

38. t-Butyl 2-bromo-3-formyloxypropionate A mixture of t-butyl acrylate (12.8 g) in chloroform (50 ml) and formic acid (11.3 ml) was stirred in an ice bath while being added dropwise over 2 hours. A solution of N, N-dibromobenzenesulfonamide (15.57 g) in a mixture of chloroform (50 ml) and formic acid (5.7 ml). The mixture was further stirred for 16 hours at room temperature and then filtered. The filtrate was then washed with water, pH buffer (3 times) and brine. The solution was dried, the solvent evaporated and the residue distilled to give the title compound (20.47 g), b.p. 69-71 ° C / 1.0 Torr, (CDCl 3, 60 MHz) 1.93 (s, formyl) and 8.48 (t-butyl protons).

39. N- (1-t-butoxycarbonyl-2-formyloxyethoxy) phthalimide t-butyl 2-bromo-3-formyloxypropionate (50.6 g) was added to a solution of N-hydroxyphthalimide (32.6 g) and triethylamine (60 ml) in dry dimethylformamide (120 ml) and a mixture of 31 652 5 8 were stirred for 18 hours at room temperature. The mixture was poured into ice water (1 L) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with sodium bicarbonate solution until the washings were colorless, and then with water and brine. The ethyl acetate solution was dried and evaporated under reduced pressure to an oily solid (53.2 g) which was crystallized from ethanol to give the title compound (20.85 g), m.p.

64.5-67.5 ° C,% (DMSO-d 6, 60 MHz) 1.67 (s, formyl), 2.11 (s, phthalimide protons), 4.99 (t, J 4 Hz, O -CH-C

40. N- (1-t-butoxycarbonyl-2-hydroxyethoxy) phthalimide A solution of phosphorus oxychloride (2.46 mL) in chloroform (35 mL) was added to a stirred ice-cold solution of N- (1-t-butoxycarbonyl-2 -formyloxyethoxy) phthalimide (10.3 g) in a mixture of chloroform (185 ml) and methanol (235 ml). The mixture was stirred for a further 1/2 hour at room temperature and then treated with sodium bicarbonate (ca. 10 g) before evaporating to dryness. The residue was partitioned between ether and water-soluble portions and the aqueous phase was extracted with additional ether. The combined extracts were then washed with sodium bicarbonate solution (twice), water and brine. Evaporation of the dried ether extracts gave a yellow gummy solid (7.01 g) which was crystallized from ether to give the title compound (2.81 g), m.p. 86.8 ° C, T (CDCl 3/60 MHz) 2.14 (broad s, phthalimide protons), 5.42 (m, O-CH-), 6.01 (m, CH 2) and 8.44 (t-butyl protons).

41. N- (1-t-butoxycarbonyl-2-mesyloxyethoxy) phthalimide

Methanesulfonyl chloride (1.35 ml) was added to a solution of N- (1-t-butoxycarbonyl-2-hydroxyethoxy) phthalimide (2.65 g) in pyridine (25 ml), and the mixture was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and then washed with water, dilute hydrochloric acid, sodium bicarbonate solution and water. Evaporation of the dried ethyl acetate solution gave a residue which was crystallized from ethanol to give the title compound (0.47 g), m.p. 108.0-109.2 ° C, δ (DMSO-d 6, 60 MHz) 2.08 (s, phthalimide protons), 4.88 (m, O-CH CO 2 tBu), 5.34 (m, -CH 2 -), 6.70 (s, CH 2) and 8.51 (s, t-butyl).

____ 1- 32 6 5 2 5 8 42. N- (1-t-butoxycarbonylvinyl) oxyphthalimide

A mixture of N- (1-t-butoxycarbonyl-2-mesyloxyethoxy) phthalimide (1.44 g) and triethylamine (0.60 ml) dissolved in ethyl acetate (20 ml) was stirred for 24 hours at room temperature. The mixture was then washed with water, dilute hydrochloric acid and water. Evaporation of the dried ethyl acetate solution gave a solid (0.967 g) which was crystallized from ethanol to give the title compound (0.491 g), m.p. 115.4-116.2 ° C,% (DMSO-d 6, 60 MHz) 2.09 (s, phthalimide protons), 4.54 (q, J 4

Hz = CH 2) and 8.46 (s, t-butyl).

^ 1 43. t-butyl 3-phthalimidooxy-Δ-pyrazoline-3-carboxylate

A stirred solution of N- (1-t-butoxycarbonylvinyl) oxyphthalimide (8.0 g) in ether (400 ml) was treated portionwise at 0 ° C with ethereal diazomethane (prepared from N-methyl-N-nitrosourea (12.0 g)). until a permanent yellow color was obtained. The mixture was stirred at room temperature overnight and then treated with diazomethane for another two days. During this time, part of the solvent evaporated and the white solid precipitated and separated and washed with ether to give the title pyrazoline derivative (5.697 g), m.p. 123.1 ° C, λ <ethanol) 236.5 (infl) (6 10 900) and 294 nm (£ 1900).

44. t-butyl 1-phthalimidooxycyclopropanecarboxylate

A solution of t-butyl 3-phthalimidooxy-pyrazoline-3-carboxylate (17.0 g) in toluene (510 ml) was heated at reflux for 5 hours, after which the solvent was evaporated. off under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with 2N hydrochloric acid, saturated sodium hydrogen carbonate solution and water, and dried and evaporated. The resulting yellow solid (16.02 g) was chromatographed on Merck silica gel (400 g) eluting with ether to give a gummy product which was crystallized from a mixture of ether and fuel oil to give the title compound (8.73 g), m.p. 78.6 ° C, (ethanol) 236.5 (infl) (£ 10,600) and 293 nm (£ 1,900).

33 65258 45. t-Butyl 1-aminooxycyclopropanecarboxylate t-Butyl 1-phthalimidooxycyclopropanecarboxylate (3.4 g) in dry dichloromethane (55 ml) was stirred with hydrazine hydrate (1.17 ml) for 1 hour at room temperature. The precipitate was filtered off and washed with dichloromethane, and the filtrate was then washed with 5N ammonium hydroxide, water and brine, dried and evaporated to give the oxamine amine as a yellow oil (1.832 g), T (CDCl 3) 4.2 (2H, br, s, NH 2 ), 8.50 (9H, s, -C (CH 3) 3), 8.75 (4H, m, -CH 2 CH 2 -).

46. (1-t-Butoxycarbonylcyclopropyl) oxyiminofur-2-ylacetic acid t-butyl 1-aminooxycyclopropanecarboxylate (1.83 g) in ethanol was added to a solution of fur-2-ylglyoxanoic acid (1.33 g) in water ( 27.5 ml). The pH was adjusted to 4.5 by the addition of 2N sodium hydroxide, and sufficient ethanol was added to give a homogeneous solution (total ethanol about 30 ml). The mixture was stirred at room temperature for 5 hours and 2-N sodium hydroxide was added as needed to maintain the pH at 4.5. The ethanol was removed under reduced pressure and the residue was diluted with water and the pH was adjusted to 9 by the addition of 2N sodium hydroxide. The solution was washed with ether, acidified to pH 1.5 with concentrated hydrochloric acid and extracted with ether. The extract was washed with water, dried and evaporated to a yellow-green gum (81.957 g). Crystallization from nitromethane gave the title compound (426 mg), m.p. 118-119 ° C, max (CHBr 3) 3500-2400 (CO 2 H), 1756 (CC> 2R) and 1690 cm -1 (CC> 2H).

Example 1 a) (6R, 7R) -3-Acetoxymethyl-7- [t-butoxycarbonylmethoxy-amino-2- (fur-2-yl) acetamido] -7-ceph-3-em-4-carboxylic acid (syn isomer) 0.45 ml of oxalyl chloride was added at 5 ° C to a stirred solution of 1.35 g of 2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn-isomer) in 50 ml of dry dichloromethane containing 0.7 ml of triethylamine and 1 drop of dimethylformamide. The solution was stirred at 5 ° C for 1 hour and then evaporated to dryness at 5 ° C. The residue was suspended in 50 ml of acetone and added over 30 minutes to a stirred, ice-cooled solution of 1.36 g of (6R, 7R) -3-acetoxyacetyl-7-aminoceph-3-em. 4-carboxylic acid in 100 ml of water and 50 ml of acetone containing 1.0 g of sodium bicarbonate. The reaction mixture was stirred for 1 hour and the acetone was evaporated off under reduced pressure. The residue was acidified to pH 1.8 and the mixture was extracted with ether. The combined extracts were washed (water, saturated brine), dried and evaporated to give the title compound (2.52 g, 96%) as a pale yellow foam; = + 28.5 ° (c = 0.96, dimethyl sulfoxide); (pH 6 phosphate buffer) 276.5 nm (S 17,900).

b) (6R, 7R) “3-Acetoxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylic acid disodium salt (syn isomer)

A solution of 1.422 g of (6R, 7R) -3-acetoxymethyl-7- [2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid and 0.25 ml anisole in 5 ml of trifluoroacetic acid, was kept at room temperature for 5 minutes. The mixture was concentrated under reduced pressure, 10 ml of ethyl acetate were added and the mixture was evaporated again. The residue was treated with a mixture of ether and sodium bicarbonate solution. The ether layer was extracted with sodium bicarbonate solution and the combined alkaline extracts were acidified to pH 1.8 with ether. The acidic mixture was extracted with ether and the combined ether extracts were washed (water, brine), dried and evaporated to give the title compound dicarboxylic acid (942 mg, 74%), Z (DMSO-d 6) 0.24 (d, J 8Hz). , NH), 4.13 (dd, 7-H) and 5.31 (s, CH 2 Cl 2> 2H).

This diacid (900 mg) in acetone (9 ml) was neutralized with a solution of sodium 2-ethylhexanoate (700 mg) in acetone (5 ml). The mixture was stirred for 10 minutes, the precipitate was filtered off, washed with a small amount of acetone and dried to give the title compound (807 mg, 60%), εCX7n = + 15 ° (c = 1.08, μl dimethyl sulfoxide); Λ max ^ g (Nujol) 1766 cm (β-lactam).

35 65258

Examples 2-26

General Procedure (6R, 7R) -7- (2-Aryl-2-carboxy-R, 4-oxyiminoacetamido) -3- (substituted) -cef-3-em-4-carboxylic acids (syn-isomers) and and / or their salts

Method A

According to the procedure described in Example 1, a solution of 2-aryl-2-t-butoxycarbonyl-Rq-oxyiminoacetic acid (syn-isomer) (1 equivalent) in methylene chloride, optionally containing a few drops of Ν, Ν-dimethylformamide, and triethylamine (1 equivalent) with oxalyl chloride (1 equivalent) at 0 -5 ° C for about 1 hour. The mixture was then evaporated to dryness. The residue was suspended or dissolved in acetone and added to a stirred, ice-cold solution of (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (1 to 1.2 equivalents) in water or a mixture of acetone and water which contained sodium bicarbonate (2 to 2.5 equivalents). The reaction mixture was stirred for 0.5-2.5 hours, allowed to warm to room temperature, after which the acetone was removed under reduced pressure. The pH was adjusted to 1.5-2.0 and the product was extracted into ethyl acetate (alternatively ether or methylene chloride may be used). The organic layer was washed with water and / or brine, dried and evaporated to give the corresponding (6R, 7R) -3-acetoxymethyl-7- (2-aryl-2-t-butoxycarbonyl-R, oxyiminoacetamido) -cef- 3-Eemi-4-carboxylic acid (syn-isomer) determined by optical rotation and / or spectroscopy.

The t-butyl esters were deprotected by treatment with trifluoroacetic acid containing anisole at room temperature for at least 5 minutes. The reaction mixture was evaporated in vacuo and the product was isolated by stirring or treating with a mixture of ethyl acetate (or ether) and aqueous sodium hydrogen carbonate. The aqueous extracts were separated, acidified with ethyl acetate and the title carboxylic acid separated in the usual manner. The products are listed in Table 3.

6 5 2 5 8 36

Method B

Method A was followed except that 2-aryl-2-diphenylmethoxycarbonyl-R 2 -oxyiminoacetic acid (syn-isomer) was used instead of t-butyl ester. The products are listed in Table 3.

Method C

Method A or B was followed except that the dicarboxylic acid was converted to the sodium salt by treating a solution of the acid in acetone with a solution of sodium 2-ethylhexanoate in acetone. The precipitated disodium salt was washed and dried. The products are listed in Table 3.

Method D

Method A was followed except that (6R, 7R) -3- (substituted) -methyl-7-aminoceph-3-em-4-carboxylic acid or its salt (6R, 7R) -3-acetoxymethyl-7-aminocef-3 was used. instead of -em-4-carboxylic acid. The products are listed in Table 4.

37 6 5 2 5 8 5 2 - Λ (N - ro to ro tr cn r ~ ·· 'n S r-

as ro (N ttcn O O

~ mm · »i oo £ oo g oi n cn) in -jo cn in oo 3 ° --- 4-1 10 ro“ ^ --1 0 01 ^ somom “^ -ho - ^ o ro -rf TT o ^ ^ J · - -

(OF

K

m vo o σ> cvj ▼ H CM CNJ ro) {· »· * · *. ·> O O ΓΠ o o r

O

r> «h 5 f Λ 5 ^ cn ω αο υ · οο 3 Z <£ o yo £ £ vo vo I id M * ~ · η h * Γ ** Γ" · Γ * “

o .H «J I 3 H * -H * -f tH

cm i 6 a z g ^ f> «-

/ -1 * o. o o O o o O

'vi o · tr »cn r ~ r« oo oo «) —υ U) \ / tt o σι oo ιο vo PJ. - Λ 2 -H -H * - <- * - t ~ x e in> 1 _ «n E ->.

~ χ "'/ \\ 8 βιϊ oo cn cn t" m / o tr 5 i a vo σι ko r · »t" t> -

- / «« JC CN CN CN CN CN, - ^ * N

Kies »i ~ as o - / aa z - 'n - o, - o / ___ ^ -_ V_ / ~ Γ ~ η -P § 5 o- ° o ° s _ / ίΐ · m ro ·> τ cocn ¾ V «§ + + ++ +«> υ υ u! i <<- | a -H -h o il i i | s ^ »S g ·, • H * H O) m Ό * D a)

j E

* 5 - * vo 3 I I ^ CN ._ 5 CN CN .C - · | o MM a ro ro _ «^ uukaan κ I i G ou 5e z \ a ~ v_- xx υ um ___ / \ ^ \ n> 6 X)" ö ° ö ° 0 ° i jj 2 ^ ro ^ m \ o CO cw J_______ 38 6 5 2 5 8 -, ---------- co CN «*»

* CD CO O CO CO

co * · co m o co _ tj «_ ^ 'VO' ~ 2 CC <0 or ^ CO CO co oo 2 • f <'r; ~ · * · · »Co - - t: S O - '^ fO vO O o .z.

J σ.-1 CO CM LT) CO CO ^ o r ^^ LOCO r ** LOC0 O _ 8 X O in m vö σ »\ o Q * -» i- <o i-h I> t · * ^ ^ +.

l CO O CO Γ "1-H ΓΟ ro CN o ro ro no Ä" ** · »» * s «.

O 0.0 o o o <n m i '' ”” '"" X £ U *

I «o ^ O 10 O O O

R 10 <£> ω σι V IS 5- £ £ £ £ r- r- r- <n 1 ε e z s ° ~

/ Λ “cm O O O O O O

/ \ ι O 0 0.0 O O O

o »y— ο ^ 00 tI * m --1 cO cm« .Λ_ * vo m in o if r-

^ H »H» H H H

-. X g> »4 m c in in w * - / - \ o M«. k / ο σ '5 i 5 VO m Tf -d · in ^. / ° a «2 C' r- ~ r- t" r- r>

X 'I exe <N CM CM CM CM CM

'X o y O. 3 § / a / ^ --- \ __ o o' 000 f - g ~ CM o VO CO CO 1-1

/. ° 8 Vp 'd' r ~ ^ CM CM

J ^ + + + + + * <, £

B

® u ο u ω 8 E * <£ <<<<_ o + J I I 2 * I s s' s

^ + J Ό S

"<β CM E

S * o * + j * 3 · * “h ^ -v. a ^ y \ wwti - «o O 8" 5 "0> Cs" -> c | xv V vs ~ J ^ 06 6 61! eoo »- <cm!" i- * co σ —i .- <»- ii

ω π I

U_ L _ _______ 39 6 5 2 5 8

· «. CM

VO * * ΤΊ Φ ω ς? ,. : ο. ™ S- ° 51 ^ °? o g «cd 1/1 ^ i ^ no05 m O '_ ^.« σ, in co ^ a Ο ΰ ™ ·· - in in .2,

2 ° <M

g in ® 1,1 ® oo inoo10 m t "*" ro cT "

«» H rH

o - ** W VO ^ CO ^

g * -H «H * iH iM

‘(O ^ ^ o * · o

* 0 H H

if rf fc> "

* -i LO tH r ^ CD

ro ro ^ ro ^ ro * 0 0 0 0 0 0 ro «H 1 Γ 33 g Ϊ 5 w 10 <n OCN * ig Is« 'o ^ i'- n- oococo f «S, * * - -n Γ ** · f * Γ- * Γ * · * P-

O r-4 fl> I 3 H ψ-4 H ^ H

M 16 6 23 S 8-, -1 as ö o O o o o / λ m x o o o m o

'Yl O' 'OOOICM-H

m y-U (n ^ \ / (Ticor ^ iooooo

PJ. . A I M 2 H fH nH tH iH rH

- ® g in>. _ c * c ~ * '' *** / \ 1 8 βιϊ ^ CN m «Ί en / o σ J * <o 3 n- f". r »t" r- r- ~

^ / K «J * CN CM Oi CM CN CM

X I 6 33 a 33 O ^ a 3 \ / - ^ --- 1 / n ?? in r »rr m —i en / pCw '» in ^' in ^ io o. ' <P g + + + + + +

* Vsj S

B

V

„« Oam «m C 6 a» s § λ a * Ä 1 ...... so _ „oi m co co eo ¥ ~ 8 5-ΪΓ 8 - * - ¥ ~ J'1 2 ä · * m * m cn * cm * * m -h 5 M ö in CM r 0 υ ω a _ m (N m ca il «S u ö», CN um - fr> 05 u UTO 2

Sm ~ b b w 5 y a u u o X> _ ✓N / \ _ X \ _ / \ / \ / \ _ -g // \ r ^ \ r ^ X r ^ \ | 5

k / ° k / ° O 'Q ° Q ° Q ° __i J

»N 51« m ω r »co! I „» H vH «* H * H '

0) C

w J_ __ _ _ __ ’40 65258 g- σ * ro * Γ" r- ^ σν co · * »_ LO C0 ··» Ν - lo co

SC CO “kO

as lo o ^ o__________ _______

O

w q o σ »r-!>» »- * VO * ^ · * 2 rj · e r- co ro ro oj ro

KO O O

<o -h '~~ ~ «e V S ~ ^ ^ co o 2„ rH ro ω co 0>; ατ o Γ "* r- r- *

1 id * - T- »v-H» H * -H

o «H ui I 3

n i E 6 SS

S

J-1 «o o o

/ Λ M O O LD

«V-8 (Λ ω rN

\ r ro ΙΟ Γ- SC · - - · '** S8 tH tH * -h -rap> * «--- L 1 G * C ^ 4 CN oo / v υ eiu vD r- / O o * Jisoa cm es rs

^ / PC «X

K 6 s n ^ s o ^ a 3 2 o * w cl g / -5-- \ / ° «V - g! Λ * -0 0 / O O ^ ^ / r ^ i w ιο ro o. tT * - + + + «Cj £

B

«C E <C ffl« * a 2 8 '' '2% + J a> ro Λ L.

Λ <- * ---- a> m cn i \? ε S m "X 8 Ä * ä« "m-N λ u u υ (/> 6 0 1 ω - * —— ---—--—- CO 0> O» H -ii

5 * · es CN -K

W C. - "UJ ___ li 65258 _41_ o

CO T-H

tr ^

Ä * -i CO ΓΟ CO CM

ä ro ro m N "· '*“ · - ** »m in in co ac o> m 0 Γ» Γ-

1 - I ..... -— - - - 'I

2 o oo ro cm m

q tH iH »H H

1> 1 - "* * · *« O ^ ^ ^ 3 t »^ co m ^ * -ι ^ cm ro X * o o o o o w4

E

«J

5 ^ o o o cd m Λ m 'o I "CD P ~ CD t" id j <«- T-. r »r ~ r- ~ r ~ i—

^ ^ I 3 t * 4 r <«H» H H

i e e z. o o o o o> "o in o o in CN cn oo σ ^ σι ® [/} U m r ~ cn m

I ^ H * -H dH dH

/ V_ ° "TI r \ / °» ax ^ “i 1/3 m - Λ— * ^ w 2 Tl m r- ~ r» n · S e o. N- r »io r * r- cln) cm cn cn

s ri iO

w * '"7- ^ 8 c r / o tr 5 m - /« 2 ίο o o - - “jg ° ^ § O .2 -. ™ o ^ § o 8 oo

O / VT * -3 ino-H'-iWP-S IOS3 «N

O / O3. Zj fi ifD cn Q dftn \ / '»J 3 + Ό + Q + -' + - λ“ “~ T ~ '-: - -

£ L O

06 -M

g ^ Q O Q O Q

t. | : g m -H Ή

"UM

O -P 4J

3 I I (0 I «J

M c e Ή * rl Ό Ό m cm „e s I -? i § - '"5 (-¾ f. ___ _Ά * p ό & όο ö ° 1

S CM ro in KO

n c CM CM CN CM CM

'<1 42 6 5 2 5 8

Example 27 (6R, 7R) -7- [2-Carboxymethoxyimino-2- (fur-2-yl) acetamido] -3- (1-methyltetrazol-5-ylthiomethyl) -cef-3-em-4-carboxy- silicic acid (syn isomer)

A solution of 0.97 g of 2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn-isomer) in 20 ml of methylene chloride was added dropwise at room temperature over 15 minutes to a stirred solution of 1.484 g. g of diphenylmethyl (6R, 7R) -7-amino-3- (1-methyltetrazol-5-ylthiomethyl) -cef-3-em-4-carboxylate and 0.743 g of dicyclohexylcarbodiimide in 45 ml of methylene chloride. After stirring for a further 2 hours, the solvent was removed by evaporation, the residue was stirred for 5 minutes with 50 ml of ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution, diluted with an equal volume of water and then brine (25 ml each), dried and evaporated to a foam (2.5 g) which was dissolved in benzene and purified by chromatography on silica gel (70 g). Elution with benzene / ethyl acetate (10: 1), combined fractions and evaporation to dryness gave a foam (2.05 g) which was dissolved in ethyl acetate and poured into petroleum ether to give diphenylmethyl- (6R, 7R) -7- [2-t-butoxy- carbonylmethoxyimino-2- (fur-2-yl) acetamide-3- (1-methyltetrazol-5-ylthiomethyl) cef-3-em-4-carboxylate (syn-isomer) (2.02 g, 90 %) as a white amorphous substance, λmax = -102 ° (c = 0.99, CHCl3), λmax (ethanol) 278 nm (£ 19,800).

A solution of this diester in a mixture of 7.7 ml of trifluoroacetic acid and 1.9 ml of anisole was kept at 0 ° C for 10 minutes and then added to a mixture of saturated sodium bicarbonate and water (1: 3, 850 ml). After stirring for 10 minutes, the mixture was washed with ethyl acetate, covered with additional ethyl acetate (200 mL) and acidified to pH 2 with concentrated hydrochloric acid. The organic phase was separated, washed with water and brine, dried and evaporated to a foam (1.54 g). Thin layer chromatography showed that the deprotection was incomplete and the product was re-treated with trifluoroacetic acid (4.3 ml) and anisole (1.1 ml) at 20 ° C for 15 minutes, whereupon the product was separated as a foam. (1.3 g) as described above.

This foam in ethyl acetate was added to petroleum ether to give the title dicarboxyl (0.8 g, 59%) as a white 23 ° amorphous substance, = “99 ° (c = 1.05, acetone), λ (0.1-m pH 6). phosphate buffer) 277 nm (£ 21,900), λ max (Nujol) 1780 cm -1,% (dg-DMSO) values 0.19 (d, NH), 4.14 (dd, 7H), 5.30 (s, CH 2 Cl 2 (2H). Example 28 (6R, 7R) -3-Carbamoyloxymethyl-7- (4-carboxymethoxyimino-2- (fur-2-yl) acetamido] -7-ceph-3-em-4-carboxylic acid (syn isomer) 2.08 g the diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethyl-cef-3-em-4-carboxylate-toluene-p-sulfonic acid salt was dissolved in a mixture of 60 ml of ethyl acetate and 60 ml of saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was separated, washed with water, dried and evaporated to a foam.

1.0 g of 2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) e-thiacetic acid (syn-isomer) and 0.76 g of dicyclohexylcarbodiimide dissolved in a small amount of anhydrous dichloromethane were added dissolved in a solution of the above amine. To 20 ml of anhydrous dichloromethane. The reaction mixture was stirred at 3 ° C for 35 minutes, during which time Ν, Ν'-dicyclohexylurea crystallized. This was filtered and the filtrate evaporated to an oil which solidified on stirring with diisopropyl ether. The solid product was dissolved in ethanol and purified on activated carbon. Evaporation of the solution gave diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamide] cef-3-em-4-carboxylate (syn-isomer). ) (2.08 g, 86%), m.p. 97-98 ° C, CaJD = + 5.5 ° (c = 1.00 DMSO), λ (ethanol) 276.5 nm (g 17 250).

max 6 ml of trifluoroacetic acid were added to a slurry of 2.08 g of the above diester in 6 ral of anisole and the reaction mixture was stirred at 20 ° C for 25 minutes. The solution was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate, the aqueous layer was separated and washed with ethyl acetate. 100 ml of ethyl acetate and 2N hydrochloric acid were added to adjust the pH to 2. The organic layer was separated, washed with water, dried and evaporated to a yellow oil. PMR showed that the product was (6R, 7R) -3-carbamoyloxymethyl-7- [2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) -acetamide] -ceph-3-em-4- carboxylic acid (syn isomer).

____ -cr j i 44 65258 t This acid was treated with 4 ml of anisole and 4 ml of tri-

O

fluoroacetic acid at 20 ° C for 30 minutes and the reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was washed with ethyl acetate and acidified to pH 2 with n-hydrochloric acid in ethyl acetate. Evaporation of the ethyl acetate layer gave a solid which was purified by precipitation from ethyl acetate with diisopropyl ether and filtration to give the title dicarboxylic acid (620 mg, 44%), m.p. 159-161 ° C, [α] D = + 35 ° (c = 1.0 DMSO), λmax (pH 6 phosphate buffer) 275 nm (S 15 400) λmax (Nu3ol) 1778 cm -1, t (dg-DMSO) values 0.20 (d, NH), 4.15 (dd, 7H), 5.32 (s, C (CH 3> 2)).

Examples 29 to 42

General Procedure for (6R, 7R) -7- [2-carboxy-Rq-oxyimino-2- (fur-2-yl) acetamido] -3- (substituted) -cef-3-em-4-carboxylic acids ( syn isomers) using dicyclohexylcarbodiimide (i) To a solution of diphenylmethyl (6R, 7R) -7-amino-3- (substituted) -cef-3-em-4-carboxylate (1 equivalent) and dicyclohexylcarbodiimide. imide (1 to 1.3 equivalents) in dry methylene chloride, 2-t-butoxycarbonyl-R, oxyimino-2- (fur-2-yl) acetic acid (syn-isomer) was added at 0-25 ° C. (1 to 1.15 equivalents) solution in dry methylene chloride. After stirring for 0.5-5.0 hours, the dicyclohexylurea was removed by filtration and the filtrate was evaporated. The residue in ethyl acetate or methylene chloride was washed successively with aqueous sodium bicarbonate, water and brine, dried and evaporated. The diester was purified by chromatography on silica gel. The product was identified by PMR spectrum and thin layer chromatography.

If the 7-amino starting material was used in the form of an acid addition salt, the free base was liberated by shaking with a mixture of ethyl acetate (or methylene chloride) and excess aqueous sodium bicarbonate. After washing with water and brine, the organic layer was evaporated to dryness and the free amine was used as described above.

(ii) Method A. The resulting intermediate diesters were deprotected by dissolving in a mixture of trifluoroacetic acid (3-10 ml / g diester) and anisole (0.8-12 rol / g diester) and allowing the mixture to stand at 0 ° C. at room temperature for 5 minutes to 2.5 hours. The mixture was concentrated under reduced pressure and added to a mixture of ethyl acetate or ether and excess aqueous sodium bicarbonate solution, and the aqueous layer was washed with ethyl acetate. The aqueous phase was covered with ethyl acetate and acidified to pH 1-2 with hydrochloric acid. The organic layer was washed, dried and evaporated to give the desired dicarboxylic acid.

(iii) Method B. In some cases where treatment with trifluoroacetic acid was insufficient to deprotect the intermediate monoester (usually the 5-butoxycarbonyl group cleaves more slowly than the diphenylmethoxycarbonyl group), the treatment with trifluoroacetic acid and anisole was repeated as described above and the diacid separated.

(iv) Method C. The 3-carboxyvinyl derivative described in Example 36 was prepared from a 7-amino derivative, wherein both carboxy groups were protected as diphenylmethyl ester. The resulting triester was deprotected as described in Method B to give the desired tricarboxylic acid.

The properties of the reaction products are shown in Table 5.

~ 46 "65 25 8

“I

ty CN (N ιΠ «η ro oc, m m ro« * 10 * * 00 00 co oo m oo ϋ <Τι <r> 3 o - Γ- + j 2 _ — _ °° __ m o

W

S

Q. -¾1 00 * -h O

Vo ^ * · 4 * “· O * -H, -H

• 0 "* ** ^« - ^ <d * ^ f ~

O '* Ί · O 00 • tj * CN

χ 00 CM CN 00 CO

o o o o o o

** H - I —I

«J -« - <mmoo (n U - ^ 00 P · 00 oo r- «?. £ ^ ^ f" p-> CE fc ^ <> u ~ Λ ooooooomoooom ,, m co cn oo ίο σι m (X , wo • "i1 lO» h ifl co * -h

1 O 1-i CN CN t-η CN CN

/ L “<N --- - '-1 ---- 1--1 -, _ I

m \ -8 C% ZiZ £! «Tw ^ \ /» Tl “ft-H> £» ο, -τπ ®αΛ ω o.

tE- - Λ_ ζ Λ «" IHII Μ C7> j1. Ρ ι j CM Β cm ι - 3 2 ^ ιΟ 3 Μ «) 3 ^ iDM ^ ioofO Ιβ-Η β§2 μ χ g ^ g cm 4J -m «A ai jj, ih hb 3

- X Λί cl ° <ft Oi n, Ä ^ CM O, X

- X --- / - \ O --- 1 --—----- / No υ c O Oo ^ / ° ° L -H «N - O - X 'f jj a Tuo - m, -.

- X O QO "OB OOrH o g s p> a -p o ce wmu w

8 / e * -n 0 O W CO 2 OS - B OS

υν / Cjr-I «n cn o CO o CM U σι 3 \ / ^ ^» H VO τΗ - (Tl ^ 0Qw jr '^ - 1 —————— S / S \ s I CE «mm- im <N'S ^ Γ0 -------- M____ T% δ "<* € vK © I y S cr / ri

1ι 1 8 SS \ ° V

<N CVI II It) ω T

M B B P CM UI

υ υ u + j a cm in i i 'h w »j a I u o --—----—-. *

X

3 r4 2 CM CM CN CM I-1! Ό - - - - I 1

Eh no ro co i ro CO l \;

«A a cm aa \ V

υ u a u o u ui o u / \ / \ / \ g n ΟΊ O ^ CN ro 53 * cn roro roro ro

<U C

-1 -—- 1 ---- 7 ~~ - ~ 652 58 p

00 ιΛ Ln VO

CO CN CN CN * ro - * CO.

os - oo oo oo co -, CO §

N., .. - - O <N

5 (Tl <D (DO) CD 1 /) ^ 0 r- Γ 'r- r- oo' o - 1 1 1,1 1 "~ ........, - - - - 8

Jg Gs Γ- in ^ if) CT>

Q O O O O

1> t - - - JO vf ^ ^ ^ ττ oo oo cm ld mn ro ry ro no oooooo Ή 6 <0 «3 - 4J ^ -ho <r> o co ο σ 'm or o oo r * co r- oo r- 5 * S 7 '7 r- r * r-? g e »^ ^ ^ ^ o o o o o o o o o o o o

. CN CN Ο Γ- 00 CN

n Ιύ H> VO.-1 CN i /) CO t'-

I CN CO CN.-1 CN CN

/ vJ> "1 Γ7 ^ ^ ^ \ _j2 - w q ™ 8 8

* ----- 2 3W "2 SC σι £ CN CN

a e Λι σ 'CD o-

. § I CN CN CN CN

X BEL. ^ _> 1 fM --------- λ ___ ^ ^ 8 2 '- υ o / O tr .5 - co a ο υ - / OS rj co O - - ^ TT wi _ Λαό oo ooaz * (3 5 ® r «f § U OB ^ HOOO ^ zo / iO -ä OB ιηιβου cn + j ld dp o

u /, °. 7 00 (0 h2 -h b in W 00 H dP

\> / I 5 I - i ~~ U + -110 I lo Λ:: 7 Sb «u <<m« _ * ______

iO CO., LTD

BJ Z = Z \ J’1 ^ ®

CN. \ B3 BJ U

UB - Z-CJ CN U cn - CN— CN U) I / a CN - O0) ο οι oaz = / »o co oc • oc υ rt fo oc a® n. Aid am * ya ia and 3 w O ^ Ö4JCQ OOMII +) 3 Π +) II - CN CN II +1 a “a: a— äaaa ^ u

. „+> Ο ο α ο o I

10 λ I I I I I

τι ________ 0 Λ! a: i -. <3 - i x x υ __Ä a 'm 9. VO VO Γ-- CO CD O! 2C co ro co co co tj ·

- HO '·> i-Γ'> k, D

LO

O * CN

«M — i ^ Γ0 00 N“ Ä ^ · ’s: σ> § ___ ^ o <9 CO m

Q O O

'xp ^ ^ ^ 2 cr> r- «h ro x * * o o!

S o £ {C

to λ: * - r-. ^ M 10 l 3 Γ ** Γ-

I £ β 55 H H

^ <> u “o o 0 o

T-I CO., LTD

p, te m ro

rH H

/ w * n \ / - ° »% 3 ~ _ \ _ L a: - m M - ro * ----- * g sm oo

• B S CU 00 OH

J C I CM

3) Οι Ό -a —J-k * “*“ ~ de / 'V, υ c ~ m / ° ¾ -H inro — ro - = O O O ~ 8 O 8 l s S3 ° * 3 3¾ \ y' vj cl? 5 vz A ~ T ~~ Γ ~ k / _JL____ »n. o «3 3

ΙΛ M

+ J ___ 0 «*

Ji

1 · O

* s X

s -to r; 3 o »c 49 65258

Example 43 (6R / 7R) -7- [2- (1-Carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamido] cefe-3-ene-4-carboxylic acid (syn-isomer) a) A stirred solution of 5.50 g of diphenylmethyl (6R, 7R) - * 7-aminocef-3-eme-4-carboxylate and 5.23 g of propylene oxide in dry methylene chloride (100 ml) at -5 ° C: was treated dropwise over 20 minutes with a solution of 2- (1-t-butoxycarbonylcyclopent-1-yloxyimino) -2- (fur-2-yl) acetyl chloride (syn-isomer) in methylene chloride. The resulting solution was stirred at 0 ° C for 40 minutes and allowed to warm to 22 ° C with stirring for an additional hour. Methanol (15 ml) was added and stirring was continued for 15 minutes. The solution was washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. After drying and clarification on carbon, the solution was evaporated to a foam which was dissolved in ether and added dropwise to petroleum ether to give diphenylmethyl- (6R, 7R) -1- (2- (1-t-butoxycarbonylcyclopent-1-yloxyimino) -2- (fur - 2-yl) acetamide cef-3-em-4-carboxylate (syn-isomer) as a colorless powder (8.3 g, 83%), [α] 25 D = + 43 ° (c = 0.1 CHCl 3) » Amma (ethanol) 277 nm (£ 17,300).

b) The diester prepared in a) (6 g) in anisole (30 ml) at 0 ° C was treated with trifluoroacetic acid (24 ml) and the solution was stirred for 30 minutes. The reaction mixture was allowed to warm while stirring for an additional 2 hours and then concentrated in vacuo to a volume of about 20 mL. The residual oil was treated with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was extracted with bicarbonate solution and the combined alkaline layers were washed with ethyl acetate and ether. The aqueous layer was covered with ethyl acetate and adjusted to pH 1.5 with concentrated hydrochloric acid. The resulting organic layer was washed with brine, dried and evaporated to a foam containing the title acid.

The foam was dissolved in a buffer containing 0.1 M sodium acetate, 0.1 M acetic acid and 0.2 M sodium chloride (75 mL) with sodium bicarbonate. The solution was treated with Amberlite XAD-8 (50 mL) and adjusted to pH 4.8 with 2N hydrochloric acid. The resulting stirred suspension was treated with Woelm-neutral alumina (20 g) while maintaining the pH at 4.8. The suspension was stirred for 20 minutes and applied to a column of the aforementioned Woelm neutral alumina (25 g). The title acid was eluted with the above buffer (300 mL) and 2% aqueous sodium acetate (500 mL). Eluates from cooling fibers and redissolved in as little water as possible. The pH was adjusted to 1.5 with concentrated hydrochloric acid, the acidic liquids were extracted with ethyl acetate and the combined extracts were dried and evaporated to a foam. Mixing with ethyl acetate, petroleum and ether gave the title acid as a colorless solid. as substance (3.5 g, 88%), = + 162 ° (c = 0.01, 5% NaHCO 3), λ (pH 6-phosphate buffer) 282 nm (δ 14,000), λ max (Nujol ) (β-lactam), 1710 (CO 3 H) and 1680 and 1528 cm -1 (CONH), 1 C (DMSO-d 6): 0.37 (d, J 8 Hz, CONH), 2.10, 3.24 and 3 , 31 (m, furyl protons), 4.05 (dd, J 5 and 8 Hz, 7-H), 4.80 (d, J 5 Hz, 6-H) and 7.90 and 8.25 (2 x broad m, cyclopentyl protons) .The PMR spectrum also showed the presence of half a mole of both ethyl acetate and water.

The acylating agent used in step a) was prepared as follows:

A stirred suspension of 3.75 g of phosphorus pentachloride in 120 ml of dry methylene chloride and 6.53 g of dimethylacetamide at -10 ° C was treated with 2- (1-t-butoxycarbonylcyclopent-1-yloxyimino) - With 2- (fur-2-yl) -acetic acid (syn-isomer) (5.82 g) in small portions to keep the temperature below -5 ° C. After stirring for 15 minutes, the solution was treated with ice (40 g) and stirred was taken for 20 minutes to give the corresponding acid chloride (in the organic layer).

Examples 44 to 48

General Procedure for (6R, 7R) -3- (Optionally Substituted) -7-Cl- (Carboxy-R 1 -oxyimino) -2- (fur-2-yl) acetamido-7-ceph-3-em-4-carboxylic acids (syn-isomers) by treating (6R, 7R) -3- (optionally substituted) -7-aminoceph-3-em-4-carboxylic acid ester with acid chloride (syn-isomer) 2- (t-butoxycarbonyl-R-oxy-). imino) -2- (fur-2-yl) acetic acid (syn isomer) was converted to the acid chloride as described in Examples 2-24. A solution of the acid chloride (1 to 1.3 equivalents) in methylene chloride was added dropwise at -5 to + 5 ° C over 10 to 30 minutes over diphenylmethyl- (6R, 7R) -3- (optionally substituted) -7-aminoceph. To a solution of 3-eme-4-carboxylate (1 equivalent) in dry methylene chloride containing propylene oxide (5-20 equivalents). The reaction mixture was stirred for about 1-3 hours at 0 ° C to room temperature, and then washed successively with 2M hydrochloric acid. aqueous sodium bicarbonate, water and / or saline. The dried organic layer was evaporated and the residue was purified by trituration, precipitation, chromatography or crystallization.

From the resulting diphenylmethyl- (6R, 7R) -3- (optionally substituted) -7- [5- (butoxycarbonyl-R, 4-oximino) -2- (fur-2-yl) acetamide] cef-3-eme The -4-carboxylate (syn isomer) was deprotected according to the procedures described in Examples 29-42, Methods A and B, for diesters. The products are listed in Table 6.

52 6 525 8 ----, • ^ ο σ \ o co

ro (N ro lD

TI tn tn m oo to

S

o O____ S ^ · «-» <jv σ> »- * • g o o * -» o <- »Q - ^ I> λ r) i xf Tj * ^

S

y

CN CO * H * -h CN

»H O CN ^ co X *.

o o o o o § S o LO m r- cn jiw oco co Γ "r * - co * -q · r- r * - r- r- r- V C 'c» ^ ^ -> o o o o o o o o o o o

Co ro CO VO ^ CT »P * I vo * -h ro ro

I ^ CN (N CN * - * CN

\ / ~ ° cn% k ~ «n« «« te- - Λ— * -S w 2 Tl * - <i "σι en

Son <n σ> r- ~ r- r-

'13 g I CN CN CN CN CN

„X CD

>. IN ______________ - ”~ y- ^ 8 e - / ° ° U Tj ^ ro 'n

X _ Aon O O O OH

- * o ° 9 I I Ui ΓΟΟ ΓΟ u o / 5 os -s «a

8 /. Λ »" j cnQ ^ ior-O

\ / Vj i-1 ro · - + Z en - —f ~ -1—— Y Se ® m <m «e _ * ____ 5-, δ p-a D-f

Ä 8 § B I? I

O H II Ui Ui

II + J 8 CN CN

a ~ ö a a vo υ i υ u

III

o

X

X

r-i CN / Λ 3 i i i ~ \ y ie <N CN CN ro

H tr g g S g A

K I II'- 'u / \ tn tn r- cd _g tj · n · n ·

-H O

M ·· j

(1) C

65258

Example 49 (a) (6R / 7R) -3-Benzoyloxymethyl-7- [2- (2-t-butoxycarbonylprop-2-yl-oxyimino-2- (fur-2-yl) -acetamide] -3-cef-3- Eem-4-carboxylic acid (syn isomer)

A suspension of 313 mg of phosphorus pentachloride in 4 ml of dry dichloromethane at -10 ° C was treated with 0.7 ml of N, N-dimethylacetimide and 446 mg of 2- (2-t-butoxycarbonylprop-2- yloxyimino) -2- (fur-2-yl) -acetic acid (syn-isomer) in portions. The resulting solution was stirred at -10 ° C for 30 minutes, treated with ice (about 1 g) and stirred at below 0 ° C for 15 minutes. The organic phase was added dropwise to a solution of 502 mg of (6R, 7R) -7-amino-3-benzoyloxymethylcef-3-em-4-carboxylic acid in 2 ml of Ν, Ν-dimethylacetamide and 2 ml of acetonitrile containing 1 .09 ml of triethylamine, below 0 ° C. The solution was stirred at 0-5 ° C for 2 hours, 0.3 ml of methanol was added and stirring was continued for 15 minutes. The solution was diluted with 20 ml of dichloromethane and washed successively with 2N hydrochloric acid, water and brine, dried and evaporated to a gum (1.02 g). This solution of the resin in ethyl acetate (6 mL) was added dropwise to stirred petroleum ether (b.p. 40-60 ° C, 200 mL) to give the title acid as a cream powder (769 mg, 83%); C & J-q + 26 ° (c = 1.05, acetone), λ (pH 6 phosphate buffer) 233.5 nm (δ 19,200) and 274 nm (f '18,600), λ max (Nujol) 1790 cm-2 (γ2-lactam), T (dg-DMSO) values 0.29 (d, J8Hz, NH), 4.03 (dd, J8 and J5Hz, 7-H), 8.50 (s, C (CH3) 2) and 8.58 (s, C (CH3) 3 · (b) (6R, 7R) -3-benzoyloxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) ) -2- (fur-2-yl) acetamido] cef-3-em-4-carboxylic acid (syn isomer)

A solution of 620 mg of (6R, 7R) -3-benzoyloxymethyl-7- [2-t-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) -acetamide-7-cef-3-emine- 4-Carboxylic acid (syn-isomer) in 0.6 ml of anisole and 3 ml of trifluoroacetic acid was stirred at 20 ° C for 25 minutes. The solution was partitioned between ethyl acetate and aqueous sodium bicarbonate and the pH was adjusted to 8 by the addition of solid sodium bicarbonate. The aqueous phase was separated, washed with ethyl acetate, covered with ethyl acetate and the pH was adjusted to 54 65258 1.5 by the addition of concentrated hydrochloric acid. The organic phase was separated, washed successively with water and brine, dried and evaporated to an oily foam (584 mg). A solution of this foam in ethyl acetate was added dropwise to stirred petroleum ether (b.p. 40-60 ° C) to give the title dicarboxylic acid as a white solid (384 mg, 67%), δ = + 30.4 ° (c = 1.0 , acetone), λ max <PH 6 phosphate buffer) 234 nm (£ 19,700) and 273 nm (£ 18,450),>? (Nujol) 1784 cm -1 (β-lactam), δ (d 2 -DMSO) values 0.03 (d, J 8 Hz, NH), 4.07 (dd, J 8 and J 5 Hz, 7-H), and 8.50 (s, c (ch3) 2).

Example 50

Potassium (6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamide] -3-pyridiniummethyl-cef-3-em-4-carboxylate (syn-isomer)

A mixture of 3.26 g of (6R, 7R) -3-acetoxymethyl-7- [5-carboxymethoxyimino-2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid (syn isomer), 5.25 g of potassium thiocyanate, 0.72 ml of pyridine and 2 ml of water, were stirred and heated for 40 minutes at 80 ° C. * The cooled reaction mixture was diluted with 5 ml of water and adsorbed onto a column containing XAD-2 resin ( 500 g). The components of the reaction mixture were eluted first with water and then with aqueous ethanol (1: 3) and collected using an automatic fraction collector. Fractions whose ultraviolet absorption corresponded to the desired product were combined and the solution was evaporated to dryness in vacuo below 35 ° C. The crude product (600 mg) was crystallized from aqueous acetone (1: 9) to give the title compound (295 mg), λmax PH® phosphate buffer) at 261 nm (S 19,000), 275 nm (£ 18,400).

Example 51

Potassium (6R, 7R) -7-Z2-carboxyprop-2-yloxy-amino-2- (fur-2-yl) acetamide [3-7-pyridiniummethyl-cef-3-em-4-carboxylate (syn isomer)

A mixture of 4.0 g of (6R, 7R) -3-acetoxymethyl-7- [2- (carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetaroid] cef-3-ene-4- carboxylic acid (syn isomer), 4 ml of pyridine and 40 ml of water, 55 65258 were heated at 80 ° C for 1 hour, after which the mixture was allowed to cool. The cooled mixture was diluted with water (50 ml) and extracted five times with methylene chloride (25 ml) and the combined organic extracts were washed with water · The combined aqueous phases were evaporated in vacuo below 35 ° C to a volume of about 50 ml and acidified to pH 2 with 2N hydrochloric acid. The precipitate was removed by filtration, the filtrate was adjusted to pH 6.5 with potassium bicarbonate, and the solution was concentrated in vacuo below 35 ° C to a volume of about 40 mL. The product was purified on a column of XAD resin (500 g) eluting with water followed by aqueous ethanol (1: 3). Fractions with ultraviolet absorption corresponding to the product were combined and evaporated to dryness in vacuo below 35 ° C to give the title compound (880 mg), λ max (water) 261 and 277 nm (£ 17,000 and 16,950).

Example 52

Sodium (6R, 7R) -7- [2- (carboxyprop-2-yloxyimino) -2-fur-2-yl) acetamido] -3-pyridinium methylcef-3-em-4-carboxylate (syn isomer)

A mixture of 50.0 g of sodium iodide, 15.5 ml of water and 14 ml of pyridine was heated to 80 ° C and stirred vigorously while 14.4 g of (6R, 7R) -3-acetoxymethyl 7- [2- (Carboxyprop-2-yloxyimino-2- (fur-2-yl) acetamide] -ceph-3-em-4-carboxylic acid (syn-isomer) The mixture was stirred at 80 ° C for 55 minutes and then cooled and diluted to a volume of about 400 ml with water, 0.1 N sodium hydroxide was added to pH 6.5 and the solution was concentrated under reduced pressure at less than 40 ° C to a volume of about 100 ml, the resulting solution was diluted to a volume of about 400 ml with water, 0 , 3 ml of methyl isobutyl ketone and the stirred solution were acidified with 2N hydrochloric acid (15 ml) to pH 1-2, collected, washed with water and discarded, the filtrate and washings were treated with 2N hydrochloric acid (about 10 ml) and was extracted with ethyl acetate and the organic layer was re-extracted with a small amount of water the matter was adjusted to pH 6 with n-sodium hydroxide (about 43 ml) and evaporated under reduced pressure below 40 ° C to a volume of about 75 ml. The solution was passed to a 56,6258 bottle of XAD resin (700 g, 42 cm x 5.5 cm) previously washed with water (2 liters). The column was eluted with water, whereupon the fractions were collected automatically and their ultraviolet spectra were determined. After removal of inorganic salts and impurities, the eluent was changed to a mixture of ethanol and water (1: 4). Fractions with ultraviolet absorption of the desired product were combined, concentrated under reduced pressure below 40 ° C and lyophilized. The product was dried over phosphorus pentoxide in vacuo to give the title salt (4.10 g, / Gt7D + 10.5 ° (c = 1.00, water), Λ (pH 6 buffer) at 261.5 and 278.5 nm (£ 20,100, 19,200), max (Nujol) 1770 cm -1 (β-lactam), δ (D 2 O, 100 MHz) values 1.03, 1.43, 1.91 (pyridinium protons), 4.12 ( dd, 7-H) and 8.50 (s, C (CH 3) 2).

Examples 53-57

As described in Example 52, (6R, 7R) -3-acetoxymethyl-7- [2- (carboxy-Rq-oxyimino) -2- (fur-2-yl) acetamide] cef-3-em-4-carboxylic acid ( syn isomers) the acetoxy group was removed by treatment with pyridine or substituted pyridine in aqueous sodium iodide for 45-60 minutes at 20 ° C. The products were purified as the sodium salt by XAD-2 chromatography and their physical properties are shown in Table 7.

57 6 5 2 5 8 cn O o ro · »tr - co oi m oo co co ^ £ * m co co cn co g <r uo o r- o __'__

^ «Ή 10» H

¢) 10, -H * - «* - ♦ * - * (N ^ ** Q> i ·. - * tJ * rj t> K 1 '' '1 i« -

4J „^ O

^ tn o i

iö x r- r-, 1 L

h «i ^ 52 i e ε% ^ ^ <> u ~ o o o o o o o 0 o o o o o m • in * -h h ^ in

CL U) I

Γ * · ςΤ ^ <T CT «T CT» 00

J «H H H tH rH« H rH

/ —L p -; - ------- m V \ _fi ta 3 m ui in in ui \ / «I 0 | ^ Λ '' '_ \ L Λ! - in -H O CO o oo oo «----- z« j a W iö r- i r- vero o oo

g g Q, es CN CM CM CN CM CN

- »S Ό> 1 IN ____ - a -> - \ o ~ / ° -h ~ ΐ 'f p o

e s O d Q I I · · _ N

Z ^ r ^. 3 o * \ XS 3 5 "- _ _ _ \ o. On Pnon I ym * o« J <oo λ «» c H c I *? * @ (O) CoT3 (A) Θ cn + 2 + 2 + 2 +2 ta cn cn cn cn

· "Υ S S 8 S

o 1 3 i 3 I CN I \ / \ i <0 CN ^ CM I l \ /

e-ι tr ta ro - * k P X

1 o a N! o '/ V o i --- 1 a! • H O j tn „m td · m ιο r ~ (o p m in m m m.

__) I 58 65258 f

Example 58 (6R, 7R) -7- [2- (2-Carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamide] -3-pyridazinium methylcef-3-em-4-carboxylic acid -trifluoroacetate (syn-isomer) (a) A suspension of 1.51 g of diphenylmethyl- (1S, 6R, 7R) -3-bromomethyl-7- [2- (2-t-butoxycarbonylprop-2-yloxy) imino) -2- (fur-2-yl) acetamido / cef-3-em-4-carboxylate-1-oxide (syn-isomer) in 1 ml of Ν, Ν-dimethylformamide, treated with 400 mg of pyridazine . The mixture was stirred for 2 hours at 25 ° C to give a clear solution which was slowly diluted with ether (50 mL) with stirring. The resulting precipitate was filtered, washed with ether and dried to give diphenylmethyl- (1S, 6R, 7R) -7- [2- (2-t-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetamide-3-3-pyridazinium methylcef-3-em-4-carboxylate-1-oxide bromide (syn-isomer) as a red powder (1.59 g, 94%), [+] D + 13 ° (c = 1.07, dimethyl sulfoxide), λmax (ethanol) 277 nm (£ 21,200); (Nujol) 1790 cm-1 (β-lactam), δ (dg-DMSO) value 1.21 (d, J 8Hz, NH), 3.76 (dd, J 4 and 8Hz, 7-H) , 8.51 (s, C (CH 3) 2 and 8.61 C (CH 3) 3).

(b) 1.49 g of the product of (a) in 5 ml of N, N-dimethylformamide at -10 ° C were treated with 1.33 g of potassium iodide followed by 0.28 ml of acetyl chloride. The mixture was stirred for 1 hour while the temperature slowly rose to 0 ° C and then added dropwise to a stirred solution of 1 g of sodium metabisulfite in 50 ml of water. The resulting suspension was stirred for 10 minutes and the solid was filtered off, washed with water and dried over phosphorus pentoxide to give a light brown powder (1.28 g). This material was dissolved in 20 mL of acetone / ethanol (9: 1) and applied to a column of Deacidite FF resin (trifluoroacetate form, 15 cm x 2.5 cm column) eluted with the same solvent mixture. The eluate fractions containing ultraviolet light were combined and evaporated and the residue triturated with ether to give diphenylmethyl- (6R, 7R) -7- [1,2- (2-t-butoxycarbonylprop-2-yloxyimino) -2- (fur 2-yl) acetamide-β-3-pyridazinium methylmethyl-ceph-3-em-4-carboxylate trifluoroacetate (syn-isomer), (1.24 g, 82%), EO-? -20 ° (c = 0.76 dimethyl sulfoxide ), 59 6 5 2 5 8 \ kg (ethanol) 278 nm (£ 18,300), V makg (Nujol) 1780 cm -1 1780 dll ', T (dg-DMSO) value 0.30 (d, J 9Hz, NH), 3.95 (dd, J 5 and 8 Hz, 7-H), 8.55 (s, C (CH 3) 2) and 8.59 (s, CiCH 2).

(c) 1.13 g of the product of (b) mixed with 1.5 ml of anisole were treated with 6 ml of trifluoroacetic acid for 5 minutes at 5 ° C and then for 55 minutes at 20 ° C. The solution was evaporated in vacuo, the residue was taken up in ethyl acetate and the evaporation was repeated. The resulting gum was triturated with ether to give the crude product as a light brown material which was filtered, washed with ether and dried. It was extracted with water (3 x 150 ml), the extracts filtered, washed with ethyl acetate and then ether and finally freeze-dried. The combined residues were triturated with ether to give the title salt as a white powder (586 g, 72%), λ max = + 48 ° (c = 0.98, dimethyl sulfoxide), λmakg (pH 6 phosphate buffer) 277 nm (£ 18,100), V max (Nujol) 1776 era 1 (β-lactam), δ (dg-DMSO) 0.37 (d, J 8Hz, NH), 4.09 (dd, J 5 and 8Hz, 7-H) and 8, 53 (s, C (CH 3) 2).

Examples 59-64

The trifluoroacetate salts shown in Table 8 were prepared by reacting 3-bromomethyl ester with a tertiary base (or quaternary mercaptan obtained according to Example 61), reducing the sulfoxide, and removing both protecting groups as described in Example 58. The starting material was prepared as follows:

A solution of 5.20 g of phosphorus pentachloride in 60 ml of dry dichloromethane at -10 ° C was treated with 12 ml of N, N-dimethylacetimide and then 6.43 g of 2- (2-t-butoxycarbonylpropionate) were added portionwise. 2-yloxyimino) -2- (fur-2-yl) -acetic acid (syn isomer). The solution was stirred for 15 minutes at -10 ° C and then ice (14 g) was added slowly and the temperature was allowed to rise to 0 ° C over 10 minutes. The organic layer was separated and a suspension of 10.62 g of diphenylmethyl (1S, 6R, 7R) -7-amino-3-bromomethylcef-3-em-4-carboxylate-1-oxide hydrobromide 80 was added dropwise. in dichloromethane containing 15 ml of propylene oxide at 0 ° C. The mixture was stirred for 1 hour, 60 65258 at which time the temperature rose to 20 ° C and the suspension clarified. The resulting yellow solution was washed with 2.5% aqueous sodium bicarbonate (50 ml) and then with 2N hydrochloric acid (50 ml), after which the solution was dried and evaporated to a yellow oil. This material in ethyl acetate (20 mL) was added dropwise to stirred petroleum (b.p. 40-60 ° C) to give a gummy precipitate. The supernatant was decanted off and the gum was chromatographed on a silica gel column eluting with dichloromethane containing 0-10% acetone. The eluate fractions containing the main product were combined and evaporated to a foam. Trituration with cyclohexane gave diphenylmethyl (1S, 6R, 7R) -3-bromomethyl-7- [2- (2-t-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetamido] cef- 3-Eemi-4-carboxylate-1-oxide (syn isomer) as a pale yellow microcrystalline powder (13.61 g, 90%), ε = -22 ° (c = 1.0, dimethyl sulfoxide), λ makg (ethanol) 281 nm (ε 22,200), λmax (CHBr3) 1800 cm-1 (β-lactam), T (dg-DMSO) value 1.26 (d, J 8Hz, NH), 3.86 ( dd, J 4 and 8 Hz, 7-H), 8.51 (s, C (CH 3) 2) and 8.61 (s, CiCH 2).

----------------------- 61 ö 5 2 5 8 tr _

Ci LO ^ CO 10.

* m tn m ^ | CO 00 CO 00 3 g i ° ---_ m o 10 g * - »^ * £>? >, Ί ^ Ί °.

• 0 ° Tl * TT

CO ^ ro ί · o o '

»» Tl · CN

x O ° 'x o ° «J - • * J _> * 2 m ^ cn o

iS J! .- · ?, f "00 00 S

* «I 3 t- r- r- 1 n C 5! T-4 rt rt ^ ^ «> ° w o o o o g o Q O O g vo co cn m cn

^ rt Tf 00 rt CN

I CM rt rt CN CN

/ V_öM ΓΤ "p —V- * w 3 TJ -s> £ -, sai ^. C i 'd ·

_ s Λ / Cfi CN

>> CM I UM. ________

~ M ^ \ O

/ v υ O O

/ ° ° L - Ln m ~ / “n o o_“ z ^, ° »s? a LO 5 rt »n

8 / $ S

/ = z -: is $ ---—

/ 10 Q MJ

Ή 3 (0 \ 0 r-N (0 "o 3 m + J = = I y ω -h ai ^, / n m _____- μ (0__ CN ®_ tn ro

I / - \ + frf S

- isr Ö <§c (s) 4s 2f + ^ 2 W +2

CN CN CN CN

»S S g S

O 'x 3 i — 1 3

<0 ro CN CN CN

H o · _ - - n; ro ro ro ro «33 aa n: υ υ υ uoou υ ___ A __ / \ _ / \ a -ho O 'o H cn ui m vo vo vo o> c __i 62 6 5 2 5 8 ö * O m, oi m vn

H K

Ti 00 oo 3 o o tr- - - - - - ———- · - · -

O

“* 2

\ 0 * * -H

Ό “• t>“ 00 o x Γ0 ° o Ή _ · § tO ~ ^ 0V O -Π ^ »H RS ί 3 Γ" "* p" i c G r- r-

ζΟ L> - '* - * «-H

o o o o o o P, 0J ^ ^ I vo ω oo

I »H» H

/ \ _ÖN i ^ ----

«0 N) —υ« D

\ / tn a λ; tn

te - Λ_ z ^ tn H

<0 3 M in ^ rj.

• S S ft cn γ ~ r-

J C I CN CN CN

-. x Λ / vo> i ra —--.

- ') - \ 8 --- / O tr _

X '* f O O O

w * o o '52 σι cn S s «' n 5 · t" co 8 /. ^ £ 1 | vh ^ -

v Q Ήi ID

O 3 M-l 4-1 s L · / W * W 0)

Ni / vt tn _____40 m_ n aa i - <a ^ +2 + 2 ^

_ Ό CN CN

w i 'aa k o o O --—-—

M

X

3 * Ή j 3

«CN

E-ι CT ro

: “S” S

___ Λ s "„ ^

• HO c ° VO

tn vo tu c 63 65258

Example 65 (6R, 7R) -3- (Benzotriazol-1-ylmethyl) -7- [2- (2-carboxy-prop-2-yloxy-imino) -2- (fur-2-yl) -acetamide] -3-cef-3- Eem-4-carboxylic acid (syn-isomer) 1.51 g diphenylmethyl- (1X, 6R, 7R) -3-bromomethyl-7-62- (2-t-butoxycarbonylprop-2-yloxyimino) -2- (fur 2-yl) acetamide-7-ceph-3-em-4-carboxylate-1-oxide (syn-isomer) in 3 ml of N, N-dimethylformamide was stirred with 480 mg of benzotriazole for 4 days. The solution was diluted with dichloromethane and then washed twice with 2N hydrochloric acid; then the solution was dried and evaporated and the main product was separated from the residue by chromatography on a column of silica gel, eluting with chloroform containing 0-10% by volume of acetone. A mixture of 700 mg of the obtained intermediate, 2 ml of Ν, Ν-dimethylformamide and 665 mg of potassium iodide was treated at -10 ° C with acetyl chloride (0.14 ml). The suspension was stirred for 1.25 hours and allowed to slowly warm to 0 ° C and then added dropwise to water (40 ml) containing sodium metabisulphite (0.5 g). The precipitate was filtered, washed with water, dried and purified by chromatography on silica gel eluting with dichloromethane containing 0-3% by volume of acetone.

520 mg of the obtained diester together with 0.5 ml of anisole were treated with 2 ml of trifluoroacetic acid for 1 hour at 25 ° C. The solution was then added dropwise with stirring to a saturated aqueous solution of sodium bicarbonate (50 ml) and ice (25 g). The mixture was stirred and then ethyl acetate was added. The aqueous layer was separated and acidified with ethyl acetate to pH 2. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried and concentrated to an oil which was added dropwise to stirred petroleum (b.p. 40-60 ° C). The white precipitate was filtered, washed with petroleum and dried to give the title dicarboxylic acid as a white powder (350 mg, 31%), = + 37 ° (c = 1.02, dimethyl sulfoxide), λmax 3 (pH 6 phosphate buffer) 269 nm (8 23 600), (Nujol) 1780 cm-1

(β-lactam), δ (dg-DMSO) values 0.40 (d, J 8Hz, NH), 4.11 (dd, J

5 and 8Hz, 7-H) and 8.53 (s, C (CH 3) 2).

Example 66

The compound shown in Table 9 was prepared from the nucleophile using the method of Example 65.

--- - · r ~ cr

06 CN

λ in N * $ 00 o o

O

w X 1-

0 II

1> 1 * 1 • 0 ° ^ (J 't ““ X * * o Ή * -.

«* · Η <—> x w ο Js; »H (Q I D π ιο π 55 o ο. Ω ° _ | - 5 Γγ-ζ" "71" ~ \ / ιλ x- _ Λ_ z a: * - οι ή cn «3 w r ~ · I E g a cn

- * vO

> 1 (N ---- - '7— \ s ---- * I Ä · 0

~ * O Q O CN

8 /. g I

^ -v— ζ / _s__; _

Pa # 25

CN

S

CTi Q - —- a: a:

3 * —I

«_T * H O '' Ί 05 s

O

/ \

B

-WO

in

(DC 'O

65 65258

Example 67

Pivaloyloxymethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -7-ceph-3-em-4-carboxylate (syn-isomer)

A stirred solution of 8.50 g of sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2-t-butoxycarbonylmethoxyimino) -2- (fur-2-yl) acetamethyl] -ceph-3-emetic acid 4-carboxylate in 100 ml of dimethylformamide, treated with chloromethyl pivalate (4.68 ml). The solution was stirred at room temperature for 25 hours and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed successively with brine, saturated sodium bicarbonate solution, and brine, and then dried and evaporated to a small volume. The residue was added slowly to stirred petroleum (b.p.

40-60 ° C, 1.5 L) and the precipitate was collected, washed with white spirit and dried in vacuo to give a mixture of the t-butyl ester of the title compound and its Δ analog (8.32 g), ratio 2 3 Δ: Δ about 3: 2 according to PMR).

A solution of this mixture of isomers (8.1 g) in dichloromethane (75 ml) was cooled to -40 ° C and stirred while m-chlorobenzoic acid (2.41 g) in dichloromethane (65 ml) was added dropwise. The solution was stirred at -40 ° C for 1.25 hours and additional m-chlorobenzoic acid (1.2 g) in dichloromethane was added. After stirring for an additional 40 minutes, the solvent was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate solution was washed with sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to a yellow foam (9.77 g). This was triturated with ether and the resulting yellow material was filtered, washed with ether and dried in vacuo to give 7.27 g of t-butyl ester 1-oxide of the title compound.

A solution of 7.07 g of this sulfoxide and 14.34 g of potassium iodide in 100 ml of dimethylformamide was covered with an ice-salt bath and stirred while 3.08 ml of acetyl chloride in 15 ml of diraethylformamide was added. The solution was stirred for 3.5 hours and acetyl chloride (1.54 ml) in dimethylformamide was added. The solution was stirred for 1 hour and partitioned between sodium urea metabisulfite solution and ethyl acetate. The organic layer was washed with sodium metabisulfite solution and water and then dried and evaporated to a small volume. The resulting solution was slowly added to excess stirred petroleum (b.p. 40-60 ° C) and the resulting precipitate was collected, washed with white spirit and dried in vacuo to give pivaloyloxymethyl- (6R, 7R) -3-carboamoyloxymethyl-H-7- [2- ( t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -ceph-3-eme-4-carboxylate (syn isomer; 7 g), λmax (ethanol) 277 nm (λ, 16,540) , Omajts (Nujol) 1782 cm -1 (β-lactam), 1740 and 1720 cm -1 (CONH 2), T (d 6 -DMSO) values 0.25 (d, NH), 3.40 (s, NH 2) and 8 , 8 (s, C (CH 3) 3).

1.0 g of this diester was dissolved in 5 ml of trifluoroacetic acid and this solution was stirred at room temperature for 15 minutes and then diluted with ether, washed with water and evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution, and the organic layer was re-extracted with sodium bicarbonate solution. The combined aqueous layers were washed with ethyl acetate, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to an oil. This was dissolved in a small volume of ethyl acetate and slowly added to excess stirred petroleum (b.p. 40-60 ° C). The white precipitate was collected, washed with white spirit and dried in vacuo to give the title ester (0.645 9) λmax (ethanol) at 278 nm (6 16,900), 1? max (Nu-joi) 1778 cm -1 (γS-lactam), T (dg-DMSO) values 0.25 (d, NH), 2.16, 3.26, 3.38 (fur-2-yl) protons) and 4.10 (dd, 7-H).

The starting sodium salt was obtained as follows: 2.58 ml of triethylamine and 2 drops of dimethylformamide were added to a solution of 5 g of 2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn-isomer) in 200 ml of dry dichloromethane. The stirred solution was cooled to 0 ° C and 1.58 ml of oxalyl chloride was added. The solution was stirred for 1 hour and then evaporated. The residue was suspended in acetone (150 ml) and added over 0.5 hours to a stirred ice-cold solution of 5.08 g of (6R, 7R) -3-carbamoyloxymethyl-7-aminoceph-3-enem-67 65258 4-carboxylic acid in 150 ml: in acetone and 300 ml of water containing 3.74 g of sodium bicarbonate. The reaction mixture was stirred for 1 hour and evaporated to remove acetone. The aqueous residue was acidified with ether (pH 1.8) with dilute hydrochloric acid and the layers separated. The aqueous layer was further extracted with ether and the combined extracts were washed with water and brine, dried and evaporated to give (6R, 7R) -3-carbamoyloxymethyl-7- [2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acet-amido-7-cef-3-em-4-carboxylic acid (syn-isomer), Λ-max 6 phosphate buffer) 274.5 nm (S 17 520), Ό (CHBr) 1785 (β-lactam), 1686 and 1530 cm -1 (CONH), T (d 6 DMSO) values 0.29 (d, NH), 4.19 (dd, 7-H) and 4.79 (d, 6-H).

A stirred solution of 0.02 g of the above acid in 40 ml of acetone was treated with a solution of 2.86 g of sodium 2-ethylhexanoate in 40 ml of acetone. The resulting solution was added slowly to stirred white spirit (1600 mL, b.p. 40-60 ° C) and the precipitate was collected, washed and dried in vacuo to give sodium (6R, 7R) -3-carbamoyloxymethyl-7- (2-butoxycarbonylmethoxy). -imino-2- (fur-2-yl) acetamide-7-ceph-3-em-4-carboxylate (syn-isomer) (8.71 g), λmax (pH 6 buffer) 274.5 nm (S17 650),? Max (Nujol) 1755 [β-lactam) and 1608 cm -1 (CO 2 -), 1 C (d 6 -DMSO) values 0.4 (d, NH), 4.4 (dd, 7- H) and 4.98 (d, 6-H) Example 68 (6R, 7R) -3-Carbamoyloxyethyl 11-7- (Z) - (1-carboxycyclopropyloxyimino) -fur-2-yl asetamido7kef-3-em-4-carboxylic-oksyy1ihappo

0.39 ml of oxalyl chloride at 0 ° C was added to a solution of 1.1 g of (tert-butyloxycarbonylcyclopropyl) oxyimino-fur-2-ylacetic acid in 25 ml of dichloromethane and 3 drops of Ν, Ν-dimethylformamide and 0 , 52 ml of triethylamine. The solution was stirred at room temperature for 1 hour and evaporated to dryness. The residue was dissolved in 20 ml of dry acetone, and then poured into a mixture of 1.035 g of (6R, 7R) -3-carbamoyloxymethyl-7-amino-ceph-3-em-4-carboxylic acid and 784 mg of sodium hydrogencarbonate dissolved in 25 ml. in water, and 5 ml of acetone. The mixture was stirred at room temperature for 4 hours, after which the acetone was evaporated off under reduced pressure. The residue was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was separated and washed with water, dried and evaporated. 1.95 g of (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) - (1-t-butyloxycarbonylcyclopropyloxyimino) -fur-2-yl-acetamide-dichloro-3-em-4-carboxylic acid were obtained in yellow. foam. The obtained compound was treated with a mixture of 1.95 ml of anisole and 5.07 ml of trifluoroacetic acid at room temperature for 20 minutes. The solvents were then evaporated off with toluene and the residue was treated with a mixture of ethyl acetate and aqueous sodium hydrogen carbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 1.789 g of a yellow foam. Crystallization twice from ethanol gave the title product as a white crystalline solid (540 mg), = + 35.3 ° (c = 1.00, dimethyl sulfoxide), λ max pH 6 phosphate buffer) 276 nm (0 18 400).

Example 69 a) (6R, 7R) -3-Acetoxymethyl-7 - [(Z) - (1-carboxycyclopropyloxyimino) -fur-2-yl-acetamido] ceph-3-em-4-carboxylic acid

At 0 ° C, 1.05 ml of oxalyl chloride was added to a solution of 2.95 g of (1-t-butyloxycarbonylcyclopropyl) oxyimino-fur-2-ylacetic acid, dissolved in 70 ml of dichloromethane and 10 drops p, Ν -dimethylformamide and 1.4 ml of triethylamine, and stirred for 1 hour without cooling the mixture. Evaporated to dryness, the residue was treated with acetone (60 ml) and filtered. The filtrate was poured into a solution of 2.72 g of (6R, 7R) -3-acetoxymethyl-7-amino-ceph-3-em-4-carboxylic acid and 2.1 g of sodium bicarbonate and 70 ml of water and 15 ml of acetone. The mixture was stirred at room temperature overnight, after which the acetone was evaporated off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phase was then extracted with 5% sodium hydrogen carbonate solution, after which it was poured off. The aqueous phase was acidified with 2N hydrochloric acid, whereupon Ethyl acetate was added and stirred. The aqueous phase was then separated and extracted once more with ethyl acetate. The organic phases were combined, washed with water, dried and evaporated to dryness. 5.08 g of (6R, 7R) -3-acetoxymethyl-7 - [(Z) - (1-t-butyloxycarbonylcyclopropyloxyimino) fur-2-yl-acetamido / cef-3-em-4-carboxylic acid were obtained in the form of a light brown product. The resulting material was treated with a mixture of anisole and trifluoroacetic acid (5.1 mL vs. 13.3 mL) at room temperature for 20 minutes, the solvents were evaporated with toluene and the brown gum was triturated with ether. the title compound as a light brown foam (4.48) (max) (Nujol) 3260-2200 (OH), 1788 (γS-lactam), 1720 (CO 2 H), 1680 and 1536 cm -1 (CONH), (dg-DMSO): 0.37 (1H, d, J 8Hz, NH), 2.09 (1H, s, 5'-H), 3.22 (1H, d, J 3Hz, 3 * -H), 3.33 (1H, dd, J 2 and 3Hz, 4'-H), 4.09 (1H, dd, J 5 and 8Hz, 7-H), 4.75 (1H, d, J 5Hz, 6-H), 4.94 and 5.28 (2H, ABq, J 12Hz, -CH 2 OAc), 6.38 (2H, d, J 6Hz, -S-CH 2 -), 7 , 93 (3H, s, OCOCH 3) and 8.4-8.8 (4H, m, cyclopropyl protons).

b) Sodium salt of (6R, 7R) -3-acetoxymethyl-7 - [(Z) - (1-carboxycyclopropyloxyimino) -fur-2-yl-acetamido] ceph-3-em-4-carboxylic acid

984 mg of (6R, 7R) -3-acetoxymethyl-7- (Z) - (1-carboxycyclopropyloxyimino) fur-2-yl-acetamide / cef-3-em-4-carboxylic acid were dissolved in 15 ml of acetone and 700 mg of sodium octoate dissolved in acetone (10 ml) were added in small portions. After stirring for 20 minutes, the precipitate formed was filtered off (under nitrogen) and washed with acetone. The precipitate was sintered in vacuo and removed with acetone (50 mL); the resulting acetone suspension was stirred for 30 minutes, then filtered.

758 mg of the title compound, A., (pH 6 phosphate-nicotinic droplet buffer) were obtained at 276 nm (c 19,300) and 233 nm (£ 10,600), max (Nu3o1) 3190 (NH), 1765 (yi -1 actazone). ), 1740 (acetate) and 1680 cm -1 (carboxylate).

70 65258

Example 70 (6R, 7R) -7- [2- (1-Carboxycyclopropyloxyimino) fur-2-yl-acetcunido] -3- (1-pyridiniummethyl) cef-3-em-4-carboxylic acid, sodium salt

To a stirred mixture of 13.0 g of sodium iodide, 3.9 ml of water, 3.5 ml of pyridine at 80 ° C was added 3.3 g of (6R, 7R) -3-acetoxymethyl-7 - / z (1-carboxy-cyclopropyloxy-imino) fur-2-yl-asetamido7kef-3-em-4-carboxylic acid. Stirring was continued at 80 ° C for 1 hour, then the mixture was allowed to cool and diluted with water to a volume of 100 ml. The pH was adjusted to 6.5 with dilute sodium hydroxide and the solution was evaporated to a small volume under reduced pressure below 40 ° C. About 100 ml of water and 2 drops of methyl isobutyl ketone were added to the residue, while stirring while adjusting the pH to 2 with dilute hydrochloric acid. The precipitated light brown solid was removed by filtration and the filtrate was extracted 3 times with ethyl acetate. The ethyl acetate extracts were washed with water, after which they were poured off; the washings were combined with the aqueous phase. Dilute sodium hydroxide was added to the aqueous solution in such an amount that the pH rose to 6.0, and the solution was evaporated to a small volume. It was diluted with 50 ml of water, and the solution was poured onto a column of 300 g of XAD-2 resin. Eluted first with water and then with 20% ethanol solution. Fractions containing the desired product were combined (characteristic UV absorption) and evaporated to a small volume. The solution was treated with activated carbon, adjusted to pH 6.5, and lyophilized; 425 mg of the title compound were obtained, λ (λg (pH 6 phosphate buffer) 260 nm (δ 16,700) and 280 nm (δ 16,600), λ (100 MHz, D 2 O): 1.06, 1.43 and 1, 94 (pyridinium protons), 2.34, 3.13 and 3.39 (fur-2-yl protons), 4.18 (d, J 4 Hz, 7-H), 4.73 (d, J 4 Hz, 6-H), 4.42 and 4.63 (ABq, J 14 Hz, CH 2 N®), 6.38 and 6.81 (ABq, J 18 Hz, 2-CH 2) and 8.70 (broad d, -CH2CH2 ~).

I '71 65258

Example 71 (6R, 7R) -7- (1Z) -2- (1-Carboxycycloprop-1-yloxyimino) -2- (fur-2-yl) acetamide-N- (3-methyl-1, 3,4-Thiadiazol-2-yl) -thiomethyl} -cef-3-em-4-carboxylic acid 298 mg of 2- (1-t-butoxycarbonylcycloprop-1-yloxyimino) -2- (fur-2-yl) acetic acid 3 were dissolved. To 5 ml of dichloromethane (3.5 ml) was cooled to 0 ° C and 0.14 ml of triethylamine was added followed by 0.09 ml of oxalyl chloride and 1 drop of N, N-diraethylformamide. The mixture was stirred at 0-5 ° C for 1 hour and then evaporated to dryness. The residue was dissolved in acetone (about 10 ml) and after filtration the solution was added slowly (about 30 minutes) at 0 ° C to a stirred solution of 346 mg of (6R, 7R) -7-amino-3- (η 5 -methyl). 1,3,4-Thiadiazol-2-yl) thiomethyl-7-ceph-3-em-4-carboxylic acid and 210 mg of sodium bicarbonate dissolved in a mixture of water (20 ml) and acetone (10 ml). After stirring for another 15 minutes, the temperature of the solution was allowed to rise to 10 ° C. Washed with ether, added 100 mL of a mixture of ether and ethyl acetate (1: 1), and acidified with concentrated hydrochloric acid, followed by filtration. The organic phase of the filtrate was washed with brine and dried over magnesium sulfate; evaporated to dryness to give 574 mg of (6R, 7R) -7- (Z) -2- (1-t-butoxycarbonylcycloprop-1-yloxyimino) -2- (fur-2-yl) -acetamido-7- 3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl] cef-3-em-4-carboxylic acid as a yellow foam. A portion of the resulting material was treated with a mixture of anisole (0.1 mL) and trifluoroacetic acid (2 mL) at 24 ° C for 5 minutes. The solvents were evaporated off with ethyl acetate and the residue was treated with a mixture of 3% sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase was separated and washed with ethyl acetate, then a mixture of ether and ethyl acetate (1: 1) was added and acidified with concentrated hydrochloric acid. The organic phase was washed with brine and dried over magnesium sulfate? evaporated to dryness to give 438 mg of a light brown foam. The resulting material was triturated with a mixture of ether and gasoline (1: 3) to give 354 mg of the title compound as an off-white crystalline solid, λ = -103 ° (c = 0.81, acetone), λ max 6 phosphate buffer). 279 nm (δ 25,200).

72 65258

Example 72 (6R, 7R) -7 - [(Z) -2- (1-Carboxycycloprop-1-yloxyimino) -2- (fur-2-yl) acetamido] -3- (1-methyltetrazol-5-ylthio) methyl) ceph-3-em-4-carboxylic acid

296 mg of 2- (1-t-butoxycarbonylcycloprop-1-yloxyimino) -2- (fur-2-yl) acetic acid were dissolved in dichloromethane (3.5 ml) and 0.14 ml of triethylamine and its addition were added at 0 ° C. then 0.09 ml of oxalyl chloride and 1 drop of Ν, Ν-dimethylformamide. The mixture was stirred at 0-5 ° C for 1 hour and then evaporated to dryness. The residue was dissolved in acetone (about 10 ml) and after filtration the solution was added slowly (30 minutes) at 0 ° C to a stirred solution of 330 mg of (6R, 7R) -7-amino-3- (1-methyltetrazol-5-ylthiomethyl). ) cef-3-eme-4-carboxylic acid and 210 mg of sodium bicarbonate and 20 ml of water and 10 ml of acetone. Stirring was continued for 5 minutes during which time the temperature of the mixture rose to 20 ° C, after which it was evaporated to half volume. 100 ml of a mixture of ether and ethyl acetate (1: 1) were added and acidified with concentrated hydrochloric acid (0.2 ml) and filtered. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to dryness to give 552 mg of (6R, 7R) -7- (1Z) -2- (1-t-butoxycarbonylcycloprop-1-yloxyimino) -2- (fur-2- yl) acetamido-3- (1-methyltetrazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid as a pale yellow foam. A portion of the resulting material (453 mg) was treated with a mixture of anisole (0.1 mL) and trifluoroacetic acid (2.0 mL) at 25 ° C for 5 minutes. The solvents were evaporated with ethyl acetate and the residue was treated with a mixture of 2% sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase was washed with ethyl acetate, then a mixture of ethyl acetate and ether (1: 1) was added and acidified with concentrated hydrochloric acid. The organic phase was separated and washed with brine, dried and evaporated to give 417 mg of a light brown foam; the material obtained was triturated with a mixture of ether and petrol (1: 3) to give 315 mg of the title compound as an off-white solid, ~ "* 72 ° (c» 0.67, acetone), <^ - ma] CS <PH 6 fos phosphate buffer) 278 nm (f 23 300).

73 6 5 2 5 8

Example 73 a) (6R, 7R) -3-Hydroxymethyl-7- [2- (1-t-butoxycarbonyl-cyclobut-1-oximino) -2- (fur-2-yl) -acetamido] -cef-3-eme -4-Carboxylic acid (syn-isomer) (6R, 7R) -3-acetoxymethyl-7- [2- (1-butoxycarbonylcyclo-but-1-oximono) -2- (fur-2-yl) acetamido] ceph-3 -em-4-carboxylic acid (syn-isomer (216.3 g) was dissolved in phosphate buffer (pH 7.6). The solution was degassed, Rhodosporidium toruloides CBS 349 cell suspension (prepared by the method described in DE 2 550 110) was added, and stirred for 23 hours at ambient temperature To the filtrate, methyl isobutyl ketone was added to the filtrate and acidified with concentrated hydrochloric acid (pH 2.5) The phases were separated and the aqueous phase was extracted once more with methyl isobutyl ketone. Addition of an organic base to this solution gave the salt of the title acid (yield corresponding to 173 g of acid), Έ (d, -DMS O) ar-

O

vot 5.72, 5.94 (2d, 12Hz, -CH 2 OH), 8.58 (s, C (CH 3) 3).

b) (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (1-carboxycyclobut-1-oximino) -2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid (syn-isomer) (6R, 7R) -3-hydroxymethyl-7- [2- (1-t-butyloxycarbonylcyclobut-1-oximino) -2- (fur-2-yl) -acetamide] -ceph-3- The salt of em-4-carboxylic acid (syn-isomer) (25.4 g) was added portionwise over 20 minutes to a stirred mixture of methyl isobutyl ketone (290 ml) and chlorosulfonyl isocyanate (89 ml) at -10 to -5 ° C. The resulting solution was stirred at -5 ° C for 20 minutes. Water (50 ml) was added and stirring was continued for 15 minutes with warming to 20 ° C. The phases were separated and the organic phase was washed with water (50 ml) and dried over magnesium sulphate. Addition of an organic base to this solution gave (6R, 7R) -3-carbamoyloxymethyl-7- [2- (1-t-butoxycarbonylcyclobut-1-oximino) -2- (fur-2-yl) -acetunido / cef- 3-Eemi-4-carboxylic acid salt (syn isomer) (corresponding to 26.4 g of acid). Z. (d 6 -DMSO) values 3.44 (s, -CONH 2), 5.06, 5.27 (2d, J 13 Hz, -CH 2 O), 8.55 (s, C (CH 3) 3). The product can be deprotected in the same manner as described in Example 25 to give the title compound.

74 65258

Example 74 (6R, 7R) -3-Carbamoyloxymethyl-7-Z2-carboxymethoxyimino-2- (fur-2-yl) -acetamido] cef-3-em-4-carboxylic acid (syn isomer)

In a similar manner to Example 73, (6R, 7R) -7- [4-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid (syn-isomer) was prepared. ) by enzymatic hydrolysis of the corresponding 3-acetoxymethyl compound. (6R, 7R) -7- [2-t-Butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -3-hydroxymethyl-cef-3-ether-4-carboxylic acid (syn-isomer) (7 , 23 g, as a salt with an organic base) was added to a stirred solution of chlorosulfonyl isocyanate (2.61 mL) in ethyl acetate (45 mL), initially at -25 ° C. After 45 minutes at -15 ° C, water (25 ml) was added at 0 ° C, and the mixture was stirred for 1 hour at ambient temperature. Sodium bicarbonate solution was added and the phases were separated at pH 7.5. The ethyl acetate extract was further washed with brine. The aqueous extracts were combined and acidified (pH 2) under ethyl acetate. The ethyl acetate phases were separated, washed with brine, dried and evaporated. The residue was dissolved in methyl isobutyl ketone (75 ml) and an organic base was added. The solid was collected by filtration and dried to give (6R, 7R) -3-carbamoyloxymethyl-7- [t-butoxycarbonylmethoxyimino-2- (fur-2-yl) -acetamide] cef-3-em-4 -carboxylic acid salt (syn isomer) (corresponding to 5.96 g of acid) .V values (dg-DMSO) 3.48 (s, NH) and 5.06 and 5.29 (2d, J 13 Hz, C ). The product can be deprotected in the same manner as described in Example 28 to give the title compound.

Example 75 a) Diphenylmethyl- (1S, 6R, 7R) -7- [Z-2- (1-butoxycarbonylcyclobut-1-yloxyimino) -2- (fur-2-yl) acetamido] -3- (1 -ethyltetrazol-5-ylthiomethyl) cef-3-em-4-carboxylate-1-oxide A cooled (-10 ° C) solution of diphenylmethyl- (1S, 6R, 7R) -Ί-β-2- ( 1-Butoxycarbonylcyclobut-1-yloxyimino) -2- (fur-2-yl) acetamido-3-bromomethylcef-3-em-4-carboxylate 6 5 2 5 8 1-oxide (0.165 g) in dry Ν, Ν- in dimethylformamide (0.4 ml), treated with 1-ethyltetrazolyl-5-thiol (0.026 g) followed by triethylamine (0.03 ml).

The solution was stirred at -10 ° C for 2 minutes, then allowed to warm to 25 ° C over 20 minutes. The reaction mixture was partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (30 ml). The organic phase was separated and washed successively with 2N hydrochloric acid (30 ml), water (3 x 80 ml) and brine (30 ml), dried and evaporated to give the title compound (0.159 g) as a foam = -58 ° (c = 0.65, CHCl 3), λ (ethanol) 280 nm (S 22 440).

b) Diphenylmethyl- (6R, 7R) -7- [(Z) -2- (1-t-butoxycarbonylcyclobut-1-yloxyimino) -2- (fur-2-yl) acetamido] -3- (1-ethyltetrazol-5-ylthiomethyl) ceph-3-em-4-carboxylate-methacrylate

The product of Example 75 (a) (1.92 g), purified acetone (6.4 ml) and dry powdered potassium iodide (1.56 g) were mixed at -10 ° C. Acetyl chloride (0.35 ml) was added, and the mixture was stirred at -10 ° C for 5 minutes and then at 0 ° C for 25 minutes.

The mixture was added dropwise to a stirred solution of sodium metabisulfite (1.16 g) in water (64 ml). The resulting solid was filtered off, washed with water and dried in vacuo over phosphorus pentoxide to give a solid (1.87 g).

The solid was purified by dissolving in ethyl acetate and treating the resulting solution with dilute sodium metabisulfite solution (2 x 125 mL). The organic phase was washed with water (100 ml) and brine (50 ml), dried and evaporated to give the title compound (1.826 g) as a foam, λ max = -132 ° (c = 0.31 CHCl 3), λ max (ethanol) 278.5 nm (£ 22,300).

c) (6R, 7R) -7- [Z-2- (1-Carboxycyclobut-1-yloxyimino-2- (fur-2-yl) -acetamido] -3- (1-ethyltetrazol-5-ylthiomethyl) cef -3-em-4-carboxylic acid

The product of Example 75 (b) (1.73 g) was dissolved in anisole (1.8 ml) and trifluoroacetic acid (7.2 ml). The solution was stirred at 25 ° C for 1 minute, the volatiles were removed in vacuo τ 76 6 5 2 5 8 and the residue was azeotroped with ethyl acetate (twice). The residue was triturated with ether to give a fibrous product which was dissolved in ethyl acetate (10 mL). This solution was added dropwise to stirred gasoline (400 ml), and the precipitate (1.222 g) was filtered off. Paper chromatography (n-butanol: ethanol: water, 4: 1: 5 - upper phase) showed the presence of two components. Therefore, the above solid (1.222 g), anisole (0.32 ml) and trifluoroacetic acid (6.4 ml) were stirred at 25 ° C for 6 minutes. The solvents were removed in vacuo and the residue was azeotroped with ethyl acetate (twice).

A solution of the residue in ethyl acetate (10 ml) was added dropwise to stirred petrol (450 ml). The precipitate was filtered off and dried in vacuo to give the title compound (1.162 g), m.p. 110-160 ° C (dec.), = -119 ° (c = 0.31, ethanol: water = 1: 1), λmax * pH 6 pH = 274.5 nm (0 21200).

Example 76 a) Acetoxymethyl (6R, 7R) -3-carbamoyloxymethyl-7-Z2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylate (syn-isomer)

A solution of (6R, 7R) -3-carbamoyloxymethyl-7- [2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid (syn-isomer) (2,020 g) In N, N-dimethylformamide (15 ml) was treated with finely ground potassium carbonate (270 mg) and stirred at 21 ° C for 10 minutes. A solution of acetoxymethyl bromide (933 mg) in Ν, Ν-dimethylformamide was added and the mixture was stirred at 21 ° C for 45 minutes. The reaction mixture was then poured into 2N hydrochloric acid (50 ml), water (50 ml) and ethyl acetate (100 ml), the phases were separated and the aqueous phase was further extracted with ethyl acetate (75 ml). The combined extracts were washed with 2N hydrochloric acid, water, sodium bicarbonate solution and brine, dried and evaporated to give the title compound as a foam (2.015 g), 7D = + 38 ° (1.36 DMSO), Λt, (ethanol) 276.5 nm e] * 324.

nidKS 1 cm 77 65 25 8 b) Acetoxymethyl (6R / 7R) -3-carbamoyloxymethyl-7-Z2-carboxymethoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylate (syn- isomer)

The product of a) (855 mg) was dissolved in anisole (10 ml) under ice-cooling, and the solution was treated with trifluoroacetic acid (50 ml). The mixture was warmed to 22 ° C »After 35 minutes, it was poured into excess 3% sodium bicarbonate solution (ca. 200 mL, pH ca. 7.4) and ethyl acetate was added. The aqueous phase (pH ca. 7.5) was combined with ethyl acetate (150 ml) and acidified (pH 1.4) with concentrated hydrochloric acid. The layers were separated and the aqueous phase was further extracted with ethyl acetate (150 ml). The combined extracts were washed with water and brine, dried and evaporated to give a solid. This was triturated with ether to give the title compound as a solid (640 mg), mp = + 29 ° (c = 1.2 DMSO), λ. (ethanol) 276 nm e]% 309.

max Icm

Example 77 a) NT-Butoxycarbonylglyloxymethyl (6R, 7R) -3-carbamoyloxymethyl-7-Z2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] cef-3-em-4-carboxylate Solution, with (6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamide] cef-3-em-4-carboxylic acid (syn-isomer) (2.00 g) in N, N-diraethylformamide (20 ml), treated with finely ground potassium carbonate (0.264 g). After 10 minutes, the resulting suspension was treated with a solution of N-t-butoxycarbonylglycine iodomethyl ester (2.707 g) in N, N-dimethylformamide (5 ml). The resulting mixture was stirred, and after 2 hours a second portion of iodomethyl ester (0.752 g) in Ν, Ν-dimethylformamide (ca. 4 ml) was added. After a further 3.5 hours, the reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3 x 80 mL), and the combined organic phases were washed with water, 3% sodium carbonate solution, and brine. The solution was dried and evaporated to give the crude title compound as a foam (3.856 g). This was further purified by chromatography (silica gel column, eluting with 2: 1 chloroform: acetone). The appropriate fractions were combined and evaporated in vacuo to give the title compound as a foam (1.570 g), ε = + 25.6 ° (c = 0.08, DMSO), λ. (ethanol) 277 nm e] * 218.

max 1 cm 78 65258 b) Glyloxymethyl- (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamide] L7kef-3-em-4-carboxylate trifluoroacetic acid salt (syn- isoroeer) The product of step a) (1.417 g) was dissolved in anisole (2 ml), cooled to 0 ° C and treated with trifluoroacetic acid (8 ml). The solution was stirred for 50 minutes and the temperature was adjusted again further to about 20 ° C. After an additional 50 minutes, the solution was evaporated in vacuo and the residue triturated with ether to give a solid which was filtered off. This solid was washed with ether and dried three times to give the title compound as a solid (1.186 g), = + 28.7 ° (c = 0.85, DMSO), m.p. 111.2 ° C, λ. mp (pH 6 phosphate buffer) 276 nm e]% 207.

1 cm Preparation of starting material N-t-butoxycarbonylglycine iodomethyl ester Two ampoules of potassium hydroxide (100.0 moles) in water were combined and azeotroped with methanol (anhydrous, 4 x 250 ml) and then toluene (4 x 250 ml). A solution of N-t-butoxycarbonylglycine (17.517 g) in methanol (anhydrous, 50 ml) was treated with potassium hydroxide dissolved in methanol (anhydrous, 50 ml). The solution was filtered through diatomaceous earth and then evaporated in vacuo to give a foam which was triturated with ether. The resulting solid was filtered off, washed with ether and dried in vacuo to give the potassium salt of N-t-butoxycarbonylglycine (20.166 g).

A solution of this potassium salt (6.00 g) in N, N-dimethylformamide (120 ml) was treated with iodochloromethane (24.811 g) at 20 ° C, and the mixture was stirred for 2.75 hours, after which the cloudy solution was partitioned between ethyl acetate and 2N hydrochloric acid soluble moieties. The acidified aqueous phase was extracted once more with ethyl acetate, and the combined organic phases were washed with water, dilute sodium bisulfite solution, 3% sodium carbonate solution and saturated brine. The solution was dried and evaporated in vacuo to an oil which was further partitioned between ethyl acetate and 2N hydrochloric acid. The organic phase was washed with 2N hydrochloric acid, water and brine, dried and evaporated in vacuo to give N-t-butoxycarbonyl-glycine chloromethyl ester as an oil (4.443 g).

This ester (1.126 g) was dissolved in acetone and treated with finely divided sodium iodide (7.107 g). The resulting mixture was refluxed for 2 hours. It was then cooled to room temperature and evaporated in vacuo to a solid which was partitioned between ethyl acetate and water. The organic phase was washed with water and brine and dried and evaporated in vacuo to give the title compound as a gum (0.734 g), V mafcs <cs2) 1770 (-CO2CH2I), 1720 (CO2C (CH3) 3) and 3440 cm-1 (NH ).

Example 78 a) (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-p-nitrobenzyloxycarbonylmethoxyiminoacetamido] kef-3-em-4-carboxylic acid potassium salt (syn-isomer) Potassium acetate ( 0.98 g) was added to a solution of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-p-nitrobenzyloxycarbonylmethoxyiminoacetamide] cef-3-em-4-carboxylic acid. -poa (syn isomer) (5 g) in methanol (140 ml) in acetone (140 ml). Ether (anhydrous, 500 mL) was added dropwise over 20 minutes until no more precipitation occurred. The resulting solid was washed with ether and dried at 22 ° C to give the title compound as a solid (5.2 g), C & J *. - + 51 ° (c = 0.1, Ho0), λϋ 1 a 2.

max 6 phosphate buffer) 272.5 nm 423.

b) IRS-Acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-Cl- (fur-2-yl) -2-p-nitrobenzyloxycarbonylmethoxyiminoacetamido] cef-3-em-4-carboxylate (syn-isomer) ) product (2.87 g) was dissolved in N, N-dimethylformamide (10 ml), and to this solution was added acetoxyethyl bromide (974 mg) with stirring at 25 ° C. After 45 minutes, the reaction mixture was poured into ethyl acetate (100 mL) and 2N hydrochloric acid (100 mL). The aqueous phase was extracted once more with ethyl acetate. The combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate and brine, then dried and evaporated to about 30 ml. This solution was added dropwise to petroleum ether 80 6525 8 (400 ml / bp 40-60 ° C) to precipitate a solid which was dried to give the title compound (2.17 g), λ max (ethanol) 278 nm. m 319.

c) 1RS-Acetoxyethyl- (6R, 7R) -3-carbamoyloxymethyl-7-

Zcarboxymethoxyimino-2- (fur-2-yl) acetamido] cef-3-ememicarboxylate (syn isomer)

To a solution of the product of b) (1.15 g) in ethyl acetate (23 ml) was added 20% palladium on carbon (2.3 g). The mixture was stirred under a hydrogen atmosphere (757 Torr) for 1 hour at 25 ° C.

3

A total of 225 cm of hydrogen was absorbed. The reaction mixture was diluted with ethyl acetate (200 mL) and filtered through diatomaceous earth. The residual solid was washed with ethyl acetate. The filtrate and washings were combined, evaporated to about 150 ml and then extracted with saturated sodium bicarbonate solution. The combined extracts were washed with ethyl acetate and acidified (pH 1, with concentrated hydrochloric acid). The acidic aqueous phase was extracted with ethyl acetate, and the combined extracts were washed with water and brine, dried and evaporated to a foam. This was dissolved in ethyl acetate and added to petroleum ether (b.p. 40-60 ° C) to give a solid which was dried at 25 ° C to give the title compound (407 mg), Z 2 D = + 59 ° (c * 0.9, DMSO), Λ. max (ethanol) 277.5 e% 319, inf 272.5 e]% 312.

Ί cm 1cm Preparation of (Z) -2- (p-nitrobenzyl) oxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid

Potassium furyl glycoxylate (6.04 g) was dissolved in water (80 ml), then p-nitrobenzyloxycarbonylmethoxyamine (8.4 g) and industrial denatured alcohol (80 ml) were added. The pH was adjusted to 4.6 and the mixture was stirred, and ethyl acetate was added to the residual solution. The pH was adjusted to 1.5 by the addition of concentrated hydrochloric acid, and after thorough mixing, the phases were separated. The aqueous phase was extracted once more with ethyl acetate and the organic phases were combined and evaporated to dryness to give the crude product (12.2 g). The crude product was dissolved in acetonitrile (10 ml) and the solution was cooled for 18 hours. It was then cooled in acetone / solid Cl 2 and the solid was collected by filtration to give the title compound (8.0 g), m.p. 125-127 ° C, (Nujol) contains 1752 + 1742 (ester + acid), 1510, 1340 (aromatic nitro), 1208 cm (ester), ^ (d-DMSO) 2.10 (d, 2), 3, 16 (d, 4) and 3.32 (dd, 4, 2) (furyl

O

gas protons), 1.78 (d, 9) and 2.31 (d, 9) (benzene ring protons), 4.61 (benzyl), 5.04 (O-CH0-C-O-) * no (6R, 7R) -3-Carbamoyloxymethyl-7-Z- (Z) -2-p-nitrobenzyl) oxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] ceph-3-emecarboxylic acid N, N-dimethylacetamide (5 , 7 ml) was added dropwise to a stirred solution of phosphorus pentachloride (3.378 g) in dichloromethane (30 ml) at 0 ° C. The mixture was cooled to -15 ° C whereupon (Z) -2- (p-nitrobenzyl) oxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (5.224 g) was added in one portion. The resulting solution was stirred at -15 to -10 ° C for 15 minutes. Water (9 ml) at 0 ° C was then added and the mixture was stirred vigorously at + 2 ° C for 1 minute. It was then transferred to a separatory funnel where it separated into two layers. In the meantime, (6R, 7R) -7-amino-3-carbamoyloxymethyl-ceph-3-reme-4-carboxylic acid (4.1 g), acetonitrile (19 ml), N, N-dimethylacetamide (19 ml), water (3.5 ml) and triethylamine (10.5 ml) at 20 ° C until a clear solution was obtained (ca. 10 minutes). The solution was cooled to -20 ° C, at which time a lower layer of the acid chloride solution prepared above was added over 13 minutes. The mixture was stirred for an additional 10 minutes at -8 ° C and then for 60 minutes at 0 ° C. The solution was poured at + 5 ° C into water (250 ml) containing concentrated hydrochloric acid (4.5 ml). The pH was adjusted to 2.1 and the phases were separated. The aqueous phase was washed with dichloromethane (2 x 20 ml) and then the combined dichloromethane extracts were in turn extracted with saturated sodium bicarbonate solution (50 ml). The mixture was emulsified. The dichloromethane was evaporated under reduced pressure and ethyl acetate (100 ml) was added to give two phases. The organic phase was washed with saturated aqueous sodium bicarbonate solution (15 ml), and then the combined aqueous extracts were covered with ethyl acetate (80 ml) and acidified (pH 2.1, concentrated hydrochloric acid). The phases were separated and the aqueous phase was further extracted with ethyl acetate (20 ml). The combined ethyl acetate extracts were washed successively with water and brine, dried (calcium chloride), and evaporated to a foam (7.8 g).

2.3 g of this foam was dissolved in methanol (20 ml) to give a clear solution. After several minutes, crystals precipitated. The solid was collected by filtration, washed with methanol and dried to give the title compound (1.02 g), macg (Nu3o1) containing 3460, 3360 (NH2), 3280 (NH), 2600 + 1714 (CO2H), 1796 (/ 2 β-lactam) and 1744 cm -1 (CO_R). T (d 6 -DMSO) values 0.15 (d, 9, NH),

£ O

1.75 (d, 9) and 2.25 (d, 9), p-nitrobenzyl ring), 2.07, 3.03, 3.28 (furyl ring protons), 3.38 (CONH2), 4.56 (benzyl), 5.05 (-CH 2 -COO-) and 5.01 + 5.32 (ABq, 13, -CH 2 -CONH 2).

Example 79 a) 1RS-Cyclopentylcarbonyloxyethyl- (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-p-nitrobenzyloxycarbonylmethoxyiminoacetamide] cef-3-em-4 carboxylate (syn-isomer) 1RS-cyclopentylcarbonyloxyethyl bromide (1.63 g) was added to a solution of potassium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2- p-Nitrobenzyloxycarbonylmethoxyiminoacetamido] cef-3-ene-4-carboxylate (syn-isomer) (3.998 g) in N, N-dimethylformamide (120 ml) with stirring at 0 ° C. After 1.25 h, the solution was poured into 2N hydrochloric acid (1 L), which was extracted with ethyl acetate (500 mL, 2 x 250 mL). The combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate and brine, dried and evaporated to ca. 40% which was added dropwise to petroleum ether (b.p. 40-60 ° C) to precipitate a white solid. This was dried at 25 ° C to give 29 ° to give the title compound (2.73 g), C & J-q ~ + 34 (c = 1.2 DMSO), λ, (ethanol) 272.5 nm E1% 389.

b) 1RS-Cyclopentylcarboxyethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylate (syn-isomer) 0% palladium on carbon (2.13 g) was added to a solution of the product of a) (2.13 g) in ethyl acetate (50 ml) at 25 ° C at 83 ° C and the mixture was stirred under an atmosphere of hydrogen. (slightly above atmospheric pressure) for 1 hour, at which time about 400 ml of hydrogen was absorbed. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth and extracted with pH 7 buffer. The combined extracts were washed with ethyl acetate and then acidified (pH 1, with concentrated hydrochloric acid). The aqueous phase was extracted with ethyl acetate, the combined extracts washed with water and brine, dried and evaporated to near dryness. This solution was added dropwise to petroleum ether (b.p. 40-60 °) to precipitate a solid which was dried at 25 ° C to give the title compound (617 mg), / C &7; 4 = + 40 ° (c = 1.1, DMSO), λ. (ethanol) 277 nm e]% 303.

u max 1 cm Preparation of starting material IRS-cyclopentylcarbonyloxyethyl bromide Cyclopentanecarbonyl bromide (36.7 g) was added dropwise over 30 minutes to cooled (0 ° C) and stirred acetaldehyde (12.3 ml). The solution was allowed to warm to room temperature and stirred for 2 hours. The mixture was distilled in vacuo and the title compound (26.27 g) was collected, b.p. 52-57 ° C (mainly 55-57 ° C / 0.1 Torr, 9. (CHBr,) 1744 cm -1 (c = 0).

max ό

Example 80 a) (6R, 7R) -3-Carbamoyloxymethyl-7-Z2-carboxymethoxyimino-2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid dipotassium salt (syn isomer)

Solutions of potassium n-butyrate (2.389 g) in methanol (10 ml) and (6R, 7R) -3-carbamoyloxymethyl-7- (2-carboxymethoxyimino-2- (fur-2-yl) ) -acetamide-7-cef-3-em-4-carboxylic acid (syn-isomer) (3.937 g) in methanol (20 ml) was partially stirred at 22 ° C to give a gummy solid. Additional methanol (20 mL) was added and the temperature was raised to 50 ° C. After complete mixing of the solutions and stirring for several minutes at 50 ° C, the solid dissolved. The solution was allowed to cool to 18 ° C, after which anhydrous ether (50 ml) was added dropwise over 45 minutes. A solid formed which was filtered off. After more ether (150 mL) was added to the filtrate, an additional solid was obtained which was combined with the first batch. This solid was mixed with ether (150 mL), filtered, washed several times with ether and dried at 22 ° C to give the title compound (3.611 g).

b) (1RS) -Acetoxybutyl- (6R, 7R) -7- [2- (1RS-acetoxybutoxycarbonylmethoxyimino-2- (fur-2-yl) acetamide] -3-carbamoyloxymethyl-cef-3-eme -4-Carboxylate (syn-isomer) RS-acetoxybutyl bromide (1m353 g) was added to a solution of the product of a) (1.498 g) in N, N-dimethylformamide (45 ml) with stirring at 19 ° C. After 1 h, the reaction mixture was poured into 2N hydrochloric acid (250 mL), which was extracted with ethyl acetate (100 mL, 2 x 50 mL). The combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate and brine, dried and evaporated to near dryness. This solution was added dropwise to petroleum ether (b.p. 40-60 ° C) to precipitate a solid which was filtered off and dried at 22 ° C. This solid (505 mg) together with a previously prepared batch (293 mg) was dissolved in ethyl acetate, and the solution was filtered through a cotton plug. The solution was added dropwise to petroleum ether (b.p. 40-60 ° C) to precipitate a solid which was dried at 22 ° C to give the title compound (617 mg), {α, 7 ° = + 29 ° (c = 1.1, DMSO), λ max (ethanol) 276.5 nm e] * 273.

i cm Preparation of starting material 1RS-acetoxybutylbororoid To cooled (ca. 0 ° C) acetyl bromide (1.49 ml) was added ca. butyraldehyde (1.76 ml). The reaction mixture was allowed to warm to room temperature over 1 hour to give a light brown solution. This was distilled in vacuo to give two fractions: i) b.p. 60-70 ° C / 27 Torr (0.78 g) ii) b.p. 70-80 ° C / 27 Torr (1.64 g)

Fraction ii) contained the title ester, which was characterized by its NMR (CDCl 3) and infrared (CHBr 3) spectra.

Claims (2)

85 05258 A process for the preparation of an antibiotic β-β-acylamido-cef-3-em-4-carboxylic acid of formula H H; ; R-C-CO-NH-L-! C RaH O- (CH_) -C- (CHO) -COOH 2 m · 2 n Rb where R is thienyl or furyl, di b R and R, which may be the same or different, are hydrogen atoms or C1-4 alkyl, C2-4 ~ alkenyl, C 3-7 cycloalkyl, phenyl, carboxy or C 2-3 alkoxycarbonyl groups, wherein Ra and Rb are the same groups only when they represent hydrogen atoms or C1-4 alkyl groups and / or Ra and Rb together with the carbon atom to which they are attached. attached, form a C 3-7 cycloalkylidene group, m and n are each 0 or 1, such that the sum of m + n is 0 or 1, and P represents a) a hydrogen atom, b) a halogen atom, c) a group of the formula R 1 - CH = C "" R2 1 2 wherein R and R, which may be the same or different, are hydrogen atoms or carboxy, cyano or C2-4 alkoxycarbonyl groups f or d) a group of the formula -CH2Y, where Y is: (i) a heterocyclic tertiary amine residue, (ii) an azido, (iii) a group of the formula -SR wherein R is an unsaturated heterocyclic a group having a 5- or 6-membered heterocyclic ring having up to 4 heteroatoms selected from sulfur, nitrogen or oxygen, however, the ring having at most 1 sulfur atom and at most I 16 16 i 1 oxygen atom, (iv) a group of the formula -O-CO-R wherein R is a C 1-4 alkyl or phenyl group, or (v) a group of the formula 1-4 17 17 -O-CO-NHR wherein R is a hydrogen atom or a alkyl group, or for the preparation of non-toxic salts and esters thereof, said compound being a syn isomer or present as a mixture of syn and anti isomers containing at least 90% of the syn isomer, characterized in that A) condensing a compound having is a formula (2h-o) -Ν-γΛ-ρ COOR19 19 wherein R is a hydrogen atom or a carboxyl protecting group, and P is as defined above, or an acid addition salt thereof, is reacted with an acylating agent corresponding to RC-COOH II \ Ra \ I 20 O- (CH,) -C - '(CH,) -COOR υ VI im | / n an acid according to Rb Ά b, in which R, R, R, m and n have the same meaning as above and R is a carboxyl protecting group, or B) when P in formula I is a group -Cl 2 Y, in which Y has the same meaning as above, a compound of formula 87 6 5 258 HH 1 is obtained; R-C-CO-NH -1-KS ° * 3l Il 1 N λ * -N. ^ -CH2Y * VI1 \ Lr- \ f 0- (CHo) -C- (CH-) -COOR2 in | 2 n Rb gb wherein q is 0 or 1 and R, R, R, m and n are as defined above 19, and each R may independently be a hydrogen atom or a carboxyl protecting group, and Y 'is a chlorine, bromine or iodine atom or an acetoxy group , to react with a group Y-containing nucleophilic compound, followed, if necessary and / or if desired, by any of the following reactions c) in any appropriate order: C i) reducing the compound in which q is 1 to the compound in which q is 0, C l) deacylating 3-acyloxymethyl compound to 3-hydroxymethyl compound t C iii) carbamoylating the 3-hydroxymethyl compound to an unsubstituted or substituted 3-carbamoyloxymethyl compound, and / or C iv) removing the carboxyl protecting groups, and finally D) recovering the desired compound of formula I or non-toxic salt or ester. 88 65258 For the preparation of an antibiotic network with 7- / a-acylamidocef-3-em-4-carboxylic acid in the form of HH or RC-CO-NH — fc-if '"* jn oj— \ Ra COOH 0- (CH_) -C- (CH_) -C00H 2. m I 2 n Rb color R är tienyl eller furyl, ci b R och R. Soin kan Vara dika eller olika, är väteatomer ell C1 t 1-4 alkyl-, C2_4-alkenyl -, C2-6-cycloalkyl-r-phenyl, carboxy- or C2-5 -alkoxycarbonyl group, colors dock Ra and Rb is a group which is not a specific substituent or C1, -alkyl group, or a mixture of R and och r bundna en C3_7-cycloalkylidengrupp, m och n är vardera 0 eller 1, sa att summan m + n är 0 eller 1, och P är a) en väteatom, b) en halogenatom, c) en grupp med formeln -CH = C ^ R2 1 2 color R and R, which may be dirty or ol, a hydrogen atom or a carboxy, cyano or C2-4 alkoxycarbonyl group, or d) a group of the formula -CH Y, color Y is (i) a heterocyclic 13 tertiary Amine-rest, (ii) azido, (iii) en group with formula -SR, 1 3 color R with en heterocyclic group with 5- or 6-led heterocyclic ring with a total of 4 heteroatoms, a single crystal, having 89 65258 of a single ring, colors of the dock and rings 1 is selected from the group consisting of (16) a group of the formula -O-CO-R, wherein R is an alkyl- or phenyl group, or (v) a group of the formula -O-CO-NHR17, 17 is R is not present or en _ ^ - alkylgrupp, or icke-giftiga salter och estrar av denna, varvid nämnda förening är en syn-isctner eller uppträder som en blandning av syn-och anti-isomerer innehällande ätminstone 90% syn-isomer, k ä n -netecknat därav, att A) en förening med formeln f? h2 "- | -f S J- 0 I COOR19 1 9 van R är en väteatom eller en kar boxy lb Locker ande grupp, och P betecknar decamma som tidigare, eller dess syraadditionssalt, om-sättes med ett acylerlngsmedel, som motsvarar en syra med formuleln RC-COOH II Ra \ I 20 O- (CH_) -C- (CH-) -COOR ^ U VI 2. j 2 n * b color R, Ra, r! ° fm and n is a deck of some carbon, and R20 is a carboxyl block group, or B ) if P and Formula I are groups -CK ^ Y, where Y is the same as in the case of the form, which is in the form of a form