CS205115B2 - Method of preparing 3-/thiomethyl/cephalosporin compounds - Google Patents

Abstract

3-(Thiomethyl)cephalosporins of the formula <IMAGE> in which the substituents are defined in Claim 1 are prepared by a novel process. These compounds are obtained by replacing, in a corresponding cephalosporanic acid which has an acyloxy group in the 3-position, this group by the group -SR<13> by reaction with a sulphur nucleophile in an organic solvent under virtually anhydrous conditions. The compounds obtained can be used for the control of infections in warm-blooded animals (mammals) or as an intermediate for the preparation of other cephalosporins.

Description

The present invention relates to a process for displacement of the cephalosporanic acid acetoxy group by nucleophilic sulfur compounds in an organic solvent under substantially anhydrous conditions.

Displacement of the cephalosporin acetoxy group by nucleophilic sulfur compounds is a known reaction (U.S. Patent No. 3,278,531) This patent and other publications (JD Cocker, J. Chem. Soc., 1965, 5015) disclose that the reaction takes place only in an aqueous environment. In practical displacement reactions, the salt of cephalosporanic acid in water and the nucleophilic sulfur compound or salt thereof at pH 5-8 are used. The combination of an aqueous environment, an elevated temperature (35-70 ° C) and an almost neutral to basic pH usually leads to a considerable extent. The attempt to carry out displacement on cephalosporanic acids in water at a lower pH (pH 2-3) results in a large amount of lactone formation and this side reaction greatly reduces the yield of the desired product.

It has now been found that displacement of the acetoxy group as well as other 3-acyloxy groups of cephalosporanic acids with nucleophilic sulfur compounds can be carried out in the

Organic solvents under substantially anhydrous conditions. Under these conditions, the reactions are not complicated by the formation of lactone, yields are usually higher and the products can be more easily isolated. Some of the products obtained precipitate spontaneously from the reaction mixture. The process of the invention is of a general nature and can be applied to essentially any nucleophilic sulfur compound and to any cephalosporic acid.

In particular, the invention relates to an improved process for the preparation of 3- (thiomethyl) cephalosporins.

The present invention provides a process for the preparation of cephalosporin compounds of formula (I)

where

R ¹³ represents a group

wherein A 1 is a protected amino group selected from the group consisting of C 1 -C 6 alkoxycarbonyl, dimethylureido, benzoyl, halobenzoyl, benzoyloxy, halobenzoyloxy, C 1 -C 6 alkoxycarbonyl and 4- (C 1 -C 4 alkyl) -2,3- dloxoplperazinylcarbonyl and R12 is hydrogen or C1-C441alkyl,

11. 4-oxo-4-carboxybutyl;

12. 3-carboxypropyl;

13. the remainder of the general formula

C 1 to C 4 alkyl,

R1 is hydrogen or methoxy,

R2 is phthalimido, succinimido,. the rest of the general formula

_CH3 CWj wherein L is hydrogen or nitro or a radical of formula

O

R 3 —C — NH—, where

R3 represents

1. hydrogen,

2. C 1 -C 6 alkyl,

3. —CH2— (C1-C3 chloroalkyl) group,

4. - CH2 - (C1-C3 fluoroalkyl) group,

5. C 1 -C 4 cyanoalkyl,

6. C1-C4 hydroxyalkyl;

7. p-nitrobenzyloxy,

8. tert-butoxy,

9. 2,2,2-trichloroethoxy,

10. a protected 4-amino-4-carboxybutyl group of the formula

O

R12O — C — CH— (CH2) O — CHo — wherein each of a and a1 is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, or A1CH2 — wherein A1 is as defined above Z is oxygen or sulfur and m is 0 or 1,

14. the remainder of the general formula

P — CH—,

Q wherein P represents

a) 2-thienyl, bj 3-thienyl or cj phenyl of the formula

wherein a 'and a1 are as defined above, and Q represents

(a) hydroxy,.

(b) formyloxy;

(c) acetoxy;

d] a substituted carboxy group of the formula

O ⁼ —C — O — A2, wherein A2 is diphenylmethyl, p-nitrobenzyl, benzyl, 2,2,2-trichloroethyl, tert-butyl or p-methoxybenzyl,

e) (alkali metal-oxysulfonyl) group,

f) a protected amino group selected from the group consisting of C1-C4 alkoxycarbonyl-, dimethylureldo-, benzoyl-, halobenzoyl-, benzoyloxy-, halobenzoyloxy-, C1-C4 alkoxycarbonyl- and 4- (C1-C4 alkyl) -2,3 -dioxopiperazinylcarbonylcupper,

g) an acylated amino group of the formula

A ¹

O — NH — S — Τ, where T is an amino group,

N — —N — —C — N — 2,

R7 o

I II — N — C — R ⁸ ,

R 7 O —N — C — C— = C — R ⁹ ,

wherein R ⁷ is hydrogen or C 1 -C 3 alkyl, R 8 is phenyl, halophenyl, furyl, monomethylamino, dimethylamino, monoethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, diisopropylamino, phenylamino - or diphenylamino, R ⁹ is hydrogen, C 1 -C 4 alkyl or phenyl, R ¹⁰ is hydrogen, C 1 -C 6 alkyl or methylsulfonyl and R ¹¹ is ethylene, trimethylene or vinyl,

15. the rest of the formula

N — O—,

II

P‘ — C — C—

II o

-c — fc, o

II —OCCH3, wherein P 'is P as defined above, a protected 2-amino-4-hiazolyl group containing an amino protected group selected from the group consisting of C1-C4 alkoxycarbonyl, dimethylureido, benzoyl, halobenzoyl, benzoyloxy, halobenzoyloxy, C1-C4 alkoxycarbonyl- and 4- (C1-C4 alkyl) -2,3-dioxopiperazinylcarbonyl; or represents 2-furyl,

16. the rest of the formula

V - 8 (0), - N -, where V is - CF3 - or --S -, wherein X is hydrogen, methyl, CF3, CN or 'N3 and n is 0, 1 or 2, or

17. is of the formula Y-CC-, wherein Y is

2-thienyl,

3-thienylcurine,

2-phyrylskuninu, --oazzolslskuninu, 2-thiazolylskuninu,

1-tdtrabrlylgroup,

1- Уdnzorriab01olskspinu,

2-oxazolylthirskupins,

2- thiazrlolthioykuřins,

1.2.3- triabrl-5-ylthir) Urea,

1.3.4- triabrl-2-olthirsksřins,

1,3,4-Ehiaeiabrl-2-ylthiosuccin, protected by 5-amino-1,3,4-thiaeiabol-2-olthio-ω amino protected group selected from the group consisting of C 1 -C 4 alkaloxyphenol-, eimetholureido-, benzeyl-, halobenzool-, benzoic -, halogenated C1-C4 alkoxycarbonyl-4- (C1-C-alcol) -2,3-dioxo-triazinocarboxylic acid, furthermore Y is 5-methanol-1,3,4-thiazol-2-olthioylamine,

1.2.4- thiaeLabrl-5-olthiopym,

3-mdthol-1,2,4-thiazole-5-olehioyspin,

1,2,5-thiadiabrl-3-eagylcyclyl, r, X, 4-oxad-2-isot-2-ylthio,

5-methyl-1,3,0-oxaiazo-O-ylcycline, 1-indole-5-indole-thioylspins,

4-cyano-1,2,3-triabol-1-olefin, 3-cynoo-2,4,4-l'isrol-0-yl-cucine or a protected 2-amino-4-hiazolyl-spins with an amino-protected group selected from a group consisting of C1-C4 alkoxocaprool-, dimdtholsdier-, benzoyl-, halobenzryl-, benzo-, halo-boyboyloxy-, C1-C4 alkoxocaronol- and 4- (C1-C1-alkyl) -2,3-dioxopiperazinylcaconone groups, each of the symbols R independently; represents hydrogen,

Cl — C- alcolykspm,

C2-C3 alkdnolskuřinu, coklrhdxolskuřinu nebofdnolykuřinu, each R ⁵ independently. is C1-C4 alkyl;

C1-C4 alkoxoycspine, halogen, oxo, nitro, cyano, methanesulfonamido- or trifluoromethyllycspine,

-C-CH—

AND

R ⁶ represents a unit which, with the remainder of the formula or forms an unsubstituted or substituted five- or six-membered heteroaromatic ring containing a total of 1 to 4 heteroatoms selected from the following combinations

1. a nitrogen atom and 0 to 1 oxygen or sulfur atom; 2. nitrogen atoms and 0 to 1 oxygen or sulfur atoms,

3. nitrogen atoms and 0 to 1 oxygen atoms; or

4. nitrogen atoms, wherein all other atoms in the ring are carbon atoms, or a unit with the remainder of the formula

2-benzoxazolyl or a radical of formula

characterized in that the compound of general formula (I) is a compound of formula (I)

where

R ¹ and R ² have the above meanings, and

R represents

C 1 -C 6 alkyl,

C 4 -C 6 cycloalkyl, amino, mono- or di (C 1 -C 6 alkyl) amino, a group of the formula

-с-С ^ ОН OCH ^ cOCH ₂

OSO2H is reacted with a nucleophilic sulfur compound of formula III

R ¹³ —S — R ¹⁴ , (III) wherein

R ¹³ is as defined above, and

R ¹⁴ is hydrogen, or when and only when R ¹³ is methyleneaminium, R ¹⁴ is linked to R ¹³ to form thiourea, in an organic solvent, under substantially anhydrous conditions.

The substances produced according to the invention exhibit antibacterial activity and, in addition, many of them serve as intermediates for obtaining other cephalosporin substances which also exhibit an annibacterial effect (see, for example, U.S. Patent No. 3,932,393).

In the above definitions of the individual groups, the different alkyl groups mean both straight and branched chain alkyl groups. In the definition of R ³ as "C 1 -C 6 alkyl", the alkyl group may be a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, amyl, isoamyl, hexyl, 2,3- "CH 2 - (C 1 -C 6 chloroalkyl)" and "- CH 2 - (C 1 -C 6 fluoroalkyl)" mean groups such as chloroethyl, fluoroethyl, 2-chloroethyl, 2-chloropropyl, 3-methylbutyl and the like. The term "C 1 -C 6 cyanoalkyl" refers to groups such as cyanomethyl, 2-cyanethyl-, 3-cyanopropyl and 2-cyanopropyl. The term "C 1 -C 6 hydroxyalkyl" refers to groups such as hydroxymethyl-, 2-hydroxyethyl-, 3-hydroxypropyl- and 2-hydroxypropyl.

In both the 3- (acyloxymethyl) cephalosporin of formula II and the nucleophilic sulfur compound, it is desirable that the amino groups are conveniently protected. The practice of protecting amino groups is well known, see Protectice Groups In Organic Chemistry, edited by J. T. W. McOmie (Plenum Press, London and New York, 1973). In protecting an amino group, the removability of the protecting group must be taken into account. However, this is not always the case, as in the case of the 7-acylamido group of the formula

O O

R ¹² O - C - CH - (CH 2) 2 - CH 2 - C - NH -,

A ¹ to be cleaved from cephalosporin.

Suitable protecting groups for this radical are C 2 -C 4 alkanoyl-, C 5 -C 4 chloro or fluoroalkanoyl-, benzoyl-, and substituted benzoyl. The term "C 2 -C 12 alkanoyl" refers to acetyl, propionyl, butyryl and the like. The term "C 5 -C 4 chloro or fluoroalkanoyl" refers to 3-chloropropionyl, 3-fluoropropionyl and the like. The term "substituted benzoyl" refers to halogen-substituted benzoyl groups such as 4-chlorobenzoyl-, 4-bromobenzoyl-, and 2, 4-dichlorobenzoyl. Such groups can also be used to protect amino groups at other sites of 3- (acyloxymethyl) cephalosporin and nucleophilic sulfur compounds. However, when the amino group is to be released again, readily cleavable groups must be used, see McOmie's work cited above. Suitable readily removable groups are benzyloxycarbnyl, p-nitrobenzoyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, and diphenylmethoxycarbonyl. Amino group of the formula

O O

II II

R12O — C — CH— (CH2) 2 — CH2 — C — NH—

A1 may also be protected as described in Belgian Patent No. 771,694.

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine. The term "C 1 -C 1 alkoxy" refers to methoxy, ethoxy, isopropoxy, n-butoxy and the like. The term "alkali metal" preferably refers to sodium, potassium and lithium.

Illustrative of the groups of the formula hexanamido, heptanamido,

C-chloropropianamido-,

3-chlorobutyramido-,

4-fluorobutyramido-,

5-chlorvaleramido-, cyanacetamido-,

2-cyanprcpl · onamidc- (

3- cyanpropionamido-,

4-cyanpropionamido-, hydroxyacetamido-,

2-hydroxypropionamido-,

3-hydroxybutyramido-, p-nitrobenzyloxycarbonylamino-, tert -butoxycarbonylamino- ((2,2,2-richethoxy) carbonylamino),

5- (2,5-dichlorobenzamido) -5-carboxyvaleramido-

5-acatamide O-5-carbonyloxyvelarainido-,

5-methoxycarbonyl-5- (2,4-dichloro-benzamido) valeramido-,

5-l-butoxycarbonyl-5- (2,4-dichlorobenzamide) valeramido-,

5-cacboxy-5- (2,4-diclorobenzamido) valeramido-,

5- (p-C 10 -enenzamido) -5-cacboxyvaleramido-,

5-Proclonamido-5-carboxyvalcramido-

5- (3-chloropropionamide O ') - 5-carboxy-valeramido-,

5-Eenzamino-5-carboxyveleramido-, S-oxo-S-carboxyvelaramido- and

4-carboxybutyramido.

As illustrative examples of groups of the general formula

O

R3-C-NH- wherein

R 3 represents a group of the formula

O

R3-C-NH- wherein

R 3 represents any one of (1) to (12), mentioning formamido, acetamido, propionamido, butyramido, α-methylpropionamido, valeramido, α-methylbutyramido, trimethylacetamido, where m is 0, mention phenylacetamido-

2- (p-Mateyllenes) cetamido-

2- (θπ \ 11 a c ^^ eta ^^ o

2- (p-isopropyl-propyl-yl) -cyclohexylamine

2- (o-matylleeyl acetamidoc)

2- (p-chloro) -phenyl-acetamido 10

2- (p-bbo mf eeylýa cetamidOi),

2- (2,2 (4oh-hrCrnylla cetamido-i

2- (m-bromophenyl) cetamido-,

2- (p-ureaeyl acetamidoc)

2- (o-C-fluoro) acetyl acetamido-i

2- (3,3 (4-hydroxyphenyl) acetamido-,

2- (p-hydroxyphenyl) aetamido-,

2- (m-hydroxyphenyl) acetamido-

2- (2,6-dimethoxyphenyl) acetamido-,

2- (m-Methylphenyl) acetarnido-.

2- (p-isopropoxyphenyl) acetamido-,

2- (m-ethyxyphenyl) acetarnido-

2- (p-Methylphenyl) acetamido

2- [3,3-di-methyl-phenyl] -acetamido-,

2- (p-tert-butoxyphenyl) acetamido-,

2- (p-ocetarn-omethylphenyl) and cetanedo-,

2- [p - (tert-butoxycycbuxylaminomethyl) lithium] cetcmidx-,

2- [o- - tert-butoxycarbonynylmethyl] phthyl] -

2- [m-butoxyphenyl] acelamido-, 2- (3-chloro-4-methylphenyl) acetamidide octanol.

Jakx oří-cdy sktoln in oříocOě, where ø = 1 c Z otdtdcvtjt —0—, -t include these sktoins:

ftnχyyneetnшiOx-,

2- (p-Methylphenn-y-acetamido-)

2- (m-Ethylphenxylacetamido-)

2- (p-sppor x -phenyxy facetamide);

2- (x-Methylphenoxyxy cetamido-)

2- (p-ceix-eny-y) and netamido-,

2- (p-brxmpheenxy) and cetacedo-

2- (2,4-diceio-rennxy] and cetamido-,

2- (m-brpphenoxy) and cetamido-

2- (o-t-t-c) -cid-idx-,

2- (p-uxenoxyxy) cetyl-1dx-,

2- (2,6-diethoxy-ynaphthyl) -cyclohexyl,

2- (η-eth-yyfin-yy) n-nitride-,

2- (.o-øttУχyyftnχyy) nettnøiOx-,

2- (3,4-diethoxy-ynaphthyl) -cyclohexyl-,

2- (o-tere.bttyyyí пп-уу] centc-ld--)

2- ('- - Uttpyyfen-yy] ceetcmiOp-,

2- (3-eУ-xr-4-ethoxy-phenylamino) cetyl-,

2- (3-hy Orxxy-4-ethoxy-phenyloxy)

2- (x-ehl-rfen-xy) α ^^ - ΊΟ--,

2- (3-Hydroxy-4-ethyl-piperazin-1-yl),

2- (x-ey-rftnpyy) aeetc-10--

2- (o-ls-or-oxyynynyl) ethylene-idx-,

2- (- (noneac-1d-ethyl) phth-yy] ceetc-1d-- c

2- [- (tert-Butyl-cycl-1-yn-1'-ethoxy-1-yl) -phenyl] -4- [eta] &lt; 4 &gt;

When in the above-mentioned-vz-rel - = 1 c Z denoted —S—, it is possible to mention the following:

2- (lthix) ceeta — 1d--,

2- (o-- ethyl-phenyl-thix) cett-id--,

2- (- ethyl-tert-thi] cetyl-10x-, 2- (o-isporxoylphenylthip) centyl-2- (- (ethylphenylthly) ethyl) -1d-,

2- (o-ehlxrphenyl-thl-) ceetcmidx-,

2- (o-Ur-phenylthip) ethyl-id--,

2- (1,2,4-dieh-phenylene-thi-) centylx-,

2- ('-Ur-phenyl-thix] cetcmiO--,

2- (o-f-t-rf enylthlx) ceetcmidx-

2- (--- f-t-phenylene-thl-) ceetcm10x-,

2- (3,4-dihydryyphenylthix) -acetyl-10x-,

2- (o-hyr-yyphenylthip) ceet-10--,

2- (--Hydroxyphenyltyl) non-10β-,

2- (2,6-dimethyloxyphenyl-1H) -cyclo-10-,

2- (m-eth-yyphenyl-thip) -cyclohexyl-,

2- (o-m-tH t-xy phenylthio) ceetcmiO--,

2- (3,4-diethylphenylthip) cetyl-,

2- (o-tert-Butylphenylthip) cetyl-10x-,

2- (—Ut-yyphenyl-thi-) centyl-1d--,

2- (3-chloro-4- (4-methyllenyl) hex) cetyl-,

2- (3,4-Dimethylphenylthix) cetcmidx-

2- (3,4-0ieh-rf enylthip) ceetcmiO--,

2- (2,5-dichlorophenylthio) ceteamide, 2- (3-chloro-4-chlorophenyl-thio) cetyl-, 2- (3-chloro-4- (4-chlorophenyl) thio) cetyl-10 -, 2- (2,6-Oif-t-phenyl-thl-) cetyl-10x-,

2- (η-f-t-rfenylthip) ceet-10--,

2 - (- (Cetomethylmethyl) phenyl-thi] cetyl-10-c

2- (o- [tert-Butylcarbonylamino-methyl) -phenyl-thix] -methoxy-sctoint.

When R3 is present, the P-CH2 sctoint is -ze

Q jckx iltstrective sktoins -beenéh- vzxree

O

II

R3-C-NH-thio-alpha-omega-sktoint c-O-oxo-1-oxo-1-oxo-eno-2-carboxy-2-carboxy-2-carboxy-2-carboxy-2-carboxy-2-carboxylic acid in which it is played, e.g., kcrU-ny-c-in--, tnre.btt-yyknrU-ny1n — inp-, ar1eУ1X'retУ-yykcrbxny-c-in-- or- o-nitr- Uenzyl-cyclopropyl-in-sectol, and 2- [Ceylamino] -1-phenyl-methyl-10'-sectol. There are three of them, 2-stbstitt-eternal

2-thienylceethoxy-3-thienyl-cyclohexylsulfonate in which the phenyloquinone is a 2-thienyl or 3-thienyl-ring.

Jckx iltstrdtvvní okřícdy těeht- aeetcmi0-sktoln can be created:

-andelcmlOx-, O-etet-mcnde-n-10--, o-hyrr-xymcn0e-c-10x-, -УуОг-уу-andelc-10-, 0-methχyyøcn0e1n-i0--, ш- brxmøanOe-c — id--, o-eh-yrmcnOtlcmiOp-,

3-ethyl-44-t-rmc-ee-cm1d-, x-trimethyl-c-10-O, 0-f-hexadecene-O-1s-or-O1-nnde-cm1Ox-,

3.4- 01 — etOy1-O4xr-y-cn0e-nm10--, 0-e1-r-4-ryy-mnn0t-am10x-, -is-or-o-УУ-O4-rmyl — nnde1cø1d-- , - ^ γχ —- 04χγ myl mandelc — iOx-,

O-formyl-ande1c-id--,

3,4-dimethylamino-O-oxylmethyl-O-acetyl-amino-10-O-acetyl-O-acetyl-indole-nm10β-, o- [non-methyl-10-methyl] -? -lyro-yy-Ofr-yl-anOelc-10x-,

2-Hydroxy-2-) cetcmides-

2-hydroxy-2- (3-thienyl) cyclohexyl-,

2-formyloxy-2- (2-thienyl) Jacetamido-,

2-acetoxy-2- (2-thienyl) acetamido-,

2-formyloxy-2- (3-thienyl) acetamido-,

2-acetoxy-2- (3-thienyl) acetamido-,

2- (tert-butoxycarbonyl) -2-phenylacetamido-,

2- (2,2,2, -trichloroethoxycarbonyl) -2- (p-methylphenyl) acetamido-,

2- (benzyl oxycarbonyl) -2- (p-hydroxyphenyl)

2- [tert-butoxycarbonyl] -2- (p-hydroxyphenyl) acetamido-,

2- (p-nitrobenzyloxycarbonyl) -2- (m-hydroxyphenyl) acetamido-,

2- (p-methoxybenzyloxycarbonyl) -2- (p-methoxyphenyl) acetamido-,

2- (diphenylmethoxycarbonyl) -2- (m-bromophenyl) acetamido-,

2- (t-butoxycarbonyl) -2- (p-chlorophenylacetamido-),

2- (2,2,2-Trichloroethoxycarbonyl) -2- (3-methyl-4-fluorophenyl) Jacetamido-,

2- (benzyloxycarbonyl) -2- (o-fluorophenyl) acetamido-,

2- (p-nitrobenzyloxycarbonyl) -2- (p-fluorophenyl) acetamido-,

2- (p-methoxybenzyloxycarbonyl) -2- (p-isopropylphenyl Jacetamido-),

2- (tert-butoxycarbonyl) -2- (3,4-dimethylphenyl) acetamido-,

2- (t-butoxycarbonyl) -2- (m-isopropoxyphenyl) acetamido-,

2- (diphenylmethoxycarbonyl) -2- (3,4-dimethoxyphenyl)

2- (tert-butoxycarbonyl) -2- [p- (2,5-dichlorobenzamidomethyl) phenyl] acetamido-,

2- (t-butoxycarbonyl) -2- (2-thienyl Jacetamido-),

2- (tert-butoxycarbonyl) -2- (3-thienyl) acetamido-,

2- (sodium oxysulfonyl) -2-phenylacetamido-

2- (sodium oxysulfonyl) -2- (p-methylphenyl) Jacetamido-,

2-potassium oxysulfonyl J-2- (p-hydroxyphenyl Jacetamido-),

2- (lithiumoxysulfonyl) -2- (m-hydroxyphenyl)

2- (sodium oxysulfonyl) -2- (p-methoxyphenyl)

2- (sodium oxysulfonyl) -2- (m-bromophenyl)

2- (sodium oxysulfonyl) -2- (p-chlorophenyl)

2- (sodium oxysulfonyl) -2- (3-methyl-4-fluorophenyl) acetamido-,

2- (sodium oxysulfonyl) -2- (o-fluorophenyl) acetamido-,

2- (sodium oxysulfonyl) -2- (p-fluorophenyl) acetamido-,

2- (sodium oxysulfonyl) -2- (p-acetamidomethylphenyl) acetamido-,

2- (sodium oxysulfonyl) -2- (p-isopropylphenyl)

2- (sodium oxysulfonyl) -2- [3,4-dimethylphenyl]

2- (sodium oxysulfonyl) -2- (m-isopropoxyphenyl)

2- (sodium oxysulfonyl) -2- (3,4-dimethoxyphenyl Jacetamido-,

2- (sodium oxysulfonyl) -2- (2-thienyl) acetamido-,

2- (potassium oxysulfonyl) -2- (3-thienyl) acetamido-,

2- (p-nitrobenzyloxycarbonylamino) -2-phenylacetamido-

2- (t-butoxycarbonylamino) -2- (2-thienyl) acetamido-,

2- (benzyloxycarbonylamino) -2- (m-hydroxyphenyl) acetamido-,

2- (t-butoxycarbonylamino) -2- (p-hydroxyphenyl) acetamido-,

2-ureido-2-phenylacetamido-

2-ureido-2- (2-thienyl) acetamido-,

2- (3-guanyl-1-ureido) -2-phenylacetamido-

2- (3-methylaminocarbonyl-1-ureido) -2-phenylacetamido-,

2- (3-dimethylaminocarbonyl-3-methyl-1-ureido) -2-phenylacetamido-,

2- [N- (imidazolidin-2-one-1-ylcarbonyl) amino] -2-phenylacetamido-,

2- [N- (3-Methylpyridazolidin-2-one-1-ylcarbonyl) amino] -2-phenylacetamido-,

2- [N- (hexahydropyrimidin-2-on-1-ylcarbonyl) amino] -2-phenylacetamido-, 2- [N- (3-methylhexahydropyrimidin-2-on-1-ylcarbonyl) amino) -2-phenylacetamido -, 2- [N- (3-methanesulfonylhexahydropyrimidin-2-one-1-ylcarbonyl) amino] -2-phenylacetamido-,

2- (3-di-n-propylaminocarbonyl-1-ureido) -2-phenylacetamido-,

2 - [(4-ethyl-2,3-dioxo-1-piperazinyl) carbonylamino] -2-phenylacetamido-,

2- (3- (methylsulfonyl) -2-oxo-1-imidazolidinyl) carbonylamino] -2-phenylacetamido-,

2- (2-oxo-4-imidazolin-1-yl) carbonylamino) -2-phenylacetamido-,

2 - [(4-oxo-4H-thiopyran-3-yl) carbonylamino) -2-phenylacetamido-,

2- [3-methyl-3- (methylcarbamoyl) ureido] -2-phenylacetamido-,

2- [3-Methyl-3- (cinnamoylureido)] -2-phenylacetamido-

2- [3-methyl-3- (acryloylureido)] -2-phenylacetamido-,

2 - [(4-ethyl-2,3-dioxo-1-piperazinyl) carbonylamino] -2-thienylacetamido-,

2 - [(4-ethyl-2,3-dioxo-1-piperazinyl) carbonylamino] -2- (p-hydroxyphenyl) acetamido-,

2 - [(4-ethyl-2,3-dioxo-1-piperazinyl) carbonylamino] -2-phenylacetamido-,

2 - [(2-oxoimidazolidin-1-yl) carbonylamino] -3-thienylacetamido- and 2 - ['(2-oxo-3- (methylsulfonyl) -4-imidazolin-1-yl) carbonylamino] -2- (p (hydroxyphenyl) acetamido.

As illustrative examples of groups of the general formula

O

II

R3 — C — NH—

1β where

R ³ represents a group (15), such as:

2- (hydroxyimino) -2-phenylacetamido-

2- (methoxyimino) -2-phenylacetamido-

2- (acetoxyimino) -2-phenylacetamido-

2- (hydroxyimino) -2- (2-thienyl) Jacetamido-,

2- (hydroxyimino) -2- (2-furyl) acetamido-,

2- (methoxyimino) -2- (3-thienyl) acetamido-,

2- (methoxyimino) -2- (2-fluoro) acetamido-,

2- (methoxyimino) -2- (p-hydroxyphenyl) acetamido-,

2- (hydroxyimino) -2- [2- (2,2,2-trichloroethoxycarbonylamino) -4-thiazolyl] acetamidoscupine, tautomeric with 2- (hydroxyimino) -2- [2- (2,2,2-trichloroethoxycarbonylimino) - 4-thiazolin-4-yl] acetamido,

2- (methoxyimino) -2- [2- (p-nitrobenzyloxycarbonylamino) -4-thiazolyl] acetamido tautomeric with 2- (methoxyimino) -2- [2- (p-nitrobenzyloxycarbonylimino) -4-thiazolin-4-yl] ] acetamido a

2- (methoxyimino) -2- (4-chlorophenyl) acetamido.

As illustrative examples of groups of the general formula

O II R ³ —C — NH — where

R ³ represents a group (16) include:

2- (trifluoromethylthio) acetamido-,

2- (methylsulfonyl) acetamido-

2- (cyanomethylthio) acetamido-,

2- (azidomethylthio) acetamido-

2- (ethylsulfonyl) acetamido-

2- (2,2,2-trifluoroethylthio) acetamido-,

2- (methylsulfinyl) acetamido a

2- (cyanomethylsulfinyl) acetamido.

As illustrative examples of groups of the general formula

O

II

R ³ —C — NH— in the above definition of substituents, wherein

R ³ represents a group Y-CH 2 - the following groups may be mentioned:

2- (2-thlenyl) acetamido-

2- (3-thienyl) acetamido-

2- (2-furyl) acetamido-,

2- (2-oxazolyl) acetamido-

2- (2-thiazolyl) acetamido-

2- (1-tetrazolyl)

2- (1-benzotriazolyl) acetamido-

2- (2-oxazoles lthio) acetamido-,

2- (2-thiazolithio) acetamido-,

2- (1,2,3-triazol-5-ylthio) acetamido-,

2- (1,3,4-triazol-2-yl-thio) acetamido-, (1,3,4-thiadiazol-2-ylthio) Jacetamido-, 2- (5- (protected amino) -1,3,4) -thiadiazol-2-ylthio Jacetamido-

2- (5-methyl-1,3,4-thiadiazol-2-ylthio) acetamido-,

2- (1,2,4-thiadiazol-5-ylthio) Jacetamido-

2- (3-methyl-1,2,4-thiadiazol-5-ylthio) acetamido-,

2- (1,2,5-thiadiazol-3-ylthio) acetamido-,

2- (1,3,4-Oxadiazol-2-ylthio) acetamido-, »

2- (5-methyl-1,3,4-oxadiazol-2-ylthio) acetamido-,

2- (1-methyl-5-tetrazolylthio) Jacetamido-,

2- (pyridylthio) acetamido-

2- (4-Cyano-1,2,3-triazol-1-yl) Jacetamido-,

2- (3-cyano-1,2,4-triazol-1-yl) acetamido a

2- (2- / protected amino) -4-thiazolyl) acetamido [tautomeric with 2- (2-amino-4-thiazolin-4-yl Jacetamido)].

Many of the cephalosporanic acids used in the process of the invention as starting materials are known compounds and all are prepared by methods known per se. References include "Cephalosporins and Penicillins, Chemistry and Biology," Edwin H. Flynn (Academic Press, New York, 1972), see in particular Chapters 3, 4 and 15, and references cited therein, as well as the US patent No. 3,914,157 and South African Patent No. 71/3229.

Particularly preferred nucleophilic sulfur compounds of formula III are those wherein R ¹³ is a radical of formula

Preferred five-membered heteroaromatic rings of this formula are:

pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole,

1.2.3- oxadiazole,

1.2.4- oxadiazole,

1.2.5- oxadiazole,

1,3,4-oxadiazole,

1.2.3- thiadiazole,

1.2.4- Thiazoles,

1.2.5- thiadiazole,

1,3,4-thiadiazole,

1.2.3- triazole,

1,2.4- triazole, oxatriazole and tetrazole.

Suitable six-membered circles are:

pyridine, pyridazine, pyrimidine, pyrazine,

1.2.3- triazine,

1.2.4- triazine,

1.3.5- triazine,

1.2.3.4- tetrazine and

1.2.4.5- tetrazine.

Certain heteroarylthiols as well as certain alkylthiols and phenylthiols of formula III actually exist as thiones or as tautomeric mixtures of thiols and thions. An example is 2-methyl-1,3,4-thiadiazole-5-thiol, which exists as a tautomer:

H

N - N

However, the reaction according to the invention proceeds with said classes of nucleophilic sulfur compounds regardless of whether the reactant is in thiol or thionic form. Accordingly, it is within the scope of the invention to carry out the reaction using both thiols and thiol-thionic tautomers as defined above.

The heteroarylthiols may be unsubstituted or may be substituted with one or more substituents. The identity of the substituents is usually not critical. For best results, each primary or secondary amino group should be protected. For those compounds in which the heteroarylthiol contains more than one thiol group, the thiol group not to be involved in the reaction should be protected. Methods for protecting thiols are well known and are described, for example, in the McOmie publication above. Provided that such groups are protected, the reaction proceeds regardless of the identity of the substituent.

Preferably, too large substituents are avoided, usually a substitution having a total molecular weight not exceeding about 500 is preferred. The most common substituted heteroaromatic rings are substituted such that the total molecular weight of the substituents is less than about 250.

Suitable substituents are C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 4 -C 4 alkynyl, C 5 -C 6 cycloalkyl, benzyl, phenethyl, aryl groups such as phenyl and substituted phenyl groups as defined above, halogens, -CF 3, = 0, -OH, protected aminomethyl, or Ci-C4 alkylaminomethylskupiny group -CHaSO3-alkali metal, -CHaCOOH, -CH2COOA ² or - (CH) N (CH3) and.

Representative nucleophilic sulfur compounds of formula III include:

Thioureas:

alkylthiourea, N, N'-di-n-butylthiourea, N, N'-di-tert-butylthiourea, N, N'-dicyclohexylthiourea, N, N'-diisopropylthiourea, N, N'-dimethylthiourea, N-methylthiourea, N , N, N ', N'-tetraethylthiourea, N, N, N', N'-tetramethylthiourea, thiourea,>

N-phenylthiourea, N, N‘-diphenylthiourea, Ν, Ν-dimethylthiourea, Thiobenzoic acid,

Alkylthiols:

methanthiol, ethanethiol, 1- or 2-propanethiol,

1- or 2-butanethiol,

2-methyl-1-propanethiol.

Benzenthiols:

benzenthiol,

4-bromo-3-methylbenzenethiol, p-bromobenzenethiol, p-chlorobenzenethiol,

2,5-dichlorobenzenethiol,

3,4-dichlorobenzenethiol, 4-fluorobenzenethiol, m-methoxybenzenethiol, p-methoxy benzenethiol, p-nitrobenzenethiol, p-methylbenzenethiol.

Heteroarylthiols:

2-pyrrolthiol,

3-pyrazolthiol, 2-methyl-3-pyrazolthiol, 2-methyl-4-imidazolthiol,

N E 11 5

2- imidazolthiol,

4-oxazolthiol,

3-isoxazolthiol,

2-thiazolthiol,

3-isothiazolthiol, 1-methyl-1,2,3-triazole-5-thiol,

1-Benzyl-1,2,3-triazole-4-thiol

2-Methyl-1,2,3-triazole-4-thiol

3,5-dimethyl-1,2,3-triazole-4-thiol,

1,2.4-triazole-3-thiol,

4-Methyl-1,2,4-triazole-5-thiol

3-Methyl-1,2,4-triazole-5-thiol

3,4-dimethyl-1,2,4-triazole-5-thiol, 2-methyl-1,2,4-triazole-5-thiol,

2-Benzyl-1,2,4-trlazole-5-thiol

4-Methyl-3- (trifluoromethyl) -1,2,4-triazole-5-thiol

3-carbamoyl-4-methyl-1,2,4-triazole-5-thiol,

3- (carboxymethyl) -4-methyl-1,2,4-

-trlazole-5-thiol,

3- (ethoxycarbonylmethyl) -4-methyl-1,2,4-triazole-5-thiol protected with 3-amino-4-methyl-1,2,4-triazole-5-thiol,

3-hydroxy-4-methyl-1,2,4-triazole-5-thiol,

5-Methyl-1,2,3-oxadiazole-4-thiol

1,2.4-oxadiazole-3-thiol, 3-methyl-1,2,4-oxadiazole-5-thiol,

3-Ίηβ№-11-1,2,5-οχβάίβζο1-4-ί1ι1ο1,

2-Methyl-1,3,4-oxadiazole-5-thiol

3-Methyl-1,2,4-thladiazole-5-thiol

1.3.4-thiadiazole-5-thiol,

2-methyl-1,3,4-thiadiazole-5-thiol,

2- (N-methylacetamido) -1,3,4-thiadiazole-5-thiol,

5-tetrazolthiol, 1-methyltetrazole-5-thiol, 1-benzyltetrazole-5-thiol,

1- (carboxymethyl) tetrazole-5-thiol

1 - [(sodium oxysulfonyl) methyl] tetrazole-

-5-thiol,

1- (2-dimethylaminoethyl) tetrazole-

-5-thiol,

1.2.3.4-oxatriazole-5-thiol,

2- pyridinthiol,

2-pyridinethiol, 1-oxide,

3-pyridazinthiol,

2-pyrimidine thiol,

2-pyrazinthlol,

1,2.3-triazine-4-thiol,

1,2.4-triazine-3-thiol,

4,5-Dihydro-6-hydroxy-4-methyl-5-oxo-

-1,2,4-triazine-3-thiol,

1.3.5-triazine-2-thiol,

1.2.4.5-Tetrazine-3-thiol

2-benzimidazolthlol,

2-benzothiazolthiol,

2-benzooxazolthiol, tetrazolo (1,5-b) pyridazin-6-thiol.

Most nucleophilic sulfur compounds used in the method of the invention are known compounds and all can be prepared by known methods. In the context of heteroarylthols, attention is drawn to numerous volumes of "Heterocyclic Gompounds", edited by Robert C. Elderfield (John Wiley &amp; Sons, Inc., NY J), and to various volumes relating to particular heterocyclic systems that appear in the series "The Chemistry of Heterocyclic Compounds, “edited by Weíssberger and others (John Wiley and Sons., NYj

In the process according to the invention, the reaction in an organic solvent is of decisive importance. However, the identity of the solvent is no longer critical, as it has been shown that a large number of different organic solvents can be used successfully. In general, suitable solvents include solvents in the following classes: hydrocarbons, both aliphatic and aromatic, alcohols, amides, ethers, ketones, carboxylic acids, carboxylic acid esters, halogenated hydrocarbons, nitro compounds, nitriles and thioethers. Since some nucleophilic sulfur compounds are liquid, an excess of such compounds can also be used as solvents in this case.

The solvent should be inert in the sense that it should not undergo a competitive reaction with either of the reactants.

Specific solvents suitable for the practice of the present invention include: pentane, cyclopentane, hexane, heptane, octane, benzene, toluene, o-, m- or p-xylene, cumene, mesitylene, p-cymene, 1-pentene, diethyl ether, butyl ether, diamyl ether, benzyl ether, acetone, methyl ethyl ketone, 2-butanone, 3-pentanone, methyl isobutyl ketone, cyclohexanone, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, propyl acetate, isopropyl acetate, , isobutyl acetate, sec.butyl acetate, amyl acetate, isoamyl acetate, ethylisovalerate, methylbenzoate, benzyl acetate, methylbutyrate, diethyl carbonate, dimethyl maleate, diethyloxalate, ethylene glycol diacetate, diethyl malonate, fluorobenzene, chlorobenzene, bromobenzene, o-, m- or p- fluoro, or p-chlorotoluene, o-, m- or p-bromotoluene, 2-chloroethane, 1 or 2-chloropropane, 1- or 2-chlorobutane, 1-chloro-2-methylpropane, 1, 2 or 3- chlorpentane, 1-chloronaphthalene, methylene chloride, chloroform, carbon tetrachloride,

1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, o-, m- or p-dichlorobenzene, nitromethane, nitroethane, 1- or 2-nitropropane, nitrobenzene, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, benzonitrile, phenylacetonitrile and thiophene.

Preferred solvents are:

Hydrocarbons:

benzene, toluene, o-, m- or p-xylene, cumene, mesitylene.

Halogenated hydrocarbons:

chloroethane,

1- or 2-chloropropane,

1- or 2-chlorobutane, isobutyl chloride, 1-, 2- or 3-chloropentane, methylene chloride, * chloroform,

1,2-dichloroethane, carbon tetrachloride, 1,1,1-trichloroethane, ♦ 1,1,2-trichloroethane,

1.1.2.2- tetrachloroethane, fluorobenzene, chlorobenzene, bromobenzene, o-, m- or p-fluorotoluene, o-, m- or p-chlorotoluene, o-, m- or p-bromotoluene, o-, m- or p -dichlorobenzene.

Acids:

acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid.

Esters:

methyl acetate, ethylene glycol diacetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, pentylacetate, ethyl propionate, methyl butyrate, n-butylformate, propylene carbonate, ethylene carbonate.

Nitro compounds:

nitrobenzene, nitromethane, nitroethane, nitropropane.

Nitriles:

acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, benzonitrile, phenylacetonitrile.

Ketones: methyl isobutyl ketone, methyl ethyl ketone.

Particularly suitable solvents are acetonitrile, 1,2-dichloroethane, methylene chloride, propionitrile, nitromethane, nitroethane, acetic acid, isopropyl acetate, butyl acetate and methyl isobutyl ketone.

The 3- (acyloxymethyl) cephalosporin of formula II is defined as an acid and is believed to be the acid involved in the reaction since cephalosporin salts are generally not soluble in organic solvents, except for the solubility of cephalosporin salts in carboxylic acids as solvents. Thus, the reaction of the invention can be carried out by dissolving the 3- (asloxymethyl) cephalosporin salt as a metal salt in a carboxylic acid solvent.

Regardless of the identity of the solvent, the process of the invention is required to be conducted under substantially anhydrous conditions. The reaction mixture should generally contain less than 5% water and preferably less than 10% water, more preferably less than 0.5% water. If the commercial reactants and solvents are not sufficiently dry, water can be removed therefrom by known methods such as azeotropic distillation and drying with desiccants such as aluminum oxide, silica gel, anhydrous calcium sulfate and the like.

The reaction of the invention takes place over a wide temperature range. Usually, a reaction temperature of 50 to 140 ° C can be used, but better results are usually obtained at 70 to 120 ° C. The reaction can be carried out at elevated pressures, but no advantages are achieved. For simplicity, atmospheric pressure is therefore preferred.

The amount of reagents is not critical. Usually, it is preferred to use an excess of the nucleophilic sulfur compound, such as 1.0 to 5.0 molar equivalents of the nucleophilic sulfur compound per molar equivalent of the 3- (α-alkoxymethyl) -cephalosporin reagent.

The process of the invention is particularly suitable for introducing the following 3-heteroarylthio groups into cephalosporin:

5-methyl-1,3,4-thiadiazol-2-ylthio-, 1-methyl-1H-tetrazol-5-ylthio-, 1-carboxymethyl-1H-tetrazol-5-ylthio-, 4-methyl-6-hydroxy -5-oxo-1,2,4-triazin-3-ylthio-

1-Methyl-1,3,4-triazol-2-ylthio-

2-Methyl-1,3,4-triazol-5-ylthio-

1,2-dimethyl-1,3,4-triazol-5-ylthio-

3-Methyl-1,3,4-triazol-5-ylthio-

2,3-dimethyl-1,3,4-triazol-5-ylthio-, 1-methyl-2-trifluoromethyl-1,3,4-triazol-5-ylthio-, 1-methyl-2-carboxamido-1,3, 4-triazol-5-ylthio-, 1-methyl-2-carboxymethyl-1,3,4-triazol-5-ylthio-, 1-methyl-2-alkoxycarbonyl-1,3,4-triazol-5-ylthio- 1,1-methyl-2- (protected aminomethyl) -1,3,4-triazol-5-ylthio;

1-methyl-2- (protected amino) -1,3,4-triazol-5-ylthio-, 1-methyl-2-hydroxy-1,3,4-triazol-5-ylthio-, 1H-tetrazol-5 -ylthio-,

1- (2-dimethylaminoethyl) -1H1- (sulfomethyl) -1H-tetrazol-5-ylthio in the form of an alkali metal salt, cefamandole:

5-methyl-1,3,4-oxadiazol-2-ylthio-, 1,3,4-thiadiazol-2-ylthio-,

3-methyl-1,2,4-thiadiazol-5-ylthio-a

2- (protected aminomethyl) -1,3,4-thiadiazol-5-ylthio.

Among the known known cephalosporin compounds of formula (I), which can be prepared synthetically using the process of the invention, are:

cefamandolnafát:

cefazoline:

ceftezol:

COOH cefazaflur:

O

CF 3 SCH 3 CNH

CHj

COOH

SCE-963

X

CS-1170:

O O II Ě

NCCH 3 SCH 3 CNH 1

COOH

SQ-67 590:

N ----- N

CH ^H

BBS-226

O

CH 2 CNH

COOH

SQ-14 359

CH-CNH NH i

C-0

NH *.

The compounds of the invention, their deprotected derivatives, and their pharmaceutical salts are useful in controlling infections in warm-blooded mammals when administered parenterally at non-toxic doses ranging from 10 to 500 mg / kg body weight. The processing of the compounds into dosage forms is carried out according to conventional procedures.

The following examples serve to illustrate the invention in more detail. The examples are illustrative only and do not limit the scope of the invention.

Example 1

Preparation of 3 - {[[1-methyl-1H-tetrazol-5-yl) thio] methyl} -7- [2- [2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetoniiril

7- [2- [2-Thienyl) acetamido] cep alosporanic acid [2.2 g, 5.5 mmol) and 1-methyl-1H-tetrazole-5-thiol [1.0 g, 8.6 mmol) were added to 25 ml of acetylliil in a flask equipped with a reflux condenser containing a drying tube containing anhydrous calcium sulfate (Drierite). The reaction mixture is refluxed under stirring and the progress of the reaction is monitored by thin-layer chromatography. layer [TLC]. After refluxing for 90 minutes, TLC indicated that the reaction mixture contained about two-thirds of the starting cephalosporanic acid and one-third of the desired product. After refluxing for 3 hours, TLC indicated that the reaction mixture contained about one-third of the starting cephalosporanic acid and two-thirds of the product. After 6 hours, when TLC indicated that the reaction was substantially complete, the reaction mixture was cooled to room temperature and allowed to stand overnight. Remove the solvent in a rotary evaporator. The residue is a foam which is dissolved in 10 ml of ethanol. 1 ml of dicyclohexylamine in 10 ml of ethanol is added dropwise. The product precipitated as a dicyclohexylamine salt and this salt was filtered off after 15 minutes of stirring. The isolated product was washed with 15 ml of ethanol and then dried under vacuum at 40 ° C for 2 hours. 2.50 g of product are obtained (76.1% yield), m.p. 183 DEG-184 DEG C. [decomposition]. The product was subjected to NMR, IC and TLC analysis. All these analyzes are identical to those of an authentic sample of the product prepared by the displacement procedure in an aqueous environment according to the prior art.

NMR [DMSO-d6]

3.52 (m, 2CH2),

3.76 [s, 2, —CH2 CONH—],

3.92 [s, 3, —CH 3 tetrazole),

4.35 (s, 2,3-CH2S),

5.00 [d, 1, Ce-H, J = 5 Hz),

5.55 (q, 1, C 7 -H, J = 5 Hz, J = 9 Hz),

6.95 (d, 2, thiophene 3-, and 4-H, J = 3 Hz),

7.35 [t, 1, thiophene 5-H, J = 3 Hz), and 8.75 [d, 1, -CH CONH-, J = 9 Hz).

Example 2

Preparation of 3 - [[[1-methyl-1H-tetrazol-S-yl) thio] methyl} -7- [2- [2-thienyl] acetamido] -3-cephem-4-carboxylic acid in acetone

7- [2- (4-Thienyl) acetamido] cep alosporanic acid [4.0 g, 10 mmol) and 1-methyl-1H-tetrazole-4-thiol [5.8 g, 50 mmol) were refluxed at 50 ° C. ml of dry acetonitrile (treated with anhydrous acidic ion exchange resin with Amberlite 15 sulfonic acid groups) under a dry atmosphere for 8 3/4 hours. The reaction is monitored by TLC and is virtually complete after 33/4 hours.

The solvent was evaporated and the residue was added to 125 ml of ethanol. Dicyclohexylamine (6 mL) in 75 mL of ethanol was added and the product precipitated as the dicyclohexylamine salt. The salt is filtered off, washed and dried. 4.50 g of product are obtained [yield 71.0%]. IR, NMR and TLC are identical to analyzes of the displacement sample in aqueous media. The NMR is also identical to the NMR of the product of Example 1.

Example 3

Preparation of 3 - {[[1-methyl-1H-tetrazol-4-yl) thio] methyl] -7- [2- [2-thienyl] acetamido] -3-cephem-4-carboxylic acid in 1,2- 7- [2- [2- [1 - [(1 R) -acetamido] cephalosporanic acid [2.0 g, 5 mmol] and 1-methyl-1H-tetrazol-5-thill [1] (2 g, 10 mmol) in 25 mL of 1,2-dichloroethane was refluxed in a dry atmosphere for 5.5 hours. The solvent was removed on a rotary evaporator and 25 ml of ethanol was added to the filtrate, followed by the dropwise addition of a solution of 2 ml of dicyclohexylamine in 25 ml of ethanol. The product crystallized as the dicyclohexylamine salt. The mixture is stirred at room temperature for 20 minutes, then the salt is filtered off, washed with 25 ml of ethanol and dried under vacuum at 40 ° C. 2.34 g of off-white solid are obtained (yield 73.8%). IC and NMR are identical to analyzes of a sample prepared by displacement in an aqueous medium. The NMR is also identical to the NMR of the product of Example 1.

Example 4

Preparation of 3 - ([(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7-amino-3-cephem-4-carboxylic acid in 1,2-dichloroethane

7-F'Ormamidocephalosporanic acid (3.0 g, 10 mmol) and 1-methyl-1H-tetrazole-5-thiol (2.4 g, 20 mmol) in 50 ml 1,2-dichloroethane are boiled under stirring for 7 hours The reaction mixture was cooled to room temperature and allowed to stand overnight at room temperature, whereupon a red resinous solid precipitated.The product was identified by cleavage of the 7-formyl group as follows:

The solvent was removed by rotary evaporation and the residue was dissolved in 25 ml of methanol and 2.8 ml of concentrated hydrochloric acid and allowed to stand overnight at room temperature. The solution was then diluted to 50 mL with water and the pH was raised from 0.9 to 3.6 by dropwise addition of triethylamine. The light brown crystals are filtered off, washed with water and dried. It is obtained

2.10 g of product (yield 64%). NMR is the same as NMR of the same aqueous displacement product.

NMR (D 2 O, НаНСОз) δ

3.65 (q, 2, 2-CH 2, J _A b = 16.5 Hz), 4.08 (s, 3, -CHN 2 on tetrazole), 4.16 (q, 2, 3-CH 2 S), J _AB = 12.5 Hz), 5.05 (d, 1, C0-H, J = 5 Hz) and 5.45 (d, 1, C7-H, J = 5 Hz).

Example 5

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in isopropyl acetate

7- [2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thiol (1.2 g, 10 mmol) in 2'5 milliliters of isopropyl acetate was stirred and heated at reflux (90 ° C) for 23 hours.

The reaction mixture was then cooled to room temperature. TLC shows that some of the starting cephalosporanic acid remains in the reaction mixture. The light cream colored solid was filtered off, washed with isopropyl acetate and dried. 1.60 g of product is obtained (yield 70.8%). NMR confirms the identity of the product and shows that the starting cephalosporanic acid content of the reaction mixture is below 1%.

NMR (DMSO-d 6)?

3.72 (s, 2,2-CH2J,

3.80 (s, 2, —CH2 CONH—),

3.95 (s, 3, —N-tetrazole),

4.30 (s, 2,3-CH 2 S -),

5.10 (d, 1, SA-H, J = 5 Hz),

5.70 (q, 1, C 7 -H, J = 5 Hz, J = 8 Hz),

6.92 (d, 2, thiophene 3- and 4-H, J = 3 Hz),

7.35 (t, 1, thiophene 5-H, J = 3 Hz), a

8.78 (d, 1, - CH 2 CONH -, J = 8 Hz).

Example 6

Preparation of 3-i [(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in propionitrile

7- [2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thiol (1.2 g, 10 mmol) were refluxed in 25 ml dry propionitrile (97 ° C) until TLC indicated complete disappearance of the starting cephalosporanic acid in the reaction mixture (4.5 hours). The reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation. During evaporation, some of the solution is lost as a result of boiling. The residue is dissolved in 35 ml of warm ethanol and 2 ml of dicyclohexylamine in 10 ml of ethanol are added. The product precipitated as the dicyclohexylamine salt. The mixture was stirred at room temperature for 10 minutes and then the salt was filtered off, washed with ethanol and dried. 1.24 g of product are obtained (39% yield, excluding product loss on a rotary evaporator). The NMR of the product is identical to that of Example 1.

Example 7

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetonitrile with addition of 3, 5-dichlorophenyldihydrogenphosphate

7- [2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol), 1-methyl-1H-tetrazole-5-thiol (0.87 g, 7.5 mmol) and 3, The 5-dichlorophenyldihydrogen phosphate (0.122 g, 0.5 mmol) was heated overnight in 25 mL dry acetonitrile at 70 ° C. The solvent was then evaporated in a rotary evaporator to 8-10 ml. The product begins to crystallize. After stirring for half an hour, isopropyl acetate (25 mL) was added dropwise over 1/2 hour, causing further crystallization. After stirring for a further 1/2 hour, the product was filtered off, washed with isopropyl acetate and dried. 0.98 g of product is obtained (yield 43.4%). The NMR of the product is identical to that of Example 5.

Example8

Preparation of 3- | [(1H-tetrazol-5-yl) thio] methyl | -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetic acid

7- [2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thlol (0.87 g, 7.5 mmol) were added to glacial acetic acid (25 mL). The reaction mixture was heated to 60 ° C and held at this temperature for 1 hour. Only traces of product were detected by TLC. The reaction mixture was heated to 80 ° C and held at this temperature for 5 hours. The mixture was allowed to stand overnight, the product was filtered off, washed with acetic acid and dried. 0.71 g of product is obtained (yield 31%). The NMR of the product is identical to that of Example 5.

Example 9

Preparation of 3 - ([(4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-yl) thio] methyl) -7- [2- (2-thienyl) Acetamido] -3-cephem-4-carboxylic acid in acetonitrile

7- [2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol) and 4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazine 3-thiol (1.2 g, 7.5 mmol) were added к 25 ml of dry acetonitrile in a reaction flask immersed in an oil bath heated at 84 to 85 ^Q C. the flask was fitted with a reflux condenser with a drying tube containing anhydrous calcium sulfate (Drierite). The reaction mixture was maintained under slow magnetic stirring for 16 hours under these conditions.

The product crystallized from the hot solution. The reaction mixture was cooled to room temperature, filtered, washed with acetonitrile, acetone and evaporated in vacuo. It is obtained

1.81 g of product (yield 72.6%). The product is in the form of off-white crystals, m.p. 161 DEG C. (decomposition).

On standing, a second crystal fraction settles from the filtrate. This fraction was filtered, washed with acetonitrile and dried. 0.26 g of product is obtained (yield 10.5%). Also this product has a melting point of 161 ° C (decomposition).

The total yield is thus 83.1%.

Example 10

Preparation of 3 - {[(5-methyl-1,3,4-oxadiazol-2-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1, 2-dichloroethane

7- (2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol) and 5-methyl-1,3,4-oxadiazole-2-thiol (0.87 g, 7.5 mmol) in 25 ml 1,2-dichloroethane is placed in a flask equipped with a magnetic stir bar and reflux condenser with a drying tube filled with anhydrous calcium sulfate (Drierite) .The flask is immersed in an oil bath and heated at 84-85 ° C for 8 hours. hours and then stored in the fridge for two days.

The crystallized part of the product was filtered off, washed with 1,2-dichloroethane. and dried. (1.10 g, yield 48.7%). This product was dissolved in acetone and the solution was filtered to separate any insoluble material. Then 75 ml of deionized water are added dropwise, the product is filtered off and dried. 0.61 g of product is obtained, m.p. > 114 DEG C. (decomposition).

Evaporation of the solvent from the filtrate gave 0.23 g of a mixture of product and both starting materials.

Example 11

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in nitromethane

7- [2.- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.87 g, 7.5 mmol) were added. add to 25 ml dry nitromethane in the flask. The flask was immersed in an oil bath at 100-101 ° C for 4.5 hours and then cooled to room temperature. TLC indicates the reaction is complete.

The solvent was removed by rotary evaporation and the residue was dissolved in 75 ml of warm ethyl acetate. The solution was filtered to remove a small amount of insoluble matter and then extracted with two 25 ml portions of 5% aqueous sodium bicarbonate. The combined extracts were covered with 50 mL of ethyl acetate and acidified to about 1.0 with 70% aqueous methanesulfonic acid. The ethyl acetate layer was separated and the aqueous layer was extracted with 25 mL of ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and concentrated to 25 mL in a rotary evaporator. 50 ml of diethyl ether are added dropwise, resulting in crystallization of the product. The product was filtered off, washed with diethyl ether and dried. Yield: 1.27 g (56.2% of theory), off-white crystals, m.p. 156 DEG-159 DEG C. (dec.). The identity of the product was confirmed by NMR.

Example 12

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in methylene chloride

7- (2- (2-Trenyl) acetamido] cep alosporanic acid (11.9 g, 30 mmol) and 1-methyl-1H-tetrazole-5-thiol (7.0 g, 60 mmol) in 100 mL The methylene chloride (cyclohexane stabilized) was placed in a 1 liter stainless steel autoclave equipped with a heating system, and the reaction mixture was stirred and heated to 83-86 ^° C for 16 hours to adjust the pressure to 289 kPa. TLC indicated that conversion to the final product was complete and that only traces of starting cephalosporanic acid were present in the mixture, the reaction mixture was allowed to stand at room temperature, crystallized and concentrated to 200 mL. 7.37 g (yield 54.3%) white crystals, mp 163.5 DEG-164 ^q C (dec).

A second crop of light brown crystals is obtained by diluting the filtrate with 100 ml of diethyl ether, filtering, washing the product with diethyl ether and drying. 1.40 g (10.3 percent of theory) of the product is obtained.

A third crop is obtained by diluting the filtrate with isopropyl acetate. 1.18 g of product is obtained (8.7% of theory).

The total yield is thus 73.3%.

Example 13

Preparation of 3 - {[(1- (2-thienyl) -1H-thiazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4 -carboxylic acids in fluorobenzene

7- (2- (2-Thienyl) acetamido) cephalosporanic acid (2.0 g, 5,05.04 mmol) and 1-methyl-1H-tetrazole-5-thiol (1.2 g, 10 mmol) in 75 mL of fluorobenzene (boiling point 85.1 ° C) was mixed in a flask equipped with a reflux condenser with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite. The mixture was refluxed and monitored by TLC in ethyl acetate / acetic acid 7: 1. The reaction, which is heterogeneous to the end, is complete after 72 hours.

The reaction mixture was cooled to room temperature and filtered to separate the precipitated product. The product was washed with fluorobenzene and dried under vacuum at 40 ° C for 4 hours. 2.13 g of product (93.4%) are obtained as off-white crystals, m.p. 161 DEG-162 DEG C. (decomposition). The identity of the product was confirmed by NMR.

Example 14

Preparation of 3 - [[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in thiophene

7- (2- (2-Thienyl) acetamido 1-cep alosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazol-5-thiol (0.87 g, 7.5 mmol) in 25 mL of thiophene for 7 hours The reaction mixture is cooled to room temperature, stirred for 30 minutes to complete crystallization and then filtered, and the product is washed with 0.5 ml of thiophene and then dried under vacuum for 2 hours. 1.82 g (80.2% of theory) of white crystals, m.p.

Example 15

Preparation of 3 - _{([(5-methyl-l>} 3,4-thiadlaz-ol-2-yl) thio] methyl lj- 7- (2- (lH-tetrazol-yl) acetamido] -3-cephem-4- carboxylation of the acid in the form of the acid

7- (2- (tert-butoxy) acetamido] cep alosporanic acid (0.76 g, 2 mmol) and 5-methyl-1,3,4-thiadiazole-2-thiol (0.33 g, 2, 5 mmol) in 10 ml of chemically pure acetonitrile was refluxed for 2 hours and 40 minutes, the product crystallized, cooled in an ice bath, filtered, washed with 3 ml and dried at 40 ° C under vacuum. 0.61 g (67% of theory) was confirmed by NMR.

NMR δ

2.68 (s, 3, CH tetrazot),

3.72 (s, 2, O-CH 2),

4.40 (q, 2,3-CH 2 S -, Jab = 13 Hz),

5.12 (d, 1, CeH, J = 5Hz),

5.38 (s, 2, -CH 2 CONH);

5.72 (Q, 1, C7-H, J = 5 Hz, J = 9 Hz),

9.00 (s, 1, tetrazole 5-H);

9.17 (d, 1, —CH2 CONH-).

Example 16

Preparation of 3 - {[- (1-methyl-1H-tetrazol-5-yl] thio] -methyl] -7- (2-formyl-oxy-2-phenylacetamido) -tetrafine-4-carboxylic acid in 1,2- dichloroethane

7- (2-Formyloxy-2-phenylacetamido) cep alosporanic acid (2.17 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.87 g, 7.5 mmol) were added. to 25 ml of 1,2-dichloroethane and the resulting reaction mixture was refluxed for 6 hours. After 3 and 6 hours, pro-TLC samples were taken. The reaction mixture was heated for an additional hour and then allowed to cool overnight.

The solvent was evaporated and diethyl ether was added to the residue. Thereby, the residue is first turned into a resin and then solidifies. The product is filtered off, washed with diethyl ether and dried. Yield 1.90 g (77.0% of theory).

NMR (DMSO-d 6) δ

3.52 (s, 2,2-CH 2),

3.88 (s, 3, -CHs tetrazole),

4.10 (s, 2,3-CH 2 S -),

4.92 (d, 1, C 6 -H), .....

5.62 (q, 1, CtT, J = 5 Hz, J = 9 Hz),

6.06 (s, 1, CHCONH)],

7.26 (s, 5, phenyl H) and

8.28 (s, 1, 0%).

II o

Example 17

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [5-carboxy-5- (2,4-dichlorobenzamido) valeramido] -3-cephem-4-carboxylic acid in (A) acetonitrile and (B 1, 1,2-dichloroethane (A) 7- [5-carboxy-5- (2,4-dichlorobenzamido) valeramido] cephalosporanic acid (2.9 g, 5 mmol), 1-methyl- 1 H-Tetrazole-5-thiol (1.2 g, 10 mmol) and 50 mL of acetonitrile were refluxed together for 18 hours.The TLC indicated the reaction was complete and was about 90% complete. The residue was suspended in ethyl acetate and filtered to give 1.51 g (48.3% of theory) of the product.

(B) 7- [5-carboxy-5- (2,4-dichlorobenzamido) valeramido] cephalosporanic acid (2.9 g, 5 mmol), 1-methyl-1H-tetrazole-5-thiol (1.2 g, 10 mmol) and 50 ml of 1,2-dichloroethane were refluxed together for 5.5 hours. TLC shows the reaction to be about 90% conversion.

The solvent was decanted from the reaction mixture and a plastic solid was obtained as a residue. The residue was triturated with ether at reflux. The product was filtered off to give 2.83 g (89.3% of theory) of light brown crystals. NMR confirms the identity of the product and shows that the product contains ether.

NMR (DMSO-d 6) δ

1.78 and 2.26 (each m, adipoyl side chain),

3.66 (m, 2,2-CH2),

3.95 (s, 3, —N-tetrazole),

4.30 (m, 2,3,3-CH2-),

5.08 (d, 1, Ce-H, J = 5Hz),

5.68 (q, 1, C 7 -H, J = 5 Hz),

7.50 and 7.62 (each s, 2,4-dichlorophenyl); and 9.00 (m, 2, two-CONH).

Example 18

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- [2- (2-thlenyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (0.99 g, 2.5 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.58 g, 5 mmol) were added to 12 5 ml of 1,2-dichloroethane are added and the reaction mixture is heated to reflux and acetic acid formed as by-product is removed from the reflux by returning the 1,2-dichloroethane reflux through calcium oxide.

After 5.75 hours at reflux, the reaction mixture was cooled to room temperature and filtered. The feather needles were washed with 10 ml 1,2-dichloroethane and dried. Yield: 0.77 g (66.1%).

Evaporation of the filtrate gave an additional 0.04 g of product (yield 3.5%).

The identity of the product was confirmed by TLC and NMR for the major product. NMR is identical to NMR of the product of Example 5.

Example 19

Preparation of 3 - ([(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl) -7- [2- (2-thlenyl) acetamido] -3-cephem-4-carboxylic acid in acetonitrile

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol) and 5-methyl-1,3,4-thiadiazole-2-thiol (2.64 g, 20 mmol) in 25 ml of acetonitrile is refluxed overnight at 79 DEG C. TLC shows that the reaction mixture contains only traces of starting cephalosporanic acid, the reaction mixture is filtered to remove the oily residue, and the solvent of the filtrate is evaporated on a rotary evaporator. from 1: 1 acetonitrile: isopropyl acetate, the crystals were filtered off, washed and dried under vacuum to yield 1.59 g (33.9% of theory), mp 166 DEG C. The identity of the product was confirmed by IR, UV, NMR, MS and elementary analysis.

NMR (DMSO-d 6) δ

2.68 (s, 3, —N-tetrazole),

3.68 (s, 2, 2-Min),

3.76 (s, 2, —CH2 CONH—),

4.38 (q, 2,3-CH 2 S -, J = 13 Hz),

5.10 (d, 1, C-H, J = 5 Hz),

5.70 (q, 1, C 7 -H, J = 5 Hz, J = 9 Hz).

6.92 (d, 2, thiophene 3- and 4-H),

7.37 (t, 1, thiophene 5-H) a

9.10 (d, 1, -CH 2 CONH, J = 9 Hz).

Example 20

Preparation of 3 - (((1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,1 , 2-trichloroethane

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thiol (1.2 g, 10 mmol) were added to 25 mL 1 1,2,2-trichloroethane and heated to 100-101 [deg.] C. The reaction is monitored by TLC After 4 hours of stirring at 100-101 [deg.] C, TLC shows that the reaction mixture no longer contains the starting cephalosporic acid. The product crystallizes, the solvent is filtered off, 25 ml of 1,2-dichloroethane are added, the solvent is filtered off again, the product is washed and dried under vacuum.

There were obtained 0.98 g of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-fluoro) acetamido] -3-cephem-4-carboxylic acid. m.p. 158 DEG C. (decomposition) (43.4% of theory).

They did

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in (A) (methyl) ethyl ketone and (B) 1,1,2-trichloroethane (A) 7- (2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-S -thiol (1.2 g, 10 mmol) was added to 25 mL of methyl ethyl ketone and the mixture was refluxed for 48 hours.TLC showed that only traces of starting cephalosporanic acid remained in the reaction mixture. 5 g of sodium bicarbonate in 50 ml of water, the aqueous layer was purified with 1 g of activated carbon and 50 ml of ethyl acetate were added, the pH was lowered to pH 1.6 by addition of 4 ml of methanesulfonic acid in 30 ml of water. Sodium and evaporate in a rotary evaporator to an oil.

The product is crystallized by dropwise addition of 50 ml of ether. The product is then filtered off, washed and dried under vacuum. Yield: 0.94 g (41.6% of theory). NMR is identical to NMR of the product of Example 5.

(B) The reaction was repeated using the same starting materials in the same amounts as in (A) except that 50 ml of 1,1,2-trichlorethylene was used as solvent. The reaction mixture was refluxed for 16 hours at which time TLC indicated that the reaction mixture no longer contained any starting cephalosporanic acid. The product was collected as in procedure (A). Yield: 0.47 g (20.8% of theory). NMR was identical to that of Example 5.

Example '22

Preparation of 3 - [(1-methyl-1H-tetrazol-5-yl) thio] methyl} -7- (2-phenylacetamido) -7-methoxy-3-cephem-4-carboxylic acid in 1,2- dichloroethane

7- (2-Phenol-11-yl) -7-methoxycephalosporanic acid (210 mg, 0.5 mmol); 1 H-1 H -thiazol-5-thiol (87 mg, 0.75 mmol) and 15 mL of 1,2-dichloroethane were combined and refluxed for 6 hours, TLC showed only traces of starting cephalosporan in the mixture. Additional 1-methyl-1H-tetrazole-5-thiol (29 mg, 0.25 mmol) was added to the reaction mixture and refluxed for an additional 3 hours.

The reaction mixture was washed 4 times with saturated sodium bicarbonate solution, the hydrogencarbonate layer was washed 3 times with ethyl acetate, fresh ethyl acetate was added, the mixture was cooled to 0 · 0 and the pH was adjusted to 2.2 with 20% hydrochloric acid. The layers were separated and the aqueous layer was washed with ethyl acetate. The acetate layers were combined, washed with saturated brine, dried (MgSO 4), filtered and evaporated. A pale green foam is obtained as a residue. Yield 199 g (83.6% of theory). The identity of the product was confirmed by TLC and NMR.

NMR (CDCl 3 + 1d acetone-d6) δ

3.45 (s, 3, - OCHs),

3.55 (s, 2,2-CH 2), .....

3.75 (s, 2.0 CIHCOO),

3.9 (s, 3, CH3 on tetrazole),

4.4 (s, 2, 3-OH 2 S -),

5.15 (s, 1, Co-H),

7.35 (s, 5, O).

8.0 (s, 1, CH 2 CONH) and ~ 11.2 (s, 1, J = 0 Hz, CHOOH).

Example 23

Preparation of 3 - {[(2-benzothiazazoylthio) methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichlorotethane

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (1.0 g, 2.5 mmol) and 2-mercaptobenzothiazole (0.625 g, 3.75 mmol) were placed in a flask, air was removed with a stream of nitrogen, added The reaction mixture was heated to reflux and refluxed for 24 hours with stirring, then the reaction mixture was cooled and filtered to give the product as an off-white solid in a yield of 1.1 g (m.p. M.p. 190.5-191 DEG C. (decomposition) The product is dried under vacuum at 40 DEG C. overnight and then subjected to analysis, and the identity of the product is confirmed by NMR, UV, mass spectroscopy, IR. and elementary analysis.

NMR (DMSO-d 6) δ

3.74 (s, 2,2-CH 2),

3.80 (s, 2, - CH 2 CONH -),

4.58 (q, 2,3-CH 2 S -, J = 13 Hz),

5.14 (d, 1, Ce-H, J = 5Hz),

5.73 (q, 1, C 7 -H, J = 5Hz, J = 8Hz),

6.96, 7.43 and 7.96 (each m, phenyl and thienyl ring),

9.10 (d, 1, —CH2 CONH-, J = 8 Hz).

Example 24

Preparation of 3 - {[(5- (N-methylacetamido) -1,3,4-thiadiazzl-2-yl) thio] methyl) -7- [2- (24-phenyl) acetamido] -3-cephem-4-carboxylic acid of acid in 1,2-dichloroethane

7- (2- (2-Thienyl) acetamido) cep alospora205115 new acid (2.0 g, 5 mmol) and 5- (N-methylacetamido) -1,3,4-thiadiazole-2-thio-1 (1, 2-thienyl) acetamido 42 g (7.5 mmol) are added to 50 ml of 1,2-dichloroethane and the reaction mixture is refluxed for 10 hours, then cooled, filtered, washed with 1,2-dichloroethane and washed with ethyl acetate. 178 DEG-179 DEG C. The identity of the product was confirmed by IR, UV, NMR, mass spectroscopy and elemental analysis.

NMR (DMSO-d 6) δ

2.42 (s, 3, -COCH 3),

3.74 (m, -7,2-CH 2, -CH 2 tetrazole and "CH 2 CONH"),

4.35 (q, 2,3-CH2, J = 13 Hz),

5.10 (d, 1, C 6 -H, J = 5 Hz),

5.70 (q, 1, C 7 -H, J = 5 Hz, J = 9 Hz),

6.96 and 7.36 (each m, 3, thiophene H) and

9.10 (d, 1, - CH 2 CONH -, J = 9 Hz). "

Example 25

Preparation of 3 - {[(1 R, 4-Ethyl-1 H, 4-Chloro-5-yl) thiazol-5-yl] thio] methyl [-7- [N-tert-butoxycarbonyl] -2-phenylglycylamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane

1,2-Dichloroethane (45 ml) was refluxed to remove the water-solvent azeotropes and then distilled off to a residue of 30 ml which was cooled. 7- (N-tert-butoxycarbonyl-2-phenylglycylamidoycephalosporanoic acid (253 mg, 0.5 mmol) is added and the solution is further distilled to give 15 ml of residue which is cooled again. The reaction mixture is refluxed under nitrogen and the reaction progress is monitored by TLC. According to the invention, there are only traces of the starting material in the reaction mixtures.

The reaction mixture was washed four times with saturated sodium bicarbonate solution, the bicarbonate layers were combined and washed twice with ethyl acetate. Fresh ethyl acetate was added to the washed lithium carbonate layers, the solution was cooled to 0 ° C and adjusted to pH 2.4 with 20% hydrochloric acid. The layers were separated and the aqueous layer was washed with ethyl acetate.

The ethyl acetate layers were combined, washed with saturated sodium chloride solution, dried (MgSO 4), filtered and evaporated. A white foam was obtained in an amount of - 224 mg (80% yield). The identity of the product was confirmed by TLC and NMR. NMR showed only a small amount (10 10%) of the starting -cephalosporanic acid in the reaction mixture.

The product was suspended in 10 ml of diethyl ether and triturated for 1 hour. The ether was decanted, 10 ml of fresh diethyl ether was added, and the mixture was triturated for 1 hour.

The ether was decanted and the residue was evaporated to dryness. The product is obtained in the form of a white powder. The identity of the product was confirmed by TLC and NMR.

NMR - (CDCl 3) - δ

1.45 (s, 9, - COO target C4H9),

3.6 (s, 2,2-CH 2);

3.95 (s, 3, CH 3 - on tetrazole),

4.3 (s, 2,3-CH 2 S -),

4.9 (d, 1, J = 6Hz, C 6 -JJ),

5.4 (d, 1, J = 8Hz, 0CH -), *

5.75 q, 1, J = 4 Hz, C7-H),

6.2 (d, 1, J = 8Hz, 0CH-)

AND

NH

7.4 (s, 50), ’.

7.65 (d, 1, J = 8Hz, - CONH) and ~ 9.3 (s, 1, COOH). ~

Example 26

Preparation of 3 - {((1-methyl-1H-tetrazol-5-yl) thio] methyl} -7- [N- (tert-butoxycarbonyl) -2- (p-hydroxyphenyl) glycylamido] -3 -? - 4-carboxylic acid in 1,2-dichloroethane

1,2-Dichloroethane (45 mL) was refluxed with a water separator and 16 mL of solvent was distilled off. The remaining 30 ml were cooled. 7- [N- (tert-butoxycarbonyl) -2- (p-hydroxyphenyl) glycylamidoj cephalosporanic acid (260.5 mg, 0.5 mmol) is added, the solution is distilled to a residue of 15 ml and this residue is cooled again. 1-m-tolyl-1H-t-thiazole-5-thiol (87 mg, 0.75 mmol) was added and the reaction mixture was heated to 65-70 ° C. The progress of the reaction was monitored by TLC. After 3 hours, TLC indicated that the reaction mixture was almost free of starting material and was worked up at the end of 4 hours.

The working up of the reaction mixture and purification of the product are carried out essentially as in the previous example. 189 mg of crude product (65.5% of theory) and 46 mg * of purified product (about 16% of theory) are obtained.

NMR (CDCl 3 + 3d acetone-de) δ

1.45 (s, 9, -COOter

3.35 (s, 2,2-CH 2),

3.85 (s, 3, CHs on tetrazole),

4.3 (s, 2, 3-Ch 2 -),

4.9 (d, 1, J = 6Hz, CeH),

5.3 (q, 1, J = 3Hz, C7-H),

5.4 (s, 1, HO-0CH—)

5.75 (d, 1, J = 6Hz, HOOH);

NH

6.4 (s, 1, COOH),

6.8 (d, -2, J = 8Hz,

CH-Ι ·

AND

7.9 (d, 1, -CONH). ,

Example 27

Preparation of 3 - {[(1-Methyl-1H-tetrazol-1-yl) -1H-tetrazol-1-yl] -1H-tetrazol-2-yl} -1H-tetrazol-2-yl} -2H ^| Ethyl 77 ((- phenoxyacetamide) -3-cephem-4-carboxylic acid in 1,2-dichloroethane d, 2-dichloroethane [60 ml) was refluxed using a water separator and 15 ml of solvent was distilled off. The remaining 45 mL was cooled and 7- (2-phenoxy-2-acetamido) cephalosporanic acid (406 mg, 1 mol) was added. The solution was further distilled until a residue of 30 ml was obtained and this residue was cooled again. 1-Methyl-1H-triazol-5-yl-10-ol (174 mg, 1.5 mmol) was added and the reaction mixture was refluxed under nitrogen for 12 hours. At this time, TLC using a 10: 3-diethyl ether / (3: 1 acetic acid / water) mixture indicated that the reaction mixture contained product, excess thiol reagent, a small amount of cephalosporanic acid starting material, and an unknown substance.

The reaction mixture is worked up essentially in the same manner as in the two preceding examples. The TLC of the final product is identical to that of an authentic sample of the product produced by the prior art methods.

NMR (CDCl3) δ

3.65 (s, 2,2-CH 2),

3.9 (s, 3, tetrazole CH 3),

4.35 (s, 2,3-CHaS-),

4.65 (s, 2, 0OCH2 -),

5.1 (d, 1, J = 4Hz, Co-H),

5.9 (q, 1, J = 4Hz, C7-H);

7.1 (m, 5.0—)

7.6 (d, 1, J = 10 Hz, —CONH—) and —9 (s, 1, —COOH).

Examples 28 to 31

Preparation of 3 - {[(1-methyl-1H-tetriazol-5-yl) thiomethyl] -7- [2- (2-thienyl) acetamido] -4-cephem-d-carboxylic acid in fluorobenzene

3 - [(1-Methyl-1H-tetrahydro-1-5-y-1) -thiomethyl} -7- [2- (2H-thienyl) acetamido] -3-cephem-4-carboxylic acid is prepared four different reactions, each using different starting cephalosporanic acids:

acetamido-4-cephem-4-carboxylic acid (41 mg, 0.1 mmol), Example 29:

3- (2-Methylpropionyl-oxymethyl) -7-

- [2- (2-phenyl) acetamido] -4-cephem-6-carboxylic acid (42 mg, --0.1-mmol), Example 30:

3- (n-butyloxymethyl) -7- (2- (2-thienyl) acetamido) -3-cephem-4-carboxylic acid (42 mg, 0.1 mmol), Example 31:

3- (2-cyclobutylcrbonyl) oxymeehyУ) -7-

- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid (43 mg, 0,1 0.1 m-mol).

In each case, the compound is suspended in 10 ml of fluorobenzene (dried-aluminosilicate-desiccant with 4-A Linde molecular sieve). - 1-Methyl-1H-triazole-5-thio-1 - (18 mg, 0.15 mmol for each reaction) is added and the reaction mixture is refluxed for about -24 hours. - At each of the processes, the product precipitates, - filters out - and - dries out. Tlc of the product in ethyl acetate / acetic acid shows that the displacement is quantitative. The NMR of each product is identical to that of an authentic product sample prepared by displacement in an aqueous medium.

Example 32

Preparation of 3 - {[(3-methyl-1,2,2-4xadirzolin-5-yl) thio-methyl} -7- ([2- (2-thienyl) acetamido-] -3-2efm- 2 · karb4xyl 4VE acid _1, l 2 - ti2hldrethahu

7- (2- (2-Thienyl) acetamido-cephalosporic acid (396 mg, 1 mmol) was suspended in 40 mL of 1,1,2-chloroethane - and added

3-methyl-1,2,4-oxaiazo-5-thiol (116 mg, 1 mmol). The reaction mixture was heated at 113 ° C in an oil bath for 3 hours, then allowed to cool overnight and evaporated to an oily residue. Ethyl acetate and saturated sodium bicarbonate solution were added. The ethyl acetate portion was washed again with saturated sodium bicarbonate solution, the aqueous portions were combined and extracted again with ethyl acetate. Aqueous layer is overlaid with fresh ethyl acetate, cooled in an ice bath and adjusted to pH 2.5 with 20% hydrochloric acid. The layers were separated and the aqueous layer was re-extracted. The ethyl acetate layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated. To the remainder, 1,1,2,2-1,2,4-total is added, whereby the product solidifies. Yield: 220 mg (48% of theory). The identity of the product was confirmed by NMR, IR, -UV and bioautogram.

NMR (DMSO-d 6) δ

2.35 (s, 3, CH 3 on oxadiazole), Example 28:

3- (Pr-Opionyloxymethyl) -7- (2- () 205115)

3.7 (q, 2, J = 18Hz, 2-CH-)

3.8 (s, 2, —CH2 CONH—), .....

4.4 (q, 2, J = 14Hz, 3-CH3S-),

5.1 (d, 1, J = 5Hz, C 6 -H),

5.6 (q, 1, J = 4Hz, C 2 HJ), .....

6.9, 7.3 (t, d, 3, thiophene-H) and δ 9.1 (d, 1, J = 8 Hz, —CH2 CONH-).

Example 33

Preparation of 3 - {[(1H-1,3,4-triazol-5-yl) thio] methyl-7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1, 1,2-trichloroethane

7- [2- (2-trifluoromethyl) acetamido] cephalosporan. acid [396 mg, 1 mmol] was suspended in 30 mL of 1,1,2-trichloroethane and 1H-1,3,4-triazole-5-thiol (100 mg, 1 mmol) was added. The reaction mixture was heated to 105 ° C. Within 30 minutes the product precipitated. Heating at 100 ° C was continued for about 6 hours and then the reaction mixture was cooled to room temperature. The product was filtered and washed with 1,1,2-butyloroethane 380 mg (87% yield). The identity of the product was confirmed by IC, NMR, UV and bioautogram. The bioautogram also shows the presence of the starting cephalosporanic acid. Liquid phase HPLC showed this starting acid to be 5.8% in the reaction mixture.

NMR (DMSO-d 6) δ

3.7 (s, 2,2-CH 2),

3.8 '(s, 2, —CH2 CONH—),

4.2 (q, 2, J = 5Hz, 3-CH2);

5.1 (d, 1, J = 5Hz, C 6 -JJ),

5.7 (q, 1, J = 4 Hz, CH2),

7.0, 7.4 (t, d, 3, thiophene H);

8.45 (s, 3, triazole NH) and

OF

9.13 (d, 1, J = 8 Hz, —CH2 CONH-).

Example 34

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (2-phenylacetamido) -3-cephem-4-carboxylic acid in chloroform

7- (2-Phenylacrylamino) -cephalosporanic acid (195 mg, 0.5 mmol). was suspended in 75 mL of chloroform and 1-methyl-1H-tetrazole-5-thiol (75 mg, 0.65 mmol) was added. The reaction mixture is heated to 80-85 ° C in oil. . bath for 3 hours and distilling off 60 ml of distillate. TLC shows a very small amount of product at this time. 20 ml of 1,2-dichloroethane are added and the mixture is heated overnight. TLC of the reaction mixture the following morning shows a small amount of starting cephalosporanic acid. After a total reaction time of hours, the reaction mixture was cooled to room temperature. The reaction mixture was worked up and the product purified by essentially the same procedures as in Example 32. 80 mg of purified material were obtained (35% yield). The identity of the product was confirmed by NMR, IC, UV and bioautogram.

NMR (DMSO-d 6) δ.

3.6 (s, 2,2-CH 2),

3.7 (s, · 2, —CH2 CONH—), '

4.0 (s, 3, CHs on tetrazole),

4.3 (s, 2,3-CH 2 S--),

5.1 (d, 1, J = 5Hz, C 6 H 1),

5.7 (q, 1, J = 4Hz, C7-H),

7.3 (s, 5, 0) a

9.13 (s, 1, J = 8 Hz, —CH2 CONH-).

Example 35

Preparation of 3 - {[(1-m (2-ethoxy-5H-1H-thiazol-5-yl) thio] methyl) -7-acetamido-3-cephem-4-carboxylic acid in 1, Of 2-dichloroethane

7-acetamidocephalotporanoic acid (314 mg, 1 mmol) and 1-methyl-1H-tetrazole-5-thiol (98 mg, 0.65 mmol) were combined in 70 mL 1,2-dichloroethane, 50 mL solvent was distilled off and the reaction mixture is then refluxed for about 24 hours. .

The reaction mixture was worked up essentially as described in Example 32. 120 mg of product were obtained (yield 32%). The identity of the product was confirmed by NMR, IC, UV and bioauto-.

gramem.

NMR (DMSO-d 6) δ

1.97 (s, 3, CH 3 CONH -),

3.7 (s, 2,2-CH-),

4.0 (s, 3, CHe on tetrazole),

4.35 (s, 2, T-CH 2 -),

5.1 (d, J, 5 Hz, CeH),

5.7 (q, 1, J = 4Hz, C 7 -H) a

8.8 (d, 1, J = 8Hz, —CH2 CONH).

Example 36

Preparation of 3 - {[(3-methyl-1,2,4-thiadiazol-5-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2- (2-Trenyl) acetamido) cephalosporanic acid (200 mg, 0.5 mmol) and 3-methyl-1,2,4-thiadiazole-5-thiol (85 mg, 0.65 mmol) The mixture was heated to 95 ° C in an oil bath, heated to 90 ° C for 19 hours, then removed from the bath and cooled for 1 day. 3 volumes of ethyl acetate were added and the mixture was washed with 2 x 56 mL of saturated sodium bicarbonate solution. The combined ethyl acetate phases were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 252 mg of a foam. The product identity was confirmed by NMR, UV , IC and bioautogram.

NMR (DMSO-d 6) δ

3.7 (s, 2,2-CH 2),

3.8 (s, 2, —CH 2 CONH),

4.5 (q, 2, J = 15 Hz, 3-CH 2 S-),

5.1 (d, 1, J = 5Hz, C 6 -H),

5.7 (q, 1, J = 4Hz, C ₇₁ Н),

6.96, 7.38 (t, d, 3, thiophene H) and

9.13 (d, 1, J = 8 Hz, - CH 2 CO 3 H).

Example 37

Preparation of 3 - {[(2-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetonitrile

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol) and 2-mercaptopyrimidine (0.62 g, 5.5 mmol) were combined in 25 mL dry acetonitrile and the mixture was The reaction mixture was cooled to room temperature and filtered off, then the product was washed with 50 ml of acetonitrile and dried under vacuum at 50 ° C for 4 hours. 1.86 g of off-white crystals (83% yield), m.p. 217 DEG C. (dec.) NMR in DMSO-d6 shows no starting material, and the identity of the product was confirmed by IC, UV and NMR.

NMR (DMSO-d 6) δ

3.55 (q, 2, 2-N, 1 = 18 Hz),

3.74 (s, 2, —CH2 CONH),

4.28 (q, 2,3-CH 2 S-, J = 13 Hz),

5.00 (d, 1, Ce-H, J = 5Hz),

5.64 (q, 1, C7-H, J = 5Hz, J = 9Hz),

7.08 (m) a

8.52 (dj, (6, thiophene and pyrimidine

H) a

9.00 '(d, 1, -CH 2 CONH-, J = 9 Hz).

Example 38

Preparation of 3 - {[(2-pyrimidinyl) thiomethyl] -7- (2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetic acid

7- (2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol), 2-mercaptopyrimidine (0.6 g, 5.4 mmol) and sodium acetate (0.41 g, 5 mmol) ) in 25 ml of glacial acetic acid was heated at 85 ° C for 4 hours, the product crystallized during the reaction, cooled to room temperature, filtered, washed with acetic acid and dried to give 1.58 g (70%). 218 DEG C. (decomposition) The product identity was confirmed by IC, UV, NMR and elemental analysis: NMR was identical to that of Example 37.

Example 39

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl | -7- [2- (2-thienyl Jacetamido) cephalosporanic acid in acetic acid

7- [2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol), 1-methyl-1H-tetrazole-5-thiol (0.81 g, 7 mmol) and sodium acetate ( 0.41 g, 5 mmol) in 25 mL glacial acetic acid was heated at 75-77 ° C for 8 hours. TLC was performed every hour and at the end of 8 hours TLC indicated that the reaction was complete. The reaction mixture was cooled to 40-45 ° C and acetic acid was removed in vacuo. 50 ml of ethyl acetate and 50 ml of water are then added to the residue. The aqueous layer was acidified to pH 1.5 with 1N sulfuric acid. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and the ethyl acetate was removed on a rotary evaporator. The low-density oil residue is redissolved in 50 ml of ethanol and a solution of 2 ml of dicyclohexylamine (10.2 mmol) in 10 ml of ethanol is added. The product precipitated almost immediately in the form of the dicyclohexylamine salt. The mixture was stirred for an additional 15 minutes, then the product was filtered off, washed with ethanol and dried. 1.2 g (37.8% of theory) of melting point 185 DEG-186 DEG C. are obtained. IC, NMR and UV are the same as analyzes of previously prepared samples of the same product.

Example 40

Preparation of 3 - {[(1-benzyl-1H-tetrazol-5-yl) thio) methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2- (2-Thienyl) acetamido) cep alosporanic acid (2.0 g, 5 mmol) and 1-benzyl-1H-tetrazole-5-thiol (1.44 g, 7.5 mmol) were added to the 25 ml of 1,2-dichloroethane The reaction mixture was heated to 85 ° C in an oil bath and kept overnight at this temperature with stirring, TLC showed that there was no starting cephalosporanic acid in the reaction mixture. 25 ml of methanol are added to the foam and the mixture is heated on a steam bath until the sample has dissolved, the solvent is evaporated off on a rotary evaporator and the product crystallizes. The mixture is stirred for minutes, then filtered and washed. methanol and dried under vacuum

1.6 g of product (60.6% theory), m.p. 171-171.5 ^° C.

Example 41

Preparation of 3-amidinothiomethyl-7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetonitrile

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (3.12 g, 8 mmol) and thiourea (912 mg, 12 mmol) in 15 mL of acetonitrile (which has been pre-dried with an aluminosilicate desiccant sold as molecular sieve 4- (Linde) was heated to 87 ° C with stirring for 24 hours, and during the first hour a precipitate began to form in the reaction mixture.

At the end of 24 hours, the product was filtered from the hot reaction mixture and dried. 2.5 g (76% of theory) of the product are obtained, the elemental analysis of which is calculated:

43.68 ’% C, 3.91% H, 13.58% N,

1 A 1 O * 7PΤΊ ΓΎ *

43.50% C 4.03 a / _o H, 13.29% N.

NMR confirms the identity of the product.

Example 42

Preparation of 3-benzoylthiomethyl-7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in isopropyl acetate

7- [2- (2-Thienyl) acetamido] cep alospozoic acid (1.0 g, 2.5 mmol) and thiobenzoic acid (510 mg, 3.7 mmol) were suspended in 20 mL of anhydrous isopropyl acetate and the suspension was stirred for 31 hours boils under reflux. During this time, all the reactants come into solution. The solvent was evaporated in vacuo to give a TLC residue from a mixture of 60% product and 40% unreacted starting material.

Preparative thick layer chromatography on silica gel plates using acetone / acetic acid (16: 1) as eluent gave a purified product sample.

NMR (DMSO-d 6) δ

3.50 (ABq, 2H, 2-OH, J = 6Hz, J = 19Hz),

3.82 (s, 2H, —CH2 CONH—),

4.20 (d, 2H, 3-CH 2 S -, 1 = 5 Hz),

5.03 (d, 1H, C H -H, J = 5 Hz),

5.69 (d, 1H, C 7 -H, J = 5 Hz),

6.89 to 8.0 (m, 8H, aromatic H).

Example 43

Preparation of 3 - [(phenylthio) methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol) and benzethiol (0.75 mL, 7.5 mmol) were added to 25 mL

1,2-dichloroethane. The reaction mixture was refluxed overnight. TLC: confirms that after this time no starting cephalosporanic acid remains in the reaction mixture.

The solvent is removed by rotary evaporation, 25 ml of ethanol are added to the residue and the residue is heated to partially dissolve. To dissolve the remaining product, add 25 mL of methanol and heat the mixture. The solution was filtered through cotton wool, treated with 2.0 g of decolorizing charcoal, stirred for 5 minutes and then filtered through a filter aid. The solvent was removed in a rotary evaporator. NMR of the residue shows that some of the starting thiol is present in the reaction mixture.

The residue was suspended in 25 ml of isopropyl acetate, the suspension was filtered and the filtrate was cooled in the refrigerator overnight. The filtrate was then diluted with 25 mL of ethyl acetate and washed with 25 mL of dilute sodium bicarbonate solution to remove the thiol. The ethyl acetate layer was added to 25 mL of water, and the pH of the mixture was adjusted from pH 8.5 to 1.4 with sulfuric acid. The ethyl acetate layer was then dried over magnesium sulfate, filtered and evaporated to a foam in a rotary evaporator. Yield 0.92 g (19.4% yield).

NMR (DMSO-d 6) δ

3.58 (m, 2,2-CH 2),

3.75 (s, 2, -CH 2 CONH -),

4.12 (q, 2,3-CH 2 S-, J = 13 Hz),

5.08 (d, 1, Ce-H, J = 5Hz),

5.6'6 (q, 1, C7-JH, J = 5Hz, J = 9Hz),

7.15 (m, 8, thiophene-H and phenyl-H] a

9.10 (d, 1, -CH 2 CONH 3 = 9 Hz).

Example 44

Preparation of 3 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl | -7- (2-phenylacetamido) -3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2-Phenylacetamido) cephalosporanic acid (1.95 g, 5 mmol) and 5-methyl-1,3,4-thiadiazole-2-thiol (0.99 g, 7.5 mmol) in 25 mL 1,2-dichloroethane was refluxed for 16 hours. TLC shows that there are traces of starting cephalosporanic acid in the reaction mixture. The product crystallized during the reaction.

The reaction mixture was cooled to 0-5 ° C and filtered. The reaction product was washed with cold 1,2-dichloroethane and dried in vacuo. 1.82 g (78.8% _of theory), m.p.

NMR (DMSO-d 6) δ

2.70 (s, 3, -S-thiadiazolyl),

3.58 (s, 2, -CH 2 CONH -),

3.70 (broad s, 2,2-CH2),

4.40 (q, 2,3-C, S-13 Hz),

5.12 (d, 1, SA-N, J = 5 Hz),

5.72 (q, 1, C 7 -HJ-5 Hz, J-9 Hz),

7.28 (s, 5, phenyl H),

9.08 (d, 1, -CH2CO3H-, J = 9 Hz).

Example 4 5

Preparation of 3 - [(methylthio) methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in methylene chloride

7- [2- (2-Thienyl) acetamido] cephalosporanic acid (24 g, 60 mmol), 7.0 mL of methanethiol and 600 mL of methylene chloride was stirred and heated in an autoclave at 84-86 ° C for 18 hours. The reaction mixture was then cooled to room temperature. A small amount of insoluble material was filtered off and the filtrate was evaporated. The residue was taken up in ethyl acetate and filtered. The filtrate was overlaid with about 150 ml of water and 1N sodium hydroxide was added dropwise with stirring to pH 5.5. The aqueous phase is separated, concentrated to a volume of about 75 ml, then diluted to 700 ml with water and glacial acetic acid is added until pH 3.8. An amorphous solid precipitates. The mixture was stirred in an ice bath for 3 hours and then cooled in the refrigerator overnight.

The solid was filtered off. The filtrate was overlaid with 100 ml of ethyl acetate and the pH of the mixture was adjusted to 2.0 with concentrated hydrochloric acid. The organic phase was separated and extracted with one 100 ml portion and one 150 ml portion of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was removed. An amber-colored foam is obtained as a residue. The foam was dissolved in 50 mL of ethyl acetate, and the solution was seeded with the product to be recovered and kept in the refrigerator overnight. The crystals formed are filtered off, washed with cold isopropyl acetate and dried in vacuo at 50 ° C. Yield: 3.2 g (14% of theory).

* NMR confirms product identity δ

2.00 (s, 3,3-CH 2 SCH 3),.

3.74 (m, 3-CH 2 S -, 2-CH 2, and -CH 2 CONH -),

5.14 (d, 1, C 6 -H, J = 5 Hz),

6.64 (q, 1, C 7 -H, J = 5Hz, J = 9Hz),

7.15 (m, 3, thiophene H), a

9.12 (d, 1, -CH 2 CONH-? 7 = 9 Hz).

-yl) thio] methyl] -3-cephem-4-carboxylic acid in benzene

7- (2-Formyloxy-2-phenylacetamido) cephalosporanic acid (2.17 g, 4.65 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.87 g, 7.5 mmol) in 25 mL of benzene are boiled under A reflux condenser (about 80 ° C) for 12 hours During the reaction, a plastic is deposited on the walls of the glass container After cooling the plastic solidifies to a glassy solid TLC indicates that the solution contains only traces of product and that the plastic is predominantly The reaction mixture was evaporated with acetone added to a foam which was dissolved in 35 ml of dry acetone and 10 ml of a solution of 1.25 g of sodium 2-ethylhexanoate (7.5 mmol) in acetone was added. After 1 hour the product was filtered off, washed with 20 ml of acetone and dried to give 1.38 g (58% of theory), and the identity of the product was confirmed by TLC and NMR.

NMR (D 2 O) δ

3.48 (q, 2,2-СШ, J = 18 Hz),

4.00 (s, 3, -N-tetrazole),

4.10 (m, 2.3 < 1 &gt; H 2 S 2),

5.05 (d, 1, 3-y, J-5 Hz),

5.70 (d, 1, C 7 -H 1 J = 5 Hz),

6.24 (s, 1, -CHCONH -),

7.50 (m, 5, phenyl D),

O

8.33 (s, 1, -ОСЩ).

Example 47

Preparation of 7- (2-formyl-oxy-2-phenylacetamido) -3 - {[(1-methyl-1H-tetrazol-1-yl) thio) methyl} -3-cephem-4-carboxylic acid in carbon tetrachloride

7- (2-Forms of loxy-2-phenylacetamido) cep alosporanic acid (2.17 g, 4.65 mmol) and 1-methyl-1H-tetrazole-5-thiol [0.87 g, 7.5 mmol) in 25 ml of carbon tetrachloride is refluxed at about 77 ° C for 12 hours. The reaction mixture was cooled to room temperature and the supernatant was decanted from the solidified semi-solid. 25 ml of 1,2-dichloroethane are added to the solid with heating. The product crystallizes, the mixture is cooled to room temperature, stirred for about 1 hour, then the product is filtered off, washed with 10 ml of 1,2-dichloroethane and dried in vacuo overnight at 45 ^° C. 1.54 g of white crystals are obtained (yield). 65%). The identity of the product was confirmed by NMR and TLC. TLC shows the product to contain traces of deformylated product. NMR is identical to NMR of the product of Example 16.

Example 46

Preparation of the sodium salt of 7- (2-formyloxy-2-phenylacetamido) -3 - ([(1-methyl-1H-tetrazole-5205115)

Example 4 8

Preparation of 3-Methyl-1,2,4-oxa-thiazole-O-thiol

Mix with acetamoxime (30 g, 0.4 mol), carbon disulfide (100 mL, 1.66 mol) and triethylylminine (56 mL, 0.4 mol) and stir the mixture in 1 liter of pyridine. A stream of nitrogen was bubbled through the carbon solution, and then nitrogen was passed over the reaction mixture. Heat the mixture in an oil bath at 70 ° C for 3 days, then evaporate to an oil and add ethyl acetate and saturated sodium carbonate solution to the oily residue. The layers were separated and the organic layer was washed again with saturated sodium carbonate solution. The sodium hydroxide washes were extracted with ethyl acetate and the ethyl acetate extracts were discarded. The aqueous phase was covered with fresh ethyl acetate and cooled in an ice bath. The pH was adjusted to 2.5 with 20% hydrochloric acid, and sodium chloride was added until the solution was saturated. The solution was extracted with ethyl acetate, the ethyl acetate extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solution is filtered and evaporated to half its original volume. An equal volume of carbon tetrachloride was added and the mixture was evaporated until the product crystallized. Yield: 24.8 g (52% of theory).

Example 49

Preparation of 3 - ([(3-methyl-1,2,4-oxadiazol-0-yl) thio] methyl | -7- [2- (2-henyl) acetamido] -3-cephem-4-carboxylic acid of acid in 1,2-0-chloroethene

7- (2- (2-Thienyl) acetamido] -3-carbamoyloxymethyl) -3-cephem-4-carboxylic acid (100 mg, 0.25 mmol) was suspended in 25 mL 1,2-dichloroethane and with stirring, 3-methyl-1,2,4-oxadiazole-5-thiol (35 mg, 0.30 mmol) was added. The reaction mixture was heated in an oil bath at 110 ° C and 5 mL of solvent was distilled off along with any traces of water. The temperature of the oil bath was lowered to 90-95 ° C, the reaction mixture was maintained at this temperature for 19 hours and then. is cooled to room temperature. The insoluble material was filtered off and washed with 1,2-dichloroethane and diethyl ether. TLC revealed to be unreacted starting material with only traces of product.

The filtrate was evaporated and the residual oil was partitioned between sodium bicarbonate solution and ethyl acetate. The aqueous solution was overlaid with fresh ethyl acetate, cooled in an ice bath, and adjusted to pH 2.5 with 20% hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with fresh ethyl acetate, combined. the ethyl acetate solutions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to an oil. Crystallization from 1: 1 hexane-diethyl ether solution gave 13 mg for the product (11, Co / c yield). The identity of the product was confirmed by NMR and IC, which were identical to analyzes of the same compound produced as described in Example 32.

Example 50

Preparation of 3 - ([(1-methyl-1H-tetrol-0-yl) thir] methyl) -1H-4- (2- (tert-butyl) -1H-2- phenylcetamide-3-cephem-4-carboxylic acid in nitromethane

7- (2- (Tert. -utoxycarbonyl) -2-phenylation-thiocycephalosporoforancic acid (490 mg, 1 mmol) and 1-methyl-1H-tetrazole-O-thiol (145 mg, 1.25 mmol) in 15 ml of dry nitromethane is heated at 85-90 ° C for 8 hours under nitrogen.TLC analysis of the reaction mixture shows the product, excess thiol reagent and decarboxylated product but no starting cephalosporic acid, but the nitramethane is evaporated. Dissolve in 10 ml of saturated sodium bicarbonate solution, add 29 ml of water and wash successively with ethyl acetate until the washings have cleared. of water and the mixture was cooled to 0 ° C and its pH adjusted to

2.2 20 ° / o kyseimou - llOlc ^ <^ '^ ref ^ <^ ¹ ^ <^ u · The layers were separated and the aqueous layer washed with ethyl acetate. The ethyl acetate portions were combined, washed with saturated brine, dried over magnesium sulfate, filtered and evaporated to a brown foam. Yield: 455 mg (83% yield). TLC shows product, traces of thiol and traces of decarboxylated product are present.

455 mg of the product [9.833 mmol] was dissolved in 7 ml of ethyl acetate and lithium acetate (0.833 ml) was added dropwise with stirring. The yellow salt was obtained as a brown precipitate. The salt was filtered off, washed with ethyl acetate and dried overnight in vacuo at room temperature. 368 mg of product are obtained (yield 80%). Identity of the product was confirmed by TLC, NMR, _^ aíoautcgramem, elemental analysis, IR and UV spectra. TLC shows traces of decarboxylated material.

NMR (CDCl3) δ

1.4 (s, 9, -COOterc.C 1 H 9) (

3.6 (s, 2,2-CH 2), "

3.85 (s, 3, CH? Tetlczcl),

4.3 (s, 2, 3-O-2-),

4.44 and 4.45 (2s, 1, 0CH—),

4.9 (i, 1, J = 6 Hz, C 6 -H), 5.8 (q, 1, J = 6 Hz, C-d1), 7.35 (8.5, -0),

8.2 and 7.8 (2d, 1, J = 9Hz, -CONH-);

9.3 (s, 1, -COOH 3). ‘

Example 51

Preparation of 3 - ([(1-methyl-1H-tetrazol-O-yl) 205115 thio] methyl-7- | - N - ((1,3-dimethylureido) carbonyl] -2-phenylglycylamido] -3-cephem -4-carboxylic acids in nitromethane

7- (N - [(1,3-Dimethylureido) carbonyl] -2-phenylglycylamidoycephalosporanic acid (130 mg, 0.25 mmol) was suspended in 5 mL of nitromethane and 1-methyl-1H-tetrazole-5-thiol ( 43.5 mg, 0.375 mmol) The reaction mixture was heated at 85 ° C under nitrogen for 12 h and then kept at room temperature over Saturday and Sunday, then the mixture was filtered and the solid was washed with a small amount of nitromethane and dried in a vacuum oven. ^Q at 35 C to give 83 mg (58% yield). the product identity was confirmed by TLC, NMR, IR, UV spectra, elemental analysis, and bioautogram.

NMR (DMSO-d 6) <5

2.65 (d, 3, J = 4Hz, -CONHCH 3),

3.15 (s, 3, CONCH 3 CO--),

3.6 (s, 2,2-CH 2),

3.9 (s, 3, N-tetrazole),

4.3 (s, 2,3-CH2.S-),

5.0 (d, J, 5 Hz, Ceji),

5.5 (d, 1, J = 7Hz, OCHCO),

N—

5.7 (q, 1, C7-HJ)

5.8 (q, 1, -CONHCH 3),

7.4 (s, 5, 0)

9.3 (d, 1, J = 8 Hz, OCHCONH--) and (d, 1, J = 8 Hz, 0 OH-CO-).

NH

Example 52

Preparation of 3 - ({(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetonitrile with addition of tetrabutylammonium iodide

7- (2- (2-Thienyl) acetamido] cephalosporanic acid (2.0 g, 5 mmol), 1-methyl-1H-tetrazole-5-thiol (1.2 g, 10 mmol) and tetrabutylammonium iodide (0, 2 g) is mixed in 25 ml of dry acetonitrile, the mixture is heated to boiling and boiled for 8 hours, cooled to room temperature and the solvent is removed by rotary evaporation, a hot mixture of 25 ml of isopropyl acetate and 5 ml of acetonitrile is added. The mixture is filtered and allowed to cool slowly The product precipitates in the form of light cream colored crystals The crystals are filtered off, washed with isopropyl acetate and dried to give 1.30 g of the product (yield 57.5% of theory). of Example 5.

Example 53

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane with addition of tetrabutylammonium iodide

The procedure described in Example 52 was repeated except that 1,2-dichloroethane was used as the solvent. Dicyclohexylamine (2 mL) was added and the product was converted to the dicyclohexylamine salt. Yield

1.55 g (48.9% of theory). NMR is identical to NMR of the product of Example 1.

Example 54

Preparation of 3 - [(phenylthio) methyl] -7- (2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in 1,2-dichloroethane with addition of 1-methyl-5- (methylthio) -1H -tetrazole

7- [2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol), benzenethiol (0.75 mL, 7.5 mmol), and 0.65 g of 1-methyl-5- ( methylthio] -1H-tetrazole is mixed with 25 ml

1,2-dichloroethane and the mixture is heated to boiling. The reaction mixture was monitored by TLC and the reaction was complete after 14 hours. The solvent was removed by rotary evaporation and the residue was extracted several times with diethyl ether. After complete removal of the solvent, 1.66 g of a light brown solid is obtained (74% of theory). IR and NMR analyzes are the same as those of the same product prepared by the methods described in the previous examples.

Example 55

Preparation of 3 - ([(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in isopropyl alcohol

7- (2- (2-Thienyl) acetamido] cep alosporanic acid (2.0 g, 5 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.87 g, 7.5 mmol) in 25 mL isopropanol is placed in a flask equipped with a reflux condenser with a drying tube containing anhydrous calcium sulfate (Drierite), immersed in an oil bath at 84-85 ^° C and monitored by TLC for 40 hours at 82-83 ° C. only half of cephalosporanic acid.

Example 56

Preparation of 3 - [(2-oxazolylthio) methyl] -7- (2- (1H-tetrazol-1-yl) acetamido) -3-cephem-4-carboxylic acid in nitromethane

A suspension of 7- (2- (ΙΗ-tetrazol-1-yl) acetamido] cephalosporanic acid (0.38 g, 1.0 mmol) and 2-oxazolthiol (0.11 g, 1.1 mmol) in 5 mL of nitromethane was added. immersed in an oil bath at 90-91 [deg.] C. A dry nitrogen atmosphere was maintained over the reaction mixture.After 20 minutes all reagents dissolved and after 35 minutes the product began to crystallize.After 6 hours the reaction mixture was cooled to room temperature. The product was filtered, washed with 7 ml of nitromethane, air dried and dried under vacuum at 40 DEG C. for 3 hours to give 0.36 g (85.7% of theory) of the product as off-white crystals, m.p. C (decomposition) NMR shows that the product is 70% of the desired material and 30% of the starting cephalosporic acid.

The product was recrystallized from 5 ml of DMSO-d6 and 10 ml of water, filtered off, washed with 5 ml of a 2: 1 mixture of water: DMSO-d6, air dried and dried in vacuo at 50 ° C for 6 hours. Yield 0.26 g. NMR shows that the product contains 87% of the desired material and 13% starting cephalosporanic acid. The recrystallization was repeated with 3 ml of DMSO-d6 and 6 ml of water, with stirring for 1 hour. The product yield is 0.21 g NMR (DMSO-d6) shows that the starting cephalosporanic acid content is reduced to 5% and confirms the identity of the desired compound.

NMR .delta

3.75 (s, 2,2-CH 2),

4.34 (q, 2,3-CH3 * S-, J = 14 Hz),

5.16 (d, 1, C 6 -H, J = 5 Hz),.

5.76 (q, 1, C7-H, J = 5Hz, J = 9Hz),

5.44 (s, 2, -CH 2 CONH -),

7.28 (s, 1, oxazole C + H],

8.14 (s, 1, oxazole Cs-H),

9.37 (s, 1, tetrazole H) and

9.53 (d, 1, -CONH-, J + 9 Hz).

Example 5 7

Preparation of 3 - [(2-oxazolylthio) methyl] -7- (2-formyloxy-2-phenylacetamido) -3-cephem-4-carboxylic acid in 1,2-dichloroethane

A solution of 7- (2-formyloxy-2-phenylacetamido) cephalosporanic acid solvate with methylene chloride (0.52 g, 1 mmol) and 2-oxazolthiol (0.12 g, 1.1 mmol) in 20 mL of 1,2-dichloroethane about Boil under reflux for 16 hours and then cool to room temperature. TLC shows complete conversion to product. The reaction mixture was concentrated on a rotary evaporator to 10 ml and some gelatinous crystals formed after some time of standing. The crystals were filtered off, washed with 1,2-dichloroethane and dried. 0.12 g of a gray solid is obtained.

Completely removing the solvent from the filtrate gave 0.45 g of a light yellow foam. The foam was triturated with 25 mL of diethyl ether, filtered, washed with diethyl ether and dried. 0.21 g of a pale yellow powder is obtained. The identity of the product is confirmed

NMR δ

3.56 (m, 2,2-CH 2),

4.24 (q, 2,3-CHaS-, J = 13 Hz),

5.00 (d, 1, Ce-H, J = 5Hz),

5.70 (q, 1, C7-H, _J = 5 Hz, · 1 = 9 Hz), <6.14 (s, 1, ’

7.25 (s, 1, oxazole C4-JH),

7.45 (m, 5, phenyl HJ)

8.12 (s, 1, oxazole Cs-H),

8.35 (s, 1 -CHO) and

9.40 (d, 1, -CONH-, J = 9 Hz).

Example 58

Preparation of 3 - {[(4-phenyl-2-hiazolyl) thlo] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in acetonitrile

A mixture of 7- (2- (2-phenyl) -acetamide-ocephalosporanic acid (2.0 g, 5 mmol) and 4-phenyl-2-thiazole-thiol (1.44 g, 7.5 mmol). in 35 ml of acetonirilil are refluxed for 16 hours while protecting from atmospheric moisture through a drying tube containing anhydrous calcium sulfate, sold under the designation Drierite, TLC shows complete conversion to the product (new spot).

The reaction mixture was cooled to room temperature and stirred for 2 hours. The product crystallizes and is filtered off, washed with acetonitrile and dried. Yield 2.25 g (85.6, why, theory), m.p. 180 DEG C. (decomposition). NMR confirms the identity of the product.

Example 59

Preparation of 3 - {((5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl) -7- [2- (1H-tetrazol-4-yl) acetamido] -3-cephem-4-carboxylic acid in nitromethane

7- (2- (1H-Tetrazol-1-yl) acetamido] cephalosporanic acid (1.92 g, 5 mmol) and 5-methyl-1,3,4-thiadlazole-2-thiol (0.79 g, 6 mmol) was added to 25 ml of nitromethane, předsušenému alumina and the reaction mixture was heated in an oil bath at 95 ^Q C and stirred · for 4 hours. TLC · showed conversion to the desired compound in addition to traces of the starting cephalosporanic acid (less than 2 The reaction mixture was cooled to room temperature, filtered, washed with nitromethane and dried in vacuo to give 2.11 g (92.5% yield), m.p. 183.5 ° C (dec.). NMR confirmed identity product.

0'5115

Example 60

Preparation of 3 - [[[5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl] -7- [2- (ΙΗ-tetrazobl-yl) acetamido] -3-cephem-4-carboxylic acid of acid in propionitrile

7- [2- (1H-Tetrazol-1-yl) acetamido] cef alosporanic acid (1.92 g, 5 mmol) and 5-methylthi-3,4,4-hiadiazole-2-thiol (0.99 g, 7.5 mmol) was added to 25 ml of neutralized alumina-treated propionitrile and the mixture was heated to reflux (97 [deg.] C.) The reaction mixture was stirred and refluxed for 9 hours, TLC showed only traces of starting cephalosporanic acid. The reaction mixture was cooled to room temperature, filtered, washed with propionitrile and dried in vacuo to give 2.04 g (89.51% yield) of the product, mp 186.5 ° C (dec.), NMR confirmed the identity of the product.

Example 61

Preparation of 3 - ([(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- (2-formyl-oxy-2-phenylacetamido) -3-cephem-4-carboxylic acid in 1,1-dicetoethane

7-ACA (7-aminocephalosporanic acid) (13.62 g, 0.05 mol) was suspended in 100 mL

1,2-lichloroethane and trimethylsilylacetamide (26.25 g, 0.200 mol) was added. The reaction mixture was warmed to 40 ° C and the solid dissolved in a cloudy solution, which was cooled to 20 ° C.

To this solution was added dropwise a solution of 2-formyloxy-2-phenyl-acetyl chloride (10.92 g, 0.055 mol) in 25 mL of 1,2-dichloroethane over 20 minutes, raising the temperature to 30 ° C. The reaction mixture was stirred for 2 hours, 100 mL of 1,2-dichloroethane was added, and then the reaction mixture was washed with three 100 mL portions of water. The aqueous washings were combined and extracted with two 50 ml portions of 1,2-dichloroethane, which were washed again with 40 ml water.

The 1,2-dichloroethane layers were combined, stirred with 2.0 g of Darco G-60 activated carbon for 20 minutes, and filtered through Hyflo diatomaceous earth. The total volume of the solution which. contains the desired 7- (2-formyloxy-2-phenylacetamido) cep alosporanoic acid is 375 ml.

The solution is concentrated to 336 g at 30 DEG C., this mixture consisting of about 250 ml of 1,2-dichloroethane and 22 g of 7- (2-formyloxy-2-phenylationeamidoycephalosporanic acid) and 1-methyl-1H-tetrazole is added. -5-thiol (6.39 grams, 55 mmol) in 250 mL of 1.2 L / L and the reaction mixture was heated to reflux and water that was likely to remain in the mixture from the previous wash was removed by azeotropic distillation using After 12 hours at reflux, TLC indicated that the reaction was over, the reaction mixture was cooled to room temperature and seeded with the product, precipitating 3 - {[(1-methyl- 1 H-Tetrazol-5-yl) thio] methyl 1 H -7- (2-formyloxy) -2-phenylacetamido) -3-cephem-4-carboxylic acid. After 2 hours, the product was filtered off and washed with 63 ml

1,2-ΰΜ ± ^ θ11ΐ3ηυ. 13.90 g (56.7% of theory, based on 7-ACA) of the product is obtained which is pure by TLC analysis. NMR confirms the identity of the product and is the same as that of the product prepared according to Example 16.

Example 62

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -7- (2-trimethyl-2-phenyl-ethoxy) -3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2-Formyloxy-2-phenylacetamido) cep alosporanic acid (2.33 g, 5 mmol) and 1-methyl-1H-tetrazol-5-ol (0.64 g, 5.5 mmol) were added to the 25 ml of 1,2-dichloroethane and the mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature, then reheated to boiling and 10 ml of solvent was distilled off. 10 ml of carbon tetrachloride are then added dropwise at near boiling point (77 DEG C.). The resulting mixture was allowed to cool to room temperature and stirred for 1 hour with 14 mL of 40% carbon tetrachloride in 1,2-dichloroate. The product is filtered off, washed with ethane and dried under vacuum at 50 cc. It is obtained

2.12 g of a light colored solid (86.5% yield). NMR is identical to NMR of the product prepared according to Example 16.

Example 63

Preparation of 3 - {[(3-benzyloxycarbonyl-aminomethyl-1,2,4-triazol-5-yl) thio] methyl (-7- (2- (2-hienyl) acetamido) -3-cephem-4- carboxylic acids in nitromethane

7- (2- (2-Thienyl) acetamido] cep alosporanic acid (2 g, 5 mmol) and 3- (benzylthoxycarbonyl-aminomethyl) -1,2,4-triazole-5-thiol (2 g, 7, 6 mmol) in 15 ml of nitromethane is heated to 80-90 [deg.] C. with stirring for 6 hours, the reaction mixture is cooled and filtered to separate the product, and the product is recrystallized twice from aqueous acetone to give 1.2 g of cream. 174 DEG-178 DEG C. (decomposition) (40% yield).

Analysis for C25H24N6O6S3:

calculated:

49.99% C, 4.03% H, 13.99% N, 16.01% S, found:

% C, 50.20;% H, 4.03;% N, 13.76.

Example 64

Preparation of 3 - {[(1- (carbomethoxymethyl) -1H-tetrazol-5-yl) thio] methyl-7- [2- (2-thiophene) 205115 acetamido] -3-cephem-4-carboxylic acid in acetonitrile

7- [2- (2-Thienyl) acetamido] cep alosporanic acid (1.0 g, 2.5 mmol) and 1- (carboxymethyl) -1H-tetrazole-5-thiol (0.61 g, 3.8 mmol) The reaction mixture was then heated at reflux for 13 hours, cooled, filtered and concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid and concentrated in vacuo. Hexane was added, the resulting precipitate was collected and triturated with ether to give 0.475 g of a light brown solid (yield 38%) .The identity of the product was confirmed by comparison with an authentic sample prepared by another synthesis method.

Example 65

Preparation of 3 - {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl) -7- (1-chloro-thionamido) -3-cephem-4-carboxylic acid in nitromethane

Suspension of 7- (1-chloro-thioniazole) cephalosporanic acid (1.0 g, 2.5 mmol) and 5-methyl-1,3,4-thiadiazole-2-thiol (0.4 g, 3 mmol) in 20 ml The nitromethane was immersed in a 95-96 ° C oil bath with stirring. TLC indicated that the reaction was complete in 3 hours. The reaction mixture was cooled to room temperature, filtered and evaporated in vacuo. A pale red oil is obtained as a residue which crystallizes on standing at room temperature for 2 hours. The residue was triturated with 15 ml of ethyl acetate, filtered, washed with ethyl acetate and dried. 0.64 g (55.2% of theory) of the product is obtained. The identity of the product was confirmed by IC, UV, titration, microanalysis and NMR.

Analysis for C1 & H19CIN4O4S3:

calculated:

41.51 _0/0 C, 4.14% H, 12.10% N, 20.78% S,

7.66% Cl, on climbing:

C 41.70, H 4.23, N 11.84, S 20.51,

7.88% Cl.

Example 1 6 d

Preparation of 3 - ([(1-benzyl-1H-1,2,3-triazol-5-yl) thio] methyl) -7- [2- (2-thienyl Jacetamido) -3-cephem-4-carboxylic acid in 1 , 2-dichloroethane

7- [2- (2-Thienyl jacetamido) cep alosporanic acid (200 mg, 0.5 mmol) and 1-benzyl-1H-1,2,3-triazole-5-thiol (140 mg, 0.7 mmol) The mixture was stirred in 15 ml of 1,2-dichloroethane and heated at 65-70 ° C for 21 hours.

The solvent was evaporated under reduced pressure, saturated sodium bicarbonate solution (25 ml) was added and the mixture was extracted with two portions of ethyl acetate. The remaining aqueous solution was cooled in an ice bath, fresh ethyl acetate was added and its pH adjusted to 2.5 with 20% hydrochloric acid. The acidic product was extracted with two portions of ethyl acetate with brine, and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the acetate was distilled off under reduced pressure. Yield: 76 mg. Thin layer chromatography showed a mixture of the starting material and the product (based on comparison with an authentic sample of the product and starting materials).

Examples 67 to 72

Displacement of 3-acyloxy-7-methoxy-7- [2- (1H-tetrazolyl) acetamido] cephalosporanic acid by various thiols in nitromethane

7-Methoxy-7- [2- (1H-tetrazoH-yl) acetamido] -cephalosporanic acid is reacted with various thiols in nitromethane. Substantially the same procedures as described above were used except that the products were purified from the unreacted starting material by high pressure liquid phase chromatography. The products obtained and their identification are listed below:

3- {I (1-Methyl-1H-tetrazol-5-yl) thio] methyl [7-methoxy-7- [2- (1H-tetrazol-1-yl) acetamide-o] - 3-cephem-4-carboxylic acid, UV max (ethanol-ol) 273 nm (ε 9082 ').

3 - {[(5-Methyl-3,4 - hiadiazoll2 - llthю] meth ^yl ll- ^7-methoxy-7 - ^[2 - ^ ^H-tetrazol-1 y j acetamido] -3-cephem-4 -carboxylic acid, UV max (ethanol) 273 nm (ε 12 785).

Analysis for C15H16N8O5S3:

calculated:

% C, 37.18;% H, 3.333;% N, 223.13.

% H, 33.86;% N, 22.86.

3 - ([(5-Methyl-1,3,4-oxadiazol-2-yl) thio] -methyl) -7-methoxy-7- [2- (1H-tetrazol-1-yl) acetamido] -3- cefem-4-carboxylic acid, UV max (ethanol-ol) 269 nm (ε 8910). »

Analysis for C15H16N8O6S2:

calculated:

% C, 38.46;% H, 3.44;% N, 23.92.

% H, 3.69;% H, 23.91%;

3 - ([(1- (Carboxymethyl) -1H-tetrazol-5-yl) thiol] methyl) -7-methoxy-7- [2- (1H-tetrajzo-1-yl) acetamido] -3-cephem- 4-carboxylic acid, UV max (ethanol) 269 nm (ε 7669).

Analysis for C15H16N10O7S2:

calculated:

% C, 35.16;% H, 3.15;% N, 27.33.

35.42% C 3.38 a / _o H, 27.39% N.

3 - [(4,5-Dihydro-6-hydroxy-4-methyl-5'-oxo-1,2,4-triazin-3-yl) thio] methyl) -7-methoxy-7- [2 - (1H-tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid, UV max (ethanol) 274 nm (ε 11 967).

Analysis for C16H17N9O7S2:

calculated:

% C, 37.57;% H, 3.35;% N, 24.65.

36.96% C 3.86 _0/0 H, 27.63% N.

3- | [(1,3,4-Triazol-5-yl) thiilo] methyl] -7-methoxy-7- [2- (ΙΗ-tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid

Analysis for C14H15N9O5S2:

calculated:

% C, 37.08;% H, 3.33;% N, 27.80.

C, 36.98; H, 3.43; N, 27.79.

Example 73

Preparation of 3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -7- (2- (4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino) -2-phenylacetamido) - Of 3-cep-4-carboxylic acid in nitromethane

7- [2- (4-ethyl-2,3-dioxopiperazinylcarbonylamino) -2-phenylacetamido] cephalosporanic acid hydrate (0.3 g, 0.5 mmol) and 1-methyl-1H-tetrazole-5-thiol (0 (0725 g, 0.625 mmol) was added to 6 mL of alumina pre-nitromethane and the mixture was heated to 85 ° C under nitrogen for 12 hours, the nitromethane was evaporated, the residual brown foam was redissolved in sodium bicarbonate solution and washed twice with ethyl acetate. fresh ethyl acetate, cool ^L to 0 ° C and adjust its pH to 2.3.

The layers were separated and the aqueous layer was washed with ethyl acetate. The ethyl acetate solutions were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. A pale yellow powder was obtained in a yield of 130 mg (40% of theory). The identity of the product is confirmed.

NMR

1.2 (t, 3, —NCH 2 CH 3, J = 7 Hz),

3.65 (m, 6, N-CH 2 CH 3 and piperazinyl H),

4.0 (s, 3, -N-tetrazole),

4.4 (s, 2,3-CH 2 SO 2),

5.1 (d, 1, Ce-JH, J = 6Hz),

5.8 (d, 1, C 7 -H, J = 7 Hz),

6.0 (d, 1)

7.4 (m, 5, phenyl);

8.4 (d, 1, -CHCONH3, J = 8 Hz) a

10.0 (d, 1, -CHCONH-, J = 6 Hz).

AND

NH

Example 74

Preparation of 3 - {[(1-carboxymethyl) -1H-tetrazol-5-yl) thio) methyl] -7- (2- (4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino) -2-phenylacetamido) Of 3-cephem-4-carboxylic acid in 1,2-dichloroethane

7- (2- (4-ethyl-2,3-dioxopiperazinylcarbonylamino) -2-phenylacetamido) cephalosporanic acid hydrate (0.3 g, 0.5 mmol) was dissolved in 45 mL of 1,2-dichloroethane pre-dried with aluminum oxide and The solution was heated to 95 ° C to azeotropically distill off water, after distilling off 40 mL of solvent, nitromethane (10ml) α1- (carboxymethyl) -1H-tetrazole-5-thiol (0.160 g, 1 mmol) was added and the reaction mixture was maintained The reaction mixture was filtered and the solvent was evaporated to give a resin, to which ethyl acetate and saturated sodium bicarbonate solution were added, the mixture was washed twice with ethyl acetate, fresh ethyl acetate was added, and the mixture was cooled to 0 ^° C. The pH is adjusted to 2.3 with 20% hydrochloric acid, the layers are separated, the aqueous layer is washed with ethyl acetate, and the ethyl acetate layers are combined and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, dried over MgSO4 and concentrated. The mixture was filtered, evaporated and dried at room temperature to yield 123 mg

NMR δ

1.2 (t, 3, -NCH 2 CH 3, J = 7 Hz),

3,6 (n>, 4, N-N-N-N and piperazinyl 5-H),

4.1 (m, 2, piperazinyl 4-H),

4.4 (s, 2,3-CH 2 S-),

5.1. (D, 1, Сб-Η, J = 5Hz)

5.3 (s, 2, tetrazole 1-CH 2 COOH),

5.75 (d, 1, C 7 -H, J = 6 Hz) T

5.9 (d, 1)

N

AND

CH-J-Hz)

7.4 (m, 5, phenyl HJ, a

9.9 (d, 1, y-CH-, J = 7 Hz).

Example 75

3-i [(4,5-Dihydro-4-methyl-6-hydroxy-5-oxo-1,2,4-triazin-3-yl) thio] methyl} -7- [2- (4-ethyl) -2,3-diO'-O-1-piperazinylcarbonylamino-2-phenylacetamido) -3-cephem-4-carbooylic acid in nitromethane

7- [2- (4-ethyl-2,3-dihydro-4- (1-piperazinylcarbonylamino) -2-phenylacetamido) cephalosporanic acid hydrate (0.3 g, 0.5 mmol) ad, 5- dihyro-e-methyl-6-hydroxy-5-O2O-1,2,4-triazine-3-thiol (0.111 g, 0.625 mmol) was dissolved in 10 mL of nitrile / methane under nitrogen at room temperature and The reaction mixture was heated at 85 ° C for about 12 hours. The resulting brown resin precipitate is discarded. The solvent was slowly evaporated and a yellow precipitate formed. The residue was cooled, filtered and washed with diethyl ether. Two fractions with identical TLC are obtained, in a similar off-white solid. The total yield is 80 mg (24 why, yield). The identity of the product is confirmed

NMR .delta

1.1. (t, 3, -NCH 2 CH 3, J = 6 Hz),

3.3 (s, 3, triazine -CHg),

3.65 (m, 4, N-CH 2 CH 3 and piperazinyl)

5-H),

4.0 (m, 2, piperazinyl 6-H),

4.6 (s, 2, -3-CCHS-),

5.1 (d, 1, C 6 -H, J = 5 Hz),

5.75 (m, 2)

7.45 (m; 5, phenyl, H);

9.5 (d, 1, -CHCONH-, J = 8 Hz) a

10.0 (d, 1,

Example 76

Preparation of 3 - {[(5-methylthio-1,3,4-thiazolyl-2-yl) -1] methyl [-7- [2- (1H-tetrazol-1-yl) ac] -4-amido) -3- of cefem-4-carbooylic acid in nitric methane

7- (2- (1H-Tetriazol-1-yl) acetamido) cep allyspyranic acid (15.0 g, 39.2 mmol) and

The 5- (methylthio) -1,3,4-thiazol-2-thiyl (6.43 g, 39.2 mmol) was suspended in 500 mL of nitromethane, which was pre-filtered through a column of neutral alumina. The mixture was heated to 95 ° C and held at this temperature for 6 hours. The mixture was then cooled overnight, filtered, washed with 250 ml of nitromethane and dried at 45 ° C for 4 hours. Yield: 18.08 g (94.9% of theory).

This product was added to M50 mL of water and 4.0 mL of acetic acid. The pH was adjusted to 6.3 with 107 N NaOH and the mixture was stirred for 1 hour. A solution of 257 ml of 60% sodium lactate and 65 ml of ethanol was then added and the resulting mixture was allowed to stand for 45 minutes. The mixture was stirred for 45 minutes, filtered, washed with 30% ethanol and dried. Yield 18.1 g.

The product was suspended in 300 ml of ethanol for 3 hours, filtered, washed with ethanol and dried. Yield 14.85 g. The identity of the product was confirmed by HPLC.

Examples 77 to 84

Preparation of 3 - [(5-methyl- [1,3 (1,4-thiadiazol-2-yl] -4-yl) -1-iodo] methyl] -7- [2- (1H-tetrazo-X-yl) acetamido] -3-cep-4-carbyoyl acid in various solvents

7- (2- (1H-Tetriazyl-4 ') acetamido) cep alosporanic acid is reacted with 5-methyl-1,3,4-thiadiazyl-2-thiol in various solvents. Essential details of the individual reactions are summarized in the following table. All other aspects of the reaction are the same as those described in the preceding examples.

Amount Amount Solvent Temperature Time Yield Analysis cephalosporan thiol [° C] [h] [° / o 1 (acid temperature [g] [g] melting ° C)

1.91 0.86 acetonitrile (molecular sieve pre-dried) at reflux 24 87 190

00 00 CM IX CT)

00 00 CM CM 00 00

CD 00

CD IX s s o IX

CM

IX

ID xT Ю Ю Ю IX

CD G) G 00 G

WHAT CD 00 G) cn 00 ID Ю СП O) □ O cd CD O ~ rd CD rH (D

♦

CD CD CD CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM

CD 00 rd C-f-T

4D α

T3

Example 85

Preparation of Lithium 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl [-7- (2-hydroxy-2-phenylacetamido) -3-cephem-4-carboxylate] in glacial acetic acid

7- (2-Hydroxy-2-phenylacetamido) cephalosporanic acid (0.48 g, 1 mmol) and 1-methyl-1H-tetrazol-5-ylthio (0.5 g, 4.3 mmol) were reacted in 15 ml glacial acetic acid at 84-86 ° C for 8 hours. The reaction mixture was cooled to room temperature and iodine (0.4 g, 1.6 mmol) was added to convert the unreacted thiol to the disulfide, and the mixture was stirred at room temperature for 20 minutes, then poured into 100 mL of ethyl acetate and 50 mL. The layers were separated and the ethyl acetate layer was washed with two 100 ml portions of water and one 50 ml portion of 20% sodium chloride solution and dried over anhydrous sodium sulfate. Lithium acetate dihydrate (0.21 g, 2 mmol) was added and the mixture was stirred at room temperature for 20 minutes, and the product which crystallized was filtered off, washed with 5 ml of methanol and dried to give 0.34 g of white crystals ( 69.4% yield) The identity of the product was confirmed

NMR δ

3.50 (ABq, Js17 Hz),

3.92 (s, -CH tetrazole),

4.20 (s, 3-CH 3 -),

5.04 (d, C 6 -H, J = 5 Hz),

5.24 (s, OCHCONH -),

5.64 (d, C 7 -H 1 J = 5 Hz) a

7.44 (s, O-H).

The NMR spectrum is identical to that of an authentic sample of the product prepared by displacement in an aqueous medium.

Example 86

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- {2- [o- (tert-butoxycarbonylaminomethyl) phenyl] acetamido] -3-cephem-4-carboxylic acid in nitromethane

7- (2- [o- (tert-Butoxycarbonylaminomethyl) phenyl] acetamido] cephalosporanic acid (0.2 g, 0.386 mmol) and 1-methyl-1H-tetrazole-5-thlol (0.047 g, 0.405 mmol) were allowed to react in 5 ml of nitromethane at 85 ^DEG C. under nitrogen for 12 hours to give 3 - [(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- [o- (tert-butoxycarbonylaminomethyl)]. (phenyl) acetamido] -3-cephem-4-carboxylic acid The identity of the product was confirmed

NMR .delta

1.45 [s, 9, -С (СНз) з]

3.65 (s, 4,2-CH 2 and -CH 2 CONH -),

3.85 (s, 3, -S-tetrazole),

4.3 (m, 4, 3-CH 2 S- and -CHaNHCOO-t-C4H 9),

5.0 (d, 2, Ce-H, J = 4Hz),

5.7 (q, 1, C 7 -H),

7.25 (s, 5, phenyl-H and -CONH-) a

8.9 (s, 1, -COOH)

Example 87

Preparation of 3 - ([(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (2-ureido-2-phenylacetamido) -3-cephem-4-carboxylic acid in nitromethane

7- (2-Ureido-2-phenylacetamido) cephalosporanic acid (0.224 g, 0.5 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.061 g, 0.525 mmol) were reacted in 8 mL of nitromethane at 85 ° C 12 hours to give 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (2-ureido-2-phenylacetamido) -3-cephem-4-carboxylic acid The identity of the product was confirmed

NMR .delta

3.5 (d, 2,2-N, J = 3 Hz),

3.83 (s, 3, -N-tetrazole),

4.17 (d, 2,3-CH 2 S, J = 3 Hz),

4.9 (d, 1, C 5 -H, J = 5 Hz),

5.4 (d, 1, -CH 2 CONH -, J = 8 Hz),

5.6 (m, 3, С--and -ΝΉ2),

6.7 (d, 1, 0 ° C, J = 8 Hz),

NH

7.25 (m, 5, phenyl H 1 a)

9.2 (d, 1, -CH 2 CONH-J = 8 Hz).

Example 88

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl} -7- (2-cyanoacetamido) -3-cephem-4-carboxylic acid in nitromethane

7- (2-Cyanoacetamido) cephalosporanic acid (0.339 g, 1 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.122 g, 1.05 mol) were reacted in 10 mL of nitromethane at 85 ° C under nitrogen for 12 hours. There was obtained 3 - ([(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (2-cyanoacetamido) -3-cephem-4-carboxylic acid.

NMR δ

3.5 (s, 2,2-CH 2),

3.65 (s, 2, CNCH 2 CONH -),

3.95 (s, 3, -S-tetrazole),

5.35 (s, 2,3-CH 2 S -),

5.1 (d, 1, C 6 -H, 1 = 6 Hz),

5.75 (q, 1, C 7 -HJ = 4 Hz),

7.8 (s, 1, -COOH);

8.7 (d, 1, -CHaCONH-, J = 9 Hz).

Example 89

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-ylthio) methyl] -7- [2- (m-chlorophenylthio) acetamido] -3-cephem-4-carboxylic acid in nitromethane 7- (2- (m-Chlorophenylthio) acetamido] cephalosporanic acid (0.390 g, 0.855 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.104 g, 0.9 mmol) were reacted in 10 mL nitrile at 85 ° C C under nitrogen for 12 hours to give 3 - [(1-methyl-1H-tetrazol-5-ylthiol) methyl] -7- [2- (m-chlorophenylthio) acetamido] -3-cephem-4- carboxylic acid The product was identified

NMR .delta

3.6 (s, 2,2-CH 2),

3.75 (s, 2, -CH 2 CONH -),

3.9 (s, 3, -S-tetrazole),

4.4 (s, 2,3-CH 2 S -),

5.0 (d, 1, C 6 -H, J = 5 Hz),

5.8 (q, 1, C7-H, J = 4Hz)

7.15 (m, 4, phenyl-H),

7.7 (d, 1, -CH 2 CONH -, J = 8 Hz) a

8.5 (s, 1, COOH).

Example 90

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl) -7- (2- (phenylthio) acetamido] -3-cephem-4-carboxylic acid in nitromethane

7- (2- (Phenylthio) acetamido] cep alosporanic acid (0.422 g, 1 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.122 g, 1.05 mmol) were treated with 10 mL of nitromethane at 85 ° C under nitrogen for 12 hours to give 3 - ([(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (phenyl thio) acetamido] -3-cephem-4 The product is identified

NMR δ and 3.7 (s, 4, -CH 2 CONH - α 2 -CH 2),

3.9 (s, 3, -S-tetrazole),

4.35 (s, 2, 2Hz),

4.9 (d, 1, C 6 -f J = 6 Hz),

5.8 (q, 1, C7-H, J = 4Hz)

7.25 (s, 5, phenyl-H),

7.7 (d, 1, -CH 2 CONHX, J = 8 Hz) a

9.4 (s, 1, -COOH).

The new acid (3.96 g, 10 mmol) and 1-methyl-1H-tetrazole-5-thiol (1.28 g, 11 mmol) were reacted in 98 mL of n-butylformate at 84-86 ° C for 48 min. hours. There was thus obtained 3 - {[(1-methyl-1H-tetrazol-5-ylthio) methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid, m.p. 167.5; Yield: 79.9% of theory The NMR spectrum of the product is identical to that of Example 5.

Example 1 a d 9 2

Preparation of 3-i [(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in toluene

The reaction described in Example 91 was repeated on the same scale, but in 150 ml of toluene at 84-86 ° C for 136 hours. The product melts at 163-163.5 ° C and is obtained in 88.5% yield. The NMR spectrum of the product is identical to that of Example 5.

Example 1 a d 9 3

Preparation of 3-i [(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (tert-butoxycarbonylamino) -3-cephem-4-carboxylic acid in nitromethane

7- (tert-butoxycarbonylamino) cephalosporanic acid (0.372 g, 1 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.122 g, 1.05 mmol) were reacted in 10 mL of nitromethane at 80 ° C for 12 hours to give 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (tert-butoxycarbonylamino) -3-cephem-4-carboxylic acid.

NMR .delta

1.45 [s, 9, -С (СНз) з)]

3.7 (s, 2, 2-NE),

3.95 (s, 3, -S-tetrazole),

4.4 (s, 2,3-CH 2 S-),

5.0 (s, 1, C 6 -H),

5.6 (s, 2, C 7 - and -CH 2 CONH), and (s, 1, -COOH).

Example 94

Preparation of 3 -) ((1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- [2- (4-ethyl-2,3-dioxopiperazinylcarbonylamino) -2- (p-hydroxyphenyl) acetamido] -3 -cephem-4-carboxylic acid

7- (2- (4-Ethyl-2 ₎ 3-dioxopiperazinylcarbonylamino) -2- (p-hydroxyphenyl) acetamido] cep alosporanic acid (0.180 g, 0.306 mmol) and 1-methyl-1H-tetrazole-5-thiol (0.0374 g, 0.322 mmol) was reacted in ml of nitromethane at 80 ° C for 12 hours. 3 - {[(1-methyl-1H-tetrazol-5-yl) Example 91 was obtained

Preparation of 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl} -8- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid in n-butyl formate

7- (2- (2-Thienyl) acetamido] cep alospora205115 thio] methyl) * 7- [2- [4-ethyl-2,3-dioxopiperazinylcarbonylamino] -2- [p-hydroxyphenyl] acetamido] - 3-Cephem-4-carboxylic acid. The product is identified

NMR δ

1.2 [t, 3, N-CH 2 CH 3.},

3.6. [M, 6,2-CH 2, piperazinyl 6-H a

N-CH 2 CH 3),

3.9 [m, 2, piperazinyl 5HJ,

3.95 [s, 3, -C_H3 tetrazole],

4.4 [s, 2,3-OH2-],

5.0 '[d, 1, C 6 -H, J = 6 Hz),

5.6 [d, 1, C 7 -H]. J = 6Hz)

5.8 [d, 1, CHCONH-, J = 8Hz],

6.8 [d, 2, phenyl-H, J = 8Hz],

7.3 [d, 2, phenyl (H, J = 8 Hz),

8.3 [d, 1, -CHCONH-, J = 8 Hz) a

9.9 [d, 1, -CHCONH-, J = 6 Hz).

AND

-NH

Example 95

Preparation of 3 - {[[1,3,4-thiadlazol-2-yl) thio) methyl] -7- [2- [1H-tetrazol-1-yl] acetamido] -3-cephem-4-carboxylic acid in acetonitrile

7- [2- [1H-TetrazoM-yl [acetamido] cep alosporanic acid [0.38 g, 1 mm ^ 1] α1,4,4-iiadiazole-2-thiol [0,15 g, 1, 27 mmol) were reacted in 15 ml of acetomiril under nitrogen for 24 hours. 3 - {[[1,3,4-Thihdiazol-2-yl) trifluoro] methyl] -7-

- [2- [ШШ а ^ооМММ acet] acetamido] -3-cephem-N-carboxylic acid. The product is identified

NMR δ

3.74 (m, 2, 2-CH 2 -),

4.43 (q, 2,3-CH22 -, J _{and ab} = 14),

5.16 [d, 1, Cs-H. J — 5),

5.42 (s, 2, -CH 3 tetrazole),

5.76 (q, 1, C 7 -H, 1.7 = 5, J ₇ nh = 8),

8.87 [s, 1, tetriazole ring],

9.40 [s, 1, thihdihalthiol starting material),

9.53 [d, 1, -CH 2 CONH -, J = 8 Hz) a

9.57 [s, 1, thihddisulfur ring].

Example 96

Preparation of 3 - ([[5-methyl-1,3,4-thihihihal-a-yl) thio] methyl] -7- [5-ethoxycarbanyl-5-

- (α, 4-Dichloro-benzamido) -tramido] -3-cephem-4-carbonic acid in 1,2-dichloroethane

7- [5-Methoxycarbonyl-5- [2,4-biphenyl] benzamide] acetyl] acetic acid [0.3 g, 0.5 mmol] and 5-methyl-1,3,4-

-thihdihzal-α-thial [0.1 g, 0.75 mmol] was reacted in 1,2-dichloroethane at reflux for 16 1/2 hours. There was thus obtained 3-i [(5-methyl-1,3,4-thiadihzol-2-yl) thio] methyl] -7- [5-methoxycarbonyl-5- [2,4-dichlorobenzamido] -amido] -3-cephem. -4-khgbaxylic acid.

Example 97

Preparation of lithium 3 - {[[1-methyl-1H-tetrazal-5-yl) thio] methyl | -7- [2- (1H-triazol-5-yl) acethidine] -3-cephem-4-carboxylate α7- [2- [1H-Tetraza-1-yl) acetamido] cep alosparic acid [1.91 g, 5 mmol) and 1-methyl-1H-totrhzal-5-ylthio [0.7 g, 6 mmol] in 50 mL The mixture was refluxed for 24 hours and then cooled to room temperature. Evaporate the solvent to about 10 ml in a rotary evaporator. Ethanol (40 ml) was added followed by a solution of 0.3 g lithium hydroxide in 10 ml methanol. The product, which is lithium 3 - {[(1-methyl-1H-tetrazol-5-yl) thio] methyl | -7- [2- [1H-totrazol-1-yl) acethidine] -3-cephem-4-carbaxylate, crystallizes . The reaction mixture was stirred at room temperature for 45 minutes, the product was filtered off, washed with ethanol and dried under vacuum at 40 ° C. Yield 1.60 g (72% of theory). The identity of the product was confirmed by NMR.

Example 98

Preparation of 3 - [[[5-Methyl-1,3,4-thihedihal-2-yl) thio] methyl 1-7- [2-formyl-oxy-2-phenyl-acetamide] -3-cephem-4- khrbaxyl acids in 1, .alpha.-dichlorotthin

7- (.alpha.-Formylaxy-.alpha.-phenylheptthmida) cep alasporbic acid [4.6 g, 8.8 mmol] and 5-methyl-1,3,4-thihihiazole-2-thial [1.52 g, 11.5 mmol) in 50 ml 1,2-dichloroethane was refluxed for 12 hours and then cooled to room temperature. The product 3 - ([[5-methyl-1,3,4-thihdihzo-2-yl) thio) methyl] -7- (2-phenylaxyphenylphenamide) -3-cephem-4-carbamaxylic acid precipitates in The mixture was diluted with an additional 50 ml of 1,2-dichloroethane and stirred at room temperature for 4 hours.The product was filtered off, washed with 1,2-dichloroethane until a clear filtrate was obtained, and then dried at 40-45 ° C under vacuum. , 2.8 g [63% yield). Product Identity se. confirmed by NMR.

Example 99

Preparation of 3 - {[[4,5-ihydro-6-hydroxy-oxa-4-methyl-5-axo-1,2,4-triazol-3-ylthio] methyl-7- [2] - [ΙΗ-tetrazol-yl) acetamide] -3-cephem-4-carbaxylic acid in acetonitrile

7- [2- [1H-Tetrazol-yl] acetamido] cephalaspartaric acid [8.9 g, 23.2 mmol) and

4,5-Dihydro-6-hydroxy-4-methyl-5-axa-1,2,4203115

-triazine-3-thiol (4.1 g, 25.8 mmol) in 200 mL acetone / tril was refluxed for 23 h and then cooled to room temperature. The product crystallizes during the reaction, is filtered off, washed with 50 ml of acetonitrile and dried under vacuum at 40-50 ° C. Yield 9.70 g (86.6%). Product identity

3 - [[(4,5-dihydro-O-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-yl) thio] methyl] -7- [2- (1H-tetrazol-1)] (yl) acetamido) -3-cephem-4-carboxylic acid was confirmed by NMR.

Claims (18)

OBJECT OF THE INVENTION A process for the preparation of 3- (thiomethyl) cephalosporin compounds of the general formula I wherein R ¹³ represents a group C 1 to C 1 alkyl O R ³ —C — NH — where R ³ represents 1. hydrogen, 2. C 1 -C 6 alkyl, 3. - CH2 - (C1-C8 chloralkyl) group, 4. —CH2— (C1-8 fluoroalkyl) group, 5. C 1 -C 4 cyanoalkyl, 6. C 1 -C 4 hydroxyalkyl, 7. p-nitrobenzyloxy, 8. tert-butoxy, 9. 2,2,2-trichloroethoxy, 10. a protected 4-amino-4-carboxybutyl group of the formula O ll · R ¹² O-C-CH- (CH 2) 2 -CH 2 -, A ¹ wherein A ¹ is an amino-protected group selected from the group consisting of C 1 -C 4 alkoxycarbonyl, dimethylureido, benzoyl, halobenzoyl, benzoyloxy, halobenzoyloxy, C 1 -C 4 alkoxycarbonyl 4- (C 1 -C 4 alkyl) -2,3-dioxopiperazinylcarbonyl and R ¹² is hydrogen or C 1 -C 4 alkyl, 11. 4-oxo-4-carboxybutyl; 12. 3-carboxypropyl; 13. the rest of the formula R ¹ is hydrogen or methoxy, R ² is phthalimido, succinimido, a radical of formula wherein each of aa and ^{1 is} independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy or A ¹ CH ² - wherein A ¹ is as defined above, Z is oxygen or sulfur and m is 0 or 1, 14. the rest of the formula P — CH—, Q wherein P represents (a) 2-thienyl, (b) 3-thienyl; or c) a phenyl group of formula wherein L is hydrogen or nitro, or a radical of formula wherein aa and ¹ are as defined above, and Q is (a) hydroxy; (b) formyloxy; (c) acetoxy; d) substituted carboxy of the formula Q-C-O-A ² , wherein A ² is diphenylmethyl, pnitrobenzyl, benzyl, 2,2,2-trichloroethyl, tert-butyl, or p-methoxybenzyl, such as [alkali metal-oxysulfonyl], f) an amino group protected by a group selected from the group consisting of C1-C6 alkoxycarbonyl, dimethylureido, benzoyl, halobenzoyl, benzoyloxy, halobenzoyloxy, C1-alkoxycarbonyl and 4- [C1-C1 alkyl] -2,3-dioxopipe 'Razinylcarbonyl, g) an acylated amino group of the formula O II — NH — S — T, where T is an amino group, NH II — NH — C — NHz, R ⁷ O I II — N — C — R ⁸ , R ⁷ O - N - C - CH = CHR ⁹ , wherein R ⁷ is hydrogen or C 1-6 alkyl, R ⁸ is phenyl, halophenyl, furyl, monomethylamino, dlmethylamino, monoethylamino, di-ethylamino, methylethylamino- , propylamino-, dipropyl-amino-, diisopropylamino-, phenylamino- or diphenylamino, R ⁹ is hydrogen, C 1 -C 6 alkyl- or phenyl, R ¹⁰ is hydrogen, C 1-6 alkyl-, or methylsulfonyl, and R ¹¹ is ethylene-, trimethylene-, or vinylene, 15. the rest of the formula N — OH, P‘ — C — C— About —ОСНз, O Wherein —P 'is P as defined above, a protected 2-amino-4-thiazolyl group containing an amino protected group selected from the group consisting of C1-C12 alkoxycarbonyl-, dimethylureido-, benzoyl-, halobenzoyl-, benzoyloxy-, halobenzoyloxy-, C1- —C4 alkoxycarbonyl- and 4- (C1-C4 alkyl) -2,3-dioxopiperazinescarbonyl or 2-furyl, 16. A radical of formula V — S (O) _{n —} СНг—, wherein V is —CF3 or —CH2 —X, wherein X is hydrogen, methyl, —CF3, —CN or —N3 and n is 0, 1, or 2, or 17. A radical of formula Y-CH2-, wherein Y is 2- thienylskuplnu, 3-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 1-tetrazolyl, 1-benzotriazolyl, 2-oxazolylthio, 2-thiazolylthio, 1,2.3-triazol-5-ylthio, 1.3.4-triazol-2-ylthio, 1,3,4-thiadiazol-2-ylthioscycline, protected 5-amino-1,3,4-thiadiazol-2-ylthio with an amino-protected group selected from the group consisting of: C 1 -C 4 alkoxycarbonyl-, dimethylureido-, benzoyl-, halobenzoyl-, benzoyloxy-, haloigenbenzoyloxy-, C 1 -C 4 alkoxycarbonyl-, and 4- (C1-C6 alkyl) -2,3-dioxopiperazinylcarbonyl, furthermore Y is 5-methyl-1,3,4-thiadiazol-2-yl-thio, 1,2,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, 1,2,5-thiadiazol-3-ylthio, 1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4- Oxadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, pyridylthio, 4-cyano-1,2,3-triazol-1-yl, 3-cyano-1,2,4-triazol-1-yl, or a protected 2-amino-4-thiazolyl group with an amino protected group selected from the group consisting of C1-C12 alkoxycarbonyl, dimethylureido, benzoyl, halobenzoyl, benzoyloxy- , halobenzoyloxy, C 1 -C 6 alkoxycarbonyl and 4- (C 1 -C 6 alkyl) -4 S -dioxo-piperazinylcarbonyl, each of R ⁴ independently represents hydrogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, cyclohexyl or phenyl, each of R ^{5 is} independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-, hydroxy-, nitro-cyano-, methanesulfonamido- or trifluoromethyl; and R ⁶ represents a unit which, with the remainder of the formula, forms an unsubstituted or substituted five- or six-membered heteroaromatic ring containing a total of 1 to 4 heteroatoms selected from the following combinations 1. a nitrogen atom and 0 to 1 oxygen or sulfur atom; 2. nitrogen atoms and 0 to 1 oxygen or sulfur atoms, 3. nitrogen atoms and 0 to 1 oxygen atoms; or 4. nitrogen atoms, wherein all other atoms in the ring are carbon atoms, or a unit which, with the remainder of the formula, forms a 2-benzoxazolyl group or a radical of formula wherein: R ¹ and R ² have the above meanings, and R is C 1 -C 6 alkyl, C 4 -C 8 cycloalkyl, amino mono- or di (C 1 -C 6 alkyl) amino, a group of the formula -C-CW I OCH ₃ or och ₃ is reacted with a nucleophilic sulfur compound of formula III R 13 - S - R 14, (III) wherein R ¹³ is as defined above, and R ¹⁴ represents hydrogen or when and only when R ¹³ represents a methyleneamine group, the R ¹⁴ group is linked to the R ¹³ group to form the thiourea, in an organic solvent, under substantially anhydrous conditions. 2. The process of item 1 for the preparation of compounds of formula I, wherein all the general symbols are as defined in item 1, provided that R ^{3 is} not a protected 4-Amino-4-carboxybutyl, characterized in that the compound of formula (II) is one in which all the radicals are as defined in (1), provided that R ^{3 is} not a protected 4-amino-4-carboxybutyl group. 3. The process according to claim 1, wherein the reaction is carried out at a temperature of 50 to 140 [deg.] C. 4. A process according to claim 3 wherein the reaction is carried out at a temperature of 70 to 120 ° C. characterized in that the compound of formula (II) 5. A process according to any one of claims 1 to 4 wherein the solvent is a hydrocarbon, alcohol, amide, ether, ketone, carboxylic acid, carboxylic acid ester, halogenated hydrocarbon, nitro compound, nitrile or thioether. 6. A process according to claim 5, wherein the solvent is acetonitrile, 1,2-dichloroethane, methylene chloride, propionitrile, nitromethane, nitroethane, acetic acid, isopropyl acetate, butyl acetate, methyl isobutyl ketone, fluorobenzene, thiophene, methylethyl ketone, 1,1,2-trichloroethane, chloroform, benzene, carbon tetrachloride, carbonate, propylene carbonate, isopropyl acetate , 2-nitropropane or n-butylformate. 7. A process according to any one of claims 1 to 6, wherein R is methyl or amino and the other symbols are as defined above. 8. Process according to claims 1-7 for the preparation of compounds of formula I wherein R ¹ represents hydrogen, R ² is 2- (2-thienyl] acetamido and R ¹³ is as defined above, characterized in that as compounds of formula II uses compounds wherein R ¹ and R ² are as defined in this point and R is as defined above. 9. Process according to claims 1-7 for the preparation of compounds of formula I wherein R ¹ represents hydrogen, R ² is 2- (lH-tetrazol-1-yl) acetamido, and R @ ¹³ has the abovementioned meaning, characterized in that as compounds of formula II will use compounds wherein R ¹ and R ² are as defined in this point and R is as defined above. 10. The method of item 9 for the preparation of 3 [(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl] -7- [2- (1H-tetrazol-1-yl) acetamido] -3 4-carboxylic acid, characterized in that 7- [2- (1H-tetrazol-1-yl) acetamido] -cephalosporanic acid is reacted with 5-methyl-1,3,4-thiadiazole-2-thiol. 11. The method of item 9 for preparation 3-11 (1,3,4-thiadiazol-2-yl) thio] methyl | -7- - [2- (1H-Tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid, characterized in that 7- [2- (1H-tetrazol-1-yl) acetamido] cephalosporanic acid is reacted with 1,3,4-thiadiazole-2-thiol. 12. The method according to claims 1-7 for the preparation of compounds of formula I wherein R ¹ represents hydrogen, R ² is 2-hydroxy-2- and R ¹³ is as defined above, wherein the compounds of formula (II) are those wherein R ¹ and R ² are as defined in this point and R is as defined above. 13. The method of item 12 for preparation 3 - {[(1-methyl-1H-tetrazol-5-yl] thio] methyl-7- (2-hydroxy-2-phenylacetamido) -3-cephem-4-carboxylic acid, characterized in that - (2-Hydroxy-2-phenylacetamido) cephalosporanic acid is reacted with 1-methyl-1H-tetrazole-5-thiol. 14. The method according to claims 1-7 for the preparation of compounds of formula I wherein R ¹ represents hydrogen, R ² is 2-formyloxy-2-phenylacetamido and R ¹³ is as defined above, characterized in that as compounds of formula II is compounds wherein R ¹ and R ² are as defined in this point, and R is as defined above. 15. The process of clause 14 for the preparation of 3-i [(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7- (2-formyloxy-2-phenylacetamido) -3-cephem-4-carboxylic acid, characterized in that 7- (2-phenyloxy-2-phenylacetamido) -cephalosporanic acid is reacted with 1-methyl-1H-tetrazole-5-thiol. 16. The method according to claims 1-7 for the preparation of compounds of formula I wherein R ¹ is methoxy, R ² is 2-phenylacetamido, and R ¹³ is as defined above, characterized in that as compounds of formula II is a compound wherein R ¹ and R ² are as defined in this point and R is as defined above. 17. The method according to claims 1-7 for the preparation of compounds of formula I wherein R ¹ represents hydrogen, R ² is 2-fenoxyacetamidoskupinu and R ¹³ is as defined above, characterized in that as compounds of formula II is a compound wherein R ¹ and R ² are as defined in this point and R is as defined above. 18. The process of items 1 to 7 for preparing compounds of formula I wherein R ¹ is hydrogen, R ² is 5- (protected amino) -5 - (COOR ¹² ) -valeramido, wherein the amino group is protected as set forth in point 1, and R ¹² is as defined above, and R ¹³ is as defined above, wherein compounds of formula (II) are those wherein R ¹ and R ² are as defined herein and R is as defined above.