DE3040257A1 - 7 - ((2-AMINO-4-THIAZOLYL) -OXIMINO) -CEPHALOSPORINE DERIVATIVES - Google Patents

Description

The invention relates to cephalosporin derivatives of the general formula I.

CD

in which R is a hydrogen or alkali metal atom, the remainder of Formula * 7

20 -CHO-CO-lower alkyl,

a trimethylsilyl, p-methoxybenzyl, diphenylmethyl, benzyl or trichloroethyl group, the group of the formula

or a lower alkyl radical, R _{1 is} a hydrogen atom or a methyl group, Rp is a hydrogen atom or a methyl group, R is a hydrogen atom or a methyl group, Rh is a hydrogen atom or one of the radicals of the formulas

• Rr

-KQ

, I -S

.Jl- or -OC-lower alkylj

R, - a hydrogen atom or a methyl group,

13ÖÖ19 / 0854

R, - a hydrogen atom, a methyl, benzyl or acetyl

group,

R _{7 is} a hydrogen atom or a lower alkyl radical, Rg is a hydrogen atom or the radical of the formula -CONH ₂ , Rq is a hydrogen atom, a lower alkyl radical or one of the radicals of the formulas

- (CH ₂ ) _p -Ö-OR _{i: L} , j - (CH ₂ ) p- | -0R _{1: L} or- (CH ₂ ) -N - _{lower alkyl) 2} ,

R ₁ Q is a hydrogen atom or a lower alkyl radical and R _1. Is a hydrogen, sodium or potassium atom, η is the value 1, 2, 3 or 4,
m has the value 0, 1 or 2 and
ρ have the value 1, 2, 3 or H.

If the radical R _{1 represents} a pyridinium group or a pyridinium group substituted by a carbamic group, the compounds have the general formula Ia

R ₁ - (C) _n -R

_n -R ₂

₅ X

DJ

in which Rg represents a hydrogen atom or a carbamoyl group.

The invention also relates to cephalosporin derivatives in general Formula II

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13 0019 / 085A

S ^E 16 ⁽ ?> M

NC — CN =? = F " ^ü " N

^ UN H λ -N _n ^ -TCH ₂ X

| 'ff T - (ID

O COOR ₁₂

¹¹ LS

* 14

10 _s

in the R.p a hydrogen, sodium or potassium atom, a Benzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, diphenyl methyl or tert-butyl group or one of the radicals of the formein

-CH ^ -O-lower alkyl. -CH-OC-lower alkyl ^{or ο / γΛ.}

^2; i Y To 1 »

R and B..U independently of one another hydrogen atoms, methyl, ethyl, i-propyl, ii-propyl or carboxyl groups, R ₁ C is a hydrogen or alkali metal atom, for example a sodium or potassium atom or a methyl group , R _{1fi is} in the oC configuration and a hydrogen atom or

^ represents a methoxy group, m has the value 0, 1 or 2,

η has the value 0 or represents an integer from 1 to 4

R ₁ 7 is a hydrogen atom or a lower alkyl radical, X is a hydrogen atom or one of the radicals of the formulas

L. . J

130019/0854

O Π

II ¥

-OC-lower alkyl -O-CNH ^ ₁ NN

ü "H ₂ -sJyL

R ₁₉

R ^ g is a hydrogen atom or a lower alkyl radical, R ₁ O is a hydrogen atom, a lower alkyl radical or one of the radicals of the formulas ~ (CH ₂ ) _p -COOR ₂₀ , - (CH ₂ ) _p -SO ₃ R _{30 or} - (CH ₂ ) - (| lower alkyl) ₂ , and

Rp ₀ denotes a hydrogen, sodium or potassium atom and ρ represents an integer from 1 to H.

If in the compounds of general formula II X one Pyridinium group or a pyridinium group substituted by a carbamoyl group, the compounds can are represented by the formula Hb,

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130019/0854

3O40257

N - = - N

in which Z is a hydrogen atom or a carbamoyl group.

The term "lower alkyl" includes branched and unbranched Hydrocarbon radicals with 1 to 4 carbon atoms, such as the methyl, ethyl, isopropyl and tert-butyl groups.

The compounds of the general formulas I, Ia, II and Hb
and their intermediates, which ^{contain a 2-AmInO-1} J-thiazolyl group in their structure, are in tautomeric forms and can contain a 2-imino group. The compounds of the general formula I can therefore also by the general formula III

CH ₂ R ₄

COOR

(III)

and the compounds of general formula II by the general Formula IV are reproduced.

130019/0854

The intermediate and end products are always referred to and shown below as 2-amino-4-thiazoles, although both tautomeric forms are the subject of the invention.

The compounds of the general formulas I and II and their intermediates, described below, with the oximino group of the formula _ (-> _ '

20 Υ

can be used as syn or anti isomers or as a mixture of isomers can be obtained. All of these isomeric forms are the subject of the invention. However, preferred are generally among the End products are those in the syn form, as this isomeric form has the greater activity.

The symbol (o) denotes a sulfide group to which optionally \ sin or two oxygen atoms are bonded.

If the sulfide only carries one oxygen atom, you can

the sulfoxides of the general formulas I and II and the various Intermediate products described below are either in iX or ß configuration. When the sulfoxide is only available in ß-configuration, it is indicated with the symbol C ^, and if it is only in the ctf configuration then S. it is represented by the symbol q_ '.

130019/0854

Γ Π

The cephalosporins of the general formula I can be obtained by various processes. For example, the compounds of the general formula I in which Ru is a radical of the formulas

■■ -

-OCONH ₂₇ -OC-'lower alkyl, ~ S-

or S

and Rg and R _{10 have} the meanings given above, by acylating an ester of the general formula V

H ₂ N

h ₂ r ₄

j in Rj. and m have the meaning given above and R is an ester protective group, for example a benzyl, diphenymethyl, tert-butyl, p-methoxybenzyl or trichloroethyl group, with a compound of the general formula VE

(VI) 25

■ 30 in which R ₁ , Rp, R ^ ₃ Rn, Rg and η have the meaning given above, are converted to an intermediate of the general formula VII.

130019/0854

- 19 -

: ooR

CH ₂ R ₄

(VII)

The acylation reaction can be carried out in the presence of a coupling agent Sj such as dicyclohexylearbodiimide.

The intermediate of the general formula VII is then treated to remove the ester protecting group, where the compounds of general formula I are obtained in the form of the acid will. In the above-mentioned compounds, R preferably denotes the diphenylmethyl group and the intermediate of the general formula VII is preferred with trifluoroacetic acid to remove the diphenylmethyl group treated.

The compounds of general formula VI are made by reaction of 2 ^ 111 ^ 0-4-thiaz oil glyoxylic acid of the formula VIII

H ₂ S

: -cooh

(VIII)

obtained with a compound of the general formula IX.

(IX)

35 ^iV 5

The compounds of the general formula IX can be

130019/0854

treatment of the sodium salt of N-hydroxyphthalimide with a Compound of the general formula X are produced,

^{5 cl} - '^ _n -I = F

³ (X)

R, -

⁶ L

whereby a compound of the general formula XI is obtained,

^^ ΓΤ R-, NO ^ -ί (χι)

when treated with hydrochloric acid the compound of the general Formula IX is obtained.

The T-amino-cephalosporanic acid esters-of- and ß-sulfoxides of the general formula V (m has the value 1) are obtained by converting 7-amino-cephalosporanic acid as the starting compound (m has the value 0) in the ester of the Schiff's base of the

25 general formula

which is then oxidized with a peroxycarboxylic acid such as m-chloroperbenzoic acid to form a mixture of the Qx and ß-sulfoxides of the Schiff base cephalosporin esters. The Sehiff base side chain is then cleaved by treatment with toluenesulfonic acid, and the oC and o-sulfoxides of the 7-amino

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130 0197 08 54

cephalosporanic acid esters are separated by chromatography. Further oxidation of the sulfoxides gives the corresponding Sulphones (m has the value 2) of the general formula V.

The compounds of the general formula Ia can be prepared by reacting a compound of the general formula I in which R a water to ff atom and R ^. one of the remnants of the formulas

0 or 0 Il It -O-C-CH -O-C-NH

mean substituted with pyridine or with a carbamoyl group Pyrldine in a polar solvent such as water in the presence of a catalyst such as an alkali metal all thiocyanate, according to the US Pat. No. 3,792,047 and US Pat DE-OS 2 234 280 known processes are produced.

The compounds of general formula I in which R ^, a Heterothiorest, i.e. one of the remainders of the formulas

represents, can also by reacting a compound of the general formula I in which R is a hydrogen atom and R ₁ . one of the remnants of the formulas

O 0

-OC-CH or -0-C-NH ₃

mean, with a mercaptan of the general formula

Straight-S-H

or an alkali metal (preferably sodium) mercaptan salt the general formula

³⁵ hetero-S ^ alkali metal

getting produced.

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130019/0854

Such a method for the incorporation of a heterothio radical in the 3-position are described, for example, in ÜS-PS 3 955 213 and 4,066,762.

The ß-sulfoxides of the general formula I (m = 1) can also by direct oxidation of the corresponding sulfides Cm = 0). Suitable oxidizing agents are peroxycarboxylic acids, such as m-chloroperbenzoic acid or peracetic acid. This reaction can be carried out at temperatures from about 0 to 25 ° C.

The sulfones of the general formula I (m = 2) can also by direct oxidation of the corresponding Of sulfoxides (m = 1) can be produced. Here, too, peroxycarboxylic acids, such as m-chloroperbenzoic acid and peracetic acid, are preferred Oxidizing agent.

The compounds of the general formula I in which R is a sodium or potassium atom are obtained by reacting the corresponding compound of general formula I in which

R represents a hydrogen atom, with the corresponding salt. forming ion obtained.

The compounds of general formula I in which R is the remainder the general formula

^R 7 0

. -CH-O-C-lower alkyl

means, can by treating the corresponding free acid of the general formula I with a compound of the general Formula ^ 7 0

Hai-CH-O-C-lower alkyl

can be obtained, in which shark means a chlorine or bromine atom. The reaction can be carried out in an inert solvent, such as dimethylformamide, at or below room temperature

take place.

130019/085 4

Γ Π

Similarly, the connections are general

Formula I, in which R is a group of the formula O ₁ ,

by treating the free acid of general formula I with a compound

5 of the general formula

O ₁

prepared in which L represents a hydroxyl group or a bromine atom; see üS-PSen 3 860 579, 3 951 95 ¹ I and 4 072 677.

The compounds of the general formula I in which the various substituents have the following meanings are preferred:

The oximino group is in the syn configuration; η has the value 1 or 2;

m has the value 0 or 1, with the proviso that the sulfoxide is in the β-configuration when m has the value 1; R represents a hydrogen, sodium or potassium atom; R ₁ , R ₂ , R, and Rj- denote, independently of one another, a hydrogen atom or a methyl group.

R ₁ J means one of the radicals of the formulas

25th ._

, -0-0-N

NH ₂ , -nQ> -V -S-II ₅ JLcH ₃ or -S

R ^ means a hydrogen atom, a methyl, benzyl or Acetyl group;

R _{7 represents} a hydrogen atom;

Rg denotes a hydrogen atom or a group of the formula

-CONH ₂ ;

Rq represents a hydrogen atom, a methyl group or a remainder of the formulas

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130019/0854

Γ Π

ο ο

1 Il [I

- (CH JO-OR ₁ " ^CCH 2 ^} D ~ ft ~ ^OR ll ' ^or - (CH) -N (CH ^) _;

R ^ ₁ means a hydrogen, sodium or potassium atom and ρ has the value 1 or 2.

Particularly preferred are the above-mentioned compounds of the general formula I, in, where R ^ is one of the radicals of Formulas ..,

10 "j]:

-0-C-CH ₃ or

CH,

means.

The cephalosporins of the general formula II can according to different processes can be produced. For example, the compounds of general formula II in which X a hydrogen atom, a group of the formulas

«■«

-0-C-CH ₃ , -0-C-NH ₂

or a heterothxo radical, i.e. one of the radicals of the formulas

or

means by acylating an ester of the general formula XII

Zl Il

(XII) 2 "

in which X, R ^ g and m have the meaning given above and R _{21 is} an ester protection group, for example a benzyl, dipheny! methyl, tert-butyl, p-methoxybenzyl or

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130019/0854

Trlehloräthylgruppe represents, with a compound of the general Formula XIII

XJ

: —CooH

(XIII)

-R

15th

in which R ₁ ^, R ^ j, and η have the meaning given above and Rj- represents a hydrogen atom or a methyl group, are converted into an intermediate of the general formula.

fl ^R ifi ⁽⁰⁾ -

(XlV)

R - (C) _n -R
13 I ⁿ 14

The acylation reaction can be carried out in the presence of a coupling agent, for example dicyclohexylcarbodiimide will. The acid of the general formula XIII is treated with monosilyltrifluoroacetamide before the acylation.

The intermediate product of the general formula XIV obtained is then treated to remove the ester protection group Rp., the compounds of the general formula II being obtained in the form of the acid. Preferably the means Rp. In the above-mentioned compounds is the diphenylmethyl group and the intermediate of the general

130019/0854

Formula XIV is preferred for removing the phenylmethyl group treated with trifluoroacetic acid and anisole.

The compounds of the general formula XIII in the syn configuration are obtained by reacting a 2-amino- ¹ i-thiazol-glyo: xylic acid of the general formula XV 'which is optionally provided with a protective group.

JL-COOH

'"(XV)

in which R _{22 is} a hydrogen atom or a customary amino protective group, such as a formyl, trityl or tert-butoxycarbonyl group, with a tetrazole of the general formula XVI. manufactured,

■ ■ '. N N

I ² Ij 11

H-N-O- (C) "-I J

Γ T (XVI)

20 ft, r

1 R ₃

in the R ^ ₁ . represents a hydrogen atom or a methyl group. The protective group Rp ₂ can be split off after the abovementioned reaction by customary processes, the intermediates of the general formula XIII being obtained in the syn configuration.

The tetrazoles of the general formula XVI can by treating N-hydroxyphthalimide with a nitrile of the general Formula XVII are produced,

Cl- (C) _n -CN _(XVII)

»13

whereby a compound of the general formula XVIII is obtained,

130019/0854 ^J.

Γ _ Π

(XVIII)

which then with sodium azide to a compound of general Formula XIX is implemented.

.13

-O- (Q) ^ - T = TN 10

j (XiXA)

By treating a compound of the general formula X with methyl iodide, a compound of the general formula is obtained XIXA received.

Treatment of a compound of the general formula XIX or XIXA with hydrochloric acid under reflux gives the compound of the general formula XVI.

The syn form of the compounds of the general formula XIII can also be achieved by reacting a £ y- (oximino) -4-thiazole-acetic acid with a protected amino group in the 2-position of the general formula XX

(XX) C 1-10 alkyl

in which R _{? 2} ^ ^e has the meaning given above and the alkyl radical is preferably an ethyl group, with a

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130019/0854 -

Γ π

Tetrazole of the general formula XXI

(XXI)

^R 14

in which Hai preferably denotes a chlorine atom and R_, a hydrogen atom or a protective group, for example a benzoyl group, or a methyl group, are obtained. The protective groups Rp ₂ and R- can be split off in the usual way after the reaction.

The anti-form of the compounds of general formula XIII can also be achieved by reacting a ^ thiazolyl-glyoxylic acid ester with a protected amino group in the 2-position of the general Formula XXII

IL-K

j-COOalkyl (XXII)

in which Rpp has the meaning given above and the alkyl radical is preferably an ethyl group, can be prepared with a tetra = ZiO 1 of the general formula XXI. If
"Protecting groups R ₀₀ and R _? , are present, they are after
split off the implementation in the usual way.

. ids 7-Ämino- = G "phalosporansäureestei ^'i = fX =' and beta-sulfoxides of allgerasiiier: ITOX ^ mel ZLI (η = 1), duroh üiiiv; andlung the ^2C T-Ainino-cephaiosporansäuren (n = 0 ) in. the Schiff base esters of the general formula XXIII. · .._-...

CH = N

/ .. döOR ^ "(XXIII)

21st

130019/0854

r ■ π

produced, which then with a peroxycarboxylic acid, such as m-chloroperbenzoic acid, to a mixture of (X- and ß-sulfoxide Schiff bases, cephalosporin esters be oxidized. The Schiff base side chain is made by treatment with toluenesulfonic acid split and the <Y- and ß-sulfoxides of the 7-amino-cephalosporanic acid ester are separated by chromatography. Further oxidation of the (/ sulfoxides gives the corresponding Sulphones (n = 2) of the general formula XII.

The compounds of the general formula Hb can be prepared by reacting a compound of the general formula II in which R _{12 is} a hydrogen atom and X is a group of the formulas

O 0

-0-C-CH, or -0-C-NH ₂ means with pyridine or a pyridine substituted with a carbamoyl group in a polar solvent], such as water, in the presence of a catalyst such as an alkali metal thiocyanate, according to the US- PS 3 792 047 and DE-OS

2 23 ^ 28Ο method described. 20th

The compounds of the general formula II in which X represents a heterothio radical, i.e. a radical of the formulas

- ³ AJj-R _{18 or} -

can also be achieved by reacting a compound of the general formula II in which R. _{2 is} a hydrogen atom and X is a group of the formulas

0 0

-0-C-CH ₃ or -0-C-NH ₂ with a mercaptan of the general formula XXIV

Hetero-S-H (XXIV)

130019/0854

Γ Π

- "^ O -

or with an alkali metal (preferably sodium) mercaptan salt of the general formula XXV

Hetero-S-alkali metal (XXV)

can be obtained. Such methods for incorporating a heterothio radical in the 3-position are, for example, in US Patents 3,955,213 and 4,066,762.

The β-sulfoxides of the general formula II (m = 1) can also be prepared by direct oxidation of the corresponding sulfides (m = 0). Suitable oxidizing agents are peroxycarboxylic acids such as m-chloroperbenzoic acid and peracetic acid. The reaction can be carried out at temperatures from about 0 to 25 ° C.
15th

The sulfones of the general formula II (m = 2) can also by direct oxidation of the corresponding 0 <-sulfoxides (m = 1) getting produced. Here too, pe ro xo carboxylic acids, such as m-chloroperbenzoic acid and peracetic acid, are the preferred oxidizing agents.

The compounds of general formula II, in which R ₁₂ * ** ir and R _{20 represent} sodium or potassium atoms, are by reacting the corresponding compounds of general formula II in which R ₁₂ , R ₁₅ and R _{30 are} hydrogen atoms, with a 3ase. made with the appropriate cation.

The compounds of general formula II in which R ^ ₂ denotes

Remainder of the formula
30 0

11

-CH-O-C-Never de ralkyI

R ₁₇

represents can by treating the appropriate free Acid of the general formula II with one or two moles of a compound of the general formula XXVI

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130019/0 854

O
Hal-CH-OC-lower alkyl (XXVI)

in which Hal represents a chlorine or bromine atom, in an inert one Solvents, such as dimethylformamide, can be obtained at or below room temperature.

In a similar way, the compounds of the general formula II, in which R _{12 represents} a group of the formula I, can be prepared by treating the free acid car of the general formula II with a compound of the general formula XXVII

τ ι r ¹ +. a

(XXVII)

are prepared, in which L represents a hydroxyl group or a bromine atom. See U.S. Patents 3,860,579, 3 951 95 ¹ J and 4,072,677.

are the compounds of general formula II, in which the radicals have the following meanings:

H ₁₂ is a hydrogen, sodium or potassium atom, R. ,, and R-η are both hydrogen atoms; η has the value 1; ■

Η ,, - means a hydrogen atom, a methyl group, a sodium or potassium atom

R ^ g denotes a hydrogen atom;

X is a hydrogen atom or a residue of the formulas

9 8 / -Λ / ~ \

-O-iJ-CH ,, -0-C-KH ₂ , - \ O), " ⁰ C Ο)"

CH-. jP the -s

130019/0854

^Γ - 32 - ^Π

R ₁₉ is a hydrogen atom, a methyl group or a radical of the formulas

-CH ₂ -COOP _{2 (i}

O S O

R ₂ Q is a hydrogen, sodium or potassium atom.

Particularly preferred among the compounds mentioned above are those in which the oximino group of the

is in the syn configuration, R ₁ j- is a hydrogen, sodium or potassium atom and X is a group of the form In ·.

-0-C-CH ₃ 20

represents.

The particularly preferred compounds of the general formula II, which have been given above, additionally have in addition to their broad antimicrobial spectrum, they also have particularly excellent activity against a number of gram-negative microorganisms, for example Serratla sp., indole-positive Proteus sp., Enterobacter sp., And strains of Klebsieila pneumoniae. These compounds have a high degree of stability against β-lactamases from both gram-positive and gram-negative bacteria.

The compounds of the general formulas I and II are useful antibacterial agents that are effective against. , various gram-negative microorganisms, such as Klebsieila, Possess Proteus and Enterobacter species. These connections

130 0 19 /0.8 5 4 ^J

Γ - "Ί

are also against strains of Escherichia CoIi, Citrobacter Freundii and Salmonella typhimurium are effective. The inventive Compounds can be used as antibacterial drugs to treat infections that are due to the the above-mentioned microorganisms are due.

In general, they can be used in a similar manner as antibacterial Agents against other gram-negative organisms can be used. For example, a compound of the general formula I or II or their physiologically acceptable salt in an amount of about 1 to 100 mg / kg daily in parenteral Form in a single dose or in two to four divided doses in different animals for the treatment of bacterial infections administered, for example in an amount of 5 mg / kg

in mice. 15th

Up to about 600 mg of an acid of the general formulas I or II or its physiologically tolerable salt or ester can be formulated into injection preparations according to customary pharmacological practice.
20th

The examples illustrate the invention.

example 1

Sodium salt of / 6R-Z ^ oG 7ß (7) J-7-3- £ (acetyl oxy) -methyl7-7- CCi 2-amino-4-thiazolyl) -Z "(1H-imidazol-2-yl-methoxy ) -imino7-acetyl7-amino7 -8 -oxo-5-thia-1 -azabicyclo / 4, 2, Q7oct-2-en-2-carboxylic acid
a) 2- (1H-Imiaazol-I-yl-methoxy) -lH-isoindole-1,3 (2H) -dione

5.1 g sodium salt of N-hydroxyphthalimide and 1.9 g 2-chloromethylimidazole hydrochloride (J. Chem. Soc, 1965, p. 4577) stirred at room temperature for 2 hours in anhydrous methanol. Thereafter, the solvent is under reduced pressure distilled off, the residue with an aqueous sodium bicarbonate

Treated carbonate solution and extracted 3 to 4 times with chloroform. The combined organic layers are over

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r - - π

Dried sodium sulfate, filtered and evaporated to dryness. Yield: 1.7 g of the title compound as a crystalline Peststoffs mp 158 to l6O ° C.

b) 2- £ (aminoxy) methyl7-lH-imidazole hydrochloride (1: 2) 1.5 g of the compound prepared above under (a) are stirred for 4 hours in 20 ml of 17> 5 percent hydrochloric acid refluxed. Thereafter, the reaction mixture is cooled to room temperature and the precipitated phthalic acid is filtered off. The mother liquor is then evaporated to dryness. Yield: 0.8 g of the title compound with a melting point of 182 bis 183 ° C.

c) 2-Amino-iX-ÄlH-imidazol-2-yl-methoxy) -imino7-4-thiazole-acetic acid hydrochloride (1: 2) (Z) 2 g of the compound obtained in (b) above and 2.24 g 2-Amino-thiazo1-4-glyoxylic acid are added to 50 ml with stirring Suspended in water. The pH is adjusted to 6 with potassium carbonate. Stirring is then continued for an additional 12 hours. The pH is then adjusted to 6.4 with hydrochloric acid. After 2 hours, 0.8 g of the crystalline title compound are obtained filtered off from the mp 153 to 160 ° C (decomp.).

d) Z5R-ZT6oi, 7β (Z) J [7-3 - /: (- Acetyloxy) -methyl7-7-Z'Z "(2-amino-4-

thiazolyl) -ZJ [1H-imidazol-2-yl-methoxy) -imino7-acetyl7-amine o7-8-oxo-5-thia-l-azabicyclo ^. 2.Q7oct-2-en-2-carbon-

acid diphenymethyl ester

1.2 g of the compound obtained under (c) above, 1.84 g 7ACA-Benzhydry! Ester and 0.54 g of hydroxybenzotriazole are in

50 ml of dimethylformamide (DMF) dissolved. The DMF solution is then cooled to 0 ° C. and treated with 1.1 g of dicyclohexylcarbodiimide added in 20 ml of acetonitrile and then stirred at Ö ° C for 24 hours. The solvent is then reduced under reduced pressure Distilled off under pressure and the residue obtained was dissolved in acetone and filtered. The mother liquor is evaporated to dryness and the oily residue obtained in aqueous jiatrium

130019/0854

r _r ■ - ■ π

solution poured at a temperature of O ^{0 C.} The crystalline precipitate is then filtered off and _{purified by column chromatography using SiO 2} and ethyl acetate as the mobile phase. Yield: 1.5 g of the title compound with a P. 115 ° C. (decomp.).

e) / BR-ZBoC, 7ß (Z) 77-3-r (acetyloxy) -methy] J-7- / Z "(2-amino-4-

thiazolyl) Γ- (IH-imidaz oil -2-y 1 -methoxy) -imino7-ace ty 17-amino7-8-oxo-5 -th la -1-azabicyclo D \. 2.07oct-2-en-2-carboxylic acid Tri f 1 uo ra ce t at

920 mg of the compound obtained above under (d) are ^{suspended in 2.5 ml of anisole at 0 °} C. with stirring. Then 5 ml of trifluoroacetic acid are added to the suspension and the mixture is stirred ^{at 0 ° C. for a further hour.} The solution is then poured into 100 ml of a mixture of diethyl ether and petroleum ether in a volume ratio of 1: 1. The precipitated acid is filtered off, washed with diethyl ether and dried. Yield: 850 mg of the title compound.

f) Sodium salt of Z5R- / C6iX, 7ß (Z) 77-3- / r (aisetyloxy) -methyl7- T-CiJ 2-amino-Jj -thiazolyl) -Z "(1H-imidazol-2-yl-methoxy) -iminoy-acety ^ -aminoJ-S-oxo-S-thia-l-azabicyclo ^ l. 2.07-oct-2-en-2-carboxylic acid

850 mg of the compound obtained in the above (e) are dissolved in 15 ml of an anhydrous mixture of acetone and methanol in a volume ratio of 1: 1 and treated at a temperature of 0 ⁰ C and 765 mg sodium ethylhexanoate in 5 ml of butanol. After stirring for 10 minutes, the mixture is poured into 100 ml of diethyl ether and the deposited precipitate is filtered off. Yield: 6 30 mg of the title compound from F.

³⁰ I63 to 165 ° C.

Example 1 2

Sodium salt of if5S £ 5tx, 6ß, 7cy (Z) 77-3- / CtAcetylöxy) -methyl7-7-2-amino-4-thiazolyl) -ZTlH-imidazol-2-yl-methoxy) -imino7-acetylZaminoJSoxoSthialazabicycloZll. 2.07oct-2-en-2-

carboxylic acid 5-oxide

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130019 / 08B4-

Γ - Π

a) Z5SZ5eC, 6ß, 7 <(Z) J7-3-ZIAcetyloxy) -inethy2j-7- ^ 2-amino-i | - thiazolyl) - / ilH-imidazol-2-yl-methoxy) -imino7-acetyl7-aminoJ-S-oxo-S-thia-1-azabicycloA .2.07oct ~ 2-en-2-carboxylic acid 5-oxide benzhyaryl ester

2.0 g of 2-amino (X- / TlH-imidazol-2-yl-methoxy) -iminctf-4-thiazole-acetic acid hydrochloride (1: 2) according to Example Ic), 2.95 g of 7ACA benzhydryl ester β-sulfoxide and 1.2 g of hydroxybenzotriazole are dissolved in 80 ml of dimethylformamide, ^{cooled to 0} ° C. and treated with 1.8 g of dicyclohexylcarbodiimide. The solution is then ^{stirred at 0 °} C. for about 15 hours. The solvent is then distilled off under reduced pressure and the oily residue is stirred at 0 ⁰ C with aqueous sodium bicarbonate solution. The deposited precipitate is then filtered off and purified by column chromatography using SiOp and acetone as the mobile phase. Yield: 2.2 g of the Tite Ive compound.

b), _J

thiazolyl) -Z "(1H-imidazol-2-yl-methoxy) -imino7-acetyl7-amino7-δ-οχο-5-thia-l-azabicyclo / ^. 2.07oct-2-en-carbon-

acid 5-oxide trifluoroacetate

A suspension of 2 g of the compound obtained above under (a) and 6 g of anisole is ^{stirred at 0 °} C., and 8 ml of trifluoroacetic acid are added. The mixture is then stirred for 45 minutes and then poured into 200 ml of diethyl ether. The deposited precipitate is filtered off and washed with diethyl ether. Yield: 1.8 g of the title compound.

c) Sodium salt of ßSZSoc, 6ß, 7 (X (Z) 77-3- £ iAcetyloxy) -methyl7-7-ZZl 2-amino-4-thiazolyl) - / "(1H-imidazol-2-yl-methoxy) iminctf-ace ty 3j-andna7-8-oxo-5-thia-l-azabicyclo /?}. 2.07-o'ct-2-en / £ carb on acid-5-oxide d

1.9 g of the compound obtained above under 2b)

5 minutes with stirring in 5 ml of a mixture of dimethylformamide and methanol treated in a volume ratio of 1: 1.

L J

130019 / 08BA

r ■ - π

Then the mixture is mixed with 200 ml of diethyl ether, and the precipitated sodium salt is filtered off. Yield: 1.1 g of the title compound from P. 140 to 145 ° C (decomp.).

5 Example3

Sodium salt of ZT6R- £ 5cx ', 7ß (Z) 77-7- / Zl2-amino-4-thiazolyl) -Zr (1H-imidazol-2-yl-methoxy) -iminQ7-acetyl7-amino7-3- ^ Z " (lmethyl-1H-tetrazo 1-5 -yl) -thio7-methyl 17-8 -oxo -5 -thia-1 -azabicyclo Ui · 2.07 oct-2-en-2-carboxylic acid

In the reaction of 2-amino- £ X-Z '(1H-imidazol-2-yl-methoxy) -iminoJ - ^ - thiazole-acetic acid hydrochloride (1: 2) from Example Ic) with 3- (1-methyl -lH-tetrazolyl) -7ACA-benzhydryl ester by the method according to Example Ib) the £ 6R- £ 6 <y, 7 & (Z) JJ-7- / Z "(amino-4-thiazolyl) -iT (1H-imidazole -2-y1-methoxy) -imino7-acetyl7-amino7-3- £ "ZX1-methyl-1H-tetrazol ~ 5-yl) -thio7-methy] J7-S-oxo-S-thia-1-azabicycloA. 2.07oct-2-en-2-carboxylic acid diphenylmethyl ester was obtained. This compound is then processed further according to Examples Ie) and f), ie the benzhydryl group is split off by treatment with trifluoroacetic acid and the sodium salt is then produced. There is obtained the title compound, melting at 198-200 ⁰ C (dec.).

Example H

Sodium salt of Z3S- ^ or, 6ß, 7oc (Z) 77-3-ZTAcetyloxy) -me thy 17-7 - / "£" (2-amino-4-thiazolyl) -r (lH-imidazol-2-yl- methoxy) - imino7 -ace ty 17 -amino7 -8 -oxo-5 -thia-1 -azabi cy clo ü \ . 2.07o et -

2-en-2-carboxylic acid-5,5-dioxide

a) ^ 5S- £ 5iX, 6s, 7oc77-3- £ TAcetyloxy) -methy] J-7-amino-8-oxo-5-thia-l-azabicyclo / ⁷ i.2.Q7oct-2-en- 2-carboxylic acid-5-oxide-diphenylmethyl ester (ß-sulfoxide) and £ 5 R-ZBpC, ^ X, 7 SjJ -3- £ (acetyloxy) -methyl7-7 ~ amino-8-oxo-5-thia-l- azabicyclor / i.2.Q7oct-2-en-2-carboxylic acid 5-oxide diphenylmethyl ester ((X -Sulf oxide)

A slurry of 50 g of 7-aminocephalosporanic acid (7-

ACA) in 1 liter of water is stirred with a magnetic stirrer, while tert-octylamine was added dropwise and the pH

L J

130019/0854

Value between 7 and 8 is kept. After 1 hour, the undissolved solid is filtered off (Celite) and the filtrate is treated with a solution which is prepared by adjusting the pH of a mixture of 10 ml of 5-ethylamine and 20 ml of v / water with 6N hydrochloric acid to a value of 8.0 became. The solution obtained is then treated with 10 ml of salicylaldehyde. After 2 minutes a solid separates out. Another 10 ml of salicylaldehyde are added 5 minutes later. The slurry is stirred for 10 minutes, then .abgekühlt 4.5 hours at 0 ⁰ C and filtered. The filter cake obtained, slurried twice with 300 ml of cold water and filtered. The wet cake is then dried under reduced pressure at a temperature of 60 ° C. over a large amount of PpO ~. Yield: 66 g of the tert-octylamine salt of 7-salicylaldiminocephalosporanic acid in the form of a yellow-brown solid.

A slurry of 25.25 g (0.05 mol) of the tert-octylamine salt obtained above (powdered with a mortar and pestle) in 250 ml of anhydrous acetonitrile is treated with 9.5 g (0.05 mol) of p-toluene sulfonic acid monohydrate . After 10 minutes, the mixture is treated with a solution of 9.7 g (0.05 mol) of diphenyldiazosethane in 50 ml of acetonitrile over the course of 15 minutes. After 1 hour the slurry is filtered, the solid obtained is washed with acetonitrile and the combined filtrates and washings are evaporated under reduced pressure. The oil obtained is purified by column chromatography on 300 g of silica gel using methylene chloride as the mobile phase. Fractions (500 ml) 2 to 3 contain 7.5 g of the desired diphenylmethyl _{ester and some impurities with a higher R f} value (determined by thin layer chromatography on silica gel with chloroform and ethyl acetate in a ratio of 3 ϊ 1 as developer). Fractions 4 to 11 contain 12.3 g of pure 7-salicylic

aldiminocephalosporanic acid diphenylmethyl ester. 35

L. ■ J

130019/08 5 4

Γ ■ Π

NMR Spectrum: (CDCl3) S 1.97 (s, 3Η, CH CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, c-2); 4.67 and 5.01 (AB q, J = 14 Hz, 2H, C-3 ^f ); 4.99 (d, J = 5 Hz, IH, c-6); 5.20 (broadened d, J = 5 Hz, IH, C-7); 6.62 - 7.60 (m, about 15I & 9.07 (wide s,

5 IH, -CH = N-).

A solution of 12.3 g (0.023 mole) of diphenylmethyl ester obtained above in 125 ml of methylene chloride is cooled to 0 ⁰ C and a solution of 4.6 g (0.023 mol) 85prozentiger m-chloroperbenzoic acid in 70 ml of methylene chloride over 15 Minutes offset. After 1 hour, the slurry is washed with a mixture of 100 ml of 5 percent sodium bicarbonate solution and 50 ml of 5 percent sodium sulfite solution. The organic layer is dried and evaporated under reduced pressure. The oil obtained crystallizes from 70 ml of ethyl acetate, 8.7 g of a mixture of and ß · sulfoxide being obtained. A second amount of 1.5 g of the mixture of (X- and ß-3-sulfoxide is also still obtained Quartet (3.57 and 4.10 ppm) at low field compared to the corresponding values of the ß-isomer obtained in lower amounts (1.97, 3.26 and 3.94 ppm).

A slurry of 10 g (0.018 mol) of the mixture obtained above of the Oi- and β-sulfoxides of 7-salicylaldiminocephalosporanic acid-diphenylmethyl ester in 100 ml of ethyl acetate is mixed with 3.2 g (0.018 mol) of p-toluenesulfonic acid monohydrate treated. After 5.5 hours, 300 ml of diethyl

ether added. The gummy solid obtained is digested, filtered and washed twice with diethyl ether. The moist solid is then dissolved in 200 ml of ethyl acetate and the solution is mixed with 100 ml of 5 percent sodium bicarbonate solution washed, dried and evaporated. the

8.0 g of residue obtained are on a column with 300 g of silica gel with a mixture of chloroform and ethyl acetate in

L J

130019/0854

Ratio 5: 1 chromatographed as eluent. Fractions of 500 ml are obtained. Fraction 3 contains 1.0 g of recovered 7-salicylaldiminocephalosporanic acid dimethyl ester. Fractions 6 to 16 contain Ί, 5 g / 5R-ZBiX, 6ot, 7ß77-3-ZT (acetyloxy) -me thy 17-7 -amino -8 -oxo-5-thia-l -azabicycloZ ⁷ t.2.0_ / ^r oct-2-en-2-carboxylic acid 5-oxide diphenylmethyl ester ((γ-sulfoxide isomer); NMR spectrum (CDCl,) <S: 2.00 (CH ₃ COO-); 3.43 and 4.06 ppm (AB q, C-2). Fractions 22 to 30 (after fraction 16 acetic acid ethy1-ester is used as the mobile phase) contain 1.5 g of Z5S- / 5 (X _i 6β, 7C £ 77-3- / (Acetyloxy) -methyl7-7-amino-8-oxo-5-thia-1-azabicycloZ ^; 2 {.2.07oct-2-en-2-carboxylic acid 5-oxide-diphenylmethyl ester (β-sulfoxide isomer); NMR- Spectrum (CDCl3) δ: 2.10 (CH C00-), 2.97 and

3.5 ^ ppm (AB q, C-2). 15th

b) Z ~ 6R- £ 5cx, 7777-3 - ^ * (acetyloxy) -methyl_7-7-amino-8-oxo-5-thia-1-azabicyclo / ¹ *, 2.0j ^r oct-2-en-2 carboxylic acid-5 _J 5-dioxide Diphsnylmethy! ester

/ * 5R ÖC, 60c, 7 Z7 -3- / TACE tyloxy) -me thy 17-7 -amino-8-oxo-5-thia- 1-azabicyclo {H ^.2: 37oct-2-ene-2- 5-oxide diphenyl methyl carboxylic acid ester from Example 4a) is added to methylene chloride and the mixture is cooled to 0.degree. An equimolar amount of m-chloroperbenzoic acid in methylene chloride is then added to the mixture. When the reaction is complete, the slurry is treated with 5 percent sodium bicarbonate solution and 6 percent sodium sulfite solution. The organic layer is dried and evaporated under reduced pressure. By prepared thin layer chromatography of the residue

the title compound is obtained. 30th

c) / 3S-ZBor, 6β, 7tX (Z) 77-3-Z "(Acetyloxy) -methy ΐ7-7-Γ / Γ (2-amino-4-thiazolyl) -ZI lH-imidazol-2-yl -methoxy) -imino7-ace ty 17-amino7-8 -oxo-5-thia-l-azabicyclo D \ » 2.07oct-2-en-2-car-

5,5-dioxide diphenylmethyl ester 35

Example Id) is repeated with the change that instead of

130019/0854

of 7-ACA-Diphenylmethylester der £ jS- £ "5cxv6ß, lx77-3- £ (acetyloxy) -methyl7-7-amino-S-oxo-S-thia-l-azabicyclo /? *. 2. Ojoct-2-en-2-carboxylic acid-5,5-dioxide-Dlphenylmethylester is used. The title compound is obtained.

thiazolyl) -ZTlH-imidazol-2-yl-irie thoxy) -imino7-acetyl7-amino7-8-oxo ~ 5-thia-1-azabicycloZ ^I i.2.07oct-2-en-2-carboxylic acid-5, 5- dioxide trifluoro acetate

Example Ie) is repeated with the change that instead of the Z5R- £ 50r, 7β (Z UJ-3-Π. Acetyloxy) -methyX7-7- £ T (2-amino-4-thiazolyl) -ZTlH-imidazole-2 -yl-methoxy) -imino7-acetyl7-amino7-8 -oxo-5 -thia-1 -azabi cy clo O \ . 2 «07oct-2-en-2-carbonic acid di phenylmethyl ester of £ 5S ~ / 5ör, 6ß, 7iy (Z) 77-3- £ TAcetyloxy) methyl7-7- / 7r (2-amino-4-thiazolyl ) -ifilH-iinidazol-2-yl-meth- oxy) -imino7-acetyl7-amino7-8-oxo-5 ~ thia-1-azabicyclo £ ^I 1.2.07-oct-2-en-2-carboxylic acid-5, 5-dioxide diphenylmethyl ester is used. The title compound is obtained.

e) Sodium salt of Z5S-Z50i, 6ß, 7cx (Z) 77-3-r (acetyloxy) -methyl? - 7-Γ £ ( 2-amino- ⁱ } -thiazolyl) -AtlH-imidazol-2-y 1- methoxy) 1min o7-acetyl7-amino7-8-ο xo-5-thia-l-azabicyclo ^. 2.07-oct-2-en-2-carboxylic acid-5 »5-dioxide Example If) is repeated with the change that instead of the ZBR- £ 5cy, 7β (Z) 77-3-Z" (acetyloxy) -methy 17 -7-ZT (2-amino-4-thiazolyl) -ZIlH-imidazol-2-yl-methoxy) -imino7-acetyl7-amino7-8-O xo-5-thia-l-azabicy 010 ^ .2.Q7oct- 2-en-2-carboxylic acid trifluroacetates the Z3S- (5 {V, 6β, 7oi) 7-3-r (acetyloxy) -methyl7-7- ΠΧ 2-amino-4-thiazolyl) -r (1H-imidazole- 2-yl-methoxy) -imino7-acetyl7-amino7-8-oxo-5-thia-l-azabicycloZ ^I l.2.a7oct-2-ene-2-carboxylic acid-5,5-dioxide trifluoroacetate used Es. the title compound is obtained.

130019/0854

Γ -Π

r Example 5

Sodium salt of £ 5'R- {50 ( _s Soc _t 7SJJ-3 - ^ (kcetoyloxy) -mBthylJ-7 · 'ΓΠ. 2-amino-4-thiazolyl) -Z ~ (1H-imidazol-2-yl-methoxy ) -imino7-acetyl7-amino7-8-oxo-5-thia-1-azabicyclo D \ . 2.07oct-2-en-2-

5 carboxylic acid 5-oxide ((X-sulfoxide)

a) Z5R-Z50C, 6 (Y, 7ß77-3- £ "(acetyloxy) -methyl7-7- / r (2-amino-4-thiazolyl) ~ / JlH-imidazol-2-yl-methoxy) -imino7- acetyl7-arainQ7-8-oxo-5-thia-l-azabicyclo / ^ . 2.07oct-2-en-2-car-

5-oxide diphenylmethyl ester 10

Example Id) is repeated with the change that instead of of the 7-A CA -diphenylmethyl ester of the Z5R- £ 5 (y, 6o-, 7ß77-3- / ~ (acetyloxy) -methyl7-7-amino-8-oxo-5-thia-1-azabicycloZ? i .2.07oct-2-en-2-carboxylic acid 5-oxide diphenylinethyl ester (Or-SuIfoxid) is used. The title compound is obtained

b) Z5R-Z5DT, 6of, 7- £ 77-3-r (acetyloxy) -methy l7-7-ZZ "(2-amino-il thiazolyl) - / (1H-imidazol-2-yl-methoxy) -imino7 -acety17-amino7-8-oxo-5-thia-l-azabicy, clo / ^. 2.07oct-2-en-2-carbon-

²⁰ acid-5-oxide trifluoroacetate

Example Ie) is repeated with the change that instead of the / J5R-Z "60f, 7β (Z) J7-3-iT (acetyloxy _i ) -methyl7-7- / Z '(2-amino-i | - thiazolyl) - / T (1H-imidazol-2-yl-methoxy) -imino7-acetyl7-amino7-δ-οχο-5-thia-1-azabicycloZ?}. 2.Q7oct-2-en-2-carboxylic acid dipheny Methy! esters of the ZT5R- ^ 5o <', 6or, 7ß77-3- £ iAcetyloxy) -methyl7-7-ZZ "(2-amino-4-thiazolyl) -Zn; iH-imidazol-2-yl-methoxy) - iinino7-acetyiy-aminoT'-So xo -5-thia-l -azabicyclo D \ . 2.07oct-2-en-2-carboxylic acid 5-oxide diphenylmethyl ester is obtained. It

the title compound is obtained. 30th

c) £ "5R-Z: 50f, 6i> f, 7ß77-3- / ZiAcetyloxy) -methy! 7-7-

4-thiazo Iy 1) -2T (IH-imidazol-2-yl-methoxy) -irainoy-ace ty 3J- -amino7-8-o xo-5-thia-l-azabicyclo / ^. 2.07oct-2-en-2-carboxylic acid-5-oxide

Example If) is repeated with the change that instead of des ZSR-ZSCV, 7ß (Z) 77-3-ZUcetyloxy) -methy 17-7- / T (2-amino-4-

L J

130019/0854

thiazolyl) -ZIlH-imidazol-2-yl-methoxy) -iminoJZ-acetyU-amino.7-8 -oxo-5-thia-1 -azabicyclo / ¹ !. 2.0_7oct-2-en-2-carboxylic acid trifluoroacetates the Z5R- / 50f, 6CV, 7Ji7J-3- £ "(acetyloxy) -methyl7-7- / Z" (2-amino-4-thiazolyl) - / "( lH-imidazol-2-yl-methoxy) -imino7-acetyl7-amino7-8-oxo-5-thia-l-azabicyclo -

is set. The title compound is obtained.

10 15

Examples 6 to 31

Following the procedure of Examples 1 to 5 using the esters shown in column I and the in Acids shown in column II obtained the esters listed in column III. By splitting off the ester protection group the acids listed in column IV are obtained.

20th

Column I.

OOR

25th 30th

35

Column II

-C-COOH

R ₁ (C) _n -R ₂

jN

_C rl

6 R

130019/0854

Soalte III

JCJTT

COOR

\ ^R 5

Column IV

CH ₂ R ₄

COOH

1.30019 / 0854

CM

cn ro η ro M. K ro ro W. te ι I. V £> | O O O O O O OU ι I.

to

ro

O I.

O
I.

ro

O I.

ro

te

O I

ro

O I

ro K O

ro

U I

te

ro

O 1

ro

te

as

■ ro

ro ro

te

O O

ro

a:

m ro ro ro ro ro te

a: 'te te as as c

ooocj υ ο

ρ-Λ O = OO = OO = OO = OO = OO = O I
O

I.
O
1

i
ο

O I

I O

as

in

as

CM O

O = O O

ta <H φ CQ.

co

ro H

130019/0854

Example r -

-O-C-NH,

15 16 17 18 19 20 -S 21- £

-O-C-NH.

ft

-O-C-NH,

-O-C-NH,

-O-C

NH,

-H -H

-H -H

), -CH, -CH.

-CH-KO))

CH ₃ -CH- ^) ₂

22 -S- ^ ₃ ; * - CH ₃ - ^CH -f \ 27> 2

23 -S-JIgJ ^ -CH ₃ -CH-f ^ 0)) ₂

-H -H

-CH., -H

-H -H

-H -H

-H

-H

-H

-H

-H

-H

-H

-H

-H

-H

-H

-H

-H

"~ CH

-CH ₃

-CH ₃

-CH

-CH.

-CH,

-H

-H

m
O

1
1
2

O
O
O

Example r

24

_4_

,1

R ₁ R ₂ R ₃ R, - R, - m η

-H -H -Ή -Η -CH ₃ O

CH,

25th

^H ~ ^H

CH-

26th

_CH-f <O>)

-H -H -CH ₃ 1

I,

27

-CH-KO))

-CH ₃ -CH ₃ -H

-CH ₃ O

28

-CH-KO)) "-H -H -H -H -CH ₃ O

CH ₂ SO ₃ H

CaJ. "
O/

Example 29

-CH-f / o))

-H

CH

COOH

30th

■ A ■

3ΐ

- ^CI1 ? - (O) "Η -H

-H -H -H

m n

-H -CH ₃ O 1

"Η -H -CH.

-H -CH.

Γ Π

The acids obtained as the product in Examples 6 to 31 can be converted into the corresponding sodium or potassium salts by known processes.

The products of Examples 6 to 31 are different depending on the configuration of the acid shown in column II as syn or anti isomers. If the remainders R. and R “not the have the same meaning, the products are also obtained in the D, L or D, L form, depending on the optical activity the acid indicated in column II.

Example 32

Z5R- / i5 (X, 7β (Z) J7-3- / Z4-f-aminocarbony 1) -pyridino_7-methy: U-7- ΓΓ ( 2-amino -4 -thiazole 1) - £ ( IH -imi dazo 1 -2-y 1-methoxy) -imino? acety 0jWmino_7-8-oxo-5-thia-l-azabicyclo / ⁷ !. 2.Q7oct-2-en-2-carboxylic acid (syη isomer)

A mixture of 0.005 mol of the product of Example 1 (sodium salt), 0.0075 mol of 4-Pyridincarboximid, 12 g of potassium thiocyanate and 7.5 ml of water is ER- 24 hours on 50 ⁰ C

warms. The solution is then passed through a chromatography filled with the ion exchanger Amberlit XAD-2. The column is washed with water, and the title compound is eluted with a mixture of water and methanol in the ratio 8: 2. The methanol is distilled off from the eluate

and lyophilizing the aqueous solution. The amorphous residue obtained is digested with diethyl ether and filtered off with suction. It the titanium compound is preserved.

S e "i Ί5 -ρ i e" 1 e 3 5 ils 4 0 30th

Following the procedure of Example 32, iant use the cephalosporanic acid sodium salts listed in column I below and the pyridine linkages shown in column II obtained the products shown in column III.

130019 / Ό854

N; π C-C-N

, AJ

-50-

Column I.

,oil

CH

COONa

-rf "

Column II

HI

130019 / 08S ^

example

R-,

R.

33 34 35 36 37 38 39 40

-H

-CH.

-CH.

-H

-H

-H

-H

-H

-H

-H

-H

-H

-H

H -CH ₃ 1 O O
ti
-CNH ₂ (4) H -CH ₃ 2 O O
11
-CNH ₂ (3) ΓΙ -CH ₃ O 1 -H

* -H -H

-H _Μι τ.τ

-H

-CH ₃ -H

O
I /
-CNH ₂ (4) O
Ii Il
-CNH ₂ (2) -H O
1 I. -CNH ₂ (4)

Γ ■ ~ l

The products of Examples 33 to 40 are obtained in the syn or anti configuration, depending on the configuration of the 3-acetoxymethyl compound used according to column I. In a similar way, the compounds are obtained as & .- or ß-sulfoxides when m has the value 1, depending on the orientation of the 3-acetoxymethyl sulfoxide used as the starting compound. If the radicals R. and R ₂ do not have the same meaning, the products are furthermore obtained as D, L or D, L isomers, depending on the optical activity of the starting compounds listed in column I.

Example 4 1

Sodium salt of {^ R-ZScy, 7ß (Z ) Jl-H € (2-kmlno-h -thiazolyl) - / "(IH imidazol-2-yl-methoxy) -iminci7-acetyl7-amino7-3- / ir ( 5-methyl--!, Sj ^ -thiadiazolyD-thioJ-methyiy-S-oxo-S-thia-1-azabicyclo-Z5.2.Q7oct-2-en-2-carboxylic acid

0.002 mol of the product from Example 1 (sodium salt) are dissolved in 100 ml of phosphate buffer at a pH of 6.4 and then with 0.0024 mol of 5-methyl-1,3,4-thiadiazolyl-2-thiol offset. The solution is then heated to 60 ° C. for 6 hours. After cooling, the pH becomes 7.0 set and the solution on the ion exchange resin Amberlit XAD-2 chromatographed. The fractions containing the product are freeze-dried. The title compound is obtained.

Examples 42-47 Following the procedure of Example 41 using the in the following column I ge showed '<! ephalosporic acid-Na-

trium salts and the thiols shown in column II

Products shown in column III.

L J

130019/08 54

H,

- 53 column I.

CH ₂ -OC-CH ₃

COONa

II

HS hetero

¹ ^

Column III

-f

H ₂ -S hetero

00Na

130019/0854

-th

4 «

304Q257

CVJ

ro

S3

ro

S3

in

λ CVJ

Η— ^ S — f S f 2! f

¹ Z -ro O cn cvj

te

Z-CJ

-Z cvj 3—5

- ⁷ X te ι -

id

O O U rv

CJ

^ H

CvI

vol
Pi I ro
K
U
I. cn
S3
U ro
U
I. K ta
I. I. in j
Pi I K 53 I. S3 ro
S3
U
I. ro η Pi 1 \ U ID j S3 S3
r CVJj
Ci J co
■ EC
U S3 S3
-I S3
I.

019 / 05'S U

The products of Examples 4 2 to 47 are obtained in the syn or anti configuration, depending on the configuration of the 3-acetoxymethyl starting compounds shown in column I. Similarly, if m has the value 1, the compounds are obtained as 0 (- or β-sulfoxides, depending on the orientation of the 3-aceto xy methyl sulfoxides used as the starting compound. If the radicals PL and R1 are not the same Have meaning, the products are also obtained in the form of the D, L or D, L isomers, depending on the optical activity of the starting compounds shown in column I.

Example 48

Sodium salt of Z5S- £ 5c ^/ > 6ß, 7o <. (Z) JJ-3 - / ^ Acetyloxy) -methyl7-7-Z7T (2-amino-4-thiazolyl.) - ZIlH-iinidazol-2-yl- methoxy) -imino7-acetylT-aminoT'-S-oxo-S-thia-1 -azabicyclo ^. 2.07oct-2-en-2-carboxylic acid-5-oxide (ß-sulfoxide, syn-I so me res') The product of Example 2 can also be prepared by the following process:
168 g ZToR-ZBo /, 7ß (Z) 77-3- / CUcetyloxy) -methy 17-7 - ZTZ ~ (2-amin ο 4-thiazolyl) -ZT (1H-imidazol-2-yl-methoxy) -imino7 -ace ty l7-amino7-8-oxo-5-thia-l-azabicycloZ! 4.2.07oct-2-en-2-carboxylic acid are prepared according to Example Ie), dissolved in 35 ml of methylene chloride and cooled to ^{0 ° C.} 17 ml of trifluoroacetic acid are then added to the solution while stirring.

Then 0.459 g of m-chloroperbenzoic acid are added and

stirred for a further 2.5 hours. The solvent will .under distilled off under reduced pressure. 400 ml of diethyl ether are then added to the residue obtained. The unusual one Precipitate is filtered off and treated with diethyl ether

to wash. Yield: 1.5 g of the title compound in the form of the trifluoroacetate from 160 to l65 ° C. This compound, can be converted into the sodium salt by the method according to Example If).

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130019/0854

Examples 49 to 5 J.

Following the procedure of Example 48, the sulfides listed below in column I can be added to those shown in column II ß-sulfoxides are oxidized.

Column I.

H,

j-C-N-

N \

• N

-Rr

H _n R.

OOH

Column II

R ₁ - (C) _n -R ₂

COOH

^H 2 ^R 4

130 0-19 / 08

ro

SO Sr ₁ S _x ro
2-0 K cc ro JS
te ι
υ j / · --— / O
O = O
I. O
O = O t I
O S3 I. cn O
I. O
I. 1 co
I. I. O

Γ0 ro a CO I. O O I. I.

η cn

* Tj ^ r * * r *

ο ι ο

j ι

ml K te CC CC K ta

i I ι ι ι iii

"I κ κ a a cc a

c «I ι ο ι iii

ro

■ a cc υ a a

1 ~ t I J ^

ro

cc a u

i 4 1

in en α% ^ tn in

130019/0854

CN CN CN

"t crrrj o =: u σ-ο

i I ι ι ι

O O O

ι ι ι

ro cn ro

. EQ E ffi

pi J υ υ ο

ι ι t

ml κ ta te i I ι ι ι

in 1 B E EC

Pi 1 I I 1

oil

Pi I

in

ΓΟ

Ci i I 1

Γ '

The products of Examples 49 to 57 are obtained in the syn or anti configuration, depending on the configuration of the sulfide starting compound shown in column I. If the radicals R ₁ and R ₂ do not have the same meaning, the products are also obtained in the form of the D, L or D, L isomers, depending on the optical activity of the starting compound shown in column I.

The acids obtained as products in Examples 1 to 57 can be converted into various esters by known processes being transformed. For example, the radical R in general formula I can have the meanings

15 * ■ "' ^c '" ^c ' ^CH 3) 3 or

obtain.

Example 58 Disodium Salt of £ oR - / '6a', 7β (Z) 7J-3-Z "(Acetyloxy) -methyl7-7- / Z (2-amino-4-thiazolyl) -Z" (1H-tetrazole-5 -yl-methoxy) -imino7-acetyl7-amino7-8-oxo-5-thia-1-azabicycloZ4.2.07oct-2-en-2-carboxylic acid (syn isomer)

a) 2-Cyanomethoxy-1H-isoindole-1,3 (2H) dione

400 ml of a solution of 50 g (0.31 mol) of N-hydroxyphthalimide, 25.4 g (0.34 mol) of chloroacetonitrile and 37.2 g (0.37 mol) of triethylamine in dimethylformamide become colorless touched. The solution is then poured into 2 liters of water. The precipitated compound is filtered off and washed with water and dried. Yield: 65.8 g of the title compound with a melting point of 150 to 152 ° C.

b) 2- (1H-Tetrazol-5-yl-methoxy) -1H-isoindole-1,3 (2H) -dione 56.8 g (0.28 mol) of the compound obtained under (a) above are dissolved in 500 ml of anhydrous tetrahydrofuran and with stirring with 55.5 g (0 ^ 85 mol) sodium azide

130019/0854

Γ "" I.

puts. A solution of 40.1 g of aluminum chloride in 250 ml of anhydrous tetrahydrofuran is then added to the mixture with cooling. The resulting solution is refluxed for 32 hours. After cooling to ⁰ ° C., about 250 ml of 2N hydrochloric acid are added dropwise, and then a sufficient amount of water is added to obtain a clear solution. The organic layer is separated off, the aqueous phase is saturated with sodium chloride and extracted twice with 200 ml of tetrahydrofuran. The combined organic layers are dried with sodium sulfate and evaporated to dryness. The oily residue obtained is treated with alcohol and the precipitated tetrazole is filtered off. It is the title compound from P. 227 bis

228 ⁰ C received.

15 .- ■.: ■

c) 5-ZTAminoxy) -methyU-1H-tetrazole hydrochloride

70.8 g (0.29 mol) of the compound obtained above under Cb) Vierden in 700 ml of 20 percent hydrochloric acid - under Boiled under reflux and stirred. The solution is then

cools and filtered. The piltrate is evaporated to dryness. The residue obtained is mixed with 150 ml of water and filtered. After the solvent has been distilled off , hj> g of crude title compound with a melting point of 163 ° G

after recrystallization from a mixture of ethanol and 25th

Obtain diethyl ether. ·

d) 2-Amino-O <-ZIIH-tetjrazol-5-yl-methoxy) -imihoJ - ^ - thiazole-acetic acid (syn isomer)

1.0g of the compound obtained above under (c) and 30th

Heated 1.3 g of 2-Forn5ri- ^ain ino-4-thiazo l glyoxylsäüre -Be 24 hours on 50 ⁰ C and stirred. Then = wia? D / the 'solution: cooled to room temperature and the precipitated compound removed'. Yield: H0 ^ g 'of the -TüelV connection from

F.- 192 bJLs'.l-93 ° C after .dem-Umkri'S'tallize from * water.

L _ J

_0RlGiN AL INSPECTED

- 6i -

e) ZBR- £ 5tX, 7ß (Zi77-3- £ iAcetyloxy) -niethyi7-7-ZZX2-and.no-4-thiazolyl) -ZX1H-tetrazol-5-yl-niethoxy) -imino7-acetyl7-amino7-8 -oxo-5-thia-l-azabicyclo / ¹ !. 2.07oct-2-en-2-carboxylic acid diphenylmethyl ester (syn isomer) H g of the compound obtained above under (d) are mixed with 6.1 ml of monosilyl trifluoroacetamide in 50 ml of anhydrous dimethylformamide at a temperature of 60 ° C. for 15 minutes while stirring treated. The cooled solution is then mixed with 7.5 g of 3- <£ KAcetyloxy) -methyl7-7-amino-8-oxo-5-thia-1-azabicyCloZ ¹ 1.2.07oct-2-en-2-carboxylic acid diphenylmethyl ester in 100% mT anhydrous acetonitrile added. The solution is cooled to 15 ° C. and 4.4 g of dicyclohexylcarbodiimide in 100 ml of acetonitrile are slowly added dropwise, the specified temperature being maintained for 12 hours. The urea formed is filtered off and the solvent is distilled off under reduced pressure. The residue obtained is treated with 500 ml of saturated sodium chloride solution and extracted 3 times with 200 ml of ethyl acetate each time. The organic layers are saturated 10 times with 30 ml

Sodium bicarbonate solution extracted. The sodium bicarbonate extracts are combined, treated with 300 ml of ethyl acetate, and the mixture is acidified with 2N phosphoric acid. The aqueous layer is then extracted again with 100 ml of ethyl acetate. The organic extracts

are now dried with sodium sulfate and the solvent is distilled off under reduced pressure. The received The residue is dissolved in 50 ml of acetone and, while stirring, in a mixture of diethyl ether and petroleum ether in the ratio 2 t 1 cast. The ^ precipitated diphenylmethyl ester is

filtered off. Yield; 5 g the title connection from the F * 4 38

rock ° f)

carboxylic acid TriTluoroacet at ^ syn ^ Isomere sp

r π

5 B of the diphenylmethyl ester according to Example le) are suspended in 14 ml of anisole and cooled to ^{0 ° C. with stirring.} At this temperature dropwise 28 g of trifluoroacetic acid are .zugesetzt, and the temperature is held for 30 minutes at 0 ⁰ C. 100 ml of methanol are then added and the mixture obtained is poured into 1 liter of diethyl ether with vigorous stirring. The compound is filtered off and dried under reduced pressure. Yield: 3.5 g of the title compound of P. 130 to 135 ° C (decomp.).
10

g) Z ^ R- £ 5cx _a 7fi (Z) 77-3-ZiAcetyloxy) -methyl7-7- £ Zl2-ainlno-4-thiazo IyI) -ZTC lH-te t razo 1-5 -y 1 -me thoxy ) -imino_7-ace ty 17 amino7-8-oxo-5-thia-l-azabicyclo ^. 2.07oct-2-en-2-

carboxylic acid (syη isomer)

5 g of the product from Example If) are in 20 ml of a mixture, dissolved by methanol and acetonitrile in a ratio of 1: 1. The solution obtained is mixed with 20 ml of an In sodium ethylhexanoate solution added in butanol, and the mixture is then poured into 500 ml of diethyl ether. The unusual one

20 "

Crude disodium sal is filtered off. The compound is about 60 % pure. Yield: 3.6 45 of the title compound with a P. greater than 300 ° C. A further purification is carried out by high-performance liquid chromatography using LiChrosorb RP 13 (10 μm) Hibor III column solvent with CH ₃ OH: 0.OiM HPO ₂ ^{I 2} "buffer (52 ζ 48).

■ For J3 ρ ie 1 3 9

ZiSR- ^ Of, 7ß (E) 77-3- / fTAGetyloxy) -methy 17 -1-CCi 2-amino-4-thiazolyl) - ^ "(lii-tel / razöl-5-yl-methaxy) -

-Esaigsäureäthylesfce ^ · t Sui * l ~ Isomei? Es ^ 3 g '2-PormylaMho ^ ^ I ^ iäzöiyi ^ giyoxylääure ^^ hyiesi ^ i · and 2 g 5-tXitäno ^ ty% -giasittflJ ^ acc

Belaplei ^^. 58 ^ irei »döii: l>et; - ^^« Siter ^ Tei ^ ei ^ ä ^ ar of "SiO ⁰ G about

- ^β3 -

Stirred in anhydrous pyridine for 15 hours. The insoluble precipitate is then filtered off and the piltrate is evaporated to dryness. The residue obtained is chromatographed over silica gel with ethyl acetate as the mobile phase. Yield: 2.9 g of the title compound with a melting point of 88 to 96 ^° C. after recrystallization from methanol and water.

b) 2-Amino-Of- ^ (1H-tetrazol-5-yl-methoxy) -imino7- ^ - thiazole-acetic acid (anti isomer)

0, - ^ g of the product obtained above in Example 59a) are stirred in 6.6 ml of concentrated hydrochloric acid and 3.3 ml of water at a temperature of 30 ° C. for 40 hours. After cooling, the title compound crystallizes out. Yield: 0.25 g of P. 17 ¹ I ⁰ C.

c) / "6R-Z5CX, 7β (E) J7-3-Z '(acetyloxy) -methyl7-7-Z" Zr (2-amino ^ - thiazolylJ-ZTlH-tetrazol-S-yl-methoxyO-iminoZ-acetylJ-amino7-8-oxo-5-thia-1-azabicyclo / ^. 2.07oct-2-en-2-carboxylic acid diphenylmethyl ester (anti-isomer)

In the reaction of 2-amino-OC-Z "(1H-tetrazol-5-yl-methoxy) iminoj -H -thiazole-acetic acid (an ti-isomer) with 3- £ (acetyloxy) -methyl7-7-amino -8-oxo-5-thia-l-azabicyclo / ^. 2.07oct-2-ene-2-carboxylic acid diphenylmethyl ester gemüß example 58e), the title compound, melting at 118-120 ⁰ C (dec. gets hurt)

th.

d) ZHR- / f6cx, 7ß (E) JJ-3-Z "(Acetylaxy) -methyl7 -7 -2T (2-amino-iJ-thiazolyl) - ^ * (1H-tetrazol-5-yl-niethoxy) - imino7-acety37 ~ amino7-8-oxo-5-thia-l-azabicycloZ ¹ 1.2.07oct-2-en'-2-

carbons aire (anti-isomer) -.- ■.-...

In the treatment of the above in Example 5Sc) "obtained

NEN diphenyl methyl ester with trifluoroacetic acids according to-Beispie 1 58f) 'becomes the' corresponding Cephälös'pbranstiure 'in the anti-form obtained from m.p. 142 to 150 ° C- (dec. "). If this Treated acid according to Example 58g) with sodium ethylhexane oil

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1.3 0019/0854

Γ "I.

the title compound is obtained with a temperature greater than 280 ° C.

Example 6 0.

Disodium salt of / 3R-ZBcV, 7ß (Z) 77-7-ZZT2-AmInO- ¹ I-thiazolyl) -ZtlH-tetrazol-5-yl-methoxy) -imino7-acetyl7-amino7-3- ££ "(l- methyl-lH-tetrazol-5-yl) -thio7-methyl7-8-oxo-5-thia - l-azabicycloZ4. 2.07oct-2-en-2-carboxylic acid (syn-isomer)

a) 2- (Tritylamino) -CV-ZXl-benzoyl-1H-te trazol-5-yl-methoxy) -imino7-4-thiazole-ethyl acetate (syn-Isomeres) 1.2 g of 2- (tritylamino) -G '- (oximino) -4-thiazole-ethyl acetate, 0.6 g of 1-Benzoy1-5-chloromethyl-IH-tetrazo1 and 0.5 g Potassium carbonate are added together in 20 ml of dimethylformamide Stirred at room temperature for about 15 hours. Then the mixture is mixed with 20 ml of acetone and the insoluble potassium chloride filtered off. The mother liquor is evaporated to dryness and using ethyl acetate, chloroform and diethyl ether in a ratio of 3: 2: 1 as eluent on silica gel column chromatography. Yield: 1.4 g

The title connection from P. 132 to 134 ⁰ Cr 20

b) 2- (Amino J-CX-Zv IH-te trazol-5-yl-methoxy) -imine-7-4-thiazole-acetic acid (syn isomer)

1.4 g of the product obtained above in Example 60a) are about 15 hours at room temperature in 20 ml of 5 percent

tiger hydrochloric acid stirred. The precipitate is then filtered off and washed with diethyl ether. Yield: 0.5 g of the title compound.

c) disodium salt of ZbR-ZSOf, 7ß (Z ) J2 -7-Z7 "(2-amino-4-thiazolyl) - / ΠH-tetrazol-5-yl-methoxy) -iminoZ-ac amino7-3- / 7Ti- methyl-1H-tetrazol-5-yl) -thioZ-8-OXO-5-thia-1 -azabicyclo / 4. 2 .jVoct ^ -en ^ -carboxylic acid (syn-isomer)

In the reaction of the carboxylic acid obtained above in Example 60b) according to Example 58e) using 7-amino-3-ZT (l-methyl) -lH-tetrazol-5-yl) -thio7-ynethyl7-8-oxo-5- thial-azabicycloZTl ^ .Ojoct ^ -en ^ -carboxylic acid diphenylmethyl ester instead of 3 - / * (acetyloxy) -methoxy7-7-amino-8-oxo-5-

130.019 / 0854

Γ Π

" ⁶⁵ " 304Ü257

thia-1-azabicyclo [Ά .2.07oct-2-en-2-carboxylic acid diphenylmethyl ester, followed by the cleavage of the ester protective group according to Example 58f) and the formation of the disodium salt according to Example 58g), the title compound from P.

5 240 to 21.5 ° C (dec.) Obtained.

Example 6 1

Disodium salt of ^ R- / T6o ^ 7ß (E) 77-7-ZZ (2-amino-iJ-thiazolyl) -Z (1H-tetrazol-5-yl-methoxy) -imono7-acetyl7-amino7-3- / Z ~ (1-methyl-1H-tetrazol-5-yl) -thio7-methyl7-8-oxo-5-thia-1-azabicyclo / 4 .2.Q7oct-2-en-2-carboxylic acid (anti-isomer) Das Corresponding anti-isomer is obtained if 2-amino- & -C ( IH -te trazo 1-5 -y 1 -metho xy) -imino7 -4 -thlazo 1 -Es si gic acid (anti-isomer) of example 59b) according to example 60c)

^ is set.

Example 62

Disodium salt of Z5R- / f6CX, 7β {Z) 77-3-Z "(acetyloxy) -methyX7-7-rZT (2-amino-4-thiazolyl) -Zi lH-tetrazol-5-yl-dimethylmethoxy) -iminoJ-acetyli'-aminoT'-e-oxo-S-thia-l-azabicycloZ ^^. Qjoct- 2-en-2-carboxylic acid (syn isomer)

When 5-Zi- (aminoxy ^ -l-methylethyl7-lH-tetrazole hydrochloride (which is obtained when chloroacetonitrile in Example 58a) is replaced by bromo-isobutyronitrile and the resulting Compound is then treated according to Example 58b) and 58c)) according to Example 58d), 58e), 58f) and 58g) implemented the title compound is obtained.

Example 63 Sodium Salt of Z5R-Z "6 (y, 7ß (Z) j ^r 7-3-r (acetyloxy) -methyl7-7-

2-amino-4-thiazolyl) -Z "(1-methyl-1H-tetraizol-5-yl-ynethoxy) imino7" -acetyl7-amino7-8-oxo-5-thia-1-azabicy CIoZ ¹ 1.2. Q7o ct-2-en-2-carboxylic acid (syn isomer)

a) 2- (1-Methyl-1H-tetrazol-5-yl-methoxy) -1H-isoindole-1,335

(2H) dione

5 g of 2- (1H-tetrazol-5-yl-methoxy) -1H-isoindole-1,3 (2H) dione

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130019/0854

Γ Π

according to Example 58b) is stirred at room temperature for 24 hours in 50 ml of dimethylformamide with 5 g of methyl iodide in the presence of 5 g of potassium carbonate. The insoluble inorganic precipitates are then filtered off, the mother liquor is evaporated to dryness and the residue obtained is crystallized with ethanol. Yield: 4.8 of title compound, P. 128 g to 1-30 ⁰ C.

b) S-ZlAminoxyJ-methyU-l-niethyl-lH-tetrazole hydrochloride According to Example 58c), when using 2- (l-methyl-lH-tetra2ol-5-yl-methoxy) -lH-isoindole-1,3 (2H) dione instead of 2- (1H-tetrazol-5-yl-methoxy) -lH-isoindole-1,3 (2H) dione obtained the title compound.

c) Sodium salt of / 5'R- ^ fHtV, 7S (Z) 77-3-ZTAcetyloxy) -methylJ-

7-Z "Zl2-amino-4-thiazo" lyl) -Zr (1-methyl-1H-tetrazol-5-ylmethoxy ) -imino7'-ace ty l7-amino7-8-oxo-5-thia-1-azabicyclo- £ 4. 2.07oct-2-en-2-carboxylic acid (syn isomer) If the compound obtained above in Example 63b) according to Example 53d) with 2-formylamino-4-thiazolyl-glyoxylic acid is treated, becomes the corresponding syn isomer of 2-amino- £ X - / "(1-methyl-1H-tetrazol-5-yl-methoxy) -imino7-4-thiazole-acetic acid obtain. This compound is processed further according to Examples 58e), 58f) and 58g). It will be the Title compound obtained.

Example 64

Disodium salt of / BS-ZBctf, 6ß, 7cx (Z) 77-3- £ "(acetyloxy) -methyl7- T-LCi 2-amino-4-thiazolyl) - £ T lH-tetrazol-5-yl-methoxy) - imino7-acety37-amino7-8-oxO-5-thia-i-azabieycloZ ⁷ 1.2.07oct-2-en-2-carb on acid-5-oxide (ß-sulfoxide, syn-isomer) 10 mmol / 5R- £ "6oc, 7ß (Z) 77-3- / TAcetyloxy) -methyl7-7- / r (2- amino-k -thiazolyl) -ZKlH-tet razol-5-yl-methoxy) -imin o7-acetyl7- amino7-8-oxo-5-thia-1-azabicyclo Pi .2.07oct-2-en-2-carbon-

acid according to Example 58f) is suspended in 20 ml of anhydrous methylene chloride and cooled to 0 ⁰ C. At this

^L 130019/0 854

" ^β7

10 ml of trifluorosypic acid are added at temperature, and the mixture is stirred further until it is completely dissolved. 10 mmol of m-chloroperbenzoic acid are then added and the mixture is ^{stirred at 0} ° C. for 3 hours. The solvent is then distilled off under reduced pressure, the residue obtained is stirred with ethyl acetate and filtered. The precipitate is then dissolved in a mixture of methanol and acetone in a ratio of 1: 1, an equivalent amount of sodium ethylhexanoate in butyl alcohol (in solution) is added and the mixture is stirred. After 10 minutes the mixture is poured into 200 ml of diethyl ether. The deposited precipitate is filtered off. The title compound of P. 250 to 256 ° C. is obtained.

¹⁵ Example65

Disodium salt of Z5S-Z3öf> 6β, 70c (Z) 7J-3-iT (acetyloxy) -methyl "7 7-ZZ '(2-amino- ¹ } -thiazolyl) - / (1H-tetrazol-5-yl-methoxy ) -iminoJ-acetyU-amino_7-8-oxo-5-thia-l-azabicyeloZ ¹ U2.Q7oct-2-en-2-

carboxylic acid 5-oxide (ß-sulfoxide, syn-isomer) 20

a) £ * 5S-ZBo-, 6ß, 7iX ^ -3- £ (acetyloxy) -methy3j-7-amino-8-oxo-5-thia-1-azabicycloZ ^^. Qjoct ^ -en ^ -carboxylic acid-S oxide - diphenylmethyl ester (ß-sulfoxide) and ZBR-Z5 (X, 60f, 7ß77-3- / r (acetyloxy) -methyl7-7-amino-8-oxo-5-thia-l-azabicyclo Lh. 2. Q7oct-2-en-2-carboxylic acid 5-oxide diphenylmethyl ester (Cx sulfoxide) ""'

A slurry of 50 g of 7-aminocephalosporanic acid (7-ACA) in 1 liter of water is stirred with the magnetic stirrer and

tert-Octylamine is added dropwise, whereby the pH value between 7 and 8 is held. After 1 hour the undissolved pesticide is filtered off (Celite), and the filtrate is with a solution treated by adjusting the pH

a mixture of 10 ml of tert-octylamine and 20 ml of water 35

with 6N hydrochloric acid to a value of 8.0. The resulting solution is then treated with 10 ml of salicylaldehyde.

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130019/0854

γ π

After 2 minutes, a solid separates out. After 5 minutes, a further 10 ml of sodium cyanide are added. The suspension is then stirred for a further 10 minutes, then ^{cooled to 0 °} C. for 4.5 hours and filtered. The filter cake obtained is slurried twice with 300 ml of cold water and filtered. The moist cake is then dried at a temperature of 60 ° C under reduced pressure over a large amount of Ρρ ^ ς. Yield: 66 g of the tert-octylamine salt of 7-salicylaldimino-cephalosporic acid as a yellow-brown pesticide.

A slurry of 25.25 g (0.05 mol) of the above obtained tert-octylamine salt (powdered with a mortar and pestle) in 250 ml of anhydrous acetonitrile is added to 9.5 g (0.05 mol) p-toluenesulfonic acid monohydrate. To

A solution of 9.7 g (0.05 mol) of diphenyldiazomethane is obtained for 10 minutes in 50 ml of acetonitrile added over 15 minutes. After 1 hour the slurry is filtered, the solid is washed with acetonitrile and the combined

Filtrates and liquids are reduced Pressure evaporated, the oil obtained is on a 300 g gravel Igel column chromatographed with methylene chloride as the mobile phase » The fractions (500 ml) 2 to 3 contain 7.5 g of the desired di-phenyl ester product and some additional

Impurity with a higher R value (determined by silica gel thin layer chromatography with chloroform and ethyl acetate in a ratio of 3: 1 for development); the fractions 4 bis

11 contain 12.3 g of pure 7-salicylaldimino-cephalosporic acid -Diphenyimethvlester.

NMR Spectrum (CDCl ₅ ) δ 1.97 (a, 3H, CH CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, C-2); 4.67 and 5.01 (AB q, J = 14 Hz, 2H, C-3 ^1); 4.99 (d, J = 5 Hz, IH, c-6); 5.20 (broadened d, J = 5 Hz, IH, c-7); 6.62 - 7.60 (m, about 15H); 9.07 (broad s, IH, -CH = N-).

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130019/0854

Γ ~ 1

A solution of 12.3 g (0.023 mol) of the diphenylmethyl ester obtained above in 125 ml of methylene chloride is ^{cooled to 0} ° C. and treated with 4.6 g (0.023 mol) of 85% m-chloroperbenzoic acid in 70 ml of methylene chloride over the course of 15 Minutes offset. After 1 hour, the slurry is washed with a mixture of 100 ml of 5 percent sodium carbonate solution and 50 ml of 6 percent sodium sulfite solution. The organic layer is dried and evaporated under reduced pressure. The oil obtained crystallizes from 70 ml of ethyl acetate to give 8.7 g of a mixture of (X- and β-sulfoxide. A second amount of 1.5 g of the mixture of o (- and β-sulfoxide is also obtained. The mainly formed pe In the NMR spectrum, isomers has signals for the acetate methyl protons (2.02 ppm) and the C-2 quartet (3.57 and 4.10 ppm) at a low field compared to those of the ß-isomer formed in a smaller amount (1.97, 3j26 and 3.94 ppm).

A slurry of 10 g (0.018 mol) of the above

holding mixture of CX and ß-sulfoxides of 7-salicylic

aldimino-aephalosporanic acid diphenylmethyl ester in 100 ml Ethyl acetate is mixed with 3.42 g (0.018 mol) of p-toluenesulfonic acid monohydrate treated. After 5.5 hours, 300 ml of diethyl ether are added to the mixture, and the gummy one 25th

Solid is digested, filtered and washed twice with diethyl ether. The moist solid is then in 200 ml Acetic acid ethyl ester dissolved, the solution is made with 100 ml 5% sodium carbonate solution washed, dried

and umäamoft. 8.0 g of residue are obtained 30th

chromatographically on 300 g of silica gel with a mixture of Chloroform and ethyl acetate in a ratio of 3! 1 as Solvent must be cleaned. Fractions of 500 ml are obtained. Fraction 3 contains 1.0 g of recovered 7-salicylaldimino-cephalosporanic acid diphenylmethyl ester. Fractions 6 to 16 contain 4.5 g of Z5R- / 5 (X, 6 (y, 7ß7-7-3-ZlAcetyloxyJ-methyl / ^ - amino-S-oxo-S-thia-l-azabicyclo-

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Γ ~ l

Ζ4. 2.0_7oct-2-en-2- carboxylic acid 5-oxide diphenylmethyl ester (Cf sulfoxide isomer);

NMR Spectrum (CDCl ₃ ): S 2.00 (CH ₃ COO-); 3.43 and 4.06 ppm (AB q, C-2).

Fractions 22 to 30 (after fraction 16 change of eluent to ethyl acetate) contain 1.5 g £ SS ~ r5cC _i 6 & 3- £ (Aee tyloxy) -me thy 17 -7 -amino -8 -oxo -5 -thia-1 - azabicyclo Z ² U2,0.7oct-2-en-2-carboxylic acid-5-oxide-diphenylmethyl ester (β-sulfoxide isomer);

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 6 2.10 (CH COO-); 2.97 and 3.54 ppm (AB q, C-2).

b) Z5S-ZBo ^, 6ß, 7oKZ) 77-3- £ U ce ty Io xy) -methy Ij-7-ZT (2-amino-4-thiazolyl) - ^ 1H-tetrazol-5-yl-methoxy) -imino7-aeetyl7-aminc? -8-oxo-5-thia-1-azabicyclo / 4.2.0_7o et-2-en-2-carboxylic acid 5-oxide diphenylmethyl ester

2-Amino-0f-ZT1H-tetraz.ol-5-yl-methoxy) -imino_7-4-thiazole-acetic acid from Example 58d) that obtained under (a) above

β-sulfoxide methyl ester and N-hydroxybenzotriazole 20th

are dissolved in 5O ml of biniethyl sulfoxide. After adding 25 ml of acetonitrile, the solution is cooled ^{to 0 ° C. while stirring.} Dicyclohexylcarbodiimide is then added and the mixture is ^{stirred at 0} ° C. for a further 15 hours. After this time, insoluble urea is filtered off. The mother liquor is poured onto ice and the resulting precipitate is filtered off and washed with water. The crude product is suspended in 20 ml of cold sodium bicarbonate solution and extracted 3 times with methyl ethyl ketone. The aqueous phase is then filtered, acidified with phosphoric acid in the cold and 3

extracted more times with methyl ethyl ketone. The organic layers are combined, dried and evaporated. The residue is dissolved in a few ml of methanol and in diet ether poured. The title compound is obtained as a precipitate.

130019/0854

Γ Π

c) Din atriums al ζ of Z5S-Z5iX, 6 &, ¹ TiX (Z) 77-3- £ (acetyloxy) -methyl7-7-Z7 "(2-amino-4-thiazolyl) -i; i ^H -feetrazole- 5-ylme thoxy) -imino7-a ce ty 17 ^ 111x ^ 7-8-0x0-5-thia-1-azabicyclo ^. 2.07oct-2-en-2-carboxylic acid-5-oxide (ß-sulfoxide; syn -Isomer)

The diphenylmethyl ester obtained above under (b) is ^{suspended in 3 ml of anisole at 0} ° C. and slowly added dropwise

6 ml of trifluoroacetic acid are added while stirring. After full 10

With constant addition, the mixture is stirred at 0 ° C. for a further hour. The solution is then stirred into 200 ml of diethyl ether poured. The precipitation is / 5S- / 5O :, oß ^ iX-

tetrazol-5-y1-methoxy) -imino7-acetyl7-amino7-8-oxo-5-thia-

1-azabicyclo / ^. 2.07oct-2-en-2-carboxylic acid obtained. 15th

This acid is dissolved in 20 ml of methanol and treated at a temperature of 0 ⁰ C under stirring with an equivalent amount Add sodium ethylhexanoate in butanol. After 30 minutes, 200 ml of diethyl ether are added, the title 20

compound with a temperature of 250 to 256 ° C (decomposition) fails.

Example 66

Disodium salt of ZBR- / 5 (X _J 6o <', 7fi> (Z) 77-3-Z' (acetyloxy) -methyl7-7 -Z "ZT (2-amino-4-thiazolyl) - £ ~ (lH- te trazol-5-y 1-methoxy) i3rino7-acety; ij ^r -amino7-3-oxo ~ 5-thia-; i-azabicycloA.2.o7oct-

2-en-2-carboxylic acid 5-oxide (C * sulfoxide, syn isomer) a) / BR-ZBcx, Sex, 7S> (Z) 77 -3- £ T Ace tyloxy) -methy l7-7- / f (2-amino-4 -thiazolyi) -Z "(iH-te trazol-5-y 1-methoxy) -imino7-

-1 -azabicyclo £ 4.2.07oct-2-

en-2-carboxylic acid 5-oxide diphenylmethyl ester

2-Amino-0 (-ZXlH-tetrazol-5-yl-methoxy) -imino7- ⁱ t-thiazole-acetic acid and the Oc-sulfoxide diphenylmethyl ester from Example 65a) are in the presence of N-hydroxybenzotriazole and di- _3S cyclohexylcarbodiimide according to Example 65b) implemented. The title compound is obtained.

L J

130019 // OSS4

b) Z "5R-ß ^, 60c, 7ß (Z) 77-3-Zr (acetyloxy) -methyl7-7-fZ: (2-amlno-

amino7-8 -οxo -5-thIa-I-azabl cyclo D \ ... 2.07 -oct -2-en-2-carboxylic acid-5-oxide (C ^ -Sulfoxide, syn-isomer) The above under (a) The diphenylmethyl ester obtained is treated with anisole and trifluoroacetic ^{acid at 0 ° C. according to Example 65c).} The / 5R-ZSOc, 6cy, 7ß (Z) 77-3-ZlAcetyloxy) -methyl7-7-ZTZl2-amino- ¹ l-thiazolyl) -Zr (lH-tetrazol-5-yl-methoxy) imino7- acetyl7-amino7-8-oxo-5-thia-1 -azabicyclo Z ² J. 2. Q7oct-2-en-2-carboxylic acid-5-oxide.

The acid obtained is treated with sodium ethyl hexanoate. The Tite! Connection will be preserved.

¹⁵ Example67.

Disodium salt of Z5S- £ 5 <*, 6ß, 70f (Z) 77-7-Zr (2-AmIno-4-thiazolyl) - ((1H-tetrazol-5-yl-niethoxy) -imino7-acetyl7-arπinQ7-3-ZZ "( 1-me thy 1-lH-te trazol-5-yl) -thlo7-me thy 17-8-oxo-5-thia-1-azabicyclo / ^. 2.07oct-2-en-2-carboxylic acid 5-oxide (ß-sulfoxide, syn isomer)

a) / 3S-B = K ₁ OB ^ ix77-7-Amino-3-2: T (l-ynethyl-lH-tetrazol-5-yl) -thio7-methyl7-3-oxo-5-thia-l- azabicyclo /! j ¹ 1.2.07oct-2-en-2-carboxylic acid 5-oxide-diphenylmethyl ester (β-sulfoxide) and. .

/ BR-Z5 «', 6 £ X, 7ß77-7-Araino-3-Zr (1-methyl-1H-tetrazol-5-yl) -

2-carboxylic acid-5-oxide-diphenylmethyl ^{ester (0} ^ -sulfoxide) According to example o5a) one obtains when using 7-amino-3-ZZ "(1-methyl-1H-tetrazol-5-yl) -thIo7" -methyl7 -8-oxo-5-thia-l-. azabicyclo / ^. 2.07oct-2-en-2-carboxylic acid instead of J-ACk is a mixture of the desired sulfoxides, which are then separated chromatographically into the oC and β-sulfoxide.

b) Z5S- / 51V, 6ß, 7 <y (Zl77-7- / T (2-amino-4-thiazolyl) -Z "(1H- 35 -

tetrazol-5-yl-ynethoxy) -imino7-acetyl7-amino7-3-i methyl-1H-tetrazol-5-yl) -thioT-ine thy 17-8-0x0-5 _ '

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130019/0854

Γ 'Π

1-azabicyclo £ 4.2.Q7oct-2-en-2-carboxylic acid-5-oxide-di-

phenylmethyl ester

1 g of 2-amino-Cy-Zr (lH-tetrazol-5-yl-methoxy) -imino7- ¹ i-thiazol-acetic acid of Example 58d), 1.82 g of .beta.-sulfoxide of Example 67a) and 0.52 g of N-hydroxybenzotriazole are dissolved in 100 ml of dimethyl sulfoxide and 150 ml of acetonitrile. The solution obtained is ^{cooled to 0} ° C. and, while stirring, 1.04 g of dicyclohexylearbodiimide in 20 ml of acetonitrile are added dropwise. The temperature is ^{kept at 0 °} C. for 12 hours. Then insoluble urea is filtered off. The mother liquor is poured onto 500 ml of ice water and the precipitated product is filtered off, washed with water and dried. The title compound is obtained.

c) Z5S- £ 5i * ', 6ß, 7bi (Z) J7-7-Zr (2-Amlno-4-thia2olyl) - £ {1H-

methyl-lH-tetrazol-5-yl) -thio7-methyU-8-oxo-5-thia-lazabicycloZ / t .2.07oct-2-en-2-carboxylic acid-5-oxide (ß-sulfoxide, syn-isomer)
The phenylmethyl ester from Example 67b) is suspended in 3 ml of anisole at a temperature of 0 C. 6 ml of trifluoroacetic acid are added to the suspension with vigorous stirring, and stirring is continued for a further hour. The resulting solution is then poured into 500 ml of diethyl ether and the crystalline product is filtered off. It becomes the £ 5S- ^ 5CV, 6ß, 7 (X (Z) 77-7- £ Z '(3Amino-4-thiazolyl) -ilH-tetrazol-5-yl-i ^v nsthoxy) -imino7-acetyl7-amino / -3- / r (l-methyl-IH-tetrazol-S-yli-thictT-methylT'-S-oxo-S-thia-l-azabicyclo-

/i.2.Q7oct-2-en-2-carboxylic acid-5- oxide obtained. 30th

This acid is obtained by suspending it in 10 ml of methanol and adding 6.3 ml of sodium ethylhexanoate solution in butanol converted to their disodium salt. The mixture is stirred for 30 minutes and then treated with 200 ml of diethyl ester. It

the Tite! compound crystallizes.

L- J

130019/0854

Example 68

Disodium salt of 15R- £ 5 (y, 1ky, 7 & (Z) JJ-7-Z ~ £ (2-Ami-no- ^l i-thla.zoly ±) ZIlH-tetrazol-5-yl ~ methoxy) -iminc7 -acetyl7-arnino7-3-Z '£ "(l-

bicycloZ? l.2.07oct-2-en-2-carboxylic acid-5-oxide (Of-SuIfoxid; syn isomer)

a) i5R-Z5fX, 6CX; 7ß (Z) J7-7- / r (2-amino-4-thiiazolyl) - / f (1H-tetrazol-5-yl-me thoxy) -imino7-acetyl7-amino7-3- £ f (l -methyllH-te trazol-5-yl) -thio7 -me thy l7-8 -oxo -5-thia-l -azabicyclo Z3. 2.07 * oct-2-en-2-carboxylic acid -5-oxide-diphenylmethyl-1-ester

According to Example 67b), when using £ 5R-f5K 6iV7ß77-7-amino-3-ZT (I-methyl-IH-tetrazol-5-yl) -thio7-methyI? -8-0xo-5-thia-l- azabicycloZ ¹ ! .2.07oct-2-ene-2-carboxylic acid-5-oxide _T Diphenylmethy ester, the title compound! From Example 67a) in place of .beta.-sulfoxide.

b) disodium salt of Z5H- / 50c; 6of, 7a (Z) 77-7- ^ Z (2-Ainino - ^ -

thi azoly I) -ZT (I H-te trazol-5-yl-methoxy) -imino7-acetyl7-

20 -

amino7-3-Z * i. (i-rne thy i-lH-te trazol-5-yl) -thio7 -me thy 17-8 -

oxo-S-thia-l-aaabicycloZTi. 2.07oct-2-en-2-carboxylic acid-5-oxide (Of-sulfoxide; syn-isomer) The diphenylmethyl obtained above according to Example 68a)

Ester is at ^{0 0} C according to Example 10c) with anisole and Tri-25

treated fluoroacetic acid. The Z5R- / 3o <', 6 (y, 7β (Z) 77- T-CiX 2-amino-4.-thiazolyl) -ZT (1H-tetrazol-5-yl-methoxy) -imino7-ace ty 17 -amino7-3 -LR. 1 -me thy 1-lH-te trazol -5 -yl) -thio7-nie thy 37 8-οxo-5-thia-l-azabicycloZTt. 2 »07oct-2-en-2-carboxylic acid-5-oxide obtained.

This acid is obtained by treatment with sodium ethyl hexanoate converted into the disodium salt of the Ti te! compound.

L- J

130019/0854

1 example 69

Disodium salt of Z6R-ZSOr, 7ß (Z) 77-3-Z- (acetyloxy) -methyl7-7-Z £ (2-amino-4-thiazolyl) -Z '(1H-tetrazOl-5-yl-methoxy) - imino7-acetyl7-amino7-8-oxo-5-thia-1-azabicyclo ^. 2.07oct-2-en-2 ~

5 carboxylic acid-5,5-dioxide (syn isomer)

a) ZBR-ZB (X, 777-3-Z "(Acetyloxy) -methy l7-7-amino-8-oxo-5-thia-1-azabicy 010 ^ .2.07oct-2-en-2-carboxylic acid-5,5-dioxide-diphenylmethyl ester

C $ R - & W , 6oc, 7 $ J1 - 3rd-Zi A ce ty Io xy) -me thy U- 7 -amino -8 -ο xo -5 -thia-1 -azabicyclo / 4. . 2 ^ / oct ^ -en ^ -carboxylic acid-S-oxide diphenylmethyl ester according to 65a) is introduced in methylene chloride and cooled to 0 ⁰ C. An equimolar amount of m-chloroperbenzoic acid in methylene chloride is then added. When the reaction is complete, the slurry is ^{treated with 5} percent sodium bicarbonate solution and 5 percent sodium sulfite solution. The organic layer is dried and evaporated under reduced pressure. By preparative thin layer chromatography of the residue

the title compound is obtained. 20th

b) / "6R-ZB [X, 7β (Z) -77-3-ZUcetyloxy) -methy] 7-7-ZZ" (2-amino-4-thiazolyl) -Z (1H-tetrazol-5-yl- methoxy) -imino7- ace tyl7-amino7-8-oxo -5-thia-1 -azabicy cIqZ ¹ J. 2.07oct-2-

en-2-carboxylic acid-5,5-dioxide-diphenylmethyl ester

2-Amino-OC-Z (1H-tetrazol-5-yl-methoxy) -imino7- ⁱ t-thiazole-acetic acid according to Example Id) and the diphenylmethyl ester obtained above in Example 69a) are in the presence of N-hydroxybenzotriazole and dicyclohexylcarbodiimide

implemented according to Example 65b) to the title compound. 30th

c) Disodium salt of Z6R- £ 6iY, 7ß (Z) 77-3-Z ~ (acetyloxyJ-

7-Z * Z (2-amino-4-thiazolyl) -Z '(1H-tetrazol-5-yl-methoxy) -imino7-acetyl7-amino7-8-oxo-5-thia-1-azabicyclo Z ² 1.2. 07-oct-2-ene-2-carboxylic acid-5,5-dioxide (syn-isomer) The diphenylmethyl ester of example 69b) 65c) at 0 ⁰ C according to example with anisole and trifluoroacetic acid. It is the Z5R-ZBor, 7ß (Z) 77-3-ZlAcetyloxy) -methyl7-

13 0.01 9/08 5 A

7-Ζ7Γ (2-amino-4-thiazolyl) - ^ lH-tetrazol-5-yl-methoxy) -iraino7-acetyl7-amineq7-8-oxo-5-thia-l-azabicyclo £ H. 2.Q7oct-2-en-2-carboxylic acid-5,5 ~ dioxide obtained.

This acid is obtained by treatment with sodium ethyl hexanoate converted to the disodium salt of the title compound.

Examples 70 to 9 5

Following the procedures of Examples 58 'to 63 and 65 to 69 using the esters shown in column I below and the acids shown in column II below, the esters shown in column III are obtained. Cleavage of the ester protection group gives the acids shown in column IV.

Column I.

Column II

¹ HJ

-C-COOH

R - (C) -R

13 in 14

R -KT L

¹⁵ II

N -N

130019/0854

1 column III

1 -

N-

X>

? ^Ö COOR ₂₁

: h "x

RH 10 ^Χ

Column IV 15

R16 <? '

ία

J]

N = N 25

130019/0854

example

70 71

73 74 75 76 i

78

• Β

-O-C-CH.

O J

KJ ν_ *

-oil-

-O-C-CH- -O-C-CH-

C (CH ₃ )

-CH-K D))

-CH-KO))

-CH-KO))

-CH-KO))

-CH-KO))

-H

-H

-II

OCH ₃ -H

-H

-H

-H

-H

-H

HI. ti Xl

-COOH * H '

r> u, -ti

J-H -H

1 O

^H -H -H 2 "" ^C 2 ^H 5 -H 0 H -H -H 0 H -H -H 0 CH ₃ -H 0

Example

79

-0-C-NH

21st

15th

80 i If
-0-C-NH ₂
-0-C-NII ₂ 81 84; -0-C-NH ₂
-0-C-NH ₂ 82 N-N 83 85. -S— * lg> -CH 86 N - N -S-ksi ^ -CH -s-LIsÜ-ch,

2 2

-H

-H

-H

-H

-H

—Ti

-H

-H

-H

"-ti

-H

-CH

-OCH., -H

-CH

-H

-H

-CH

-H

-H

-H

-H

-H

-H

-H

-COOH -H

1 1 i CVI 1 - "* VO I. 0 ' 1 '0 1 0 1 0 1 1 - 1 co O -P-- O K) cn -J

example

91 i

N N

CH-

CIL

- ■■

■■ V

CH

CH

-S-

-CH-KO

Ν — Ν rCR-UO))

Il Ii ^^

-CH-KO))

CH ₂ SO ₃ H

R 12

-H -H

-OCH ₃ -H

-H

■ • Μ

-CH-K O)) ο " ^H

Ü14 L ₅

-H -H

-COOH "Η

m η

-CH ₃ -C ₂ H ₅ -H

-CH ₃ -CH ₃ -H

-H -H

O CD OI

Example 93

Ν, —ν

II ₂ COOH

N-N

-s-LIn

N-N

-CH,

16

-H

-H

^R 13 ^R 14 ^R 15

-H -H

-H -H

-H -H

_au TT

-H

-H

Γ Π

The ones in the examples _; 70 to 95 acids obtained can be converted into the sodium or potassium salts by known processes. The products of Examples 70 to 95 are obtained as syn or anti isomers, depending on the configuration of the acid shown in column II. If the residues R., uml R. 2; do not have the same meaning, the products are obtained in the D-, L- or D, L-form ^ depending on the optical activity of the acid shown in column II.

¹⁰ Example 9 6

, 7ß (Z) 7 / -3-ZZ4-CAminocarbonyl) -pyridino7 -me thy 17-7- / Z (2-amino -4 -thiazolyl) -ZTlH-tetrazo 1-5 -y 1-methoxy) -iminojacety] 7-amino_7-8-oxo-5-thia-l-azäbieyclo Ik . 2.0_7oct-2 ~ en-2-carboxylic acid (syn isomer)

A mixture of 0.05 moles of the disodium salt _; of Example 58, 0.0075 mol of 4-pyridinecarboxamide, 12 g of sodium thiocyanate and 7.5 ml of water are ^{heated to 50 °} C. for 24 hours. The resulting solution is then passed through a chromatography column filled with Amberlite XAD-2. The column is washed with water and the title compound is eluted with a mixture of water and methanol in a ratio of "8: 2. The methanol is distilled off from the eluate and the aqueous solution is lyophilized. The amorphous residue is treated with di-

äthylether digested and filtered off with suction. It will be the title connection

receive dung.

Examples 97 to 10-1 Follow the procedure of Example 96 if using

of the sodium salts of the cephalosporan 30 shown in column I.

acids and the pyridine compounds shown in column II

gen obtained the products shown in column III.

SDold I.

Η-, Ν

^R 15f Τ

N- = N

Column II

Column III

1 C

C-C-:

rK O

COO

1 30019/0854

example

9S ₁

99 y

100 j

ιοί j

102 j 103

104

-OH

-H

-H

-H

-H

-H

-H

-H

_H

-H

-CH

-C ₃ H ₅

-H

-H

-H

-H

-H

-H

-CH

-H

1 -CNH ₂ (4) ί 2 -Bnh ₂ (3) 00
.Cr
I. 0 -H 0 -H 1 -CNH ₂ (4)

-CNH ₂ (2)

0 ·- H
ff
-CNH ₂ (4) KjJ
CD 0 ; 025

The products of Examples 97 to 104 are obtained in the syn or anti configuration, depending on the configuration of the 3-acetoxymethyl starting verb shown in column I. Similarly, if m is 1, the compounds are obtained as "i- or β-sulfoxides, depending on the orientation of the 3-acetoxymethyl sulfoxide starting compound. If the radicals IL, and R ₁ ^ do not have the same meaning the products are obtained in the form of the D, L or D, L isomers, depending on the optical activity of the starting compounds shown in column I.

Example 105 Disodium salt of ZT6R-Z6cv, 7β (ζ) 77-7-ZZX2-amino-4-thiazolyl) -Z "(1H-tetrazol-5-yl-methoxy) -iminoj'-acetyl7-amino7" -3-ZZ "(5- methyl-1,3,4-thladiazolyl) -thio7-methyl7-8-oxo-5-thia-lazabicyclo £ 4 .2.07oct-2-en-2-carboxylic acid 0.002 mol of the disodium salt prepared in Example 58 are brought into solution in 100 ml of phosphate buffer at a pH of 6.4 and with 0.0024 mol of 5-methyl-1,3,4-thiadiazolyl-2-thiol offset. The solution is then heated to 60 ° C. for 6 hours. After cooling, the pH becomes 7.0 adjusted and the solution chromatographed on the ion exchange resin Amberlit XAD-2. The product-containing fractions are freeze dried. The title compound is obtained.

Examples 106 to 111

Following the procedure of Example 105, if using of the sodium salts of

Csphalosporanic acids and the thiols shown in column II receive the products listed in column III.

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130019/0854

- 86 column I.

Sl ₃ - ^ h-Ki ₄

R ₁ -N ^ N

^IU N N

Column II

HS-He te ro

Column III 20

CH ₂ -S-hetero COONa

N N

130019 / 08S4

example

106 '

107

108

109

110

111

-H

-II

-OH.

-H

-H

la

-H

-CIL
-CIL

—Η

-TT

-H

-H

-CH.

-H

-H

-H

-H

hetero

N .N

CH.

Ti

IT "CH ₃ SO ₃ Na

LU

N 'CH ₂ COONa

N N

-HJt

The products of Examples 106 to 111 are obtained in the syn or anti configuration, depending on the configuration of the 3-acetoxymethyl starting compound shown in column I. In the same way, if m has the value 1, the compounds are obtained as Oi- or β-sulfoxides, depending on the orientation of the 3-acetoxymethyl sulfoxide starting compound. If the radicals FL and R ₁ Ji do not have the same meaning, the products are obtained in the form of the D, L or D, L isomers, depending on the optical activity of the

starting compounds shown in column I.

Example 112

Din atrium salt of Z5S-Z5o, 6ß, 7cy (Z) 77-3-Zr (acetyloxy) -methyl7-7- / ZX 2-amino-4-thiazolyl) - / "(1H-tetrazol-5-yl-methoxy) -imino / -acetyl7amino7-8-οxo-5-thia-1-azabicyclo £ Ά . 2.07oct-2-en-2-carboxylic acid-5-oxide (β-sulfoxide, syn-isomer) The product of Example 8 can also be manufactured according to the following process:

1 g / BR-ZB0f, 73 (Z) 77-3-Zr (acetyloxy) -methyl7-7-Z "Z: (2-amino-4- 20

thiazolyl) - £ "(1H-" b5t-razol-5-yl-methoxy) -imino7-acety37- * aniinQ7- 8-oxo-5-thia-i-azabicyclo £ Ά . 2.07oct-2-ene-2-carboxylic acid of Example 58 is dissolved at 0 ⁰ C in 10 ml of trifluoroacetic acid, mixed with 0.39 g of m-Chiorperbenzoesäure and stirred for 1.5 hours at 0 ⁰ C. Then 500 ml of diethyl ether are added

and the precipitated product is filtered off. It becomes the title connection obtained in the form of the free acid. The acid can by treatment with sodium ethyl hexanoate according to example o5 can be converted into their disodium salt.

Examples 113 to 121

Following the procedure of Example 112, the sulfides shown in column I below can be converted to the β-sulfoxides of column II are oxidized.

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1 30019/0854

- 89 - Sdalte I

10

O'R

-ir— ^ώ —Τ

Soalte II

16

Xf

N N

OOH

130019/0854

example

113 114

115

116

117 118

-H

^J 0CH.

^ ₁ DD

-H

-H

'-Η

-H

"• GH-

-H

-H

-H

-CH.

-H

-.ft

-CH-

-0-C-CH ₃

. N- N

CH ₃

CH

-0-C-CH.

CH

O I

Example 119 120 121

hey

-H -II

-H

-H

-CH-

-H

-CH.

-CH.

-O-C-NH,

-O-C-NH,

-0-C-CH.

M

The products of Examples 113 to 121 are obtained in the syn or anti configuration, depending on the configuration of the sulfide starting compounds shown in column I. When the radicals R ₁ , and R ₁ ^. does not have the same meaning

ben, the products are in the form of the D, L or D, L isomers obtained, depending on the optical activity of the starting compounds shown in column I.

Example 122

Disodium salt of £ oR-ZK>, 7ß (Z) 77 "-7-Zr (2-Amino-i} -thiazolyl) - / I (1H-tetrazol-5-yl-methoxy) -imino7 ^r -acetyl7-amino7- 3-ZZ '(1-methyl-1H-tetrazol-5-yl) -thio7 "-methyl7-8-oxo-5-thia-1-azabicycloA. 2.07oct-2-en-2-carboxylic acid-5,5-diojiid Z5R-ZBor, 6oc, 7ß (Z) 7 _? - 7 - / "Zt 2-Amino-4-thiazoly 1) -ZT (1H-tetrazole- 5-yl-methoxy) -imino7-acetyl7-aminoJ7-3 - / * Z "(l-methyl-1H-tetrazol-5-yl) -thio7-inethy 17-8-oxo-5-thia-l- azabicyclo A. 2.Q7-oct-2-en-2-carboxylic acid from Example 68 is dissolved in trifluoroacetic acid and reacted with m-chloroperbenzoic acid by the method of Example 112. It becomes the free acid

obtained the title compound. This acid can through treatment with sodium ethyl hexanoate as in the preceding Examples can be converted to the disodium salt.

Examples 123 to 12 9

Following the procedure of Example 122, the (X-sulfoxides listed in column I below can be added to those in column II shown sulfones are oxidized.

L J

UOO 1 9/08 B 4

C C N-

- 93 -

Column I.

% 6 -O.

CH ₂ X

COOH

14th

Column II

ι

-C-Il

Il

-C-

16

N \

N \

COOH

130019/0854

Ix! O

in,

ι- »| S3 33 S3

ed I i ι ι

of I

S3

cn,

S3
I.

ΐΰ S3 S3 η I. S3 ο ϋ I. j ι

S3 S3 S3 S3 O I. I. O I.

al

ro

CM

■ <* in

CM CM

CM OO cn CM r-l CM CM H iH

130019/0854

The products of Examples 123 to 129 are obtained in the syn or anti configuration, depending on the configuration of the OC sulfoxides shown in column I. If the radicals FL and R ₁ I ₁ do not have the same meaning, the

Products obtained in the form of the D, L or D, L isomers, depending on the optical activity of the starting point shown in column I. links.

The acids obtained in Examples 58 to 129 can also be converted into various esters by known methods, in which R is, for example, a of the groups

means.

-CH ₂ -OCC (CH ₃ J ₃ or

L J

1 30019/0854

Claims (28)

VOSSIUSVOSSIUSTAUCHMER · H EU N Ξ: \ / 1ΑΝ Ν -RAUH PATENTANWÄLTE SIEBERTSTRASSE 4 · 8OOO MÜNCHEN 86 ■ PHONE: (O89) 47 4O75 CABLE: BEN ZOLPATENT MÜNCHEN -TELEX 5-29453 VOPAT D u # Z .: P 859 (Ra / ko) October 24, 1980 Case: V-88,276-H; V-I26,801-H VON HEYDEN, GMBH Munich, Germany 10 "7-Zri2» Amino-4-thlazolyl) -oximino_7-cephalosporin derivatives Priority: October 25, 1979, V.St.A., No. 88 276 February 28, 1980, V.St.A., No. 125 801 claims 1.Imidaz oil derivatives of 7-ZT (2-Amino-4-thiazolyl) -oximino7- cephalosporins of the general formula I 25 OH (Q). 30 I. ^C00R (D 130019 / 08SA in which R is a hydrogen or alkali metal atom or one of the radicals of the formulas -CHO-CO-lower alkyl or 5 R _{1 is} a hydrogen atom or a methyl group, R2 is a hydrogen atom or a methyl group, R is a hydrogen atom or a methyl group, Ru is a hydrogen atom or one of the radicals of the formulas -OCOSlH ₉ , ⁴ - ^A -N in the '~ ^S ~~ Si R is a hydrogen atom or a methyl group, Rg is a hydrogen atom, a methyl _S benzyl or. Acetyl group, R ~ is a hydrogen atom or a lower alkyl radical, Rg is a hydrogen atom or the radical of the formula -CONHp, R is a hydrogen atom, a lower alkyl radical or a the remnants of the formulas OO, ■ - ^(CH 2 ⁾ p "^ ~ 0R ll '- (CH ₉ ) -S-OR ₁ , or- (CH,) -N -; ( ^{lower alkyl} _{) o} , O R _{10 is} a hydrogen atom or a lower alkyl radical and R _{11 is} a hydrogen, sodium or potassium atom, η is 1, 2, 3 or 4,
m has the value 0, i or 2 and
ρ have the value 1, 2, 3 or 4, and tetrazole derivatives of 7- £ t2-amino-4-thiazolyl) -oximinoJ-cephalosporins of the general formula II ^L 130019/0854 ^{J. Γ} , "π N N. including its tautical imino form, in which the group ¹⁰ pe is in the syn or anti configuration, R _{12 is} a hydrogen, sodium or potassium atom, a benzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, diphenylmethyl or tert-buty! group or a the remnants of the formulas -ch-o-C- -CH ₂ -O-NIe de ralkyl -ch-oC -Nie the alkyl or R _-1 , and R ₁ U independently — ng- "from each other what se rs to ff atoms, methyl-, ethyl-, i-propyl-, n-Pr ^ p ;;". ..ier carboxyl groups, R ₄₁ - a hydrogen »sodium or potassium atom or a 15 Mean methyl group, R ₁ ^ is in (λ configuration and represents a hydrogen atom or a methoxy group, m has the value 0, 1 or 2, ^ _n value / η has the value 0 or an integer / from 1 to 4, R _{17 is} a hydrogen atom or a lower alkyl radical, X is a hydrogen atom or one of the radicals of the formulas 0. η _. "C -C lower alkyl _ -0-CNH, _n o- 35 Ö ^ 18 R ₁₉ ^L 130019/0854 ^J. BATH ORIGINAL Γ Π - ⁴ - · 3D40257 R ^ g is a hydrogen atom or a lower alkyl radical, R ^ g is a hydrogen atom, a lower alkyl radical or one of the radicals of the formulas -CCH ₂ > _p -COOR ₂₀ , - (CH ₂ > _p -SO ₃ R _{20 or} - (CH ₂ Jp - (liiederalkyI) ₂ , and '"Rq is a hydrogen, sodium or potassium atom and ρ is an integer from 1 to 4» 2. Compounds according to claim 1 of the general formula I 10 (D k in which R is a hydrogen or alkali metal atom or one of the radicals of the formulas' -CHO-CO-j-lower alkyl or γ τ _ ι s ' ItOI R- is a hydrogen atom or a methyl group, R _{2 is} a hydrogen atom or a methyl group, R is a hydrogen atom or a methyl group, Ri _{1 is} a hydrogen atom or one of the radicals of the formulas ^ N- N N- -N ; -S-IL β -R ₁₀ / -S-IL ₁ Jn or ^ O-C-J-lower alkyl; R is a hydrogen atom or a methyl group, Rg. A hydrogen atom, a methyl, benzyl or acetyl group, 130019/0854 R ™ is a hydrogen atom or a lower alkyl radical, Rg is a hydrogen atom or the radical of the formula -GONH ₂ , Rg is a hydrogen atom, a lower alkyl radical or one of the radicals of the formulas - (CH-JH-OR ₁ ,, j - (CH-) -S-OR ₁ jor - (CH_) -N -! (Lower _{alkyl) p} , Z * £ / XX 'ώ ρ JJ XX ^ l ρ I ^fc I ö i. ■ R ₁₀ denotes a hydrogen atom or a lower alkyl radical and R denotes a hydrogen, sodium or potassium atom, η denotes the fourth 1, 2, 3 or 4,
m has the value 0, 1 or 2 and
ρ have the value 1, 2, 3 or 4. 3. Compounds according to claim 2 of the general formula I, in which the group _r is in the syn configuration, η has the value 1 or 2, m has the fourth 0 or 1, with the proviso that the sulfoxide group is present in ß-K on figuration when m has the value 1, R is a hydrogen, sodium or potassium atom or one of the radicals of the formulas V> or -CHgO-CO-lower alkyl, R ₁ , R ₂ , R, and R ₁ - independently of one another what are atoms or methyl groups,
Rh is one of the remainders of the formulas -0-e-CH, -O- ^S 35 ³ , or r- ^L 130019/0854 ^J. Γ "1 Hr is a hydrogen atom, a methyl, benzyl or acetyl group, Rg is a hydrogen atom or the group CONHp, Rq is a hydrogen atom, a methyl group or one of the radicals 5 of the formulas R ₉ - (CH ₂ V ^ ⁰¹¹ II > - (CH ₂ ) -S-OR ₁₁ * der (CH ₂ ) _p -N (CH ₃ ) ₂ ; R ₁₁ denotes a hydrogen, sodium or potassium atom and ρ has the value 1 or 2. 4. Compounds according to claim 3 of the general formula I, in which R _{1 is} a group of the formula -0-C-CH ₃ means. 5. Sodium salt of _J ßS-Z5cy, 6ß, 7cy (Z) 77-3T ^ 'acetyloxy) -inethyl7-7-ZZJC 2-amino-4-thiazolyl) - / (1H-imidazol-2-y 1-methoxy) -iminojace ty 17-aminoZ-B-oxo-i-thia-l-azabicyclo A, 2,0_7oct-2-en-2-carboxylic acid-5-oxide. 6. Sodium salt of / 3R-ZSc ^ 7ß (Z) 77-3- / i ^r acetyloxy) -methyl7-7- / T (2-amino-4-thiazolyl) -Z "(lH, imidazol-2-yl- methoxy) -imino7 ~ ace ty l7-aniino7-8 oxo-5 -thia-1 -azäbi cy clo SSI, 2, 07oct-2-ene-2-carboxylic acid. 7. Compounds according to claim 3 of the general formula I, in the Rj, a group of the formula 130019/0854 and Rq represents a hydrogen atom or a methyl group. 8. Sodium salt of ZT6R-ZM, 73 (Z) 77-7- / tf2-Ainino-4-thiazoly I) - £ ( 1H-imidazol-2-yl-methoxy) -imin o7-ace ty 3J -aminoj -3-ZZ "(1 methyl-1H-tetrazol-5-yl) -thioJ-methylJ-S-oxo-S-thia-1-azabicyclo ^ ² *, 2.07oct-2-en-2-carboxylic acid. 9. Compounds according to claim 1 of the general formula II 10 including its tautomeric imino form in which the group is in the syn or anti configuration, R ₁ P ^e ^ ⁿ hydrogen, sodium or potassium atom, a benzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, diphenylmethyl or tert-butyl group or one of the remainders of the formulas -CHg-O-lower alkyl, -CH-OC-lower alkyl or 30 P ₁₇ R.-, and Rj independently of one another hydrogen atoms, methyl, Ethyl, i-propyl, n-propyl or carboxyl groups, R ₁ E- is a hydrogen, sodium or potassium atom or a Mean methyl group, Usually in (X configuration and a hydrogen atom or represents a methoxy group, L J 130019/0854 1 m has the value O, 1 or 2, η has the value 0 or represents an integer from 1 to 4
R _{17 is} a hydrogen atom / or a lower alkyl radical, X is a hydrogen atom or one of the radicals of the formulas -O-C-N ± ed & r.al £ yl -o- ' , -Φ 18 10 R.JO is a hydrogen atom or a lower alkyl radical, R _{19 is} a hydrogen atom, a lower alkyl radical or one of the radicals of the formulas ~ ^ ^CH 2 ^ p ~ ^COOR 20> ~ ^ ^CH 2 ^ p ~ ^SO 3 ^R 20 or - (CH ₂ ) - (WiederalkyI) -, and R _{20 represents} a hydrogen, sodium or potassium atom and ρ represents an integer from 1 to 4. 10. Compounds according to claim 9 of the general formula II in which R. _? is hydrogen, sodium or potassium, Rg is hydrogen, and R ₁ - and R. j. Denotes hydrogen atoms, m has the value 0 or 1, with the proviso that the sulfoxide group is in the β-configuration when m has the value 1, X is a hydrogen atom or one of the radicals of the formulas -O-d-CH., -O-C-NH-, t / O), - N - N is - = - ® N - f -S-ivg ^ i-CH ^ or -S . ^R 19 R ₁ - a hydrogen atom, a methyl group or one of the Remnants of the formulas -CH ₂ -COOR ₂₀ , -CH ₂ -SO ₃ R ₂₀ or - (CH ₂ ) and Rp ₀ denotes a hydrogen, sodium or potassium atom, where the group of the formula -c- I in syn configuration. N, 130019/0854 Γ - 9 _ Π 11. Compounds according to claim 10 of the general formula II, in which X is a hydrogen atom. 12. Compounds according to claim 10 of the general formula Hb in which Z is a hydrogen atom or the group -CONH ₂ . 13 «compounds according to claim 10 of the general formula II, in which X is the formula 0 ~. -0-C-NH ₂ 14. Compounds according to claim 10 of the general formula II, in which X is one of the radicals of the formulas N- R ₁₉ R ^ g is a hydrogen atom, a methyl group or a radical of the formulas -CH ₂ -COOR ₂₀ , -CH ₂ -SO ₃ R ₂₀ or - (CH ₂ ) 2N (CH ₃ ) ₂ , and R _{20 represents} a hydrogen, sodium or potassium atom. 30th 15. Compounds according to claim 14 of the general formula II, in which X is a group of the formula 35 means. CH ₃ 16. Compounds according to claim 15 of the general formula II, in which m is O. 130019/0854 Γ Π 17. Disodium salt of ZJ5R - /] So ^ 7S (Z 177-7- / 7 ^ 2-AmInO-4-thiazolyl) -Zr (1H-tetrazol-5-yl-methoxy) -imino_7-acetyl7-amino7-3- ZT (l-methyl-lH-tetrazol-5-yl) -thio7-methy17-8-oxo-S-thia-lazabicyelo £ 4, 2, Q7oct-2-en-2-carboxylic acid. 18. Compounds according to claim 15 of the general formula II, in which m is 1. 19. Disodium salt of Z5S-Z5CX '> 6ß, 7cX (Z) J7-7 - /' / '(2-Amino-4- thiazolyl) - / f (1H-tetrazol-5-yl-niethoxy) -imino7-acetyl7-amineQ7-3-rZXl-methyl-1H-tetrazol-5-yl) -thiQ7-methyU-8-oxo-5-thia- lazabicycloZ? i, 2, Q7oct-2-en-2-cartonic acid-5-oxi.d. 20. Compounds according to claim 10 of the general formula II, in which X is the group of the formula η ^! means. -0-C-CH, 21. Compounds according to claim 20 of the general formula II, in which m is zero. 22. Disodium salt of ZHR-Z "6 (y, 7β (Z) 77-3-Z! (Acetyloxy.) .- methyl7-1 -CCi. 2-amino-4-thiazo IyI) - ^ TlH-tetrazole-S -yl-methoxy) -Iralnoj ace ty17-amino7-8-oxo-5-thia-1-az ab icyclo D \ , 2,07οet-2-en-2- ²⁵ carboxylic acid. 23. Disodium salt of £ 6R-Z5oc, 7β (Z) 77-3-ZiAcetyloxy) -methyl7-7- / T (2-amino-4-thiazolyl) - £ "(1-methyl-1H-tetrazole) -5 -yl-methoxy -imino7-acetyl7-amino7-8-oxo-5-thia-l-azabicycloZ ¹ l, 2.07- oct-2-en-2-carboxylic acid. 24. Compounds according to claim 20 of the general formula II, in which m is 1. 25. Disodium salt of £ 5S- / f5of, 6ß, 7c / (Z) ^ 77-3- ^ acetyloxy) -. me thy 17-7 -ZZ "(2-amino-4-thiazolyl) - ^ TlH -tetrazol-5-yl -me thoxy) - L J 13 0019/0854 imlno7-acetyU-amino? -δ-οχο-5-thia-l-azabicyclo / ¹ *, 2.07oct-2-en-2-carboxylic acid-5-oxide. 26. Disodium salt of Z6R - / & x, 7β (E) JJ-3-ZT (acetyloxy) -methyl7-7-ZZ * (2-amino-4-thiazolyl) -ZX1H-tetrazol-5-yl-methoxy) -iinino_7 - aeetylJ-aminQj-B-oxo-S-thia-1-azabicycloZ ¹ *, 2.07oct-2-en-2-carboxylic acid. 27. Medicinal products with antibacterial properties, marked by a content of a compound according to claim 1 up to 26 and the usual carriers, auxiliaries and additives. 28. Use of the compounds according to claim 1 to 26 for Treatment of bacterial infections. 15th 30019/0854