CS195680B2 - Process for preparing derivatives of 7-/substituted phenylglycinamido/-3-substituted-3-cephem-4-carboxylic acid - Google Patents

Abstract

1473672 Cephalosporin derivatives FUJISAWA PHARMACEUTICAL CO Ltd 9 May 1974 [10 May 1973 6 July 1973 3 Dec 1973 10 Jan 1974 7 Feb 1974 8 Feb 1974 27 March 1974] 20637/74 Heading C2C Novel compounds I (in which R 1 is NO 2 , alkoxy, alkylsulphonamido, or alkylaminosulphonamido; R 2 is H or OH and must be OH if R 1 is NO 2 or alkoxy; R 3 is H or optionally alkylated heterocyclylthio provided R 3 is H if R 1 is alkoxy and R 2 is OH; X is amino or protected amino and M is H or a non-toxic cation) and their derivatives at the carboxyl group are prepared by reaction of a compound II with a compound III or by reaction of a compound IV in which R 3 <SP>11</SP> is alkanoyl and R 1 <SP>1</SP> is as R 1 except that it may not be alkoxy, with a thiol R 3 <SP>1</SP>H in which R 3 <SP>1</SP> is heterocyclylthio. Pharmaceutical compositions having antibacterial properties comprise a compound I together with a suitable carrier or diluent.

Description

(54) A process for the preparation of 7- [substituted phenylglycinamido] -3-substituted-3-cephem-4-carboxylic acid derivatives

The present invention relates to a process for the preparation of cephalosporanic acid derivatives according to the novel cephalosporanic acid derivatives according to the invention, which can be represented by the general formula I sellny which exhibit an antibacterial effect.

CH-CONH X c

COOM where

R 1 represents nitro-, C 1 -C 6. alkoxy-, C 1 -C 6 alkanesulfonamido-, C 1 -C 6 alkylaminosulfonamido-, C 1 -C 6 alkylureido-, or C 1 -C 6 alkylthioureido,

R2 is hydrogen or hydroxy, wherein R2 is hydroxy when R1 is nitro or C1-C6 alkoxy,

R 3 represents a hydrogen atom or a heterocyclic radical substituted by a thio group in which the heterocyclic radical is five-membered and contains 1 to 2 sulfur atoms and / or 1 to 4. and optionally substituted with C 1 -C 6 alkyl, wherein R 3

195880 ί / Λ represents a hydrogen atom when R 1 represents a C 1-6 alkoxy group and R 2 represents a hydroxy group,

X is C 1 -C 6 alkoxycarbonyl or C 1 -C 6 alkoxy and C 1 -C 6 alkoxycarbonyl; and X is C 1 -C 6 alkoxycarbonyl;

M represents a hydrogen atom or a non-toxic pharmaceutically acceptable cation.

. The term "alkoxy" in the meaning of R 1 means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

5 6 7 0

The term "C 1 -C 8 alkanesulfonamido" in the meaning of R 1 means mssylamino, ethanesulfonamido, propanesulfonamido, isopropanesulfonamido, butanesullonamido, isobutanesulfonamido, tert-butanesulfonamido, pentanesulfonamido, hexanes and the like.

Pod. the term "C 1-6 alkylaminosulfonylamino" in the meaning of R 1 means an alkyl-substituted aminosulfonylamino group; - in which the alkyl group has the same meaning as the alkyl group in the above-mentioned "alkanesulfonamido" group.

The term "C 1 -C 6 alkylureido" in the meaning of R 1 means an alkyl-substituted ureido group in which the alkyl group has the same meaning as the alkyl group in the above-mentioned "alkanesulfonamido" group.

The term "C 1 -C 8 alkylthioureido" in the meaning of R 1 means an alkyl substituted thiourpido group in which the alkyl group has the same meaning as the alkyl group in the above-mentioned "alkanesulfonamido group".

The term "heterocyclic-substituted thiol group" in the meaning of R3 means a heterocyclic thiol radical containing, for example, a furan, thiophene, pyrrole, pyrazole / LUfIdazole, iriazole-; thlazole, -isothlazole, oxazole, isoxazole, thiadiazole, oxadlazole, thiatrlazole, oxatriazole or tetrazole. Heterocyclic - the group "hsterocyclic-. wherein the substituted-thiocyclic radical is optionally substituted with a C 1 -C 6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, - tert -butyl, pentyl, h-xyl, and the like.

The term "non-toxic, pharmaceutically acceptable cation" in the meaning of M means an alkali metal cation such as sodium, potassium and the like. The compounds of the formula (I) according to the invention are prepared by the preparation of 7-amino-3-substituted-3-cis-4-carboxylic acid of formula (II)

R 5 and M are as defined above or its ester is reacted with a substituted phenylglycine of formula III

where. . .

R 1, R 2 and X are as defined above or with mixed anhydrides of this compound obtained using C 2 -C 7 alkanoyl halide or C 1 -C 6 -alkyl halogeno-C 2 -C 2 alkanoate, whereupon the amino protecting group is optionally cleaved from the reaction product. Suitable esters of the compound of formula (II) are: methylsstsr, sthyl ester, propylsstsr, butylsstsr, 'psntylsster, trimsthyLsilylestsr,'

2-mesylethylsstsr, 2-iodoethyl ester,

2,2,2-trichloroethylestsr, bsnzylester,

4-methoxybenzyl ester, 4-nitrobenzyl ester,.

fsnacylsstsr, fyneteylestet,. trltyLystyr, di.fsnyLmSteyLsster, bis [msthoxytenyl) msthyLsstst,

3,4-dimothryybenzyltsteг, (1-cyclopropyl) SthyLsstsr, ylsylsstsr,

4-eyedroxy-3,5-di-tert-butyl-benzylsster etc.

Suitable mixed anhydrides of the compound of formula III are, for example, a mixed anhydride of the acid of formula III and pivalic acid, pentanoic acid, isopropanoic acid, 2-steylbutyric acid or triacetate. A suitable derivative can be selected from the above compounds depending on the kind of substituted phenyl phenyl cycles of the general formula (III) used.

The reaction is conveniently carried out in solvents such as acetone, dloxane, acetonitrile, chloroform, methylsulfide, ethyl chloride, tettaeydololane, ethyl acetate, dimethylformamide, pyridine or any other organic solvents inert to the reaction. Of these solvents, the hydrophilic solvents may be used in admixture with water.

When the substituted phenylphlycine '195680 of formula III is used in the reaction according to the invention in the form of the free acid or a salt thereof, the reaction is preferably carried out in the presence of a condensing agent such as

N, N‘-dicyclohexylcarbodiimide, N-cyclohexyl-N‘-morpholinoethylcarbodiimide,

N - cyclohexyl - N - (4-diethylaminocyclohexyl) carbodiimide,.

N, N‘-diethylthiocarbodiimide,.

N, N‘-ditsopropylcarbodiimide, N-ethyl-N ‘- (3-dimethylaminopropyl) carbodiimide,

N, N'-carbonyldi (2 _; methylimidazolium),.

pentamethylketene-N-cyclphexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene,

1-alkoxy-1-chloroethylene, trialkylphosite;

ethyl polyphosphate, isopropyl polyosulfate, oxychloride. phosphorus trichloride, "phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine,

2-ethyl-7-hydroxybenzisoxazole salts, intramolecular salts of 2-ethyl-5- (m-sulfonyl) isoxazolium hydroxide, (chloromethylene) dimethylammonium chloride and the like.

As the substituted phenylglycine salt of the general formula ΙΠ, an alkali metal salt, an alkaline earth metal salt, an ammonium salt, a salt with an organic base such as trimethylamine, dicyclohexylamine and the like can be considered.

The reaction - may be carried out in the presence of a base, such as an alkali metal bicarbonate, a trialkylamine, N, N-alkyl alkylbenzylamine, pyridine and the like. When the base - or the condensing agent is liquid - they may also be used as solvents. The reaction temperature is not a limiting factor for the course of the reaction; cooling or at temperature. rooms.

Some of the amino protecting groups represented by X in the substituted phenylglycines of formula (III) may be cleaved off during the reaction or post-treatment to give directly compounds of formula (I) containing a free amino group in the meaning of X.

If the reaction product contains a protected amino group, the protecting group may optionally be cleaved from the product. Suitable cleavage reactions are given below.

Reactions in which the amino protecting group is cleaved can be carried out by conventional methods. These reactions include, for example, acid decomposition, catalytic reduction, and the like. The appropriate reaction is selected according to the type of amino protecting group. Decomposition - by acid is one of the most suitable methods and - can be used to cleave substituents such as - benzyloxycarbonyl, substituted benzyloxycarbonyl, - alkoxycarbonyl, substituted alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio-, substituted aralkylidene-, substituted-alkylidene-, substituted cycloalkylidene and the like. The acid in the above reaction is selected depending on the type of amino protecting group. Suitable acids are formic acid, trifluoroacetic acid and the like, which readily evaporate under reduced pressure. When acid decomposition is carried out in a solvent, hydrophilic organic solvents, water or mixtures thereof are sometimes used. Catalytic reduction can be used to cleave protecting-amino groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycarbonyl and the like,

A suitable catalyst is palladium, but other catalysts commonly used for catalytic reduction may also be used. Trifluoroacetyl can be cleaved by the action of water - the reaction product and the halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl - can be cleaved off by the action of a heavy metal such as copper, zinc and the like reaction product.

The amino protecting group cleavage reaction can be carried out without isolation of the reaction product from the reaction medium and without purification.

All reagents used in the various processes within the scope of the invention are commercially available or can be prepared by conventional methods well known in the art, or by methods analogous to known methods of making compounds of this type.

The precipitate formed during the reaction according to the invention is separated from the reaction mixture by methods conventionally used for this purpose and the resulting reaction. the product may be subjected to conventional purification, for example recrystallization from a suitable solvent or a mixture of these solvents.

The compounds of the present invention can be converted by methods customary for making salts from acids to their pharmaceutically acceptable, substantially non-toxic salts, for example by reaction with an alkali metal hydroxide, alkali metal bicarbonate, carbonate. alkali metal or organic base. Sodium salts are preferred. Preferably, the salt is prepared by dissolving the acid in a solvent in which the salt is insoluble and then adding a solution of the salt-forming compound or base to the resulting solution. The salt precipitates out of the reaction mixture.

Compound number,

The compounds of the invention have a high antibacterial effect and inhibit the growth of numerous microorganisms, including gram-positive and gram-negative bacteria. The minimum inhibitory concentration of some compounds of the invention in vitro against selected strains of microorganisms is illustrated by the following antibacterial assay. The assay is performed by dilution method (two-fold dilution) on agar plates. The culture of each of the soybean test strains is harvested with a wire stitch with the strypticase incubated overnight (10 ⁸ viable cells per ml). KutUra is placed on HI-agar containing agarated concentrations of antibiotics. The minimum inhibitory concentration is determined after incubation for 20 hours at 37 ° C in pg / ml.

The formula. Example Number

1 СНьО-г-ъ _H Q-fl-CHCONH-r · __ —NL ** (J СООЖ

(D-form) ···· 5 · (DL-form)

(D-form)

(D-form)

20.21

Example number

Compound number

5 880

Formula

с ^ о ^ Г \, снсоын ^ H _from &

COOH (D-form)

CH ₃ SO _Z NH

CHCONH-r o

COOH (D-form)

C ^SO SO _and NH

HIM

CHCONH

O

CH ₃ COOH (D-form)

C ^H H /HSO ^H

CHCONH

NH _Z

СН _Ъ COOH (D-form)

AND

CHNHCSNH

O (D-form)

CHCONH ^NH ZO

COOH (D-form)

Ьч

Minimum inhibitory concentration (^ g / ml)

Strain Compound number

WHAT

U0

what

iflseea cc o o oo V) CO b * r4 or CD CD CO

U0. CO CM IO in CD ri CM Ю r4 CM

ID Ю CM ^ CM ^ ir ^ CD ”CD См” UO тН СЧ ю ID ΙΌ СМ CM Ш CM what ”co” cm ”r4 гЧ

CO CD ΙΩ Ш тН Ю CM ~ CM what ”ri what” what ”

CD 00 CO CO 1П tS r4 ~ т-Ч ri O CO ”CO”

Ю CO 00 Ю

CM гЧ rH ^ см what ”what” what ”what” i ·

1.95880

For therapeutic administration, the cephalosporin compounds of the invention are used in the form of pharmaceutical compositions comprising the compounds of the invention in admixture with a pharmaceutical. suitable organic or inorganic. solid or liquid excipients suitable for oral or oral administration. parenteral administration. The pharmaceutical preparations may be in solid form, such as capsules, tablets or dragees, or in liquid form, as solutions. suspension or emulsion. If desired, adjuvants, stabilizing agents, wetting agents may be added to the above compositions. emulsifiers, pH buffering agents and other commonly used additives.

Although the dosage also depends on the age and condition of the patient, it has been shown to be useful for treating diseases caused by bacterial infection. an effective average unit dose of the compounds of the invention of about 100, 250 and 500 mg. In general, an amount ranging from 10 to 10 can be administered. about 1000 mg or even more.

The following examples serve to illustrate the invention in more detail, but do not limit the scope of the invention in any way. . ·

Example · 1

DN - tert -Butoxycarbonyl-2- (3-methoxy-4-hydroxyphenyl) glycine (2.97 g) triethylamine (1.01 g) was added to methylene chloride (50 mL) and the mixture was cooled to -10 to -15 degrees Methylene chloride solution (5 ml) containing pivaloyl chloride (1.17 g) was added to the mixture with stirring, and the resulting mixture was stirred at 0-10 ° C for 2 hours, then the mixture was cooled to -20 ° C and added. For example, a single methylene chloride solution (30 ml) containing 2,2,2-trichloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride (3.34 g) and 2,6- lutidine (1.94 g) The mixture was then stirred at -10 ° C for 1.5 hours and then at room temperature for one hour After removing the solvent from the reaction mixture under reduced pressure, ethyl acetate (80 mL) and 5% The sulfuric acid (80 ml) was shaken and the ethyl acetate layer was separated, washed first with 5% sulfuric acid (40 ml), an aqueous saturated sodium chloride solution, with saturated aqueous sodium bicarbonate solution (40 ml) and finally once with aqueous saturated sodium chloride solution, dried over magnesium sulphate and treated with activated carbon. The solvent is evaporated from the solution under reduced pressure and the residue. diisopropyl ether was treated to a powder (4.86 g). The powder was purified by silica column chromatography. kagel (120 g) [eluent: benzene: acer ton =. 5: 1]. There was obtained 2,2,2-richloroethyl 7- [DN-tert-butoxycarbonyl-2- (3-methoxy-4-hydroxyphenyl) glycinamido] -3-methyl-3 -cephem-4-carboxylate (3). 58 g).

IC.

in nujol (cm-1J):

NMR δ CDCl 3 (PPm.) ··:. ·

1.41 (9H, s),

2.17 (3Ή, s),

3.30 '(2H, AB-q);

3.83 (3 H, s),

4.88 (2H, ab-q);

4.94 (1H, d, J = 4 Hz),

5.15 (1H, d, J = 6 Hz),

5.6-6.0 (3 H, m),

6.8-7.1 (3 H, m).

2,2,2-Tris-1: η 1-7- [D-N4e tert-butoxycarbonyl-2- (3-methoxy-4-hydroxy-phenyl) glycinamido] -S-methyl-5-methyl-4- carboxylate (3.25 g), obtained in a similar manner to. according to Example 1, zinc dust (3 g) and glacial acetic acid (3 ml) were added to dimethylformamide (30 ml), and the resulting mixture was stirred under ice-cooling for 1 hour. The mixture was shaken vigorously, then the ethyl acetate layer was separated, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. There was thus obtained carbonyl-2- (3-methoxy-4-hydroxyphenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (2.31 g).

IC.

υ. Nujol (cm ^-1 ):

3350,1780,170.0,1518.

NMR ·

DMSO-d6 (PPm):

1.38 (9H, s);

1.97 (3 H, s),

3.40 (2H, AB-q).

3.78 (3 H, s),

4.99 (1H, d, J = 4.5Hz);

5.21 (1H, d, J = 8 Hz),

5.62. (IH, dd, J = 4Hz, 7Hz).

6.6-7.2 (4 H, m) ,.

8.93 (1H, d, J = 0Hz).

EXAMPLE 3 6- [N-N-tert-Butoxycarbonyl-2- (3-methoxy, -4-hydroxyphenyl) glycinamido] -4- [3- (3-cephem-4-carboxylic acid) (2.43 g), m.p. was obtained in a manner similar to that of Examples 1 and 2, added to formic acid (20 ml) and stirred at room temperature for 3 hours. Acid. ant. se

The 19S880 was removed from the reaction mixture under reduced pressure, the residue was treated with ether to a powder and 5% aqueous acetonitrile (20 mL) was added. The resulting mixture was stirred for 30 minutes and then filtered. A light yellow powder is obtained. The powder was washed successively with acetonitrile and ether and dried. There was thus obtained 7- [D-2- (3-methoxy-4-hydroxyphenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid, m.p. 183-185 ° C (dec.).

IC. 'in nujol (cm ^-1 ):

2500, 3500, 1775, 1697, 1570, 1626.

NMR <5 D 2 O 4 -DC1 (PPm):

2.10 (3 H, s),

3.36 (2H, AB-q);

3.93 (3 H, s),

5.08 (1H, d, J = 4 Hz),

5.32 (1H, s), 5.70 (1H, d, J = 4Hz),

7.0-7.3 (3 H, m).

tJV λ рнм fosioreBan Buffer 237.3 ПШ, E = 274 λ max ' ^{4 f0Sf0l} ' ^{e: nan vý out} 266 nm, E = 193 Example 4

DL-N-tert-Butoxycarbonyl-2- (3-methoxy-4-hydroxyphenyl) glycine. (2.97 g) and triethylamine (1.11 g) were added to tetrahydrofuran (25 mL) and the mixture was cooled to 0 ° C. To this mixture was added tetrahydrofuran solution (5 mL) containing pivaloyl chloride (1.36 g), and the resulting mixture was stirred at 0 ° C for 10 minutes. A solution of 7-amino-3-methyl-3-cephem-4-carboxylic acid (2.14 g) and trlethylamine (1.01 g) in 50% aqueous acetone (30 mL) was added in one portion at 0 ° C. ) and the resulting mixture was stirred at room temperature for 1.5 hours. The organic solvent was removed under reduced pressure, and an aqueous saturated solution of sodium bicarbonate (30 mL) and ethyl acetate (50 mL) were added to the residue. The aqueous layer was adjusted to pH 2 with 10% aqueous hydrochloric acid and then the ethyl acetate layer was removed. The aqueous layer was extracted twice with ethyl acetate (50 mL each) and the extract was combined with the ethyl acetate solution obtained previously. The solution was dried over magnesium sulfate and the ethyl acetate was removed under reduced pressure. The residue is treated with dilsopropyl ether to give a powder. There was obtained [DL-N-tert-butoxycarbonyl-2- (3-methoxy-4-hydroxyphenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (3 g), m.p. 127-130 ° C ( decomposition).

IR i> nujol (cm ^-1 ):

3350, 2650, 1770, 1718, 1695, 1680, 1518, 1275, 1250, 1160, 1055, 1032, 860,782,720. .

Example 5

7- [DL7N-tert-Butoxycarbonyl-2- (3-methoxy-4-hydroxyphenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (2.0 g) obtained similar to Example 4 was dissolved in formic acid (20 ml) and the solution was stirred at 40 ° C for 4 hours. The formic acid was removed from the solution under reduced pressure and the residue was converted to a powder with acetonitrile. The powder is added to a 10% aqueous acetone / tril with a glass rod to powder, which is then filtered off. The powder thus obtained was washed successively with acetonitrile and ether and then dried. 7- [DL-2- (3-Methoxy-4-hydroxyphenyl) glycinamido] -3- was obtained. methyl 3-cephem-4-carboxylic acid (1.10 g), m.p. 193-197 ° C (dec.).

IR in nujol (cm ^-1 ):

1760, 1690

UV

X pH 0.4 phosphate buffer max (nm) 237, E = 275 pH 0.4 phosphate buffer max!

(nm) 265.5, E = 189

Example 6

DN-tert-Butoxycarbonyl-2- (3-nitro-4-hydroxyphenyl) glycine (5 g) was dissolved in absolute methylene chloride (100 mL) and 2,6-lutidine (1.9 g) was added and the mixture was cooled to -10 to -15 [deg.] C. Then, pivaloyl chloride (1.9 g) is added dropwise to the mixture, and the resulting mixture is stirred at -15 [deg.] C. for 3 hours. N, O-bis (trimethylsilyl) acetamide (10 mL) was added to a suspension of 7-amino-3-methyl-3-cephem-4-carboxylic acid (3.45 g) in methylene chloride (50 mL). The resulting mixture was stirred at -10 to -15 ° C for 3 hours and then the solvent was evaporated under reduced pressure.

Ethyl acetate and 5% sulfuric acid were added to the residue, and the ethyl acetate layer was separated.

Aqueous sodium bicarbonate solution was added to the ethyl acetate extract and the aqueous layer was separated. The aqueous solution was acidified

195880 sulfuric acid and reextracted with ethyl acetate. The ethyl acetate extract was washed first with water and then with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure from the solution gave a powdery product (6.0 g) which was 7- [DN-tert-butoxycarbonyl-2- (3-nitro-4-hydroxyphenyl) glycinamido) -3-methyl-3. ceph em-4-carboxylic acid, m.p. 150-155 C. ⁶ (with decomposition). IC in nujol (cm * ¹ ):

1755, 1700, 1690, 1670.

NMR δ DMSO-d 6 (PPm):

1.40 (9 H, s),

2.03 (3 H, s),

3.38 (2H, broad s),

4.99 (1H, d, J = 4.5 Hz),. .

5.32 (1H, d, J = 8.5Hz),

5.60 (H, dd, J = 4.5, 8.0Hz),

7.10 (1H, d J = 8Hz),

7.2-7.55 (1H, m),

7.65 (1H, dd, J = 2.0, 8.0Hz),

8.05 (1 H, d, J = 2Hz),

9.13 (1H, d, J = 8Hz).

Example 7

7- [DN-tert-Butoxycarbonyl] -2- (3-nitro-4-hydroxyphenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (5 g) obtained similar to Example 6, was Dissolve in formic acid (40 mL) and stir at room temperature for 4.5 hours. The solvent was removed from the solution under reduced pressure and the residue was treated with ether to a powder and filtered off. The powder thus obtained was washed successively with ether, ethyl acetate and acetonitrile and then suspended in acetonitrile (40 ml). Water (4 ml) was added dropwise with stirring to the suspension, and the mixture was stirred overnight at room temperature. The crystals which precipitate are filtered off, washed with acetonitrile and dried. There was thus obtained 7- (β-2- (3-nitro-4-hydroxyphenyl) glycinamido) -3-methyl-3-acetem-4-carboxylic acid (2.64 g), m.p. 170-172 ° C (dec.).

IC in nujol (cm ^-1 ):

3200, 1763, 1702, 1628, 1546.

NMR <5 D 2 O + DCI (PPm):

2.15 (3H, s).

3.4 (2H, d, J = 4 Hz),

5.13 (ΪΗ, d, I = 4.5Hz)

5.54 (1H, s),

5.70 (1H, d, J = 4.5Hz),

7.38 (1 H, d, J = 8.5 Hz),

7.91 (1H, dd, J = 2.5, 8.5Hz),

8.45 (1H, d, J = 2.5Hz).

UV and pH 6.4 phosphoregnane buffer ^to max (nm) 242, E = 434

Examples

To analyze DN-tert-butoxycarbonyl-2- (3-nitro-4-hydroxyphenyl) glycine (Ig) in methylene chloride (20 ml), add 2,6-lutidine (0.38 g) and cool the mixture to -15 to —20 ° C. Methylene chloride solution (1 mL) of pivaloyl chloride (385 mg) was then added dropwise and the resulting mixture was stirred at -20 ° C for 2 hours. To the resulting mixture was added a solution at -20 ° C in one portion, which was obtained by adding 2,6-lutidine (0.64 g) to a suspension of 2,2,2-trichloroethyl-7-amino-3-methyl p-toluenesulfonate. -3-cephem-4 * carboxylate.

(1.91 g) in methylene chloride (20 mL) under ice-cooling and stirring, the resulting mixture was stirred for 15 minutes. The resulting mixture was stirred at -20 ° C for 3.5 hours and then the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the residue, and insoluble materials were filtered off. The filtrate was washed with ethyl acetate; There was obtained 2,2,2-trichloroethyl 7- [DN-tert-butoxycarbonyl-2- (3-nitro-4-hydroxyphenyl) glycinainido] -3-methyl-3-cephem-4-carboxylate (0.27 g) . After filtering off the product, the ethyl acetate layer and the ethyl acetate washes were combined, washed successively with 5% hydrochloric acid, aqueous saturated sodium bicarbonate solution and water, and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a gelatine residue which, after washing with ether, gave the same product (1.09 g). The total yield is

1,36 g.

IC in nujol (cm ^-1 ):

3320, 3270, 1775, 1735, 1685, 1650, 1630. NMR

DMSO-d6 (PPm):

1.40 (9 H, s),

2.10 (3 H, s),

3.49 (2H, broad s),

5.05 (2H, AB-q);

5.07 (1H, d, J = 4.5Hz),

5.35 (1H, d, J = 8Hzj, ´ 5.69 (1H, dd, J = 4.5Hz, 8.0Hz),

7.10 (1 H, d, 8.5Hz),

7.2-7.5 (1H, m), 7.63 (1H, dd, J = 2.0, 8.5Hz) * 8.04 (1H, d, J = 2H-Z), 9.2 (1H, d, J = 8 Hz).

Example 1 a d 9

To a suspension of 2,2,2-trichldimethyl-7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride (3820 mg) in half-methylene chloride (50 ml) was added dropwise triethylamine (810 mg) and N, N-dimethylaniline (245 mg) with ice cooling and stirring. The resulting mixture is stirred at room temperature for 30 minutes. Separately, N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine (3440 mg), triethylamine (1010 mg) and N, N-dimethylbenzylamine (4 drops) were added to absolute methylene chloride (50 mL) and the mixture was stirred while cooling in a dry ice bath and a solution of ethyl chloroformate (1085 milligrams) in absolute methylene chloride (25 ml) was added dropwise to the mixture. The addition was carried out at -25 to -30 ° C for 10 minutes. The resulting mixture was stirred at the same temperature for 15 minutes. The first mixture obtained above, precooled to -15 ° C, is added in one portion to the mixture thus formed. The resulting mixture was stirred at -25 to 30 ° C for 4 hours and then washed sequentially with water, 3% hydrochloric acid and water. The organic layer was separated, washed with 3% sodium bicarbonate solution, then with water and finally dried. The methylene chloride was removed under reduced pressure and the residue was dissolved in ethyl acetate (10 mL). Ether was added to the solution and the precipitated crystals were filtered off. It is obtained

2,2,2-trichloroethyl-7- [DN-butoxycarbonyl-2- (3-phenyl mesylaminof) glycinamldo] -3-methyl-3-cephem-4-carboxylate (4195 mg), mp 204 2Ů5 G ^O ( decomposition).

The above 2 * 2,2-trichloroethyl 7 - [[N-tert-butoxycarbonyl-24 3-mesylaminophenyl) glycinamido] -3-methyl-3-cephen-4-carboxylate (3985 mg) was dissolved in dimethylformamide (3985 mg). 17 ml). Acetic acid (5.0 ml) and zinc dust (3985 mg) were added to the solution under ice-cooling and stirring, and the mixture was stirred at the same temperature for 2 hours. After insoluble product was filtered off, the filtrate was washed with diethylformamide (3 ml). The washings and the filtrate obtained above were combined and added to 5% hydrochloric acid (100 ml) under ice-cooling, water (50 ml) was added to the resulting mixture, and the mixture was extracted three times with ethyl acetate (50 ml each). The aqueous layer was acidified with hydrochloric acid and then re-extracted with ethyl acetate, the extract was washed with water and dried, and the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (10 ml). The precipitate is allowed to stand for one hour at room temperature and then ether is added thereto. sy ^{láminofenýl)} glycinamido] -3-methyl-3-cephem-4-carboxylic acid (2687 mg) melting at 187 ažÍ89 ° C (dec).

Example 10

To a suspension of 2,2,2-trichloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate (26.8 g) in dry methylene chloride (500 mL) was added triethylamine solution (7 g) in succession with ice-cooling. ) in dry methylene chloride (25 ml) and then a solution of 2,6-lutidine (2.14 g) in methylene chloride (25 ml). Next, N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine (26.0 g) was added to the resulting mixture, followed by dicyclohexylcarbodiimide (15 g) and stirred under ice-cooling for 1 hour. 5 hours. The insoluble product was filtered off and the filtrate was washed four times with ice-cold 5% hydrochloric acid (100 ml), then once with water, 3 times with 10% aqueous sodium bicarbonate solution and once with aqueous saturated sodium chloride solution. After drying with lithium sulfate, the solution was treated with charcoal and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and allowed to stand overnight at room temperature, and the crystals which precipitated were collected by filtration to give colorless plates of 2,2,2-trichloroethyl-7- [DN-tert-butoxycarbonyl-2- ( 3-Mesylaminophenyl) glycinamido] -3-cephem-4-carboxylate (31.3 g), m.p. 189-191 ° C (dec.).

The 2,2,2-trichloroethyl 7- [D-tert-butoxycarbonyl-2- (3-mesylamino-phenyl) -glycamido] -3-methyl-3-cephem-4-carboxylate (12.01 g) obtained above was dissolved in dimethylformamide (40 g). Glacial acetic acid (15 ml) and zinc dust (12 g) were added to the solution under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, after which the insoluble product was filtered off and washed with ethyl acetate. The lyes were poured into 3% hydrochloric acid (300 mL) under ice-cooling, extracted three times with ethyl acetate (150 mL), washed with water, and then re-extracted three times with 5% aqueous sodium bicarbonate (150 mL). The reaction mixture was washed with ethyl acetate and adjusted to pH 2 with 10% hydrochloric acid, extracted three times with ethyl acetate (150 mL), washed with water, and dried (MgSO4). under reduced pressure. The crystals which formed was: washed with ethyl acetate and then ether. To give 7- [DN-butoxycarbonyl-2- (3-mesylamino-. Phenyl) -glycinamido] -3-methyl-3-cephem-4-carboxylic acid (8.38 g), mp 188 to 189 ^and C ( decomposition).

: 17.

IC, · nujol (from? ¹ ): '

3330, 3'290, - 3240, 1769, 1720, 1690,

1668, 1524, 1308. .1220, 1146, 912, -.890, 772.

NMR

á.DMSCHdíJ. (.ppm) :.

1.40 (9 H, s),

2.00 (3 H, -s),

2.99 (3H, - s j,

3.37 (2H, broad s),

4.96 (1H, -d, J = 4.4Hz),

5.30 (1H, broad d, J = 8Hz), 5.63 (1H, d, d, J = 4Hz, 7Hz),

6.90-7.50 (4 H, m).

The above 7- (DN-tert-butoxycarbonyl-2- (3-butylamino) glycinamido) -3-methyl-3-cephem-4-carboxylic acid (8.28 g) was added under cooling. The reaction mixture was stirred at room temperature for 1.5 hours, and the formic acid was removed at 35 ° C under reduced pressure and the residue dissolved in water. 5% hydrochloric acid (.30 ml). The solution is washed with ethyl acetate (20 ml), treated with activated charcoal, and set to 3 with its pH value. The crystals which precipitate - - - are filtered off, washed with water - and dried to give 7 - [[D- (3-mesylaminophenyl) glycinamido] -3-methyl]. ethyl-3-cephem-4'-carboxylic acid (6.18 g), m.p. &gt; 199-199.5 ° C (decomposition).

[Id Id ²² = 4-131 ° - (0.1 N — HCl, - C = 1) in pH 8) 4 phosphorocyanate buffer λ - - max.

(263.5 -NM -E - = 172) λ -Ph - 8; 4 - - fosforeCitanový - buffer ^л max (228 nm, E = ± 299)

NMR δ D2G4-DC1 (PPm):

2.08 - (3H, s),

3.19 (3H, s);

3.21, 3.44 (2H, AB-q, J = 18 Hz),

5.04 (1H, d, J = 5Hz)

5.37- (1H, S);

5.67 (1 H, d, J = 5 Hz),

7.477.67 (4H, - m).

IR in nujol (cm -1):

3610, 3510, -3330, 1750, 1750,

1600, 1526, 1380, 1366, 1328

Example - 11.

A solution of ethyl chloroformate (1.32 g) in dry methylene chloride (20 ml) was cooled to -10 ° C. To this solution was added dropwise a solution of N-tert-butoxycarbonyl-2- (3-ethanesulfonylamidophenyl) -D-glyeine (4.4 g) - a-tritthylamine (1.22 g) over 10 minutes. methyl chloride (20 ml) -? - N, N-dimethylbenzylamine (.2 drops) and then stirred at room temperature for 1 hour. Separately, 2,2,2-trlloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate (3.82 g), tritthylamine (0.9 g) and N, O-bis [(trimethylsilyl) acetamide (0.12 g) was dissolved - in absolute methylene chloride (40 ml). The resulting solution was added dropwise to the above mixture at -15 ° C over 10 minutes. The solution thus formed was stirred at the same temperature for 2 hours and then washed twice with 2% hydrochloric acid, aqueous sodium bicarbonate solution and aqueous saturated sodium chloride solution and finally dried with magnesium sulfate. The solvent was removed from the solution under reduced pressure, and the residue was converted to a powder with a small amount of ethanol. Colorless crystals (4.2 g) of 2,2,2-trichiorethyl-7- [DN-tert. butoxycarbonyl-2- (4-ethanesulfonamidophenyl telycinamido) -3-methyl-3-cell carboxylate, m.p. 117 DEG. IC i> - nujol, (cm)):

3400, 3230, - 1762, 1735, 1690.

NMR.

δ CDCI3-.

(PPm):

1.28 (3H, t, J = -7Hz).

1.38 (9H, s);

2.16 (3H, s)),

2.75, 3.50 (4H, m),

4.82, 4.95 (2H, AB-q, J = 12 Hz),

4.95 (1 H, d, J = 5 Hz),

5.24 (1H, d, J = 6 Hz);

5.81 (1Ή, d, d, - J = 5Hz, J = 8Hz),

7.25 (4 H, s).

The 2,2,2-trichloroethyl 7- [DN-tert-butoxycarbonylamino-2- (3-ethanesulfonamidophenyl) glycinamido] -3-methyl-3-cephem-4-carboxylate (4.2 g) was obtained as above. Dissolve in absolute dimethylformamide (15 ml) - and - acetic acid (45 ml). Zinc dust (3.6 g) was added to the solution under ice-cooling, and the mixture was stirred for 2 hours. The zinc dust was filtered off and the filtrate was poured into a mixture of 2% hydrochloric acid (40 ml) and ethyl acetate (40 ml) and

The 1S ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (20 mL). The ethyl acetate layer and the extract were combined, washed with 2% hydrochloric acid (20 ml) and aqueous saturated sodium chloride solution (20 ml) and dried over magnesium sulfate. The solvent was removed from the solution under reduced pressure and then the residue was washed with diisopropyl ether. There was thus obtained an oily product (3.2 g) which was 7- [D-N-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) glycinamido) -3-methyl-3-methyl-4-carboxylic acid.

IC in nujol (cm- ¹ ):

3300, 1765, 1700.

NMR δ CD 3 OD (ppm):

1.22 (3H, t, J = 7.5Hz), 2.09 (3H, s),

2.75-3.75 (4H, m),

4.96 (1H, d, J = 41.5Hz),. .

5.26 (1H, s),

5.67 (1H, -d, 1H = 4.5 Hz),

7.25 (4 H, s). _ч

A solution of the above-obtained 7- [DN-tert-butoxycarbonyl-2- (3-ethanesulfonamidophenyl) glycinamido-β-β-β-γ-4-carboxylic acid (3,1 g) in formic acid (15 ml) was stirred at room temperature for 2 hours. Formic acid is removed from the solution under reduced pressure at room temperature. The residue is taken up in ether and filtered. The resulting powder was added to acetonitrile (10% aqueous - solution, 20 µL), the mixture was stirred under ice-cooling for 1 hour, and the white crystals that formed were filtered off. 1.7 g of 7 - [. D-2- (3-ethanesulfonamidophenyl) glycinamido] O-O-methyl-O-cephem-4-carboxylic acid of melting point 179 DEG-182 DEG C. (decomposition) are obtained.

IC in nujol (cm-1):

1770, 1695, 1600.

NMR · $ D 2 O + NaHCO 3 (ppm):

1.29 (3H, t, J = 7.5 Hz),

1.90 - (3H, s) ,.

2.75 - 3.67 - (4H, m),

4.96 (1H, d, J = 4.5 Hz),

5.25 (1H, s).

5.59 (1H, d, J = 4.5Hz)

7.34 (4 H, s).

Example - 12,

2.2.2- ΤιΉ1ίι1θΓβΜγ1-7- [DN-tert-Butyloxycarbonyl-4- (3-mesylaminophenyl) glycinamido] -3-methyl-13-cefemol-4-carboxylate (1.0 g) by adding to ice-cold formic acid - (20 - ml) and the mixture was stirred at room temperature for 2 hours. Formic acid is removed from the reaction mixture under reduced pressure and water is added to the oily residue. The pH of the mixture is adjusted to 8-9 with an aqueous saturated sodium bicarbonate solution under ice-cooling. The crystals which precipitate are filtered off, washed with water and dried over phosphorus pentoxide. There was obtained 2, -, 2-trichloroethyl-7- [D-2- (3-esylaminophenyl) glycamido] -1,3-methyl-3-methyl-14-. carboxylate (0.78 g, m.p. 107 DEG-110 DEG C. (decomposition)).

IC.

v. nujol (cm-1): '

3350, 1785, - 1740, 1685,

Příložl3.

To a suspension of 2,2,2-tri-chloroethyl-7-amino-3-methyl-3 -cephem-14-carboxylate hydrochloride (5.9 g) in methylene chloride (100 mL) - was added a solution of triethylamine (1.55 g) in methylene chloride ( 10 ml) ^; and a solution (0.16 g) in methylene chloride (10 mL). K - the resulting solution under ice cooling their added N-tert.butoxycarbonyl-bónyll - (4lmesylaminofenyl) -D-glycine (5.8 - ^G), and - dicyclohexylcarbodiimide (3.3 g). The mixture was stirred at the same temperature for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and to the residue was added - 71806 ((200 mL). The mixture was washed with 5% hydrochloric acid, water, aqueous saturated sodium bicarbonate solution and finally water, dried and then concentrated. There was obtained - 2,2,2-richloromethyl-4- [DN-tert-butoxycarbonyl-1- (4-mesylaminophenyl) glycinamido] -3-ethyl-3-cephen-4-carboxylate (10.83 g); mp 129-136 ° C (dec.).

IC nujol (cm ^-1): 3290, 1770, 1680th

NMR δ - CDCl 3 (ppm):

1.43 (s, 9H), 2.20 (s, 3H),

3.32 (AB-q, 2H).

5.8-5.0 (m, 3H).

5.2 - 6.0 (m, 3H),

7.0-7.7- (m, -4H), 7.9 (broad s, 1H).

5 21

Acetic acid (12.5 ml) and zinc dust (10 g) were added to a solution of 2,2,2-trichloro [1- [1- (4-mesylaminophenyl) glycinamido] -3-methyl Of 3-cephem-4-carboxylate (10 g) in dimethylformamide (33 mL) under ice-cooling. The resulting mixture was stirred at the same temperature for an hour and then filtered. The filtrate was added to a mixture of 5% hydrochloric acid (100 ml), ice water (50 ml) and ethyl acetate (100 ml), and the resulting mixture was extracted three times with ethyl acetate (100 ml). The extract was re-extracted twice with 5% aqueous. sodium bicarbonate solution (100 mL). The aqueous layer was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and then the solvent was evaporated under reduced pressure. There was thus obtained 7- [D-N-tert-butoxycarbonyl-2- (4-mesylaminophenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (7.8 g), m.p. 180 DEG-200 DEG C. (dec.).

IC. 'in nujol (cm- ¹ ):

3300, 1770, 1710 (inflection), 1695, 1880.

NMR - &lt; 1 &gt; S DMSO-d6 (ppm):

1.40 (s, 9H), 2.02 (s, 3H),

2.95 (s, 3F1),

3.2-3.7 (m, 2H), 4.97 (d, 1H),

5.2-5.8 (m, 2H), 7.30 (AB-q, 4H).

: 7 - (: DN-tert-Butoxycarbonyl-2- (4-mesylaminophenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (4.6 g) was added to formic acid (70 ml) under ice-cooling. The resulting mixture was maintained at this temperature with stirring for 2 hours and then concentrated under reduced pressure, water was added to the residue, and the resulting aqueous mixture was washed with ethyl acetate, adjusted to pH 6 with aqueous sodium bicarbonate solution and then concentrated in half. The resulting solution was adsorbed onto a layer of adsorbent resin (Amber Lite XAD-2) (460 g), which had been previously washed with methanol and water, eluting with water and methanol, and the eluate was concentrated and the precipitated crystals were filtered off and washed. methanol to give 7- [D-2- (4-mesylaminophenyl) glyclnamido] -3-ethyl-3-cephem-4-carboxylic acid (2.1 g), m.p. 205-207 ° C (dec.).

0 .22 iC.

in nujol (cm ^-1 .):

.3175, 1760, 1670..

NMR

EID (PPm):

1.80 (3 H, s),

3.05 (3H, s).

3.15 (2H, AB-q);

4.85 (1 H, d),

5.12 (1 H, s),

5.54 (1 H, d);

7.35 (4H, AB-q).

Example 14

N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) -D-glycine (2.066 g), trlethylamine (0.606 g) N, N-dimethylbenzylamine (15 ml) was added to tetrahydrofuran (20 ml) and the mixture was cooled to —10 to -12 ^ 0. A solution of isubutyl chloroformate (0.820 g) in tetrahydrofuran (10 mL) was added dropwise at the same temperature over 2 minutes, and the resulting mixture was stirred for 30 minutes at the same temperature with stirring; Separately, 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.070 g and triethylamine (0.581 g) was added to 50% aqueous tetrahydrofuran (30 mL) under ice-cooling). The mixture thus obtained was stirred under ice-cooling for 1 hour and then at room temperature for 2 hours, and the tetrahydrofuran was removed under reduced pressure and an aqueous saturated solution of sodium bicarbonate (15 ml) and the resulting aqueous phase were added. The mixture was washed twice with ethyl acetate (10 mL) and the washings were extracted with an aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous extract was combined with the aqueous solution obtained above and ethyl acetate (30 mL) was added to the combined aqueous solution. The mixture was adjusted to pH 2 with 10% hydrochloric acid. The aqueous layer was shaken vigorously with the ethyl acetate layer and insoluble The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate (20 mL). The extract thus obtained and the ethyl acetate layer obtained above were combined and the mixture was washed with water (10 ml). The aqueous washings were extracted twice with ethyl acetate (5 ml) and the extract was combined with the ethyl acetate solution obtained above. The combined solution was washed with an aqueous saturated solution (10 mL) of sodium chloride, dried over magnesium sulfate and treated with charcoal. Evaporation of the solvent gave a pasty residue (3.47 g). The residue (3.42 g) was added to absolute ether (30 mL) and the mixture was stirred

išswo overnight at room temperature. The crystals formed are filtered off, washed with ether and dried. There was thus obtained 7- [D-N-tert-butoxycarbonyl-2- (3-mesylaminophenyl) glycinamido] -3-methyl-3-cephem-4-carboxylic acid (2.326 g), m.p. 174 DEG C. (dec.).

[.alpha.] D = * 57 DEG (C = 1, methanol)

Example 15

N-tert-Butoxycarbonyl-2- (3-mesylaminophenyl-D-glycine (3.44 g) and triethylamine (1.01 g) were dissolved in absolute methylene chloride (25 mL) and added dropwise to a solution of isobutyl chloroformate ( 1.36 g) in absolute methylene chloride (35 mL) at -10 to -15 ° C for 5 minutes and stirred at the same temperature for 15 minutes. Separately, N, O-bis (trimethylsilyl) acetamide (3, 5 g) dissolved in a suspension of 7-amino-3- (5-methyl-1,3,4-thiadlazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (3; 44 g) in absolute methylene chloride (30 g); The mixture thus obtained was added dropwise at -15 ° C to the above mixed anhydride solution and stirred for 1.5 hours at the same temperature and then for 3 hours at 10 ° C. The resulting mixture was washed with 5% hydrochloric acid and water. The oil-yellow residue was purified by column chromatography on silica gel (eluent: chloroform) to give an oil-yellow solid. the product consisting of 7- [DN-tert-butoxycarbonyl-2- (3-mesylaminophenyl) glycinamido] -3- (5-methyl-1,3,4-thladlazol-2-yl) thiomethyl-3-cephem -4 * carboxylic acid (3.8 g).

Film (cm ^-1 ):

3300 _f 1780, 1725, 1865, 1670.

The thus obtained 7- [D-N-tert-butoxycarbonyl-2- (3'-methylaminophenyl) glycamido] -3- (5-methyl-1,3,4-thadiazol-2-yl) thiomethyl-3-cephem- 4-Carboxylic acid (2.23 g) was dissolved in formic acid (35 ml) and stirred at 18-20 ° C for 4 hours. The resulting mixture was concentrated under reduced pressure, the product was powdered with ethyl acetate and then filtered off. There was thus obtained 7- [D-2- (3-mesylaminophenyl) glycinamido) -3- (5-methyl-1,3,4-thiodiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (1). , 95 g). The product was added to acetone (30 mL) and the mixture was stirred at 15-20 ° C for one hour, then allowed to stand and the supernatant solution decanted. Acetone (30 µL) was added to the residue, and the mixture was stirred at 15-20 ° C for 3 hours. The precipitate was filtered off, washed with acetone and then with ether. A pale yellow powder is obtained which is a pure product.

IR in nu jol (cm ¹ ):

1765, 1690,1605.

NMR

IJO-DC1 (ppm):

2.97 '(3H, s),

3.01 (3H, s);

3.38, 3.78 (2H, AB-q, J = 18 Hz),

4.26, 4.47 (2H, AB-q, J == 14HZ),

5.12 (1H, d, J = 4Hz),

5.35 (1 H, s),

5.71 (1H, d, J 4Hz).

Example 16

(d)

Dicyclohexylcarbodime (2.0 g) was added to a solution of N-tert-butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycine (5.2 g), hydrochloride 2,2,2 with ice-cooling and stirring. -trichloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate (5.52 g), and

2,6-lutidine (1.74 g) in absolute methylene chloride (18'0 .mu.l). The resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours. The insoluble product is filtered off and the filtrate is evaporated under reduced pressure. Ethyl acetate was added to the residue, and the pH of the solution was adjusted to pH 2 with phosphoric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The ethyl acetate was evaporated from the solution under reduced pressure and isopropyl ether was added to the residue. 2,2,2-Trichloroethyl-7- [N-tert-butoxycarbonyl-2- (3-methyl-4-hydroxy-phenyl) -D-glycinamido] -3-methyl-3-cephem is obtained. -4-carboxylate (6.75 g). The product is recrystallized from ethyl acetate. The purified product obtained has a melting point of 185 DEG-188.5 DEG C. (decomposition).

EW in cm (cm ¹ ):

1766.

NMR δ (Cs CsžCO (ppm):

1.40 (9 H, s),

2.16 (3 H, s),

3.01 (3 H, s),

3.34, 3.59 (2H, AB-q, JHs);

5.87, 5.07 (2H, AB-q, J 12.5Hz),

5.07 (1H, d, J * 4.5HZ),

5.35 (1 H, d, J = 8Hz),

5.80 (1H, d, d, J = 4.5Hz, 8Hz),

6.3-6.5 (1 H, m),

6.90 (1H, d, Js = 8Hz),

25ДЙО 25

7.20 (1H, d, d, J = 2Hz, 8Hz :),

7.5.2 (1H, d, J = 2HZ), 8.0-8.3 (2H, m).

(2)

Acetic acid (3.5 ml) and zinc dust (2.6 g) were added under ice-cooling to a solution of 2,2,2-trlchloroethyl-7- [N-tert-butoxycarbonyl-2- (3-mesylamino-4)]. (hydroxyphenyl) -D-glycinamido] -3-methyl-3-cephem-4-carboxylate (3.0 g) in dimethylformamide (9 ml). The mixture was kept at the same temperature with stirring for 40 minutes. After completion of the reaction, the zinc dust is filtered off and washed with a small amount of dimethylformamide. The filtrate and washings were combined and ethyl acetate was added. and dilute phosphoric acid. The ethyl acetate layer was separated. The extract was washed with water and extracted with aqueous sodium bicarbonate. The aqueous solution was acidified with ¹ HCI and then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was washed with ether; A powder-yellow product (1.58 g) is obtained, which consists of 7- [N-tert-butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycinamido] -3-methyl-3-cec. eine-4-carboxylic acid.

IC in mJ (cm ^-1 ):

1765

NMR

D2O-hNaHCO3 (ppm) :.

1.40 OH, s);

1.90 (3 H, s),

3.05 (3H, s).

3.00, 3.39 (2H, AB-q, J = 18 Hz),

4.90 (1 H, d, J = 4.5 Hz),

5.08 (1 H, s),

5.52 (1H, d, J = 4.5Hz)

6.8-7.4 (3H, D 1).

(3)

A solution of 7- [N-tert-butoxycarbonyl-2- (3-mesylamino-4-hydroxyphenyl) -D-glycinamide] -3-methyl-3-cephem-4-carboxylic acid (1.45 g) in formic acid ( 6 ml) was stirred at 40 ° C for 1.5 hours. After completion of the reaction, acetic acid was removed under reduced pressure and acetonitrile (30 ml) was added to the residue with stirring, the powder was filtered off and washed first with acetonitrile and then with ether. There was thus obtained 7- [2- (3-mesylamino-4-hydroxyphenyl) -D-glycinamido] -3-methyl-3-cephen-4-carboxylic acid (1.13 g), m.p. 186-192 ° C (dec.). ).

i.c.

in Nujol (cm ^-1 ): 1760 .. '

NMR δ D 2 Q + DC 1 or (PPm):

2.12 (3H, s); 3.20 (3H, s);

3. 25, 3.50 (2H, AB-q, J = 18 Hz),

5.09 · (1H, d J = 4.5Hz),

5.33 (1H, sj,

5.66 (1H, d, J = 4.5Hz).

7.15 (1H, d, J = 8Hz).

7.40 (1 H, d, d, J = 2Hz, 8Hz),

7.53 (1 H, d, J = 2 Hz).

Example 1 a d 1 7

A solution of triethylamine (140 mg) in methylene chloride (5 mL) and 2,6-lutidine (15 mg) was added to a solution of 2,2,2-trichloroethyl-7-amino-3-methyl-3-cephem-4- carbpxylate (540 mg) in dry methylene chloride (10 mL) under ice-cooling. Methylene chloride solution (5 ml) containing N-tert-butoxycarbonyl-2- (3-ethylamiriosulfonamidophenyl) -D-glycine (530 mg) was then added to the mixture with stirring and ice-cooling. N, N‘-Dicyclohexylcarbodiimide (320 mg) was then added and the resulting mixture was stirred at room temperature for 3 hours. The insoluble product was filtered from the resulting mixture and washed with methylene chloride. The filtrate and washings were combined and concentrated under reduced pressure. Ethyl acetate was added to the residue and the insoluble product was filtered off. The ethyl acetate layer was washed with cold 5% hydrochloric acid, water, aqueous saturated sodium bicarbonate solution and then aqueous saturated sodium chloride solution and finally dried. Ethyl acetate was added to the solution and the insoluble product was filtered off. The solution was then concentrated under reduced pressure. An amorphous product (1.07 g) is obtained, which is 2,2,2-trichloroethyl-7- [N-tert-butoxycarbonyl-2- (3-ethyl & minosulfonamidophenyl) -D-glycinamido] -3-methyl-3- cephem-4-carboxylate, m.p. 70-73 ° C (dec.).

N in nujol (cm ^-1 ): 3290, 1770, 1680.

(2)

Acetic acid (1.2 ml) and zinc dust (0.96 g) were added to a solution of 2,2,2-trichloroethyl-7- [N-tert-butoxycarbonyl-2- (3-ethylaminosulfonamido) - Of 3-cephem-4-carboxylate (0.94 g) in dimethylformamide (5 mL). The mixture was maintained at the same temperature under stirring for one hour. After completion of the reaction, the zinc dust is filtered off, washed. 5 β · 8 O ethyl acetate and washes were combined with the filtrate.

The mixture was poured into cold. 5% hydrochloric acid (20 ml) and extracted. twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and reextracted with a 5% aqueous solution of sodium bicarbonate. The aqueous layer was separated, adjusted to pH 1-2 with 10% hydrochloric acid, and extracted. twice with ethyl acetate. The extract was washed with a saturated aqueous solution. sodium chloride, dried and concentrated under reduced pressure to an amorphous product (0.68 g), which is 7- [N-tert-butoxycarbonyl-2- (3-ethylaminosulfonamidophenyl) -D-glyclnamido] -3-methyl-3- Cephem-4-carboxylic acid, m.p. 122-128 ° C (dec.).

IC in nujol (cm ^_1): 3300, 1765, 1690

NMR δ DK) + NaHCO 3 (pp ^m) :

1.03 (3 H, t),

1.40 (9H, s); 1.93 (3H, s);

2.6-3.5 (4H, m, 5.0 (1H, d),

5.30 (1H, s);

5.60 (1 H, d),

7.30 (4 H, m).

(3) A mixture of 7- [N-tert-butoxycarbonyl-2- (3-ethylaminosulfonamidophenyl) -D-glyclamido] -3-methyl-3-cephem-4-carboxylic acid (590 mg) in formic acid (8 ml) was added. Stir at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. Ethyl acetate was added to the solution and the mixture was shaken. The aqueous layer was separated, concentrated, and the pH of the residue was adjusted to 5 with 5% aqueous solution of the free hydroxide then the product was adsorbed onto an adsorbent resin (XAD-2, manufactured by Rohm and Haas Co). The resin was washed with water and eluted with methanof. The methanolic eluate was concentrated under reduced pressure and the residue was washed with acetonitrile. 7- [2- (3-ethylaminosulfonamidophenyl) -D-glycinamido] -3-methyl-3-methyl-4-carboxylic acid is obtained. (350 mg), m.p. 162-166 ° C.

ID. ' in nujol (cm -1) 3200, 1760, 1690. ..

NMR • .delta. D2O '(ppm):

1.03 (3H, t).

3.03 22H, q).

3.0, 3.45 (2H, d, d, J = 19 Hz),

4.95 (1 H, d),

5.27 (1H, broad s),

5.61 (1 H, d),

7.30 (4 H, m).

Example 18 (1)

To a suspension of 2,2,2-trifluoromethyl-7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride (3.61 g). in methylene chloride. (50 mL) add triethylamine (0.95 g) at 5 ° C at once. To this was added N-tert-butoxycarbonyl-2- [3- (3-methylureido) phenyl] -D-glycine (3.37 g) followed by N, N'-dicyclohexylcarbodiimide (2.88 g) and stirred at room temperature for 1 hour. The insoluble product was filtered off and the filtrate was concentrated under reduced pressure. pressure. Ethyl acetate was added to the residue and the resulting solution was washed with 5% hydrochloric acid (3X), water, aqueous. sodium bicarbonate solution (3X), water and aqueous sodium chloride solution (3X). After drying, the solution was concentrated. The concentrate is allowed to stand in a cool place and the precipitated crystals are filtered off. There was obtained 2,2,2,2-chloroethyl-7- [N-tert-butoxycarbonyl-2- [3- (3-methylureldo) phenyl] -D-glycinamido] -3-methyl-3-cephem-4. 152 DEG-160 DEG C. (decomposition). .

IC and nujol (cm-1):

3320, 1782, 1731

DMSO-d 6 (ppm):

1.42 (9H, s);

2.08 (3H, s);

2.63 (3 H, d, J = 5 Hz),

3.47 (2H, t, J = 20Hz);

4.8-5.4 (4H, m);

5.95 (1 H, d, J = 5 Hz),

8.7-7.6 (4 H, m),

8.37 (1 H, s).

9.05 (1H, d, J = 7Hz).

(2). Zinc dust (5.7 g) and glacial acetic acid (5.7 mL) were added at 5 ° C to a solution of 2,2,2-chloroethyl-7- [N-tert-butoxycarbonyl-2- / 3- (3- methyl-ureido) phenyl [-D-glycinamido] -3-methyl-3-methyl-4-carboxylate (5.7 g) in dimethylformamide (57 ml). The mixture was stirred for 1 hour at room temperature and then filtered. A small amount of ice, 5% hydrochloric acid and ethyl acetate were added to the filtrate. The organic layer was separated, for 29

188880 was washed twice with water and re-extracted with aqueous sodium bicarbonate. The aqueous layer was separated, extracted with ethyl acetate, acidified with 5%. hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was removed from the extract. There was thus obtained 7- [N-tert-butoxycarbonyl-2- [3- (3-methylureido) phenyl] -D-glycinamido] -3-methyl-3-cephem-4-carboxylic acid (3.29 g) at melting point. 143 DEG-150 DEG C. (decomposition).

IR in nujol (cm ^-1 ):

3370, 1780

NMR

With DMSO-de (PPm):

1.38 (9H, s);

1.99 (3 H, S),

2.63 (3 H, d, J = 5 Hz),

3.28, 3.45 (2H, AB-q, J = 18 Hz),

4.96 (1 H, d, J = 5 Hz),

5.28 (1H, broad d, J = 8Hz),

5.62 (1H, d, d, J = 5Hz, 8Hz),

5.97 (1H, broad d, J = 5 Hz),

6.8-7.6 (1 H, t),

8.44 (1 H, S),

9, Q2 (1H, high d, J = 8Hz).

(3)

7- [N-tert-Butoxycarbonyl-2- [3- (3-methylureldo) phenyl] D-glycinamido] -3-methyl-3-cephem-4-carboxylic acid (3.18 g) was added at 10 ° C. ° C to formic acid (60 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was pulverized with ether (70 mL). The powder was filtered and added to 5% aqueous acetonitrile (10 mL). The mixture was stirred for 30 minutes and then crystals (2.2 g) of 7- [2- / 3- (3-methylureido) phenyl] -D-glycinamido] -3-methyl-3-methyl-4-carboxylic acid were filtered off. mp 215-218 ° C (dec.).

IR in nujol (cm ^-1 ):

3350, 1760

NMR δ D 6 + DC 1 (PPm):

2.2 (3H, s); 2.85 (3 H, s),

3.23, 3.51 (2H, AB-q, J = 19Hz),

4.95 (1 H, d, J = 5 Hz),

5.33 (1 H, s),

5.7 (1 H, d, J = 5 Hz),

7.2-7.7 (4H, m).

Example 19 (i) '

A solution of ethyl chlorocarbonate (1.79 gj in methylene chloride (10 mL)) was added to a solution of N-tert-butoxycarbonyl-2- [3- (3-methylthioureido) phenyl] -D-glycine (6.45 g) and triethylamine (1, 82 g) in methylene chloride (75 ml) at -25 to -30 [deg.] C. for 10 minutes and stirred at the same temperature for 15 minutes.

To this mixture was added suddenly at -40 degrees Celsius a solution of 2,2,2-trichloroethyl-7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride (5.73 g) and triethylamine (1.52 g) in methylene chloride (75 mL). The resulting mixture was gradually warmed to 0 ° C with stirring over 4 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL). The solution was washed with 5% hydrochloric acid, an aqueous saturated sodium bicarbonate solution and finally an aqueous saturated sodium chloride solution. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: benzene (5 parts) - (- acetone (i-part)) to give the title compound as a white solid).

2,2,2-trichloro-1- [1- [N-tert-butoxycarbonyl-2- [3- (3-methylthiourando) phenyl] -D-glycinamido] -3-methyl-3-cephem-4-carboxylate (3) M.p. 123-130 ° C.

ic · in nujol. * ·; · (cm ^-1 ):.

3320, 1787, 1880, 1535, 1367/1306, 1243,

1217, 1162, 1110, 1050, 787,718

NMR δ DMSO-d 6 (ppm):

1.39 (9H, s);

2.08 (3H, s),. .

2.91 (3H, d, J = 4 Hz),

3.41 (2H, broad s), 4.8-5.1 (2H, m),

5.28 (ΪΗ, wide d, J = 7Hz),

5.5-5.8 (1H, s), 7.0-7.75 (5H, m), 9.10 (1H, broad d, J = 7Hz), 9.48 (1H, s). .

(2)

To a solution of 2,2,2-trichloroethyl-7- [N-tert-butoxycarbonyl-2 _? 3- (3-methylthioureido) fe? n-p-glycinamido] -3-methyl-3-cephem-4-carboxylate (3.55 g) and glacial acetic acid (3 ml) in dimethylformamide (15 ml) was added zinc dust (3.0 g) and a mixture of After stirring for 1.5 hours, the zinc dust was filtered off, washed with ethyl acetate (50 ml), then the washings and the filtrate were combined, washed with water, the aqueous layer was separated and extracted twice with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then extracted four times with an aqueous saturated sodium bicarbonate solution (40 ml). The reaction mixture was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid, then extracted five times with ethyl acetate (60 ml), washed with water, dried (MgSO4) and the solvent evaporated in vacuo. Obtain (2.45 g), which is 7- [N-tert-butoxycarbonyl-2- [3- (S-methylthioureido) phenyl] -D-glycynamido] -3-methyl-3-cephem-4; -karbo-. xylic acid.

ič;. · '·. · In nujol (cm ^-1 ) :.

. 3320, 1700, 1670, 1540, 1370, 1250, 1165,. 10.10: 1056.66f, _[ nu] _R- 8, +

NMR. . ·. · ^; · ^; :.: ·. ·.

Δ DM.sO-d6.

(ppm) :.

1.40 (9H, sj,

2.00. (3H, .- broad -s), ·

2.92 (<3H, s), 3.1-3.7 (2H, broad s), 4.99 (1H, d, J = .5Hz), 5.33 (1H, broad d, J = 8Hz, 55-5.8 (1H, m), 7.0-7.7 (4¾ m),.

9.07 (1H, broad d, - = 8Hz), 9.50 (1H, broad s).

(3) ..

- 7- [N-tert-Butoxycarbonyl-2- [3- (3-methylthourourido) phenyl] -D-glycynamido] -3-methyl-3-cephem-4-carboxylic acid solution (2, (G) in formic acid (20 ml). - stirred at room temperature for 3 hours. After completion of the reaction, formic acid is removed under reduced pressure and the residue is taken up in vacuo ^. is stirred - in 10% aqueous acetonitrile (20 mL). The precipitate was filtered off, washed with acetonitrile and dried. There was thus obtained 7- [2- [3- (3-methylthioureolinophenyl) -D-glycinamido] -3-methyl-3-cephem-4-carboxylic acid (1.21 g), m.p. 198-199. ° C (dec.).

IC in nujol (cm -1) :.

3500, 3430, 3230, 2600 - 2700, 1767, 1700,. 1608, 1550, 1412, - 1328, - 1280, - 1230; 1178,

1160, 1130, 978, 812, 788, 757, 711. NMR.

S, D 2 O -DCl (PPm) :.

2.07 (3 H, s),

3.02 (3 H, s),

3.34, 3.37 (2H, AB-q, J = 18 Hz),

5.09 (1 H, d, j = 4.5 Hz),

5.37 (1 H, s),

7.52 (4H, broad s).

Example -2 O ^: ... · - -

\ 2 / -chcooh

NH. AND

CHfC * CHCOOCig

2} HCl

N- (1-ethoxycarbonyl-1-propen-2-yl) -2- (3-mesylaminophenyl) -D-glycine sodium (4.76 grams) was suspended in methylene chloride (35 mL). N, N-dimethylbenzylamine (2 drops) and a methylene chloride solution (6 ml) containing ethyl chloroformate (2.75 g) were added dropwise at -14 to -16 ° C. The mixture was stirred at the same temperature for 10 minutes and then cooled to -50 ° C. Separately, to a suspension of 7-amino-3-methyl-3-cephem-4-carboxylic acid (2.25 g) in methanol (45 mL) was added triethylamine (4.3 mL) and a mixture. · Stir. · At room temperature; for · 30 minutes. Methanol (13.5 ml) containing hydrochloric acid (0.795 mmol / ml) was added to the solution. The resulting solution was added dropwise to the first solution described above at -50: +5 ° C over a period of 10 minutes. The resulting mixture was stirred at the same temperature for 1 hour at -30 ° C and then for 30 minutes at -15 ° C. The solvent was distilled off from the resulting solution, the residue was dissolved in ethyl acetate and aqueous sodium bicarbonate, and the sodium layer was separated. The organic layer is extracted with aqueous sodium bicarbonate,. then the aqueous layers are combined and adjusted to pH 3.5 with 10% hydrochloric acid. The solution was washed with 2 X ethyl acetate and collected. ve. nonionic-acyl resin (Amberlite XAD-4,.

Rohin and Haas (150 ml). The column is washed with water and eluted with 10% aqueous isopropyl alcohol. The eluate is concentrated under reduced pressure to a volume of 200 ml and lyophilized. A powder (2.96 g) which forms 7- [2- (3-mesylaminophenyl) -D-glycinamido] -3-methyl-3-cephem-4-carboxylic acid. acid. The product was dissolved in 1 N hydrochloric acid and the pH of the solution was adjusted to 4.5 with 1 N aqueous sodium hydroxide. The solution is allowed to stand in a cool place, the precipitated crystals are filtered off and dried. Colorless needles of the pure desired compound are obtained, m.p. 198 DEG-200 DEG C. (decomposition).

IC · · - / 'V' ·· • nujol. ., (cm-1):

3310, 1747, 1695, 1600, 1140

NMR DCI + D 2 O (ppm):

2.06 · (3H, s)

3.17 (3 H, s),

3.13, 3.50 (2H, AB-q, J = 18 Hz),

5.0 (1H, d, J = 4.5Hz)

5.41 (1 H, s),

5.65 (1 H, d, J = 4.5 Hz),

7.46 (4H, m). .....

UV phosphate buffer pH 6.4

Λ max 263 nm, E = 170.5.

Example 21.

COOH

1)

-CHCOOH.

NH

CHbCCHCOOCHy ......

2) HCt ₃ -i

CHCONH-T— к ₀ > -

COOH

1'9 58.8

To a solution of N- (1-methoxycarbonyl-1-propen-2-yl) -2- (3-mesylamino-phenyl) -D-glycine sodium salt (955.7 mL) in ethyl acetate (10 mL) was added bis- (trimethylsilyl) acetamide (2 drops) and isobutyl chloroformate (393.3 mg), and the mixture was stirred for 1 hour. A suspension of 2,2,2-richloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate (764 mg), triethylamine (212 mg), and ethyl acetate (16 mg) was added dropwise at -16 to -11 ° C. 15 ml) and the mixture was stirred at the same temperature for 2 hours. 1N Hydrochloric acid (4 ml) was added to the mixture and the organic solvent was removed under reduced pressure. To the residue was added methylene chloride (5 mL) and the solution was stirred at room temperature for 1 hour. The precipitated crystals are filtered off and dried over phosphorus pentoxide. There was obtained 2,2,2-chloroethyl 7- [2- (3-mesylaminophenyl) -D-glyclaminido] -3-methyl-3-methyl-4-carboxylate dihydrochloride (1.0525 g), m.p. 150 to 155 degrees Celsius (decomposition).

IC nujol (cm -1):

3300, 3200, 1777, 1730, 1698, 1680, 1150.

NMR

CD3OD (ppm):

2.15 (3H, s);

3.02 (3 H, S);

3.18, 3.56 (2H, AB-q, J = 18 Hz),

4.59, 5.08 (2H, AB-q, J = 12Hz), 5.03 (1H, d, J = 4.5Hz),

5.10 (1 H, s),

5.73 (1H, d, J = 4.5Hz),

7.25 to 7.50 (4H, m).

. UV: CH 3 OH λ 270 nm, E = -96.5.

To a solution of 2,2,2-trlchloroethyl 7- (2- (3-mesylaminolenyl) -D-glycidinamido) -3-methyl-3-cephem-4-carboxylate (517.8 mg) in 90% Acetic acid (5 ml) was added with zinc dust (1 g) and the mixture was stirred for 3 hours under ice-cooling. The reaction mixture was filtered and washed with 2X 90% acetic acid (5 ml). The filtrate and the washings were combined and concentrated under reduced pressure. Toluene was added to the residue, then the toluene was removed under reduced pressure, the residue was dissolved in water (3 mL) and ethyl acetate (6 mL), and the pH of the solution was concentrated. The solution was shaken, the aqueous layer was separated, washed with ethyl acetate and treated with charcoal, concentrated to a volume of 2 ml and allowed to crystallize under ice-cooling. washed sequentially with water, acetone and ether to give 7- [2- (3-mesylaminophenyl) -D-glycinamido] -3-methyl-3-cep-4-carboxylic acid and (212.4 mg), mp 194.5-195.5 ° C (dec.).

Example 2 2

In C-C — CICOOH

NhcOOBuÍUfc.)

-----, —--—>

2) HCOOH ------

^! To a solution of N-tert-butoxycarbonyl-2- (3-mesylammophenyl) -D-glycine (4.66 g), triethylamine (1.21 g) and N, N-dimethylbenzyl amine (0.1 g) in dry tetrahydrofuran with stirring isobutyl chloroformate [1.64 g) at -10 to -13 ° C and the solution was stirred at the same temperature for 30 minutes. To this solution is added, at-10 to -13 ° C, a solution of 7-amino-3- (1H-1,2,3-triazol-5-yl) thlomethyl-3-cephem-4-carboxylic acid, all at once. (3.13 g) and triethylamine (1.16 g) in tetrahydrofuran (30 ml) and water (30 ml) were stirred at -5 ° C for 1 hour and then at room temperature for 2 hours. Ethyl acetate was poured onto each layer, the aqueous layer was acidified to pH 2, and then the two layers were shaken vigorously After separating the ethyl acetate layer, the aqueous layer was extracted twice with ethyl acetate. The solution was concentrated to a pasty oil consisting of 7- [DN-t-butoxycarbonyl-2- (3-methylaminophenyl) glycinamido] -3- ( 1H-1,2,3-trriazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (6.8 g). purified by column chromatography on silica gel (eluent: ethyl acetate, benzene and acetic acid 5: 5: 1). Pure product (1.4 g) with a melting point above 160 ° C (decomposition) is obtained. '

NMR spectrum (δ, acetone-ds) ppm:

13188Q

1.4.

2.9 (3H, s);

3.40, 3.85 (2H, AB-q, J = 18 Hz),

3.9, 4.1 (2H, AB-q, J = 16 Hz),

5.0 (1H, d, J = 5 Hz),

5.4 (1 H, d, j = 10 Hz),

5.75 (4H, q, J = 5 Hz, 10 Hz),

7.15 to 7.5 (4H, m);

8.55 (1H, s).

7- [DN-tert-butoxycarbonyl-2- (3-mesylaminophenyl) glycinamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid [1 35 g) of formic acid (13.5 ml) was added and the mixture was stirred at room temperature for 2.5 hours. After removal of formic acid from the resulting solution, the residue is worked up in powder with 95% acetonitrile. The powder was filtered off and washed with acetonitrile. There was thus obtained 7- [D-2- (3-mesylaminophenyl) glycinamido) -3- (1H-1,2,3-triazol-5-yl) thlomethyl-3-cephem-4-carboxylic acid (1.13 grams). Melting point &gt; 175 ° C (decomposition).

Nuclear Magnetic Resonance Spectrum (δ, DC1 + D 6) ppm:

3.15 (3H, s).

3.6 (2H, broad s),

3.65, 4.25 (2H, AB-q, J = 16Hz).

5.1 (1H, d, [= 3.5Hz)]

5.4 (1 H, S),

5.7 (1H, d, J = 3.5H 5t),

7.5 (4H, broad s),

8.5 (1 H, S).

OBJECT OF THE INVENTION

A process for the preparation of 7- [substituted phenylglycylnamo] -3-substituted-3-cephem-4-carboxylic acid derivatives of the general formula. AND

Claims (5)

7.5 (4H, broad s), 8.5 (1 H, S). OBJECT OF THE INVENTION A process for the preparation of 7- [substituted phenylglycylnamo] -3-substituted-3-cephem-4-carboxylic acid derivatives of the general formula. I kde R 1 represents nitro-, C 1 -C 6 alkoxy-, C 1 -C 6 alkanesulfonamido-, C 1 -C 6 alkylaminosulfonamido-, C 1 -C 6 alkylureido-, or C 1 -C 6 alkylthloureido, R 2 is hydrogen or hydroxy, wherein R 2 is hydroxy when R 1 is nitro or C 1 -C 6 alkoxy, R 5 represents a hydrogen atom or a substituted thio group in which the heterocyclic radical is five-membered and contains 1 to 5 carbon atoms 2 sulfur atoms, and / or 1 to 4 nitrogen atoms, and is optionally substituted with a C 1-6 alkyl group; wherein R 5 is hydrogen when R 1 is C 1 -C 8 alkoxy and R 2 is hydroxy, X is C 1 -C 6 alkoxycarbonyl-amino or C 1 -C 6 alkoxycarbonylalkylidene and C 1 -C 6 alkyl-alkyloxy; M represents a hydrogen atom or a non-toxic pharmaceutically acceptable cation, characterized in that the 7-amino-3-substituted-3-cephem-4-carboxylic acid of formula II 195880. where. . . Кз. and .M. have. or the above meaning. The ester is reacted with a substituted phenyl glycol of formula III. ( ^IJ where R 1, R 2 and X are as defined above or with a mixed anhydride of this compound obtained using a C 2 -C 7 alkanoyl halide or a C 1 -C 6 alkyl halide of a C 2 -C 7 alkanoate, whereupon R 1, R 2 and X are as defined above. optionally, the amino protecting group and / or the ester group is cleaved from the reaction product. 2. A process according to claim 1, wherein the compound of formula (II) is a compound wherein R @ 3 is hydrogen and M is as defined above, and compounds of formula (III) are those in which R @ 1 is: nitro- or C1-C6-alkoxy; Rz represents. and X is amino. ·. 3. A process according to claim 1, wherein the compound of formula (II) is a compound in which R3 is a hydrogen atom or a heterocyclic radical a substituted thio group in which the heterocyclic radical is a radical. five - membered and contains 1 to 2. sulfur atoms and / or 1 to 4 nitrogen atoms and is optionally substituted with C 1 -C 6 alkyl and M has. as defined above, and as a compound of Formula III, wherein R 1 is C 1 -C 6 alkanesulfonamido, R 2 is. and X is an optionally protected amino group. 4. Method according to claim 1, characterized by. by using as the compound of formula (II). compounds, ve. wherein R 3 is hydrogen and M is as defined above, and as the compound of formula III, wherein R 1 is C 1 -C 6 alkanesulfonamido. R2 represents. and X is optionally protected. amino group. 5. The method of item 1,. characterized in that, as a compound of the general formula (I), it is preferred. II will apply. a compound wherein ¹ R 3 is hydrogen and M has the above. and as combined. of formula (III), a compound wherein:. R 1 represents C 1 -C 6 alkylureido-, C 1 -C 6 alkylthioureido- or C 1 -C 6 -alkylaminosulfonamido, R 2 represents a hydrogen atom and X represents. optionally protected amino.