SU446969A1 - Method for producing 7-acylamino-cef-3-em-4-carboxylic acid derivatives - Google Patents

Description

one

The invention relates to a method for producing new biologically active compounds derived from 7-acylamino cef-3-em-4-carboxylic acid.

A known method for producing 7-acylaminocef-3-em-4-carboxylic acid by acylation of 7-aminoceph-3-em-4-carboxylic acid.

A method for the preparation of new 7-acylaminoceph-3-em-4-carboxylic acid derivatives of the general formula I based on the known reaction is proposed.

h, CH-CH CH

g.,.

.sn

,

about srn

where RI is the acyl residue,

R2 is hydrogen or, if appropriate, a substituted, bound to the 3 acyl residue of the amino group, a methylene residue,

or their salts.

The method consists in that the compounds of the general formula II

sn

CH-g - CH

-N.

0-C-0-R ,,

where Cs is hydrogen or an organic residue forming together with the group

—C (O) —O— protected, for example, esterified to an ester, a carboxyl group,

or their salts, are acylated. Products are distinguished by known techniques.

or, if desired, the obtained compound of the formula I in the case when Ri is preferably a group substituted in the a-position of the glycilp, is reacted with an aldehyde or ketone.

RI is the acyl residue of an organic carboxylic acid, in particular the acyl residue of an aliphatic, cycloaliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, which has been substituted in the appropriate case

acids (including formic acid), as well as the acyl residue of the semi-derivative carbonic acid. The residue formed by Ri and R2 is an acyl residue preferably substituted in the a-position, for example, containing an aromatic or heterocyclic residue of a-amino-acetic acid, where the amino group is bonded to the nitrogen atom through a preferably substituted, for example, having two lower alkyl groups, in particular methyl groups, methylene residue. The protected carboxyl group of the formula -C (O) -O-Hz is primarily an esterified B ester of the carboxyl group, also an anhydride dislocated group. The Kz group may be an organic residue, which, together with -C (O) -O-grossing, preferably forms an easily cleaved ester esterified into an ester; such residues are, for example, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic residues, in particular substituted hydrocarbon residues of this kind, as well as heterocyclic or heterocyclic-aliphatic residues. In addition, the Na-organic silylo residue group, as well as the organometallic residue, for example, the corresponding organic stannyl residue, in particular substituted by one to three substituted hydrocarbon residues, for example, aliphatic hydrocarbon residues, silyl or stannyl residue. The C-C (: O) -O-grouping group, preferably the mixed anhydride pear, the residue Ra is preferably an acyl residue of an organic, e.g., aliphatic, cycloaliphatic, cycloaliphatic, aliphatic, aromatic or aliphatic, carboxylic acid or semi-derivative carbonic acid, e.g. . The residue 1 in the compound of the formula I is preferably Ac-NH, where Ac is the residue of the formula (I II); - C. And R is hydrogen or a cycloaliphatic or aromatic hydrocarbon residue substituted in the appropriate case or a heterocyclic residue substituted in the appropriate case , preferably of an aromatic character, functionally modified, preferably esterified to an ether, hydroxy or mercapto group, or an appropriately substituted amino group. , R is hydrogen, or, if appropriate, an aliphatic, cyclic, cyclone, aliphatic, aromatic, or araliphatic hydrocarbon residue or heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residue is preferably aromatic, and / or a quaternary nitrogen atom, functionally modified as appropriate, preferably esterified to ester or ether, hydroxy or mercaptogram an upa, a functionally modified carboxyl, an acyl group, an amino group or an azido group, as appropriate, and each of the residues R and R are an IBO hydrogen. n 1, R - aliphatic, cycloaliphatic, substituted as appropriate. cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue or a heterocyclic or heterocyclic-aliphatic residue, where appropriate, where the heterocyclic residue is preferably aromatic; in appropriate case, the amino group, functionally modified in the appropriate case, carboxyl or su a lofogroup, an azido group or a halogen atom, and RI4 is hydrogen. , each of the residues R and is functionally modified, preferably esterified to an ether or ester, or functionally modified in the appropriate case, carboxyl soil and R ™ -hydrogen. Claim 1, R is hydrogen or an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue, and, respectively, R and R- are substituted, as appropriate, through a double bond to the carbon atom, an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon residue. p 1 and R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue, substituted in the appropriate case, or an appropriately substituted heterocyclic or heterocyclic residue — an aliphatic residue, where the heterocyclic residues preferably have an aromatic character; cycloaliphatic, cycloaliphatic-aliphatic, aromatic l araliphatic hydrocarbon residue

and - hydrogen or an aliphatic, cycloalpathic, cycloaliphatic-aliphatic, aromatic, or araliphatic hydrocarbon residue, as appropriate.

In acyl groups, n is, for example, O and R is hydrogen or substituted, as appropriate, preferably in position 1, amino or in the form of a salt, for example an alkali metal salt, a sulfo-amino group cycloalkylgrunnu with 5-7 ring carbon atoms; substituted, as appropriate, preferably hydroxy, with a lower alkoxy, for example, methoxy, and / or halogen, for example, chlorine, phenyl, and naphthylyl tetrahydronaphthylgrunpa; substituted in appropriate case, for example, lower alkyl, in particular methyl, and / or phenyl, which in turn may have substituents, for example halogen - (chlorine), a heterocyclic group, for example 4-isoxazolyl group, or preferably substituted, for example, containing halogen (chlorine) lower alkyl residue amino group.

n is 1, R is substituted, as appropriate, preferably with halogen (in particular chlorine), containing ox and / or halogen, for example chlorine, phenyloxy, amino and / or carboxy, a lower alkyl group; a lower alkenyl group which is substituted, as appropriate, for example, containing hydroxy, halogen, in particular chlorine, and / or a phenyloxy, fepyl group, which is appropriately substituted; substituted, for example, with amino or aminomethyl, pyridyl, pyridinium, thienyl, 1-imidazolyl, or 1-tetrazolyl; a low alkoxy group substituted as appropriate; substituted, for example, hydroxy and / or halogen (chlorine), phenyloxy. In addition, R means a lower alkylthioyl or a lower alkenylthio group, substituted in the appropriate case, in particular, lower alkyl, for example methyl, fennthio, 2-imidazolylthio, 1,2,4-triazole-3-ylthio, 1,3, 4- triazol-2-ylthio, 1,2,4-thiadiazol-3-ylthio, for example 5-methyl-1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio , for example, 5-methyl1, 3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio, for example, 1-methyl-5-tetrazolylthio group,

a halogen atom, in particular chlorine or bromine, a functionally modified carboxy group, for example, a lower alkoxycarbonyl, cyan or N-substituted B, a corresponding case with phenyl, a carbamoyl, a correspondingly substituted lower alkanoyl or benzoyl group or an azido group R and R ™ are hydrogen.

n means 1; R is substituted as appropriate, for example, hydroxy and / or halogen, in particular chlorine, phenyl or thienyl, 1,4-cyclo1hexadienyl; R is a substituted amino, for example, a substituted carbamoylamino group, in particular, guanidinocarbonylamino, or in the form of a salt, for example, an alkali metal, a sulfoampne group, an azido group, which in the corresponding an ester of the form, for example, a lower alkoxycarbonyl group, a carboxyl group, a cyano group, a sulfo group substituted in the corresponding case, a lower alkoxy or phenyloxy group or a halogen atom, for example, chlorine or bromine, and R is hydrogen.

p 1, RI and W each is halogen, naprnmer bromine, or lower alkoxycarbon1 l, for example, methoxycarbonyl, and R is hydrogen,

item 1 and each of the groups R, R and R is lower alkyl, for example methyl.

Such acyl-residues of Ac are, for example, formyl, cyclopentylcarbopyl, aaminocyclopentylcarbonyl, or a-amino-cyclohexylcarbonyl. The latter may have a substituted amino group, for example, being in the form of a cyv salt, or an amino group, substituted by an acyl residue, preferably easily detachable, for example, by treatment with an acidic agent, trifluoroacetic acid, or by chemical reduction, with zinc in the presence of aqueous acetic acid, or an acetic acid

transferable residue, preferably an acyl residue of a carbonic acid hemi-ester, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarboiyl, 2-iodoxycarbonyl, g / oet-butyloxycarbonyl, or carbon monoamide, for example, i.a. also trityloid. Atsilostatkamn Ac are 2,6-dimetoksnbenzoil, tetragidronaftoil, metoksinaftoil-2, 2-etoksinaftoil benzyloxycarbonyl, geksagidrobenziloksikarbonil, 5-methyl - W 4izoksazolilkarbonil-phenyl-3- (2-hlorfennl) -5-methyl - 4izoksazolilkarbonil, 3- (2,6-dichlorophenyl) -5 methyl-4-isoxazolylcarbonyl, 2-chloro-ethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acryl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxy-acetyl, methylthioacetyl, a-butyl, 2-pentenoyl, 3-butenoyl, 2-pentenoyl, methoxy-acetyl, methylthioacetyl, 3-butenoyl, 2-pentenoyl, methoxy-acetyl, 2 , bromoacetyl, dibromoacetyl, 3 chloropropionyl, 3-bromopropionyl, amino cetyl or 5-amino-5-karboksilvaleril.

The latter may have a substituted amino group and / or a functionally modified carboxyl group, in particular in the form of a salt, for example sodium, or in the form of an ester, for example a lower alkyl group — methyl or ethyl. Acyl azidoacetyl, carboxyacetyl, methoxycarbonylacetyl,

ethoxycarbonylsilicate , 4, Trifit fennlglycyl, 4-oxyfbnylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4oxyphenylglycyl, and in these residues the amino group may be substituted, for example, as indicated above, further benzylthioacetyl, benzylthiopropionyl, a-carboxyphenyl-acetyl-mectfunctional, benzylthioacetyl, benzylthiopropionyl, a-carboxyphenylacetone -c-functional, and benzylthioacetyl; as indicated above, a carboxy group, 3-phenylpropionyl, 3- (3-cyanepepyl) -propionyl, 4- (Znmethoxyphenyl) -butyr.yl, 2-pyridylacetyl, 4-aminopyridinium acetyl with a substituted, for example, KaiK is indicated more strongly than the amino group, 2- thienylacetyl, 2-tetrahydrothienylacetyl, a-carbox-2-thienium lacetyl or a-carboxy-3-thienylacetyl from funa, a carboxyl group, for example, as indicated above, a carboxyl group, a-cyano-2-yenylacetyl, a-amino-2-thienylacetyl or a-amino-3-thienylacetyl with a substituted, for example, as indicated above, an amino group, a-sulfophenylacetyl with functionally modified, for example, as a carboxy group, a sulfogroup, 3-thienylacetyl, 2-furylacetyl, 1-imidazolyl acetyl, 1-tetracholyl acetyl, 3-1methyl-2-imidazolylthioacetyl, 1, 2,4-triazole-3-ylthioacetpl, 1,3,4-triazole-3-ylthioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-ti 3iltioatsetil diazole-5-methyl-1,3,4-tiadia13ol-2-iltioatsetil IPT 1-methyl-5-tetrazoliltioatsetil. The easily cleaved acylostath Ac, in particular, the complex Boluafir carbonic acid, is primarily a cleavable by reduction, for example, by treatment with a chemical reducing agent or an acid (e.g., trifluoroacetic) acyllobin of a complex hemisphere of carbonic acid, preferably repeatedly branched in the a-position or substituted acylcarbenyl-, in particular, with isoyl-islets, or in (3-position by halogen atoms, lower alkoxycarbonyl-residue, for example, tre-butyloxycarbonyl, tert-pentyloxycarbonyl, phenacyl sicarbonyl, 2,2,2-tr "chloroethoxycarbenyl or 2-iodoethoxycarbonyl or a distilled into a 2-iodoxycarbonyl residue, naimimer 2-chloro- or 2-bromoethoxycarbonyl. In addition, preferably an i-cyclic, cycloalkoxycarbonyl, such as adamantylocarbonylcarbonylcarbonyl, for example, adamantyloxycarbonyl; alkoxycarbonyl, primarily a-phenyl-lowering al.coxycarboyl, where the a-position is preferably repeatedly substituted, for example diphenylmethoxycarbonyl or cc-4-biphenylyl-a-methylethyloxycarbonyl, or furyl lower alkoxycarbonyl, First of all a-furilnizschy alkoksikarboiil example furfuryloxycarbonyl. The bivalent residue formed by the groups Ri and R2 is, for example, containing, if appropriate, substituted phenyl or thienyl, containing, in position 4, in the appropriate case, one or, preferably, two lower alkyl groups of -oxo-3-aza-1,4-butylene residue, for example 4 , 4dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene residue. The organic C3 residue, which, together with the —C (O) -0 group, preferably forms an easily removable esterified iB ester of a carboxyl group, means, for example, a 2-halogen-lower alkyl residue RJ, where halogen has an atomic weight better than 19. This residue forms together with -C (O) -O-grouper, an esterified carboxyl group that is easily cleaved when processed by chemical reducing agents in a neutral or slightly acidic medium (for example, zinc in the presence of aqueous acetic acid), or easily translated into such groups esterified to the ester and the carboxyl group is, for example, 2,2,2-trichloroethyl, 2-chloroethyl, 2-bromoethyl or 2-iodoethyl. The Ra group, which together with the -C (O) -Ogrouping group also forms a carboxyl group that is esterified into an ester which is esterified into an ester which is esterified into an ester of a neutral or weakly acidic medium, is an arylcarbonylmethyl group R | where aryl means, in particular, a phenyl group, where appropriate substituted, preferably phenacyl. Another RS group may be the residue R? - arylmethyl, -gryl means, in particular, a monocyclic, preferably substituted aromatic hydrocarbon residue. Such a residue, together with the —C (O) —O group, which is easily cleaved upon irradiation, preferably with ultraviolet light, in a neutral or acidic medium, is esterified into an ester of the carboxyl group. Such arylo residue contains as a substituent, in particular, lower alkoxy, for example, methoxy (which in the preferred phenyl residue is primarily in the 3, 4 and / or 5 position), and / or Primarily, nitro (in the preferred phenyl residue, in the 2). Such Rf residues are primarily 3- or 4-methoxybenzyl, 3,5-dimethoxybenzyl, 2-nitrobenzyl or 4-5-dimethoxy-2-nitrobenzyl. The group Ra may also mean a residue which, together with the -C (: O) -O-group, forms an easily cleavable acid in an acidic medium, for example, when treated with trifluoroacetic or formic acid, an esterified carboxyl group into an ester. Such a residue .Rs is primarily a methyl group, which may be polysubstituted with hydrocarbon residues substituted in appropriate cases or monosubstituted with a carbocyclic aryl group, with electron-giving substituents, or with an aromatic heterocyclic group having oxygen atoms or sulfur as ring members, or in a polycycloaliphatic hydrocarbon residue, means a ring member or in an oxa or thiacycloaliphatic residue, it represents the a-position to Besides oxygen-series or ring member. Preferred polysubstituted methyl groups R are, for example, tert-butyl, tert-pentylbenzhydryl, 4,4-dimethoxy-benzethryl or 2- (4-: biphenylyl) -2-propyl, while those containing the aforementioned substituted arylgroup or heterocyclic group of the methyltripe R are naimimer, 4-methoxybeisyl, 3,4-dimethoxybenzyl or 2-furyl. Polycycloaliphatic hydrocarbon residue in which the methyl group R | is preferably a triple-branched colloidal term, for example, adamantyl, for example 1-adamantyl, and the above oxa or thiacycloaliphatic residue R is 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-niranyl or the corresponding sulfur analogues. .Rs can also mean the remainder R | which, together with -C (O) -O-crushing, Forms hydrolytically, for example, in a weakly basic or acidic medium, a carboxyl group that is esterified into an ester that is cleaved into ester. Such a remainder iR | is a preferred ester-forming-C (0) -O-grouted activated residue, arimer and nitrophenyl, in particular 4-yitrophenyl or 2,4-dinitrophenyl, nitrophenyl-alkyl, for example 4-nitrobenzyl, polyhalophenyl, in particular 2.4 , 6-trichlorfefil or 2,3,4,5,6-pentachlorophenyl, then cyanmethyl, as well as acylaminomethyl, nairimer, phthalimiomethyl or succinylminomethyl, trityl, or bisaryloxymethyl, for example, bis (4-methoxyphenyloxy) meth. The group Rs also means the residue R, which together with the carboxyl group -C (O) -O-cleavable under hydrogepolytic conditions forms an esterified carboxyl group and represents, for example, a-aryl-lower alkyl residue, for example, substituted, for example, benzyl, 4- : methoxybenzyl, 4-nitrobenzyl, benzhydryl, or 4,4-dimethoxybenzhydryl. The group Rs can also mean the residue RI, which together with the carboxyl group -C (O) -O-cleavable, under physiological conditions, esterifies an esterification into an ester of a carboxyl ippy, first of all, lower alkanoyloxymethyl, for example acetyloxymethyl or pivaloyloxymethyl. Silyl or stannyl residue Rs contains preferably aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residues, for example, lower alkyl, cycloalkyl, phenyl or phenyl lower alkyl groups, and first and foremost alkyl silyl, for example, trimethylsilyl or trihydroxy, n-butylstannyl. Forming together with the -C (O) -O-group, preferably a hydrolytically cleaved mixed anhydride group, the acllobate is β-itself, naimer, the acyl residue of one of the above-mentioned organic carboxylic acids or semi-derivatives of carbonic acid, for example, lower alkanoyl — acetyl, or lower alkoxycarbonyl is ethoxycarboxylic acid, for example, lower alkanoyl is acetyl, or lower alkoxycarbonyl is ethoxycarboxylic acid; . Salts of compounds of formula I are primarily metal or ammonium salts, such as alkali and alkaline earth metals — sodium, potassium, magnesium or calcium, and ammonium salts with ammonia or appropriate organic amines, and aliphatic salts are primarily used to form salts. , cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases, for example, triethylamine, hydroxy-lower alkylamines, 2-hydroxy iethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) amine, basic aliphatic carboxylic esters, for example, 2-diethylamino-ethyl ethyl esters of 4-aminobenzoic acids, lower alkylenamines, for example, 1-ethylpiperidine, cycloalkylamines, either bicyclohexylamine, or benzylamps, for example, M, M-dibenzylethylenediamine, then bases such as pyridine, for example pyridine, collidine or quinoline. Compounds f) of formula 1, which in the residue Ri have a basic group, can also form acid addition salts, for example, with inorganic acids — hydrochloric, sulfuric or phosphoric acids, or with appropriate organic carboxylic or sulfonic acids, for example trifluoroacetic acid. The compounds of formula I, which in the residue Ri contain a basic group, can also be in the form of an internal salt, i.e. in the amphionic form. The acylation reaction can be carried out by treatment with carboxylic acids or reactive derivatives of such acids, for example halides, fluorides or chlorides, or anhydrides. The latter should also be understood as internal carboxylic anhydrides, i.e. ketes, or carbamic or tpo-carbamic acids, i.e., isocyanates or isothiocyanates, or

AND

mixed anhydrides, in particular, such that can be formed with complex lower alkyls, for example, ethyl chloroformate esters or trichloroacetic acid chloride K1 slots. It is possible to carry out the treatment with activated esters, as well as with substituted formmino derivatives, which are substituted with N, N-dimethylchloroformino derivatives or N-substituted H, H-diacylamine (N, N diacylated amine). If necessary, the reaction is carried out in the presence of condensing agents with the use of acids, e.g. carbodiimides, in particular dicyclohexylcarbodiimide, and the use of reactive acid derivatives, e.g. fixed assets such as trnethylamine or pyridine; if appropriate, it is also possible to proceed from the salts, for example the ammonium salts of the compounds of the formula II, where Ks is hydrogen.

The acyl group can also be introduced if the compounds of formula II are reacted with an aldehyde, e.g.

Acylgruyiu can also be administered stepeichato. For example, a halogen-lower alkanoyl-, nitrimer of bromo-cetylgruip, or by treatment with carbonic acid dihalogenide, such as phosgene, can be introduced into a compound of formula II, or halogenocarbonyl (chlorocarbonylgroup). Thus obtained compound L- (halogen-lower alkanoyl) or M- (halogenocarboyl) -amino can be reacted with appropriate exchange reagents, for example, the basic compounds - tetrazole, thioso compounds, in particular 2-mercaitol-1-methylimidazole, or metal salts e.g. sodium azide or alcohols and thus obtain the substituted H-lower alkanoyl or N-hydroxycarbonylamino compounds.

The resulting compound of formula I, where Ri is a preferably substituted glycin group, eg phenylglycyl, and R2 is hydrogen, is reacted with an aldehyde, such as formaldehyde, or a ketone, with a lower alkanone (acetone), present in an acyl group, RI, for example, an amino group, a carboxy acid, acetone, and , it is possible to modify functionally in a known manner — to acylate or esterify B ester or to substitute.

For example, the amino group can be converted to a sulfoamino group by reverse sulfur trioxide, preferably in the form of a complex with an organic base. Further, the reaction mixture of the acid additive salt of 4-guanyl semicarbazide can be reacted with a compound of formula I,

12

where, naimimer, acylgruppa R means substituted in the appropriate case, glycylgrunnu, and thus nerevodit amino group in the 3-guaiylurendogroup.

In the molecules of both reagents during the acylation reaction, free functional groups may temporarily be protected in a known manner and the protective groups can be cleaved after acylation by known methods. Thus, it is possible to protect the amino or carboxyl groups in the acyl residue during acylation in particular, in particular, in the form of acylamino, for example, 2,2, 2 - trichloroethoxy - carbonylamino, 2 - bromoethoxycarbonyamylamine or g / e-butyloxycarbonylamino, or in the form of esterification, or in the form of esterification. carboxy, e.g. diphenylmethoxycarbonyl, ester, and additionally, if appropriate, after conversion of the protecting group (naimer, 2-bromoethoxycarbonylgroup, to 2-iodoxycarbonylgrunpa), cleave such protected groups by restoring ovitel E, nairimer tsiikom in the presence of aqueous acetic acid or trifluoroacetic knslotoy or hydrogenolysis.

Salts of compounds of formula I can be obtained in a known manner. In this way, salts of the compounds of formula I can be formed by treatment with metal compounds — metal salts of carboxylic acids, for example, sodium salt of a-ethyl-cyonic acid, or ammonia or an organic amine, preferably using stoichiometric amounts or only a small excess of salt-forming agent. Acid addition salts of compounds of Formula I are prepared in the usual manner, for example, by treatment with an acid or an appropriate reagent of an anion exchange. The internal salts of compounds of formula I containing a free carboxyl group can be obtained by neutralizing the salts, for example acid additions, to an isoelectric point using weak bases or by treatment with liquid ion exchangers.

Salts can normally be nonreduced into free compounds, metal and ammonium salts, for example, by treatment with acids and acid addition salts, for example, by treatment with a basic agent.

The starting materials used according to the invention are prepared using lime methods.

Example 1. 0.031 g of triethylamino in 0.35 ml of methylene chloride are added to a suspension of 0.070 g of 7 p-aminoceph-3-em-4-carboxylic acid in 2 ml of absolute methylene chloride, the suspension is diluted with 5 ml of absolute tetrahydrofuran and stirred for 30 .min, sometimes in ultrasound

0.102 g of treg-butyloxycarbonyl-B-a-phenylglycine is dissolved in 5 ml of absolute methylene chloride, 0.040 g of 4methylmorpholine is added and diluted with 10 ml of aceto13 nitrile. The mixture is cooled to -20 ° C and 0.060 g of isobutyl chloroformate are added with stirring, and then left to react for 30 minutes at -15 ° C. After secondary cooling below -20 °, a cloudy suspension of the triethylammonium salt of the 7 | 3-aminoceph-3-4-carboxylic acid is added. The reaction mixture is stirred for 30 minutes at −15 °, for a further 30 minutes at O, and finally 2 hours at room temperature. It is filtered, washed with additional acetonitrile, methylene chloride and diethyl ether and the filtrate is dried, which is left to dry. The residue is dissolved in ethyl acetate and water, and the mixture is acidified with vigorous stirring and ice-cooling by the addition of 5 M aqueous phosphoric acid to pH: 2. The organic phase is separated and washed four times with a small amount of a saturated aqueous solution of sodium chloride. The aqueous extracts are further extracted with two portions of ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulphate and freed from the solvent under reduced pressure. The residue is chromatographed on 10 g of silnagel (column; addition of 5% water). Elute first unreacted g / e-butyloxycarbonyl-O-cc-phenylglycine with methylene chloride and methylene chloride, containing elevated fractions of acetone, and then 7 | -car | boom acid corresponding to the formula CH-C-NH 1, w-c1H cn, I, cn-C Hc-C-00 - C-one in amorphous form; UV Absorption Spectrum (in 95% ethanol): max 252 im (e 5100); IR Absorption Spectrum (in methylene chloride): characteristic bands at 5.61, 5.85, 5.92, and 6.12 µm; thin layer chromatogram (silica gel 6; determination with iodine vapor):, 6-0.7 (p-butanol-acetic acid system - water 44:12:44). The corresponding tertiary butyl ester 7 | 3- (M-g / 7g-butyloxycarbonyl-B-a-phenylglncyl) -aminoceph-3-em-4carboxylic acid crystallizes from a mixture of diethyl ether and pentane, m.p. 159-161 °; -1-29 + 2 ° (, 521 in chloroform); thin layer chromatography (silica gel, iodine detection);, 67 (acetic acid toluene-ethyl ester system 1: 1); UV absorption spectrum (in ethanol):

14. Mais 255 nm (8 5400); Infrared Absorption Absorption (in methylene chloride): Hao-Aer. Bands PRN 2.68, 2.89, 3.33, 5.57, 5.79, 5.88, 6.08, 6.22, 6.70, 7, 15, 7.28, 7.68, 8.04, 8.64, 9.05, 9.52, and 9.79 microns. Example 2. A solution of 0.02 g of 7p-N-rperbutyloxycarbonyl-D-a-phenylglycyl) -amino-cef-3-em-4-carboxylic acid in 3 ml of pure trifluoroacetic acid is left to stand at room temperature for 15 minutes. The resulting solution was evaporated in a rotary evaporator, to completely remove trifluoroacetic acid, evaporated twice to dryness, and 20 ml of a mixture of chloroform and toluene (1: 1) and dried for 16 hours at 0.0001 m, m Hg. Art. 7 (O-a-phenylglycyl) -amino-ceph-3-em-4-carboxylic acid is obtained as a yellowish powder by adding to the solution of the obtained salt with trifluoroacetic acid in water and methanol an equivalent amount of triethylamine, evaporated and the residue is subjected to infusion with chloride methylene. Filter and rinse with an additional approximately 150 ml of methylene chloride and dry under high vacuum. As a result of the operations performed, 7p- (O-a-phenylglycyl) -aminocepha-em-4-carboxylic acid is obtained in the form of amphoteric ions of the formula o-C-o as a slightly yellowish, amorphous powder, thin-layer chromatogram (silica gel; detection by iodine steam):, 29 (system l-butanol-pyridine-acetic acid-water 40: 24: 6: 30); UV absorption spectrum (in water): h1ax 250 nm (). Example 3. To a slurry of 0.20 g of M- (2,2,2-trichloroethoxy-carbonyl) -O-a-phenylglylin in 6 ml of a mixture of tetrahydrofuran and acetonitrile (1: 1) was added 0.085 ml of trnetilamine. After cooling to -10 ° C, the canula | M is added with the exclusion of moisture of 0.08 ml of isobutyl chloroformate and unmixed for 15 minutes at -10 °. To the mixed anhydride solution is added dropwise a solution consisting of 0.160 g of 7 p-aminoceph-3-em-4-carboxylic acid and 0.081 ml of triethylamine in 2 ml of a mixture of water and tetrahydrofurun (1: 1) so that temperature did not exceed 0 °. The reaction mixture is stirred for 30 minutes at 0 ° and 90 minutes at room temperature, then the main amount of organic solvent is evaporated under reduced pressure. The residue is diluted with 5 ml of a 0.5 M potassium dihydrogen phosphate aqueous solution and 5 ml of ethyl acetate. Undissolved filter material.

15 emerge with the aid of a glass suction filter and a clamp gauge preparation. Filter layers are separated; the organic phase is further extracted with a solution of potassium dihydrogen phosphate and discarded. The aqueous phases are washed with ethyl acetate, fresh acetic acid ethyl ester is poured, and acidified with concentrated phosphoric acid to a pH value of 2. The organic phase is separated and washed several times with saturated aqueous solution of sodium sodium chloride. The aqueous phases are extracted additionally, using 10 ml of ethyl acetate each, and discarded. The combined organic extracts are dried over sodium sulfate and freed from the solvent under reduced pressure. The crude product is chromatographed on 10 g of silica gel. Unchanged N- (2,2,2-tri-chloroethoxycarbonyl) O-a-phenylglycine is eluted with a mixture of toluene and ethyl acetate (4: 1). 7 (2,2,2-Trichloroethoxycarbonyl) -D-a-glycyl-aminoceph-3-4-carboxylic acid of the formula O, -one is eluted with a mixture of toluene-ethyl acetate (and more ethyl acetate is used); IR absorption spectrum (in mineral oil): characteristic bands at 5.61, 5.86, 5.92 and 6.12 µm; UV spectrum of -absorption (in ethanol): nm; thin layer chromatogram (silica gel; iodine vapor detection); , 8 (system n-butanol-acetic acid-water 71.5: 7.5: 21). Example 4. To a solution of 0.120 g (2,2,2-trichloroethoxycarbonyl) -D-a-phenylglycyl-aminotseph-3-em-4-carboxylic acid and 6 ml of dimethylformamide were added 10 ml of 90% aqueous acetic acid and then treated with 0.600 1G zinc dust. Move for 1 h at room temperature, filter out unreacted zinc dust, additionally wash with dimethylformamide and move the filtrate for approximately 10 minutes with 25 ml of ion exchanger (Dowex 20-50 mesh; type of sulfonic acid in the form of H-ions). The ion exchanger is filtered and washed with water. The filtrate is evaporated under high vacuum at a bath temperature below 30 ° (rotary evaporator) to dryness. The residue is dissolved in 5 ml of a mixture of methanol and water (8: 2) and 1 |% -a solution of triethylamine in methanol is adjusted to a pH value of 4.4. The mixture is stirred for 1 hour in an ice bath, evaporated to dryness, and the residue is subjected to infusion with methylene chloride. It is filtered, washed thoroughly with methylene chloride and dried under high vacuum. As a result of the operations performed, 7 p- (0-a-phenylglycyl mino) -ceph-3-em-4-carbopic acid is obtained, which is identical to the compound obtained according to example 2. Example 5. 7 | 3-Aminocef-3-em- 4-carboxylic acid is POSSIBLE according to the following common variant AB: N-acylated and converted to 7 | 3- (N-acylamino) cef-3-EM-4-carboxylic acid of the formula Ac-HNx-NI Sn A. 0.4 mmol acid (AcOH) is dissolved in 4 ml of absolute methylene chloride with the addition of 0.056 ml (0.4 mmol) of triethylamine (concentrated stock solution: 28.0 ml-200 MMOL of triethylamine, diluted with chloro methylene (up to 100 ml). To the solution cooled to -15 ° C, 0.0452 ml (0.4 mmol) of trichloroacetic acid chloride in 0.2 ml of methylene chloride (concentrated reserve solution: 22.6 ml-200 mmol of trichloroacetic acid chloride diluted with methylene chloride to a volume of 100 ml). Stir for 30 minutes at -15 °. A highly dispersed suspension cooled to -15 ° containing 0.040 g (0.02 mmol) 7 p-aminodef-3-em-4-carboxylic acid and 0.056 is added to the solution with shifted Ac-O-C (O) -COP3 anhydride. ml (0.4 mmol) of triethylamine in 4 ml of methylene chloride and subjected to vibration in an ultrasonic field — first for 30 minutes at -15 ° and then for 30 minutes at .20 °. The reaction solution, which is usually brown in color, is evaporated under reduced pressure to dryness and the resulting residue is distributed over 10 ml of a 10% aqueous solution of potassium dihydrogenphosphate (pH 8.9) and 5 ml of ethyl ester of acetic acid. The aqueous phase is brought to a pH of 2.6 with 20% aqueous phosphoric acid and then completely extracted with ethyl acetate. Acetic acid ethyl ester extract (30-50 ml) is washed with water and dissolved over sodium sulfate and evaporated under reduced pressure. The residue in a suitable solvent system is preparatively chromatographed on silica gel for 2–5 hours on a thin layer plate. After the plate is dried at room temperature in a nitrogen atmosphere, the zone of silica gel that absorbs under UV light (254 nm) is mechanically separated from the plate and extracted three times using 10-30 ml of ethanol or methanol. After evaporation of the extract under reduced pressure, 7 p-N-Ac-aminocef-3-em-4 carboxylic acid is obtained as a beige or almost colorless residue. If the thin layer plate contains more than one absorption zone in UV light, then the individual zones are separated, as described above, and processed separately. A sample of material obtained from different zones is tested against Staphylococcus aureus in a diffusion test plate. The material from the microbiologically most active zone is subjected to secondary preparative thin layer separation, and a homogeneous chromatographic product can be isolated. B. To 0.2 mmol of sodium salt of acid (AcONa) in 2 ml of absolute dimethylformamide, 0.2 mmol of trichloroacetyl chloride is added according to variant A and reacted with a solution of 0.2 mmol 7 p-a, minocef-3-om-4- carboxylic acid and 0.2 mmol of triethylamine in 2 ml of dimethylformamide, as in option A, and process. B. A mixture of 0.25 mmol of an acid chloride (AcCl) in 2 ml of methylene chloride is added. To a solution cooled to -15 °, 0.040 g (0.2 M | mol) 7 p-aminoceph-3-em-4-carboxylic acid and 0.070 ml (0.5 mmol) of triethylamine in 5 (ml of methylene chloride, is reacted according to option A and processed. Example 6. If used according to the method according to example 5, option B, sodium salt of methyl half ester of malone acid as an acylating starting material, then get 7 p- (M-.methoxycarbonylacetylamino) -ceph-3-em-4-carboxylic acid of formula I, where Ac is pred is a residue of the formula n, co - c - cn, - c and which, on thin-layer chromatograme (silica gel; acetic acid ethyl ester-acetic acid 9: 1), shows a value of 5-0.6; UV spectrum of absorption (in methanol): Xmax at 255 nm; IR spectrum absorbed (in mineral oil): characteristic bands at 5.58 μm. Example 7. If used according to the method of Example 5, option A: bromoacetic acid chloride as the acylated starting material then 7p- (Nbromoacetylamino) -cep-3-em-4 is a carboxylic acid of formula I, where Ac is t with a residue of the formula Br-CH, -Ci which on a thin-layer chromatogram (silica gel; the system n-butaiol-acetic acid - water 75: 7.5: 21) shows the value of R {0.25-0.35; UV absorption spectrum (0.1 M aqueous solution of sodium bicarbonate pH): max at 254 nm. Example 8. A mixture of 0.128 g (0.4 mmol) 7 p- (K-bromoacetylamino) -ef-3-em - 4-1 arboxylic acid in 0.5 ml of methanol and 0.047 g (0.5 mmol) of 4-amyiopyridine subjected to interaction in the presence of 0.048 g (0.5 mmol) of diisopropylethylamine at 40 ° before the conditioned reaction (control using thin-layer chromatography). It is evaporated and the residue is subjected twice to preparative thin layer chromatographic (silica gel). Thus obtained (4-aminopyridinium dedecyl) -amino-cef-3-sym4-carboxylic acid of the formula U,: HQN®-CH.-C-HN has a value of 25-0.4 on a thin-layer chromatogram (silica gel; system n-butanol pyridine-acetic acid-water 42: 24: 4: 30); UV absorption spectrum (in water): X at 262 nm: Infrared absorption spectrum (in mineral oil): characteristic bands at 5.62 µm. Example 9. If the method used according to example 5, option B, phenyloxene acetyl chloride as the acylating starting material, is used, 7 | 3- (K-phenyloxyacetylamino) -ceph-3-em-4-carboxylic acid is obtained. This formula I, Ac is a residue of the formula oh-lu-si which, on a thin-layer chromatogram (silica gel; n-butanol-acetic acid-water system 75: 7.5: 21), shows a Rf value of 0.4-0.5. Example 10. A mixture of 0.160 g of 7 p- (N-6poManethylamino) -ceph-3-em-4-carboxylic acid, 0.066 g of 4-mercaptopyridine and 0.057 g of dipzopropylethylamine in 5 ml of dimethylformamide is allowed to react for 4 hours at room temperature. It is evaporated, the residue is subjected to infusion with a mixture of acetone and diethyl ether (1: 1), filtered and thoroughly washed. Obtained in amorphous form 7 (4-pyridylthiocetyl) -amino-cef-3-em-4-carbonoB acid of formula I, where Ac means a residue of the formula, s-cu, -c- o shows on a thin-layer chromatogram (silica gel; butanol-pyridine-acetic acid-water 42: 24: 4: 30) value, 35-0.45; Infrared Absorption Spectrum (in mineral oil): characteristic prn bands 5.62 µm.5 Example 11. To a W% suspension of 0.040 g of 7 p-aminoceph-3-em-4-carboxylic acid and 0.0202 g (0 , 2 mmol) of triethylamine in methylene chloride add a 107 ° solution of 0.0218 g (0.26 mmol) of diketene in methylene chloride 10 and vibrate in an ultrasonic field for 1 hour at 22 °; after about 30 minutes, a clear solution is obtained. The reaction mixture is worked up according to example 5, variant A and 15 are thus obtained 7 | 3- (N-acetoacetylamino) -ceph-3-em-4-carboxylic acid of the formula I, where Ac is a residue of the formula Jll h Vjiv - ii 2 v which on a thin-layer chromatogram (silica gel; n-butanol-acetic acid-water system 75: 7.5: 21) shows a value of 25, 3-0.4; UV absorption spectrum (in 0.1 L1 aqueous solution of sodium bicarbonate): / max at 238 and 265 nm. Example 12. If the method of Example 5 is used, variant A of cyanacetic acid 30 as the acylating starting material, then 7 p- (L-cyanacetyl amino)-cef-3-em-4 is a carboxylic acid of formula I, where Ac is a residue of formula 35 NE cn-si which on a thin-layer chromatogram 40 (silica gel; n-butanol-pyridine-acetic acid-water 38: 24: 8:30) shows the value, 45-0.55; UV Absorption Spectrum (in 0.1 m aqueous solution of sodium bicarbonate): Yamax at 254 nm; IR-45 absorption spectrum (in mineral oil): characteristic bands at 4.32 and 5.60 microns. Example 13. If used in Example 5, option B is a-cyanopropionic acid chloride as an acylating starting material, then 7 p- (Na-cyanopropylamino)-cef-3-em-4-carboxic acid of formula I is obtained where Ac is the residue of the formula NEC — CH — C — III 5 CH3, which indicates a thin layer chromatogram (silica gel; -butanol-pyridine-acetic acid system — water 38: 24: 8: 30) 60, 6; ultraviolet adsorption spectrum (B 0.1 M aqueous solution of sodium bicarbonate): Yamax at 255 nm, infrared adsorption spectrum (in mineral oil): characteristic bands at 4.4 and 5.62 µm.65 Example 14. If used in the method Example 5, option A cc-cyanophenylacetic acid as an acylating starting material, then 7 p- (L-a-cyanphenylacetylamino)-cef-3-em-4-carboxylic acid of formula I is obtained, where Ac is the residue of formula // CH- C - / I 11 o co-indicative in a thin layer chromatogram (silica gel; system “-butanol-acetic acid - water 75: 7.5: 21), 3-0.4; ultraviolet adsorption spectrum (in 0.1 M aqueous solution of sodium bicarbonate): Yamax at 260 nm; Infrared adsorption spectrum (in mineral oil): characteristic - bands at 4.42 and 5.62 microns. Example 15. To a 10% suspension of 0.040 g (0.2 mmol) of 7 p-amino-che0-3-em-4-carboxylic acid and 0.0429 g (0.3 mmol) of three - "- butylamine in dimethylformamide Add a 10% solution of 0.0422 g (0.4 mmol) of 2-chloroethyl isocyanate in dimethylformamide and vibrate the mixture for 1 hour at 22 ° in an ultrasonic bath. Then, the process described in example 5, (variant A) is continued, and thus (2-chloroethylaminocarbonyl) -amino ceph-3m-4-carboxylic acid of formula I is obtained, where Ac is a residue of formula C1-CH, -CH , - HN - with a showing in a thin-layer chromatogram (silica gel). Rf 0.4-0.5 (system n-butanol-acetic acid-water 75: 7.5: 21); ultraviolet adsorption spectrum (in a 0.1 M aqueous solution of sodium bicarbonate): Lmax at 254 nm. Example 16. If used in the method of Example 5, variant A of dichloroacetic acid as an acylating starting material, then 7 j 3- (N-dichloroacetylamino)-cef-3-em-4-carboxylic acid of the formula I, where Ac is the residue formulas CI CH-C showing in a thin layer chromatogram (silica gel; system “-butanol-acetic acid - water 75: 7.5: 21), 50; ultraviolet adsorption spectrum (in a 0.1 M aqueous solution of sodium bicarbonate); Yamax at 253 nm; Infrared adsorption spectrum (in mineral oil): characteristic bands at 5.67 microns. Example 17. If used in Example 5, option B raminoceph-3-em-4-carboxylic ester 7, as a starting material, and phenylacetic acid chloride as the acylating agent, receive treg-butyl ester (complex) 7 p- (M-phenylacetylamino) -ceph-3-4-carboxylic acid of the formula I, where Ac is the residue of the formula

rV (

mon, sv, y. melting after crystallization from diethyl ether at 149-151 °; - | -87zfc2 ° (, 45 in chloroform); thin layer chromatogram (silica gel): Rf «:: 0.48 (system of toluene ethyl acetate 1: 1); ultraviolet adsorption spectrum (in pure ethanol): Lmaco 258 nm; infrared adsorption spectrum (in methyl chloride): characteristic bands at 3.00, 3.48, 5.81, 5.93, 6.10, 6.67, 7.15, 7.31.7.70, 8.65 and 9.03 microns. The corresponding Free Acid shows on a thin layer chromatogram (silica gel; n-butanol-pyridine-acetic acid-water system 40: 24: 6: 30), 47. Example 18. If used in Example 5, option B 2-thienylacetyl chloride as an acylating starting material, then 7 (3- (K-2-thienylacetylamino) -ceph-3-em-4 carboxylic acid of formula I is obtained, where Ac is the residue formulas C.sub.-indicative in a thin layer chromatogram (silica gel; n-butanol-pyridine-acetic acid-water 38: 24: 8: 30), 5-0.6; ultraviolet adsorption spectrum (in 0.1 M aqueous sodium bicarbonate ): Yamax at 237 nm; infrared adsorption spectrum (in mineral oil): characteristic bands at 5.62 µm. Example 19. If applicable In the method of Example 5, option A, phenylmalonic acid as an acylating starting material, then 7 p- (Na-carboxyphenylacetylamino) -ceph-3-em-4-carboxylic acid of formula I is obtained, where Ac is the residue of the formula: showing in a thin layer chromatogram (silica gel; n-butanol-pyririn-acetic acid-water 40: 24: 6: 30 system) two zones: the faster moving zone has 4-0.5 and contains 7p- (M-phenylacetylamino) - cef-3-em-4-carboxylic acid and the slower-moving zone has a Rf of 0.2-0.3 and contains the target 7p- (N-acarboxyphenylacetylamino) - cef-3-em-4 - carboxylic acid.

Example 20. If used in the method of Example 5, option B is sodium salt of DZ-a- (Nrper-butyloxycarboxylamino) -2-thienylacetic acid as an acyl-forming starting material, then (L-treg-butyloxycarbonylamino) -2-thienylacetylamino-ceph is obtained -3-em-4-cage | boic acid of formula IB, where Ac is a residue of formula CJcH-tNH 0 C-0-C (CH) 3 which is Purified in a thin-layer chromatogram (silica gel) and which shows ethyl acetate in the system - pyridine - acetic acid - water (62: 21: 6: 11), 5-0,6. You can translate it according to the method described in example 2 in 7 (a-amino-2-thienyl acetyl) -a1-amino-aef-3-em-4-carboxylic acid of formula I, where Ac is a residue of the formula O-sh $ I 11 " Ng O this acid is in the form of amphibia and shows in the thin layer chromatogram (silica gel) in the system ethyl ester of acetic acid - methyl ethyl ketone - formic acid - water (50: 30: 10: 10) Rf 0.4-0.5. Example 21. To the solution obtained in the description of Example 7 by the method of 7p- (N-6poM-acetyl-amply) -ceph-3-em-4-carboxylic acid (approximately 0.15 mmol) in 0.3 ml of a solution of 17.3 ml of diisopropylethylamine in 100 ml of methylene chloride, 0,0126 g (0.18 mmol) of tetrazole in 0.3 ml of dimethylformamide was added and allowed to react for 30 minutes at room temperature. They work according to the method described in example 5 and thus get 7 | 3- (Nl-tetrazolylacetylamino) -ceph-3-em-4-carboxylic acid of formula 1, where Ac is a residue of formula i .15-СНг-сНII showing in a thin-layer chromatogram (silica gel; n-butaiol-pyridine-acetic acid-water system (42: 24: 4: 30) Rf 0.4-0.5; ultraviolet adsorption spectrum (in methanol): max jpn 255 nm. Example 22. If to react using the method described in Example 7 of Method 7 to p- (N-bromodethylamino)-cef-3em-4-carboxylic acid (approximately 0.15 mmol) in 0.3 ml of solution 17.3 ml diiso23

propylethylamine in 100 ml of methylene chloride with 0.0205 g (0.18 mmol) of 3-mercapto-methylmethyl indazole in 0.3 ml of dimethylformamide using the method described in Example 21, and leave to react for 7 hours at 20 °, then (1-methyl - 2 - imndazolylthioacetyl) amino-cef-3-em-4-carboxylic acid of formula I, where Ac is a residue

5 SNO C

II

about

showing in a thin-layer x-rotogram (silica gel; n-butanol-pyridine-acetic acid-water system 42: 24: 4: 30), 3-0.4: ultraviolet adsorption spectrum (in methanol): Yamax at 252 nm. Example 23. A solution of 0.037 g of sodium nitrite in 0.4 ml of water was added to a cooled and stirred solution of 0.100 g of 3-guanyl semicarbicide-dihydrochloride in 0.6 ml of water. The mixture is stirred for 10 minutes at O, then added dropwise at 0 ° to a pH of 7.5 adjusted with triethylamine solution of 6.173 g 7 (O-a-phenylglycyl) -aminotsef-3-em-4-carboxylic acid in 4 ml of water. Stir for 1 h at 0 °, the precipitate is filtered, washed with water and dried. Thus, a crude 7 (- a - (3-guanilureido) -phenyl-acetylamino-cef-3-em-4-carboxylic acid of formula I is obtained, where Ac is a residue of the formula

// VCH- | HC-NH-Cf

H

and about

ItH,

showing in a thin layer chromatogram (silica gel; iodine vapor): 30–0.35 (n-butanol – acetic acid – water system 67:10:23), ultraviolet adsorption spectrum (in methanol) / max 252 nm.

Example 24. When using (Da-amipo-2-thienylacetyl) -amino-cef-3-em4-carboxylic acid, it is obtained by the method of Example 23 7p-NDa - (3-guanylureido) -2tyi1 lacetylamino-cef-3 -m-4 - carboxylic acid of the formula I, where AC-residue of the formula

ABOUT

S 1 t

NH-C-M-C

IIin

in the form of an amorphous powder.

Example 25. To a suspension of 0.100 g of (D-a-phenylglycyl) -amino-cef-3-em-4-carboxylic acid in 6 ml of absolute methylene24

chloride, 0.0364 g of triethylamine was added and stirred for 10 minutes; however, most of the material is dissolved. The mixture is cooled to -5 ° and only 0.0652 g is added in portions.

complex of triethylamine - sulfur trioxide (t. pl. 89-90 °). Continue to mix for 5 minutes at 0 ° C and for another 2 hours at .20 °. The solution is treated with 0.9 mmol of sodium o-ethyl hexanoate and the isolated product is filtered. It is washed with methylene chloride and diethyl ether and then a powdery precipitate containing disodium salt 7 (D-ayl acid and phenyl acetyl) amine-cef-3-em-4-carboxylic acid of formula I, where Ac is the residue

ABOUT

CH-JNH-50, H

dried under high vacuum; thin-layer chromatogram (silica gel): R {0.10 (n-butanol-acetic acid-water system 71.5:

: 7.5: 21); ultraviolet spectrum of adsorption (in water) Kmax 253 microns.

Example 26. With the use of (D-amino-2-thienylacetyl) -amino-cef-3-him4-carboxylic acid in Example 25,

similarly, disodium salt (D-cc-sulfoamino-2-thienylacetyl-amino cef-3-em-4 is a carboxylic acid of formula I in the form of an amorphous powder, where Ac is a residue of the formula

.,about

C LcH-t

NH-SO H

Example 27. A suspension of 0.110 g of 7 p-aminoceph-3-em - 4-carboxylic acid — is dissolved in 2 ml of water by adding 0.0635 g of sodium hydrogencarbonate at 0 ° and 0.142 g of a-sulfophenylacetyl chloride is added dropwise in

3 ml of diethyl ether. The mixture is stirred for 1 hour at -5 °, then it is treated with 1.5 mmol of cc-ethylhexanoate sodium and the isolated product is filtered. Washed with methylene chloride and diethyl ether

and then a powdery precipitate consisting of the 7 (a-cylophenyl acetyl) -amino disodium salt of the disodium salt of the formula I, where Ac is the residue of the formula

dried by high vacuum; thin-layer chromatogram (silica gel):, 5-0.2 s (system and-butanol-acetic acid-water 67:10:23).

Example 28. 0.336 g of 7 (3- (Da-phenylglycyl) -aminoceph-3-om - 4-carboxylic acid is dissolved in 15 ml of water at 5 °, 0.085 g of sodium hydrogen carbonate is added, then 0.030 g of formaldehyde. Stir for 2 hours The filtrate is filtered and lyophilized. 7 p- (5-oxo-4-phenyl-1,3 diaza-1-cycloyl) -ceph-3-e-4-carboxylic acid I -H-N-CH-CH is obtained as a residue. SNG and h, shown in a thin layer chromatogram (silica gel), 35 (system n-butanol-pyridine-acetic acid-water 40;: 24: 6: 30). Example 29. To a mixture of 1.0 g 7 p- (O -a-feiylglycyl) -amio-cef-3-em-4-carboxylic acid in 10 ml of acetone p 0.8 ml of triethylamine is added. The mixture is stirred for 24 hours at room temperature, filtered and the filtrate is then evaporated to a small volume. The residue is dissolved in water, the pH is adjusted to 2.5 using 2N hydrochloric acid and then filtered and dried Obtained in the form of a linear product 7 | 3- (2,2-dimethyl-5-oxo-4phenyl-1, 3-diaza-1-cycloyl) - cef - 3-em-4 carboxylic acid of the formula shows on a thin layer chromatogram (silica gel) Rf-ODO (system n-butanol-pyridine-acetic acid-water 40:24; : 6: 30). The initial values used in the above examples can be obtained in the following manner H1, and. 15 ml of the ion exchanger of sulfonic acid (H-form) are converted by treatment with a solution of 5 ml of triethylamine in 100 ml of water to form triethylammonium salt (the column is washed to neutrality with 300 ml of water) and treated with a solution of 2 g of sodium penicillin T salt in 10 ml of water and then eluted with water. Take a volume of 45 ml n lyophilized at a pressure of 0.01 mm Hg. Art. The penicillin-G triethylammonium salt thus obtained was dissolved in methylene chloride, the solution was dried over sodium sulfate overnight, filtered and evaporated. The solution of penicillin-triethylammonium salt obtained in this way in a mixture of 40 ml of metplenhlornd and 40 ml of tetrahydrofuran is cooled to -10 ° and added slowly to 2.9 ml of a 10 M solution of 2 ml of chlor-1-tetrahydroyl ethyl ester in tetrahydride). Stir for 90 MISH at -5 to 0 ° C, then add a solution of 0.396 g of sodium acide in 4 ml of water and stir the mixture for 30 minutes at -5 to 0 °. The mixture is diluted with 100 ml of ice water and extracted with methylene chloride three times in 75 ml each time, the organic extracts are washed with water, dried and evaporated at room temperature and reduced pressure. In this way, amorphous β-penicillinG-apid, an infrared adsorption spectrum (in methylene chloride) is obtained: characteristic tylosum NRI 3.05,4.71, 5.62, 5.80, 5.94, 6.69 and 8.50 microns. 1.5 ml of 2,2,2-trichloroethanol was added to a solution of 1.72 g of pentaxline-G-acide in 30 ml of benzene and stirred for 70 hours at 70 °. For 15 minutes, inepsbix, permanent nitrogen formation is established and after a few hours, the product of the solution is isolated. Dilute with stirring 60 ml of hexane, cool and filter 15 minutes later. The residue on the filtrate is washed with a mixture of bepzol and hexane (2: 1) and then with cold ether. Thus, pure 2.2-dimethyl-6p- (N-phenylacetylamide) -3 (L-2,2,2-trichloroethoxycarbonylamino) -3- (N2, 2.2-trichloroethoxycarbonylamino) -foams, melting at 223-223, are obtained. 5 °; a, v - -172 ° (from 1,018 in ethanol); infrared adsorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.61, 5.77, 6.97, 6.70, 8.30, 9.17, 9.62, and 11.85 microns. The product can be obtained by heating 0.03 g of penicillin-G-acid in 2 ml of benzene for 20 minutes to 70 °, by evaporation of the reaction mixture under reduced pressure; H-psocyanato-2, 2-dimethyl-6p- (K-phenylacetylamino) foams are obtained; infrared adsorption spectrum (in Lilethylene chloride): characteristic bands at 3.06,4,48. 5.62 microns, 5.96 microns, and 6.70 microns; they translate it into the desired 2.2 - dimethyl-6p- (M-pheiiacetylamio) -3- (N-2.2.2-trichloroethoxycarboiyl-amino) -penes, subjecting it to interaction with 2,2,2-trichloroethanol. To a solution of 11.0 g of 2,2-dimethyl-6p- (K-fepI: Tacetylamino) - 3 - (M-2,2,2-trichloroethoxycarbonylamino) penam in a mixture of 240 ml of water-free methylene chloride and 25.6 ml pyridine was added under a nitrogen atmosphere at -10 ° to 166 ml of a solution of phosphorus pentachloride in methylene chloride and then stirred for 30 missions and 0 °. Then, under violent cooling (-10 °), 120 ml of absolute methanol is added and the mixture is left unmixed for 2 hours. Then 80 ml of water are added, the RP (adjusted in water-diluted samples) is adjusted to 3.3 with the help of about 9 ml of 2N. an aqueous solution of hydroxide; 1 si1; 1 and leave to react for 1 h, thermocyclic 0 ° and still at 20 °. Then poured with stirring in 500 ml of 1N. aqueous buffer solution of acidic dvuzame27

potassium phosphate chips and the pH is adjusted from 6.5 to 7.0 by the addition of a 50% aqueous solution of potassium phosphate. The aqueous phase is separated and washed three times with 200 ml of methylene chloride; the three solutions obtained are trompified twice with water, combined, dried over sodium sulfate, and evaporated under reduced pressure. The crystalline residue is dissolved in 40 ml of a mixture of benzene and hexane (1: 1); the mixture is cooled for 15 minutes at 0 ° and the precipitate is filtered off. Thus, 6-amino-2, 2-dimethyl-3- (N-2,2,2-trichloroethoxanecarbonylamino) -penes are obtained, melting at 179-180 ° C (with corrosion); infrared adsorption spectrum: characteristic bands in methylene chloride at 2.90, 5.58, 6.62, 7.17, 7.72, 8.32, 8.46, 8.82, 9.25 and 9.62; in zero at 2.95, 3.01, 3.11, 5.64, 5.80, 6.35, 7.60, 7.87, 8.00, 8.27, 8.65, 8.70 , 9.16 and 9.57 microns; thin-layer chromatogram (silcagel):, 17 (in the toluene-acetone system 8: 2) and Rf 0.43 (in the toluene-acetone system 6: 4); characteristic yellow color with ingidrin-collidine (free amiaogrunia).

A mixture of 0.05 g of 6p-amio-2,2-dimethyl-3- (N2, 2.2-trichloroethoxycarbonylamino) -penam and 0.1 g of zinc dust in 2 ml of a mixture of acetone and water (1: 1) is filtered after add 0.2 ml of acetic acid for 1 hour, vibrate at 45 kHz (ultrasound), then dilute with 50 ml of ethyl acetate, dry the organic extract over sodium sulfate and evaporate it under reduced pressure. The residue is recrystallized from a mixture of methylene chloride and hexane, and thus 3-isopropyl-4-thia-2, 6-diazabicyclo-3,2,0 - heptane-7-oi is obtained, t. Pl. 151 -155 °; thin-layer chromatogram:, 17 (toluene-acetone system 8: 2) n Rf 0.38 (toluene-acetone system 6: 4). In the above process, instead of acetic acid, 0.2 g of ammonium chloride or 0.2 g of iiridihydrochloride can be used.

To a solution of 1.64 g of 3-isopropyl-4-tpa-2,6 diazabicyclo-3, 2.0-heptan-7-octa in 33 ml of a mixture of acetic acid and water (1: 1) is added over 10 minutes 71, 7 ml 0.5 n. a solution of iodine in ethanol, incubated for 1 h at a room temperature and then evaporated under reduced pressure. The residue is dried under high vacuum and suspended in 90 ml of acetonitrile and 4.5 ml of pyridine and 4.5 ml of phenylacetic acid chloride are added at 0 °. They are kept for 15 minutes at 0 ° and for 1 hour at room temperature and then boiled under reduced pressure. Triturn 30 minutes with 10 ml of a mixture of dioxa and water (1: 1) and the residue is dissolved in ethyl acetate; the solution is sprinkled with an aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried and evaporated. The oily residue is chromatographed on 100 g of pure silicate; oily bis- g {"s-2-oxo-3 | 3 - (N - phenylacetyl28

amino) -4p-acetidinyl disulfide is eluted with a mixture of ethyl acetate and acetone (19: 1) and modified by lyophilization to form a fine powder; thin layer chromatogram (splie {agel):, 36 (ethyl acetate – acetone system 1: 1); infrared adsorption spectrum (in potassium bromide): characteristic NRI tylosa 3.08, 5.62,

5.97 and 6.51 microns.

The above disulfide compound can also be obtained by following, for. To a solution of 0.317 g of 3,3-dimethyl-4-thia - 2,6-diazabpcyclo-3, 2.0-heptan-7-one in 3.0 ml of methylene chloroform and give 0.254 g of iodine in 12.0 g of benzene; at the same time, the medium forms a large brown precipitate. The mixture is shaken for 10 minutes. at room temperature, then filtered and the residue is washed

on the filter, benzene and peitan n are suspended in 8.0 ml of acetonitrile.

2.0 ml of pyridine was added to the suspension, a clear yellow solution was obtained, which was cooled to and to which 0.4 ml of phenylacetic acid chloride was added dropwise with stirring. The reaction mixture is left to stand at room temperature for 20 minutes, then concentrated under reduced pressure to obtain a weight of 1.9 tons. The yellow syrup-like residue is dissolved in 50 ml of ethyl acetate and washed with 50 ml of water, then evaporated. The residue is crystallized from the mixture of methanol, methylene chloride and hexane. Bnc- t {MC-2-oKco-3p- (Nphenylacetylamino) -4p -acetidinyl - the disulfide melts after non-recrystallization from acetone and methylene chloride at 152-155 ° (assay preparation: 156.5-158.5 °).

To a solution of 0.35 g of biscis-2-oxo-3p- (Nphenyl acetylamino) - 4 (3-acetidinyl disulfide in 16 ml of a mixture of acetic acid and water (9: 1)) is added at about 5 ° to about 3, 2 g of ethylene oxide, then 3.5 tons of zinc dust. The reaction mixture was stirred 15 minutes at about 5 ° C and 30 minutes at room temperature, then filtered. The residue on the filter was additionally washed with acetone and the filtrate was evaporated. The residue was dissolved

about 150 ml of ethyl acetate and the solution is washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and 100 ml of a saturated aqueous solution of sodium chloride, dried and evaporated. The residue, together with the obtained analogous method, from 0.58 g (wc-2-oKCO-3p- (Nphenylacetylamino) -4 (3-acetidinyl-disulfide) raw material is chromatographed on 50 g of silica gel. Eluted with a mixture of ethyl acetate and acetone ( 19: 1) 4p- (2-hydroxyethylmercapto) 3j3- (N-phenyl acetylaminoIl) -acetidium - 2-one as a homogeneous product, melting after crystallization from acetone and augmented diethyl ether at 141-120 °; 4-44 ± 2 ° (s. 0.571 in ethanol); thin layer chromatography (Silnagel, pro ;; Lenne iodine): 45 (ethyl acetate nslot-acetone 1: 1); infrared adsorption spectrum (in mineral oil): characteristic noses at 3.01, 5.68, 6.43 and 6.52 μm. To a solution of 0.61 g (2 - hydroxyethyl mercito) -3 3- (G-Phenylacetylamino) -acetidin-2-one in 10 ml of tetrahydrofuran was added at 0 ° to dropwise 1.38 g of complex 2,2,2-trnichloroethnlter chloroformate acid in 5 ml of tetrahydrofuraia, then 1.06 g of pyridine in 5 ml of tetrahydrofuran. The reaction mixture is stirred under a nitrogen atmosphere for 15 minutes and 0 ° and 2 hours at room temperature, then dissolved in 150 ml of methylene chloride. The mixture is washed with a saturated aqueous solution of sodium chloride and dried and evaporated. The residue is chromatographed on a 50-fold amount of silica gel; 3 | 3- (K-phenylacetylamino) (2,22-trichloroethoxycarbonyloxy) ethylmercaptoacetidium-2-one is eluted with a mixture of methylene chloride and ethyl acetate (1: 1). After crystallization and a single recrystallization from diethyl ether, the product is obtained in the form of colorless needles, i.e. 99-101 °, thin layer chromatogram (silica gel):, 46 (ethyl acetate system, iodine), -f3 ± 2 (with 0.518 in chloroform); infrared adsorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.58, 5.64, 5.92 and 6.62 microns. A mixture of 1.0 g of 3 (3- (N-phenylacetylamino) -4 | 3-2 (2,2,2-trichloroethoxycarbonyloxy) ethylmercapto acetidine-2-one and 3.0 g of glycolic butyl ester hydrate in 50 ml of benzene are boiled under water for 16 hours under reflux, then cooled and washed twice with 25 ml of distilled water, dried over sodium sulfate and evaporated. Thus, a complex tertiary butyl ethe-2-hydroxy-α-2-oxo is obtained. Sp - (N - phenylacetylamino) - (2,2,2-trichloroethoxycarbonyloxy) - ethyl mercapto -1-acetidinyl} acetic acid, which I process t further without purification. The crude 7reg-butyl a-hydroxy-a- {2-oxo-3p - (N-phennacetylamino) - (2,2,2-trichloroethox -carbonyloxy) ethylmercapto -1-acetidinyl obtained by the above method is α-acetic acid was dissolved in 20 ml of a mixture of dioxac and tetrahydrofuran (1: 1) and 0.54 ml of pyridine in 2 ml of dioxane and 0.48 ml of thionyl chloride in 10 ml of a mixture of dioxane and tetrahydrofuran ( eleven). The reaction mixture is stirred for 30 minutes at a temperature of from -10 to -5 ° and for 1 h under nitrogen atmosphere, the precipitate is filtered off and the filtrate is combined with t / 7e7-butnl cc-chlor-cc- {2-oxo-3 - (N - phenylacetylamio) -4 (- (2,2,2 - trichloroethoxycarboinloxm) -ethylmercapto - 1-acetylpipl} -acetic acid: procrut is processed in a crude CoK solution of the a-chloroK- complex obtained by the indicated method {2-oKco-3 {3- (N - feii acetylamino) - 4 ((2,2,2-trichloroethoxycarbonyloxy) - ethyl mercapto -1-acetidinyl} - acetic acid in 30 ml of mixture ixane and tetrahydrofuran (1: 1), add 1.15 g of triphenylphosphine and 0.35 ml of pyridine and heat at 50 ° C for 2 hours, then evaporate to dryness. The residue is chromatographed on 30 g of pure snapshot, and eluted with a mixture of toluene and C. p. ethyl ester of acetic acid (1: 1) complex g / seg-butyl efnr a- {2-oxo-Zp - (N-feiacetylamino) - 2 - (2,2,2 - trichloroethoxycarbonyloxy) - ethylmercapto - 1 - acetylnpl} - a-triphenylphosphoranylidene-acetic acid, which is polluted with insignificant amount of triphenylphosphine oxide and which is useful for the treatment of parasite toicolysis chromatography (silica gel: with iodine blinding), 57 (toluene-acetone system 1: 1), infrared adsorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.42, 5.68, 5.97, 6.10 and 6.65 microns. To a mixture of 0.225 g of tertiary butyl ester a- {2-OKCo-3 | 3- (N-phenyl acetylamino 1) - (2,2,2-trichloroethoxycarbonyloxy) ethyl mercapto-1-acetindinyl} -a-trifeiylphosphoranylidene-acetic acid in 10 ml of a mixture of acetic acid and water (9: 1) add 3.0 g of zinc acid and stir for 45 minutes at 15 °. Filtered and the filtrate is evaporated; The residue is dissolved in 50 ml of ethyl acetate and the solution is shed with 25 ml of saturated sodium bicarbonate aqueous solution and twice with 25 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. In this way, the g / er-butyl ester of (2-hydroxyethyl mercapto) -2-oxo-Sp- (K-phenylacetyl amio) -1-acetidinyl-a-triphenylphosphoranylideide acetic acid is obtained; thin layer chromatogram (silica gel, iodine): 24 (toluene – acetone system 1: 1). A mixture of 0.221 g of crude complex t / E-butyl ester (3 - (2-hydroxyethyl mercapto) 2-oxo-3 (3 - (N-phenylacetyl amide) -1-acetydinyl - a - triphenylphosphorylpdene-acetic acid in 5 ml of 5 ml the acetic anhydride is incubated for 16 hours at room temperature and then dried under reduced pressure to a small volume. The residue is dissolved in 100 ml of toluene; the organic solution is washed three times with 50 ml of distilled water, dried over sodium sulfate and evaporated. The oily residue is chromatographed on 10 g silnkagel; the desired complex tr g-butyl ester 7 (3- (M-phenylacetylamine) -cep-3m-4-carboxylic acid, which is formed by cyclization from the Intermediate, the resulting non-isolated tert-butyl ester a-4p-ford-methylmethylmercapto-2-oxo-3p- (Nepheylacetylamino) -1-aetidnyl-a-triphenylphosphono-arylidene-acetic acid, eluted with a mixture of toluene and ethyl acetate (4: 1), "melts during crystallization from 149-151 ° C ethyl acetate; a - | -87 ± 2 ° (from 0.45 in chloroform); thin-layer chromatogram (silica gel):, 48 (toluene – ethyl acetate 1: 1 system); UV adsorption spectrum (in pure ethanol): Yamax 258 nm; Infrared adsorption spectrum (in methylene chloride): characteristic bands: 3.0, 3.48, 5.62, 5.81, 5.93, 6.10, 6.67, 7.15, 7.31, 7.70 , 8.65 and 9.03 microns. A mixture of 0.03 g of 7 | 3- (N-phenyl acetylamino) -ceph-3-em-4carboxylic acid t / ze-butyl ester and 0.5 ml of trifluoroacetic acid is kept at room temperature for 1 hour. Trifluoroacetic Acid is then removed under reduced pressure and the residue is taken up twice to dry portions of 5 ml of a mixture of benzene and chloroform. The residue is chromatographed on 5 g of silica gel and 7p- (L-phenylacetylamino) -ceph-3-em-4carboxylic acid is chromatographed with methylene chloride containing 5% acetone; thin-layer chromatogram (silica gel; iodine): 47 (n-butanol-pyridine-acetic acid system - water 40: 24: 6: 30). To a solution of 1.275 g of 7 | 3-phenylacetylamino-3-em-4-carboxylic acid in 5 ml of methanol and 20 ml of dioxane, an excess of diphenyldiazomethane is added and kept at room temperature for 1 hour. A slight amount of acetic acid is added to the red reaction mixture and evaporated under reduced pressure to dryness. The yellowish oily residue is dissolved in a large amount of methylene chloride and diethyl ether is added with heating. The colorless precipitate (filter needles) is filtered off, washed with diethyl ether and then with pentane and dried; In this way, 7 | 3-phenylacetylamino cef-3m-4-carboxylic acid diphenylmethyl ester is obtained, i.e. 163.5-164.5 °; a 2 ° + 30 ± G (, 968 in dioxane). thin-layer chromium atogram (silica gel):, 55 (toluene-acetone system 4: 1), Rf 0.35 (toluene-acetone system 9: 1), and 40 (toluene-complex ethyl ester of acetic acid 4: 1); UV adsorption spectrum: Hmax 258 nm (e-6100) and nm (8 5250) (in methyl enchloride) and Yamax 259 nm (s 6050) and nm () (In 95% ethanol); infrared adsorption spectrum: characteristic bands at 2.90, 5.57, 5.76, 5.91, 6.09, 6.66, 7.13, 8.12, 8.63, 907 10.43 and 12, 22 μm (in methylene chloride) and at 3.01, 5.60, 5.82, 6.04, 6.08 (shoulder), 6.51 and 7.13 μm (in mineral oil). A solution of 1.94 g of diphenylmethyl ester 7 (3-phenyl acetyl amioceph-3-m-4-carboxylic acid in 100 ml of absolute methylene chloride is cooled to -15 °, then 3.86 ml of absolute pyridine and 31.6 ml of 8% is added phosphorus pentachloride in methylene chloride and the reaction mixture was shifted for 30 minutes at -10 ° and for another 30 minutes at -5 °. The golden yellow solution was cooled to -20 ° and 26.8 ml of absolute methanol was added so quickly that the internal temperature does not exceed 10 ° C. The reaction mixture is stirred for 1 h at -10 ° and kept 1 hour at 25-30 °, then 80 ml of a 0.5 M aqueous solution of potassium dihydrogenphosphate are added with vigorous stirring. By adding dropwise 20% phosphoric acid, the pH of the two-phase reaction mixture is adjusted to 2, stirred for 20 minutes at room temperature temperature and phase separation. The aqueous solution is washed twice with methylene chloride; the combined organic solutions are washed with two portions of 20 ml of water each and dried over water-free sulphate of magic. The solvent is removed under reduced pressure; an oily residue is fed to a column of PO g silica gel (5% water content). Elute with methylene chloride, methyl phenyl acetic acid and methylene chloride containing 3% methyl acetate of acetic acid, diphenylmethyl 7 (3-amino-3-em-4-carboxylic acid, which is crystallized by dissolving in a small amount of methylene chloride and added by heating. (needles crystals), washed with cold simple diethyl ether and dried, so on. 153-154 °. Tovolayer chromatogram (silica gel):, 50 (toluene – acetone system 4: 1), 65 (toluene – acetone system) eton 2: 1),, 40 (toluene-complex ethyl ester of acetic acid 1: 1) and, 33 (toluene-simple diethyl ether system); ultraviolet adsorption spectrum: Lmax 257 nm (e 8150) and A, nm (e 7730) (in methylene chloride) and 1 max 255 nm.) And Ktsh 236 nm (8 4650) (in 95% ethanol); infrared adsorption spectrum: characteristic bands at 2.91, 2.97, 5.61, 7.78, 6.11, 7.14, 8.29, 9.14 and 9.83 (in methylene chloride) and at 2, 99, 5.65, 5.77, 6.08, 7.14, 7.74, 7.84, 808, 8.53, 9.14, 9.85 and 10.35 microns (in mineral oil). 0.380 g of diphenylmethyl ester of 7p-aminoceph-3-em-4-carboxylic acid is poured over with 2 ml of aiisole and 8 ml of absolute trifluoroacetic acid, the clear solution is kept at room temperature for 10 minutes and then diluted with about 20 ml of absolute toluene. The mixture is evaporated under reduced pressure, the residue is dissolved two more times and dried and then suspended in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water. By adding dropwise a 5% solution of triethylamine in methanol, the pH of the solution was adjusted to 3.5, kept in an ice bath with 30 mi, and the fine precipitate was filtered with a suitable suction filter. The slightly beige residue on the filter Was washed with a mixture of methanol and methylene chloride, then with diethyl ether and dried under reduced pressure at. Thus obtained as a fine. Microcrystalline powder 7p-amiocef-3 - em-4-carboxylic acid decomposes at 215 °; thin layer chromatogram (silica gel; iodine); Rf 0.28 (n-butanol-pyridine-acetic acid-water system 40: 24: 6: 30); infrared spectrum of adsobcy (in mineral oil): characteristic bands at 3.12, 3.80 (shoulder), 4.92, 5.54, 6.05 (shoulder), 9.19, 6.55, 7.05, 7.42, 8.23, 8.79, 9.55, 12.08, 12.69, and 13.04 microns. The subject matter of the invention is 1. A method for producing 7 acylamino cef-Z-em-4-carboxylic acid derivatives of the general formula I i, j 5 R CH-CH Clb o cn Methylene residue or their salts contained in the acyl residue of the Ac amino group, characterized in that the compounds of the general formula II are 10 15 20 25 30 35 40 45 50 where Hz is hydrogen or an organic residue forming together with -C (O) -O-protected, for example, esterified into ester, carboxyl group, or their salts are subjected to acylpro followed by the transfer of the protected carboxyl group of the formula -C (0) -ORs into the free carboxyl group in the β-obtained compound and the subsequent isolation by the known methods of the desired product 1glt, if desired, the resulting compound of the formula I in the case where RI is preferably substitutedin in a- According to the glycyl group, it is further reacted with an aldehyde or ketone. 2. The method according to claim 1, wherein tl and h and y and the fact that as the starting compound using the ammonium salt of the acid of formula II. 3. A method according to claim 1, characterized in that (as an acylating agent, carboxylic acid or a reactive derivative thereof is used. 4. The method according to claim 3, characterized in that a halide is used as a reactive and carboxylic acid) for example, an acid chloride, and hydrophobic acid, a displaced anhydride, or an activated acid ester. 5. Method according to claim 1-4, characterized in that the acylation is carried out in the presence of a condensing ageit.The priority is as follows: 05.24.71 for Ra - carboxyl-protected group ; floor The compound of formula I, in the case when Ri is a glcyl group substituted in the cs-position, is reacted with an aldehyde or ketone, and according to paragraph 2 iris signs, 27.10.70 with Rs being hydrogen or esterified into a carboxy group ester and all other features.