DE2818025A1 - METHOD FOR PRODUCING CEPHEM CONNECTIONS - Google Patents

Description

2818 0 2b

Ίοheda Chemical Industries

27, Doshomachi 2-chome, Higashi-ku, Osaka, Japan

Process for the preparation of cephem compounds

BATH ORIGINAL 809 8Λ5 / 0782. -

The invention relates to a process for the production of cephem compounds, in particular cephem compounds the formula

CH ₂ OCONH ₂ ^ ₁ -J

COOE ²

2
wherein R is hydrogen or an ester radical, or their salts. The process is characterized in that a compound of the formula

E ¹ CO-NH

COOE ²

1 2

wherein R CO is an acyl radical and R has the meaning given above, or a salt of this compound with a silylating agent and thereby a compound silylated on the carbamoyl group of the 3-position forms, the silylated compound reacts with a halogenating agent and thereby the corresponding Iminohalide compound forms the iminohalide compound with a lower aliphatic Alcohol converts to the corresponding imino ether compound and the imino ether compound d ^ r solvolysis subject.

The end products mentioned above, in particular 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid

2 (compound of the formula (I) in which R is hydrogen (hereinafter sometimes referred to as "7-ACC" for short), are important intermediate products for production

809845/0782

of cephalosporin antibiotics with a carbamoyloxymethyl group in 3 position. -

Processes for the production of 7-ACC have already been used described. For example, Japanese Patent Application Laid-Open No. 32829/1973 describes a method

to produce 7-ACC using ^ -Aminocephalosporanic acid (hereinafter referred to as 7 — AGA designated) as the starting material. However, this method is technically disadvantageous because it requires numerous manufacturing steps, an expensive "..-." Starting material (7-ACA) used and a stage of Requires esterase hydrolysis. In the meantime it has been assumed by the applicant that the process for the preparation from 7-ACC from 7- (D-5-amino-5-carboxyvaleramido) -3-hydroxymethyl-3-cephem-4-carbonic acid (deacetyl-; _; Cephalosporin C, hereinafter sometimes referred to as "DCPC"), which can be obtained directly by fermentation in high Yield is produced with low production costs (Nature New Biology 246 (1973) 154, Japanese Offenlegungsschrift 491/1974), for large-scale production is the most advantageous method. However, this method is still unsatisfactory. For example becomes the 3-hydroxymethyl group in this process first converted to a carbamoyloxymethyl group, whereupon the 7-acylamide group has to be split off in order to 7 — ACC, but with the latter Reaction the carbamoyl group with the reagent for the cleavage shown by the formula below used phosphorus pentachloride reacts so that the Achieving a satisfactory result is impossible (Tetrahedron Letters 1976, 2401). Λ

803845/0782

818025

OCH.

ECONH

0 PC Z ^ / Py

CH ₂ OCIMH ₂

COOCHjO,

COOCHxL

Methanol

CH ₂ OCNHP (OCH _x ). COOCHjo,

- N - ^ s ?? - L-XIpUOJ-NLi-L \ .υυιι ^ / ρ

(RCO = acyl; φ = phenyl; Py = pyridine)

The above problem was posed by the applicant investigated, whereby it was found by NMR spectrometry that the carbamoyl group in the 3-position des Cephalosporin ring can easily be silylated with a silylating agent and that the silylated carbamoyl group Resists attack by the halogenating agent, e.g., phosphorus pentachloride. Further investigations on the basis of these findings led to the conclusion that compounds of the general Formula (I) including 7-ACC advantageously on an industrial scale from DCPC as starting material can be produced. Further investigations following these findings led to perfection the invention.

In the above general formulas, the acyl radical R ^ CO can be any acyl radical up to is known in the field of penicillins. and cephalosporins. For example, 5-amino-5-carboxyvaleryl, Phenylacetyl and phenoxyacetyl. Acyl radicals of the formula are particularly preferred

HOOC9H (CH ₉ ) oCO-R

809 845 ^3/0782

wherein R-, is a protected amino group.

In the above formulas, the protecting group on the protected amino group R-. be any protecting group known as such in cephalosporin chemistry. Examples include: phthaloyl, naphthoyl, benzoyl, benzoyl substituted with nitro groups, halogen atoms or lower alkyl radicals (C ^ -C.) (E.g. chlorobenzoyl, p-nitrobenzoyl, toluoyl and pt-benzoyl), benzene sulfonyl, with lower alkyl radicals (C ₁ -C ₄ ) substituted benzenesulfonyl groups (e.g. pt-butylbenzenesulfonyl and toluenesulfonyl), aryl-substituted acyl radicals (e.g. phenylacetyl and phenoxyacetyl), camphor sulfonyl, alkyl-substituted sulfonyl groups (e.g. methanesulfonyl), acetic, acetylated, aliphatic acid derivatives (e.g. n-decanoyl, acryloyl, pivaloyl and chloroacetyl), esterified carboxyl groups (e.g. t-butoxycarbonyl, xthoxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichlorathoxycarbonyl, benzyloxycarbonyl and ß-methyl-

sulfonylethoxycarbonyl), carbamoyl groups (e.g. Methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl) and the corresponding thiocarbamoyl groups.

The rest of the r _? is a hydrogen atom or an ester _: radical. Any ester radicals commonly used in cephalosporin chemistry are suitable. For example, R, a benzhydryl radical, t-butyl radical, 2,2,2-trichloroethyl radical, p-nitrobenzyl radical, cyanomethyl radical, methylthiomethvir radical, methoxymethyl radical or pivaloyloxymethyl radical. Due to its easy availability, it is particularly useful to use the connection in which R _? Hydrogen is to be used.

809845/0782

The compounds of the general formula (I) can form salts via their amino or carboxyl functions. For example, you can use salts with inorganic acids, e.g. hydrochloric acid, sulfuric acid and salic acid, Salts with organic acids, e.g. p-toluenesulphonic acid and oxalic acid, salts with alkali metals or alkaline earth metals "e.g., sodium, potassium, calcium and magnesium, and salts with organic Form bases, e.g. triethylamine, trimethylamine and triethanolamine.

The compounds (II) or their salts used in the process according to the invention are obtained by carbamoylation of compounds of the formula

E ¹ COMi η f ^£ >

J H ^ J- CHpOH CIII)

0 ^X T ρ COOR

1 2

wherein R CO and R have the meanings given above, or their salts are prepared. This reaction can be carried out by known methods such as the methods described in Japanese Patent Laid-Open Nos. 16494/1972, 81887/1973, 67222/1973, 67290/1973, 32829/1973 and 52083/1975. For example, a compound of the general formula (III) with an isocyanate of the general formula is normally used for the carbamoylation

R ⁵ NCO (IV)

wherein R is a hydrogen-substitutable group to a compound of the formula

CH ₂ OCOHHE ⁵ CV)

COOE ²

12 5
implemented, in which R CO, R and R have the meanings given above, whereupon the radical R in the connec-

809845/0782

- 8 - - .- "■■■

■ 2> ... 28T & Q25

dung (V) is substituted with a hydrogen atom, whereby a compound of the general formula (II) is obtained. The compound of the general formula (V) and the reaction conditions are according to the teachings of the patent publications mentioned above chosen. From the patent publications mentioned in the named isocyanates (R NCO) are compounds in which R is chlorosulfonyl, monohaloacetyl, Is dihaloacetyl or trihaloacetyl,. preferred. The compound (IV) is chlorosulfonyl isocyanate particularly useful. For example, this connection is made with a connection of general Formula (III) implemented, whereby the corresponding compound of the formula (V) is obtained. This connection can be easily converted into a compound of the general formula (II) by treatment with water under acidic conditions.

It should be noted that the great majority of the "compounds" represented by the general formula (III) are known compounds that are, however, also new connections can be easily produced using processes that are analogous to the known processes *

The compound of the general formula (II) obtained is then silylated. This silylation occurs through Reaction of the compounds of the general formula (IV) with a silylating agent.

Suitable silylating agents are compounds of the formula P ¹ PP Sl.Hai, in which P, P and P each represent a hydrocarbon radical, e.g. a lower alkyl radical with 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl and η- Butyl) or an aryl radical (for example phenyl and ToIyI) and Hal is a halogen atom, preferably chlorine or bromine, of which

1 2 3 '

Radicals P, P and P one or two for a halogen atom, preferably chlorine or bromine, and one

80984570782

12 3
the radicals P, P and P can be hydrogen. In the process according to the invention, hexa-alkyl (C.-C.) -Cyclotrisilazane, octaalkyl (C ₁ -C ₄ ) -cyclotetrasilazane, trialycl (C ₁ -C ₄ ) -silylacetamide and bis-tri-alkyl ( C.-C.) silylacetamide can be used. Preferred silylating agents are, for example, alkyl (C ₁ -C ₄ ) trihalosilane (eg trimethylsilyl chloride), dialkyl (C 1 -C 4 dihalosilane (eg dimethyldichlorosilane) and dialkoxy (C.-C.) dihalosilane (eg dimethoxydichlorosilane and diethoxydichlorosilane) is preferably carried out in the presence of a base (e.g. triethylamine, pyridine, picoline and N, N-dimethylaniline) The reaction also takes place in the absence of a solvent, but is preferably carried out in an inert solvent, e.g. dichloromethane, dichloroethane, chloroform, benzene, toluene The silylating agent is normally used in excess, preferably in an amount of 1.2 to 2 mol, based on the theoretical amount, per mole of the compound (II) moles per mole of the compound (II). the reaction temperature is normally about -20 ° to 40 ⁰ C. the reaction is usually in about 1 Stu ended. After the reaction has ended, the reaction mixture is used as such or after being concentrated to a suitable concentration in the next reaction. Through this silylation reaction, a silyl group is introduced into the carbamoyl group. if

■ γ
the acyl radical (R CO) contains a free carboxyl group and Rp in COOR "is a hydrogen atom, silyl groups are also introduced into these carboxyl groups, with silyl esters being formed. Japanese Patent Application Laid-Open No. 40899/1970 specifies

809345/0782

made that a silyl ester is an excellent protecting group for carboxyl groups in the case of removal is an acyl radical.

The silylated compound thus obtained then undergoes an amide bond cleavage reaction subject. The various known for these amide cleavage reactions in cephalosporin chemistry Procedures can be used for this purpose. For example, the processes are suitable those in Japanese Patent Publication 13 862/1966 and Japanese Laid-Open Publications 95292/1975 and 96591/1975. In the method according to the invention, the silylated Compound is converted into an imino halide and the latter is converted into an imino ether compound and the latter is finally subjected to solvolysis, the compound of general formula (I) being obtained will.

First, the silylated compound with a Halogenating agents, e.g. phosphorus pentachloride, implemented, the imino halide being obtained. Per mole of the silylated compound about 1 to 4 moles of phosphorus pentachloride are used. The reaction temperature is about -50 ° to 45 ° C. The reaction is in an inert solvent, e.g. dichloromethane, chloroform, tetrahydrofuran, benzene or Toluene. After this reaction to form the imino halide, the reaction mixture becomes usually treated with a lower aliphatic alcohol to convert the imino halide into the imino ether compound to convert. Suitable alcohols are, for example, methanol, ethanol and n-butanol. These The reaction is usually carried out in an inert solvent, e.g. dichloromethane, chloroform or tetrahydrofuran, at a temperature in the range of about

60984S / 07I2

-I-

-50 ° to +45 ⁰ C. The reaction is usually complete in about 10 minutes to 1 hour. The imino ether compound formed in this way is subjected to solvolysis. The solvolysis is usually carried out by treating the imino ether compound with an alcohol, for example the lower aliphatic alcohol mentioned as the solvent, or water or the lower aliphatic alcohol and water.

The amide bond is cleaved by solvolysis. The silyl group or groups are affected by the action the lower aliphatic alcohol or water is also removed. In this way, the Compound (I) or its salt according to the invention is obtained in excellent yield. This solvolysis is usually performed under acidic conditions. The solvent is used in excess. The reaction temperature can range from about -50 ° to about 45 ° C. The reaction is in about 10 minutes completed within 1 hour. The acidic conditions can be caused by the presence of an inorganic acid, e.g. hydrochloric acid, sulfuric acid or phosphoric acid, can be set in the reaction mixture. The pH of the Mixture usually does not exceed 1.

The amide cleavage reaction can also be carried out by reacting the imino halide with hydrogen sulfide or thioacetamide reacted, the thioamide derivative obtained in this way activated and the activated one Compound is subjected to solvolysis (e.g. Japanese Patent Laid-Open No. 96591/1975). The conditions the reaction (reaction temperature, solvent, etc.) between the imino halide and the Hydrogen sulfide or thioacetamide can be similar be as in the above-mentioned reactions for the formation of the iminohalide and the iminoether-

809845/0782

; _; : ■ "■ 28Ϊ8025Ϊ

bonds "The thioaramid compound can be activated, for example, by reaction ^: with TrichXorraethsulfenylchlorid or Schwefelraonochiorid" The solvolysis of the compound activated in this way is carried out in exactly the same way as the solvolysis of the invinoether compound "and leads to the compound of the formula (I) _β

When R in the obtained compound of the formula (X) _ ■. ' - ^: _.-..- ■ - ο "

is an ester residue, the compound in which R is hydrogen, optionally by removing the ester residue in the usual way. .Weise, .. z, B ₄ by hydrolysis, decomposition with an acid j reduction or the like. are produced by methods known per se ₃

The solution containing the compound (X) can Un- * can be used indirectly in the next reaction, or the compound (X) can be isolated beforehand. The isolation of the compound (I) can be carried out in a customary manner Wise done »If, for example, the reaction mixture is cooling down to near its isoelectric 7-ACC leaves the point Mixture from * This precipitate is filtered off with a: : organic solvent and water washed and dried · The compound can optionally in an can be further cleaned in a known manner.

An advantageous embodiment of the invention can can be represented by the following reaction scheme:

809845707t

TSL ~ '

HOOCCH (CH ₀ ) -,

CH ₀ OCONH ₂

COOH silylating agent

5 '

CCOY ¹

Halogenating agent ¹

CHC CH ₂ ) ^ C = F _n ^ ^S \

ß ⁵ JN. J-CH ₀ OY ²

o ^ r ²

CCOY

aliphatic alcohol (ROH)

OR
Y ¹ OOOCH (CS, LC = Ii

T
COOY ¹

aliphatic alcohol and / or water (solvolysis)

H ₀ N-. ^ ^S -n 0

Jv ^^ CH ₂ 0CNH _? (7-ACC) "COOH

In the above scheme, R is a protected amino

1 2

group, Y a silyl group, Y a silylated group

Carbamoyl group, X is a halogen atom, and ROH is an aliphatic one Alcohol.

809845/0782

- .14 -

The end products of the process according to the invention are valuable as starting materials for manufacture of various cephem compounds with excellent antibacterial properties. In particular 7-ACC and its salts are valuable as starting materials for the manufacture of antibiotics the formula

s "4 in which η is a number in the range of 0%. nS.1 and R is hydrogen or a lower alkyl radical, and their pharmaceutically acceptable salts. The compounds of the formula (VI) can be attached to the carboxyl function or to the group of the formula

HnJ'i -

pharmaceutically acceptable salts associated with the form with the compound (I) mentioned acids or bases.

2 The compound of formula (VI) in which R is hydrogen and R are hydrogen can be prepared, for example, by the following reaction steps:

809845/0702

7-ACC or its salt

I XCH COCHpCOX <^ L GH ₀ = r-CH-

XCHp'-CCH ₀ CCNK -τ- ^^ η

CHpOCNHp (VII '

COOH ί nitrosating agent

XCH ₂ COCCONH

i {

OH

COOH

CIXD

COOH

Here, η has the meaning already mentioned, while X stands for chlorine or bromine.

A compound of formula (VII) is prepared from 7-ACC by reacting the latter with 1 to 1.5 molar equivalents of a 4-halo-3-oxobutyryl halide. This acylation reaction is carried out in a solvent, e.g. dimethylformamide, dichloromethane, dimethylacetamide, dimethyl sulfoxide, chloroform or acetonitrile or a mixture of these solvents in the presence of 1 to 3 molar equivalents of an organic base, e.g. triethylamine, Ν, Ν-dimethylaniline or pyridine, at a temperature between -40 ° and +40 ⁰ C, preferably with cooling to a temperature of -40 ° to ^{0 0} C.

809845/0782

leads. The compound (VII) formed here is in Form of crystals by extraction, concentration, etc. Isolated.

The compound CVIi) is then nitrosated to the compound (VIII). For this purpose, the compound (VII) is previously in a; Solvent, for example acetic acid or aqueous acetic acid, dissolved. 1 to 2 molar equivalents of a nitrosating agent, for example sodium nitrate, are added to the solution. The reaction is conducted at -40 ° to + -2q ⁰ C cftirciigefuEtrt. "■ The encryption thus formed

".binding. CVIIlJ becomes! by extraction and phase transition Isolated in the form of a powder.

The connection; CViDLI ί becomes; then reacted with 1 to 2 molar equivalents of 1 ml of urea to give compound (IX). This reaction; will; at 0 ° ,, ζ to 20 "C in a solvent, .3 * dimethylformamide, dimethylacetamide, / Dlmethy / Isttlf ydi ^ od he conducted acetonitrile or a mixture of these Lasusntgjsmlfefeel The case gesblMete;!. V / erbintditicigj iJXl after Verfahxeni as

2CS Extraction ^ - Phasemobergjang »pH adjustment ^ crystal l— satloim, »Säuslenchromatagiraphle etc. isolated and · ge—

Warn d & n Werblctdiniigeim der Fernrei (VI) can be a Ver-CXJ, dl.hi «d! Ie V / er / feimdlemg (VI), In der R ²

Hydrogen tends K elmi näledterer / Alkylres.t _r z

ÄtBüy / I ,, cc- & ϊ: αψψ1 oxäer Jsepropyl, is:

COOH

0 (XJ

wherein Y is the above-mentioned lower alkyl group and η has the meaning given above, by reaction of a carboxylic acid of the formula

ZH ₁ N

HnIi

CXI] IJ

OY

in which Y and η have the meanings given above and Z is hydrogen or a protective group _r or a reactive derivative of this carboxylic acid can be prepared with 7-ACC. In this compound (XI) for example, the following protecting groups are Z: aromatic acyl groups _R, for example, benzoyl, halogen atoms, nitro groups or lower alkyl groups (. C ₁ -C) substituted benzoyl (eg chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl and toluoyl ) , Naphthoyl, phenylacetyl, phenoxyacetyl, benzenesulfonyl, benzene sulfonyl groups substituted with lower alkyl radicals (C 1 -C 6) (for example p-t-butylbenzenesulfonyl and toluenesulfonyl), camphor sulfonyl, methanesulfonyl, (for example acetic acid radicals derived from aliphatic or halogenated aliphatic carboxylic acids , Valeryl, caprilyl, n-decanoyl, acryloyl, pivaloyl,

Haloacetyl (such as monochloroacetyl, monobromoacetyl, dichloroacetyl and trichloroacetyl), esterified carboxyl (eg Xthoxycarbonyl, t-butyloxycarbonyl _r isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl and Benz.yloxycarbonyl) yl groups carbamoyl groups (such as methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl) and the corresponding Thiocarbamo-. The protected in this way or the unprotected carboxylic acid can be used as such or as SO reactive öerivrafe as acylating agent for the

dter Ί— Äncictcigjoiippe of connection (Iί ver—

-HJ-

be turned. For example, the free acid (XI), its salt with an alkali or alkaline earth metal (e.g. sodium, potassium and calcium) or with an organic amine (e.g. trimethylamine or pyridine) or its reactive derivative, e.g. an acid halide (e.g. the acid chloride or acid bromide ), the acid anhydride, the mixed acid anhydride, an active amide or an activated ester or the like. can be used for the purpose of the aforementioned acylation. Examples of the activated esters are the p-nitrophenyl ester, the 2,4-dinitrophenyl ester, the pentachlorophenyl ester, the N-hydroxysuccinimide ester and the N-hydroxyphthalimide ester. As mixed acid anhydrides, for example, mixed anhydrides with carbonic acid monoesters (e.g. monomethyl carbonate and monoisobutyl carbonate) and mixed anhydrides with lower alkanoic acids, which can optionally be substituted by halogen atoms (e.g. pivalic acid and trichloroacetic acid), are suitable. When the protected or unprotected carboxylic acid (XI) is used as it is or in the form of a salt, an appropriate condensing agent is used. Suitable condensing agents are, for example, N, N'-disubstituted carbodiimides, ¹ ZiB. N, N ¹ -dicyclohexylcarbodiimide, azolides, for example N, N * -carbonylimidazole and NjN'-thionyldiimidazole, dehydrating agents, for example N-ethoxycarbonyl ^ -ethoxy-l ^ -dihydroquinoline, phosphorus oxychloride and alkoxyacetylene (e.g. methyl iodide and 2-fluoropyridinium methyl iodide). When such condensing agents are used, the reaction appears to proceed via a reactive derivative of the carboxylic acid (XI). The reaction is generally carried out in a suitable solvent. Examples of suitable solvents are

809845/0782

halogenated hydrocarbons, for example chloroform and methylene chloride, ethers, for example tetrahydrofuran and dioxane, dimethylformamide, dimethylacetamide, acetone, water and mixtures of these solvents. The carboxylic acid (XI) or its reactive derivative is usually used in an amount of about 1 to several molar equivalents per mole of the compound (I). This reaction is generally carried out at a temperature ranging from -50 ° to +40 ⁰ C. After the acylation reaction, the protecting group can be removed. A protective group of the amino group can be removed by processes known per se, for example by the processes described in Japanese laid-open specification 52083/1975 and in Pure and Applied Chemistry 7 (1963) 335, or by analogous processes. For example, when the protecting group Z is a monohaloacetyl group (e.g., monochloroacetyl), the monohaloacetyl group can be removed from the amino group by reacting the acylated compound, the amino group of which is thus protected, with thiourea and a basic reagent. This reaction is usually carried out in a solvent near room temperature and is completed in 1 to 10 and more hours in many cases. Any solvents that do not interfere with the reaction are suitable, e.g. ethers (e.g. ethyl ether, tetrahydrofuran and dioxane), lower alcohols (e.g. methanol and ethanol), halogenated hydrocarbons (e.g. chloroform and methylene dichloride), esters (e.g. ethyl acetate and butyl acetate), ketones (e.g. acetone and methyl ethyl ketone), water and mixtures of these solvents.

The reaction of the protected compound (X) with thiourea and a basic reagent results in a selective and smooth course of the reaction to

809845/0762

desired removal of the monohaloacety! group and thus to the formation of the compound (X). Suitable basic reagents for this reaction are, for example, alkali and alkaline earth salts of lower aliphatic carboxylic acids and inorganic or organic bases with pKa values of not less than 955, preferably with pKa values in the range from 9.8 to 12.0 * Examples of the salts of lower aliphatic carboxylic acids are the salts of lower aliphatic Cj-Cg carboxylic acids (e.g. sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium, sodium formate, sodium propionate and potassium hexanoate). Examples of these inorganic bases are the alkali salts of carbonic acid (e.g. Sodium carbonate and potassium carbonate) = Suitable as organic bases are, for example, amines which are singly, doubly or triply substituted with lower C * - C. and butylamine) and 5- to 6-membered cyclic amines with lower ^C 4- ^C 2 ~ alkyl radicals N- (z _e as N-methylpyrrolidine, N-Äthylpyrrolidiri, N-methylpiperazine and N-Äthylpiperazin) As substituted already mentioned, thiourea used in this reaction, but can also be N- or N, N-substituted thiourea (eg Methyl ! thiourea, N, N-diethylthiourea and NjN-hexamethylene thiourea) can be used in place of thiourea.

The starting material (XI), e.g., 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid (syn-isomeres), may can be prepared, for example, by the method described in detail below.

First, a ^ halo-S-oxo ^ -hydroxyiminobutyric acid derivative the general formula

YfCE CCG-CCOi ⁷
2 ti

OE ⁺

2 4 ¹

wherein X is a halogen atom (z _o B _o chlorine or bromine), R

is a lower alkyl radical (eg, Bo methyl) and R is a lower C - C ₃ »alkyl radical (eg _o ethyl), reacted with thiourea, with a 2- (2-aminothiazol-4-yl) = 2-methoxyiminoacetic acid derivative of the general formula

HnN "-C-COOR '

LXIII)

Λ t 7

in which R and R have the meanings given above, is obtained. In this case, the compound (XIII) falls as a mixture of the syn and anti isomers at. The reaction is usually carried out by reacting thiourea to the compound (XII) in an organic solvent such as ethanol, methanol or tetrahydrofuran at room temperature or lets act at elevated temperature. The amount of the thiourea can be about 1 to 3 moles per mole of the compound (XII) amount «,

The desired syn isomer can be obtained from the mixture of the syn and anti forms of the compound (XIII) according to the known method or that described in Japanese Patent Application 1o8 1o2 / 1976 Process can be separated and recovered. The obtained compound (XI) wherein Z is hydrogen can optionally after introducing a protective group Z in a manner known per se after a likewise known one Process can be converted into a reactive derivative.

809845/0782

Note that in the above formulas, it is assumed that the components

and ^ZH ln ^N

HnI J— ^ - HnN

tautomeric structures of the 2-aminothiazole and 2-iminothiazoline forms assume as follows:

F., !! " ■ HIi. r- ~

N-

ZHIJ _c , - ZH

N U-

(2-aminothiazole form) (2-iminothiazoline form)

The compounds (VI) and their pharmacologically acceptable salts can also be used as injection solutions how the well-known cephalosporin and penicillin drugs are administered. These connections are new and have excellent activity against a wide range of microorganisms including gram-negative bacteria such as Escherichia coli, Serratia marcescens, Proteus rettgeri, Enterobacter cloacae and Citrobacter freundii and are persistent against ß-lactamase. The compounds can be used, for example, as disinfectants to remove the aforementioned Microorganisms from surgical instruments or as medicines for the treatment of infectious diseases be used. When using the compounds (VI) or their salts as agents for Therapy of infectious diseases, e.g. peritonitis, Inflammation of the respiratory system, urinary tract and other infections, they can harmlessly warm-blooded animals including humans,

SD9845 / 0782

the mouse and the rat parenterally in a daily dose of 1 to 20 mg / kg body weight in three to four doses distributed throughout the day. The compounds can be used in conventional drug forms be formulated. For example, injection solutions prepared by methods known per se can be administered intramuscularly or intravenously will. As a carrier for these injection solutions, for example, distilled water and physiological Saline solution can be used.

example 1

427 mg of benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate are suspended in 6 ml of dichloromethane. After adding 300 mg of pyridine, 150 mg of dimethyldichlorosilane are added while cooling with ice. The mixture is stirred for one hour at room temperature, the ester being completely dissolved. The solution is cooled to -20 ⁰ C. After adding 600 mg of phosphorus pentachloride, the mixture is stirred for 30 minutes. During this time the temperature rises to -10 ° C. The mixture is cooled to -40 ° C. and 4 ml of methanol are added. The mixture is then stirred for 15 minutes, after which 6 ml of water and 4 ml of tetrahydrofuran are added. The layers are separated, the aqueous layer is removed and the organic layer is extracted with water. The aqueous layers are combined, washed once with dichloromethane and neutralized with sodium hydrogen carbonate. It is then extracted with a solvent mixture of dichloromethane and tetrahydrofuran and the extract is washed with aqueous sodium chloride solution, dried, filtered and concentrated. Petroleum ether is added to the residue, crystals separating out. Benzhydryl-V-amino-S-carbamoyloxymethyl-

809845/0782

S-cepherrMU-carboxyiate in the form of crystals from Melting point 120 to 122 ° C obtained.

, .- cm *): 1775, 1728 - ■ ;. ".

WMRCd ₆ -IMSO):. = Δ 3.53 (2H, ABq ₅ J = 2OHs, 2-CH ₂ ), 4-.66 (2H, '.-. ABq; J = IJHz, 3-CH ₂ ) ;, 4 -.8KlH, - d, J = 5Hz, 6-H), 5.03 (IH, d, J = 5Hz, .7-H) ₁ 6.55C2H, broad, a -OCNH ^ ⁶ · ⁹⁰ (IH, s, - CH ^ ₂ ), 7.39C1OH, m) _e ".. / \

■ "■ - ■ - ■■ Example 2" ■■ "" .. "- ■■ - ..: ■ -"_;

8.6 l of dichloromethane are cooled to -30 ° C. in flowing nitrogen, whereupon 1.7 kg of the ditriethylamine salt of 7- (D-5 ~ pt-butylbenzamido-5-carboxyvaleramido) -3-hydrQXymethyl-3-cephem-4- carboxylic acid can be added. The mixture is stirred while 450 g of anhydrous potassium carbonate is added and suspended. At -25 ⁰ C the cooling bath is removed. Then 1 1 of dichloromethane containing 450 g of chlorosulfonyl isocyanate was added within a time of about 5 minutes, and the mixture is stirred for 40 minutes at -10 ⁰ C .. The mixture is prepared by adding 3 N hydrochloric acid to pH 0.1 to 0.2 and stirred for 30 minutes at room temperature. It is then adjusted to pH 2.7 with potassium carbonate and extracted with 12 l of tetrahydrofuran. After addition of 580 g of triethylamine, the extract is concentrated, dissolved in 15 l of dichloromethane, dried over anhydrous Magnösiuims "ulfate, filtered and concentrated, whereby a syrupy substance is obtained. After addition of 5 l of ether, the syrup turns into a powder. The powder is filtered off and dried, 1.7 kg of the ditriethylamine salt of 7- (D-5-pt-butylbenzamido-5-carboxyvaleramido) -s-carbamoyloxymethyl-S-cephem-A-carboxylic acid in the form of a crude powder This product contains, which is lactone

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- 35 -

^ 28Ί8025

but completely suitable for the next Deacylierungsrt.aktion, 3 g of the raw powder are purified by column chromatography on the ion exchange resins "Amberlite XAD-2" and "Sephadex LH-20" and freeze-dried. Here, I ₅ 12 g of Ditriäthylaminsalzes of 7- (D-5-p ~ t-Butylbenzamido-5-carboxyvaleramido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid of high purity.

IF (KBr, cm " ¹ ): 1770, I33O

NMLCd ₆ -FMSO): δ 1.1 * (18H, t, J = 6Hz, Et ₅ NxS), 1.3l (9H, s, t-ßu), 1.4-2.0 (4H, m- -CH (CHO ₂ -CH ₂ -), 2.20 (2H, t, J = 6Hz, -CH (CH ₂ ) ₂ CH ₂ -), 2.9K12H, q, J = 6Hz, Et _x Nx2), 5.17 &? Λ8 (2Η, ABq, J = 18Hz, 2-CH ₂ ), 4.24 (1H, m, -OH (CIy ₃ -), 4.66 & 4.87 (2H, ABq, J = IJHz ₅ 3 "CH ₂ ), 4.94 (1H ₁ d, J = 5Hz, 6-H), 5.5O (1H, dd, J = 5 & 8Hz, 7-H), 6.4 ^ (2H, broad-s, -OCONH ₂ ), 7.46 (2H, d, J = 8Hz, arom -H), 7.79 (2H, d, J = 8Hz, Arom-H), 8.03 (IH, d, J = 8Hz, -CONH-), 8.64 (IH, d, J = 8Hz, -CONH-)

Elemental analysis for ^C ₈ ^H ₆₂ ^N 3 ⁰ 9 6 ^{S 'H} 2 ⁰ Calculated: C 57.26; H 8.09; N 10 "54 Found: C 57.17; H 8.41; N. 10.38 Under flowing nitrogen, 1.7 kg of the ditriethylamine salt of 7- (D-5-pt-butylbenzamido-5-carboxyvaleramidoJ-S-carbamoyloxymethyl-S-cephem-A-carboxylic acid / are dissolved. 2, . 6 1 N, N-dimethylaniline and 970 ml Dimethyidichlorsilan added The mixture is stirred for 40 minutes at 20 to 30 ⁰ C. After cooling to -35 ⁰ C. 1.25 kg of phosphorus pentachloride was added in one The mixture is for 15 minutes at.. - stirred for 20 ⁰ C. Then 5.0 1 of methanol are added dropwise at -30 to -25 ° C. The mixture is for 20 minutes at

/ in 7.3 l of dichloromethane

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-2O ° C stirred. After adding 4.0 l of water, the The mixture was stirred at 10 to 13 ° C. for a further 30 minutes. It is adjusted to pH 3.5 with 20% sodium carbonate. The precipitate formed in this way is filtered off and washed with 5 l of dichloromethane and 5 l of methanol. Here, 600 g of T-amino-S-carbamoyloxymethyl-3-cephem-4-carboxylic acid are used obtained in the form of a raw powder. The powder is added to 2 1 4N hydrochloric acid. The mixture is 15 minutes at room temperature stirred, whereupon the insoluble substances are filtered off. 300 ml of ethyl acetate are added to the filtrate. The mixture is adjusted to pH 3.5 with 20% sodium carbonate. After adding 2 l of methanol the mixture is stirred for 30 minutes and cooled with ice. The crystals formed are filtered off, washed three times with 300 ml of water each time and three times with 400 ml of acetone each time. 175 g 7-Amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid obtained of high purity.

UVA.max (pH 6.5, phosphate) 265 m (£ 7885) It (KBr, cm " ¹ ): 1800, I710, I333

KMECd ₆ -IMSO): δ 3.34 &. 3.57 (2H, ABq, J = 18Hz, 2-CH ₂ ), 4.58 & 4.87C2H, ABq, J = 13Hz, 3-CH ₂ ), 4.76ClH, d, J = 5Hz, 6-H), 4.96C1H, d, J = 5Hz, 7-H), 6.50 (2H _f broad s, -OCONH ₂ )

Elemental analysis for: C ^ H ₁ ^, 0 ^ E · 0.5 "H ₃ O Calculated: C 38.29; H 4.29; N 14.89 Found: C 38.84; H _/ 4.25; N 14.12

Example 3
5.21 g of 7- (D-5-phthalimido-5-carboxyvaleramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid are in a

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Dissolved mixture of tetrahydrofuran and dichloromethane (volume ratio 1: 1). The solution is cooled to -35 ° C. While stirring, a mixture of 2 ml of chlorosulfonyl isocyanate and 2 ml of dichloromethane is added over the course of 10 minutes. During this time the temperature is kept at -35 to -3O ° C. The temperature is then increased to 13 ^° C. After adding 10 ml of 3N hydrochloric acid, the mixture is stirred for 30 minutes. After adding 30 ml of saturated aqueous sodium chloride solution, the organic layer is separated. To the organic layer are added 10 ml of a saturated sodium chloride aqueous solution and 10 ml of water. The mixture is adjusted to pH 4.0 with aqueous sodium carbonate while stirring. The aqueous layer is separated and washed with a mixture of 20 ml of tetrahydrofuran and 20 ml of dichloromethane. After adding 50 ml of a mixture of tetrahydrofuran and dichloromethane (volume ratio 1: 1), the mixture is adjusted to pH 2.5 with hydrochloric acid while stirring. The organic layer is separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained is dissolved in 20 ml of tetrahydrofuran. 100 ml of ethyl acetate are added to the solution. The mixture is concentrated to about 60 ml and the precipitate is filtered off. 200 ml of ether are added to the filtrate. The precipitate is filtered off, washed with ether and dried over phosphorus pentoxide. This gives 4.6 g of 7- (D-5-phthalimido-5-carboxyvaleramido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.

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1789, "1330 '■''-.' ■ -

JME (d ₆ -rMS0) ;: δ 1.26-2.36 (6H ₃ m _? - (CH ^ -), 3 .45 (2H, ABq,

J = 18Hz, 2-CH ₂ ), 4.Tf (IH ,. t, J = 7Hz, -CH-), 4.77 (2H, \ IBq, J = 43.Hz, 3-CH ₂ ), 5.06 (IH _r d, J = ^ Hz, 6-H), 5.62. ^: (IH, dd, J = 5 & 8 Hz, .7-H), 6:56 (. 2H ₁ 3, COKH _2), 7.92 (4Ή, s, arom-H), 8.74 (1H, d, J ^ 8Hz, -GONH-)

4.6 g of V-iD-S-Phthalimido-S-carboxyvaleramidoJ-S-carbamoyloxymethyl-3-cephem-4-carboxylic acid are added in a mixture of 30 ml of dichloromethane, 1.8 ml of triethylamine and 6, S ml of N, N- Dissolved dimethylaniline. After addition of 3.0 ml of dimethyldichlorosilane, the mixture is stirred for one hour at room temperature, then cooled to -35 ⁰ C and mixed with g-2.J75 Phosphorpentaehlorid. The mixture is stirred for 15 minutes at -30 to -25 ° C, then cooled to -40 ° C and gradually mixed with 15 ml of methanol. During this time, the temperature of the solution is kept between -30 and -20 ° C.

The mixture is then stirred for 20 minutes at -20 to -17 ⁰ C. After this time 15 ml of water are added. The mixture is adjusted to pH 3.7 with aqueous sodium carbonate and stirred for one hour while cooling with ice. The precipitate formed is filtered off, washed with dichloromethane, methanol and water in this order and dried over phosphorus pentachloride. This gives 1.70 g of T-amino-S-carbamoyloxymethyl-S-cephem-A-carboxylic acid. The infrared spectrum of this product agrees with that of the product prepared according to Example 2.

Example 4

7.0 g of deacetylcephalosporin C sodium monohydrate are added to 19 ml of water solved. The solution is 9 ml

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Tetrahydrofuran and 6.8 g of N-Carboäthoxyphthalimid added "with stirring, an aqueous potassium carbonate solution is added so that the pH value of the mixture _f 30 minutes at 9 to 9.3 l, and during the following hour at 9.7 to 9.8 is held. Then 26 ml of tetrahydrofuran and 32 ml of dichloromethane are added = while cooling with ice and stirring, the mixture is adjusted to pH 2.5 with 3N hydrochloric acid ml of dichloromethane extracted. The organic layers are combined, washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off, a syrupy product being obtained as a residue. This residue is dissolved in 25 ml of tetrahydrofuran. 25 ml of dichloromethane are added to the solution. The mixture is cooled to -35 ° C. With stirring, a mixture of 2 ml of chlorosulfonyl isocyanate and 2 ml of dichloromethane is added over a period of 10 minutes. During this time, the temperature of the solution is kept at -35 ° to -30 ° C. The temperature is increased to 13 ° C within 30 minutes. After adding 10 ml of 3N hydrochloric acid, the mixture is stirred for 30 minutes. After adding 30 ml of aqueous sodium chloride, the organic layer is separated, washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After 6.3 ml of triethylamine have been added, the solvent is distilled off, a syrupy residue being obtained. This residue is dissolved in 50 ml of dichloromethane. 13 ml of N, N-dimethylaniline and then 6 ml of dimethyldichlorosilane are added to the solution. The mixture is stirred for one hour at room tempera door, then cooled to -40 ⁰ C and under stirring

809845/0782

mixed with 5.5 g of phosphorus pentachloride. The mixture is kept at -30 ° to -25 ° C for 15 minutes and then cooled to -40 ° C. At this temperature, 30 ml Methanol added gradually. During this time, the temperature of the solution is kept at -30 to -17 ° C. The temperature is then held at -17 ° C. for 20 minutes. After this time the mixture becomes more aqueous Sodium carbonate solution adjusted to pH 3.7 and stirred for one hour while cooling with ice.

IC The precipitate is filtered off, washed with dichloromethane, methanol, water and acetone in this order and dried over phosphorus pentoxide. 2.32 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid are thereby obtained obtain. The infrared spectrum of this product agrees with that obtained according to Example 2 Product.

Reference example 1

139 mg of benzhydryl-7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate are suspended in 2 ml of dichloromethane. After adding 100 mg of pyridine, 50 mg of dimethyldichlorosilane are added while cooling with ice. The mixture is stirred for about 50 minutes, a homogeneous solution being obtained. After addition of a further amount of 50 mg of pyridine, the mixture cooled to -20 ⁰ C, are added followed by 200 mg of phosphorus pentachloride. The mixture is then stirred for 30 minutes and cooled with ice. After this time it is cooled to -10 ° C. and 2 ml of water and 2 ml of tetrahydrofuran are added. The mixture is separated into phases. The organic layer is removed and analyzed by thin layer chromatography. The chromatogram shows only one spot at the same Rf value as that of the starting compound. The mixture is dried and concentrated and the residue is treated with ether. The here formed

80S8A5 / 0782

Crystals are filtered off. The infrared spectrum of this product agrees with that of benzhydryl 7-phenylacetamido-S-carbamoyloxymethyl-S-cephern-'i-carboxylate completely agree.

The above reaction is repeated without using dimethyldichlorosilane. The thin layer chromatogram this reaction product mixture shows no stain of the starting compound. Of the Stains without migration are made visible (solvent for development: mixture of ethyl acetate and Dichloromethane in a ratio of 8: 2).

Reference example 2

1). 189 g of diketene are dissolved in 945 ml of dichloromethane. While cooling to -5O ° C, 159 g Chlorine added. Separately from this are 410 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 334 g of triethylamine dissolved in a mixture of 1.5 l of dimethylformamide and 1.5 l of dichloromethane. the Solution is cooled to -25 ° C and then added dropwise with the above reaction mixture at a temperature not exceeding -18 ° C. The mixture is stirred at this temperature for 30 minutes. Then 1 kg of phosphoric acid, 3.75 1 of water, 8.5 1 of methyl ethyl ketone and 3 1 of ethyl acetate are added to the reaction mixture added. Sodium chloride is added with stirring until it is saturated. The organic Layer is removed and the aqueous layer extracted with 4.2 1 methyl ethyl ketone and 1.5 1 ethyl acetate. The organic layers are combined, washed three times with 1.5 1 aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off. The residue 500 ml of ethyl acetate are added. The crystals formed in this way are filtered off and dried. Here, 463 g of 7- (3-oxo-4-chlorobuty-

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rylaminoJ-S-carbamoyloxymethyl-S-cephem-A-carboxylic acid obtain.

IR (KBr, cm ^ ¹ ) ^; 1773, a745 (sir.), 1720 _r . 1660, 1540, 1535 NMECd ₆ -CMSO): 5'3 Λ2 & 5.66 (2H, ABq, J = 18Hz, 2-CH ₂ ),; 3.60 (2H, s, -GOCH ₂ GO-), 4.56 (2H, s, C ^ CH ₂ ), 4.64 & 4. ° A (2H, ABq, J = IJHz, 3-GH ₂ ), 5.12ClH, d , J = 5H &, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 6.52 (2H, broad s, COEH ₂ ), 9.02 (1H, d, J = 8Hz, -COlTO -).

2) In a mixture of 2.8 1 acetic acid and 0.7 1 463 g of 7- (3-oxo-4-chlorobutyrylamino) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid become water suspended. The suspension contains 81.5 g of sodium nitrite of 10 minutes with the temperature at 0 ° is kept up to 3 ° C. After the addition, the Mixture stirred for 30 minutes at the same temperature, whereupon 500 ml of phosphoric acid, 15 l of ethyl acetate and 4.5 l of water are added. Then sodium chloride is added to saturation. The organic Layer is removed and the aqueous layer extracted with 5 liters of ethyl acetate. The organic layers are combined, twice with 3.5 l of saturated aqueous Sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off, whereupon 500 ml of dichloromethane and 2 liters of petroleum ether are added. The here formed Precipitation is filtered off and dried. 433 g of 7- (2-hydroxyimino-3-oxo'-4-chlorobutyrylamino) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid are thereby obtained (syn-isomeres) obtained «

809845/0702

IK (KBr, cnT ¹ ): 1785, 173O (sh), 1715, 1660, 1545, 1J30 m (d ₆ -mS0): 63 Λ2 & 3.64 (2H, ABq, J = 18Hz, 2-CH ₂ ), 4.62 & 4.92 (2H, ABq, J = 13Hz, 3-CH ₂ ), 4.81 (2H, s, COT ₂ -), 5.15 (1H, d, J = 5Hz, 6-H), 5.78 (1H, dd, J = 5 & 8Hz, 7-H), 6.52 (2H, broad_ _s? CONH ₂ ), 9.26 (1H, d, J = 8Hz, -CONH-), 13.12 (IH, s, = N-0H).

3) 400 g of 7- (2-hydroxyimino-3-oxo-4-chl orbutyrylami.no) -3-carbamoyl oxymethyl-3-cephem-4-carboxylic acid (syn-isomeres) with 76.1g Thiourea suspended. The suspension is stirred for 6 hours at room temperature. After that time will be 3 1 ether added. The mixture is stirred and the supernatant is then discarded.

2 l of methanol are added to the remaining mixture.

The resulting mixture is added dropwise to 24 liters of ethyl acetate. The precipitate formed is filtered off, dissolved in 1 l of methanol and added dropwise to 20 l of ethyl acetate. The precipitate is filtered off and dried, dissolved in an aqueous solution of sodium hydrogen carbonate (160 g) and attached to a column of the ion exchange resin "Amberlite XAD-2" was chromatographed. The development is done with water. The active factions will be poured together, concentrated and freeze-dried. The lyophilizate will purified by column chromatography on "Sephadex LH-20". The active fractions are concentrated and freeze-dried. 118.5 g of sodium / 2- (2-imino-4-thiazolin-4-yl) -2-hydroxyiminoacetamide 7-3-carbamoyloxymethyl-3-cephem-4-carboxylate are thereby obtained (syn isomer) obtained. '

809845/0782

IB (KBr, cm " ¹ ): 1770, 1710, 1670, 1610, 1540, 1330 ₂ O): δ 3.39 & 3.?Ο(2Η, ABq, J = ISHz, 2-CHp), 4.70 & 4.9? ( 2Η, ABq, J = I ^ Hz, 3 "CH ₂ ), 5.24 (1H ₁ d, J = 5Hz, .6-H), 5.86 (1Η, d, J = 5Hz, 7-Η), 6.98 (1H / s, thiazoline

5-Η).

UVX ^H 2 ° ran (S): 225 (19700), 258 (15000) max

Reference example 3

1) 121 g of ethyl ^ -chloro-S-oxo ^ -hydroxyiminoacetate and 47.6 g of thiourea are added to 600 ml of ethanol.

The mixture is stirred for 3 hours at room temperature. The ethanol is distilled off under reduced pressure. 350 ml of water are added to the residue. The watery Layer is washed with ether, neutralized with sodium hydrogen carbonate (pH 7.5) and with a Extracted mixture of ethyl acetate and tetrahydrofuran (volume ratio 1: 1). The organic layer is washed with water and dried. The solvent is then distilled off, 45 g of one crystalline product can be obtained.

This product is purified by chromatography on silica gel (developer system: ethyl acetate-n-hexane). The anti-form of Ethy1-2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetate is released from the front part of the eluate obtained while the syn form of the same compound is obtained from the trailing part of the eluate.

syn isomer: White crystals with a pale yellow Stich, melting point 185.5 ° C.

Elemental analysis for Cr ₇ HqN ^ O _x S

Calculated: C 39.06; H 4.21; N 19.52

Found: C 39.28; H 4.10; W 19.63

809845/0762

: δ 6.80 (1Η, S, thiazole 5-H), 7.12 (2H _} broad s., NH ₂ ) ,. 11.6C1H, s, OH)

2) 10.6 g of sodium carbonate are dissolved in 150 ml of water. The solution becomes a solution of 10.7 g Ethyl 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetate (syn-Isomeres) was added in a mixture of 150 ml of tetrahydrofuran and 50 ml of methanol. While with ice is cooled, 12.6 g of dimethyl sulfate are added dropwise over a period of 5 minutes. To When the addition is complete, the ice bath is removed and the mixture is stirred at room temperature. Here begins the deposition of a white crystalline substance. After 3 hours, more of the organic becomes The solvent is distilled off and the residue is cooled with ice. The precipitate formed is filtered off, rinsed with water and dried. Here, Xthy1- (2-aminothiazol-4-yl) -2-methoxyiminoacetate (syn-Isomeres) obtained in the form of white crystals with a melting point of 163-164 ° C.

Elemental analysis for π ττ w η ς

Calculated: _c 41.91 ', H 4.84; N 18.33 Found: _c 41.57; H 4.76; N 18.07 NMF (CrCe ₃ ) δ: 4.02 (3H, s, OCH ₅ ), 5.80 (2H, broad s, NH ₂ ) 6.74 (IH, s, thiazole 5-H)

3) 2.15 g of xthyl-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetate are added to 10 ml of Ν, Ν-dimethylformamide (syn isomer, melting point 163-164 ° C) dissolved. While cooling with ice, the solution .1.27 g of chloroacetyl chloride added dropwise. The mixture is cooled with ice for 30 minutes and then at room temperature Stirred for 30 minutes. Then apply 50 ml of water added. The mixture is washed twice with 100 ml of ethyl acetate each time

809845/0782

extracted. The extracts are combined, washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution in this order and dried. The solvent being ethyl-2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetate (syn isomer) is obtained in the form of crystals of melting point 111-112 ⁰ C is distilled off.

Elemental Analysis for C ₁₀ H ₁₂ N ₃ O Calculated: C 39.29; H 3.96; N I3.74 Found: c 39.15; H 3.91; N 13.69 NME (CDC ^): δ 4.00 (3H, s, ^ STILL ₅ ), 4.24- (2H, s, 7.15 (1H, s, thiazole 5-H)

4) 9.62 g of ethyl 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetate (Syn-Isomeres) are dissolved in a solution containing 85 ml of water, 452 ml of ethanol and Contains 9 g of potassium hydroxide. The mixture is stirred for 2 hours at room temperature. The ethanol is under distilled off under reduced pressure. 85 ml of water are added to the residue. The mixture is made with 100 ml Washed ethyl acetate and the aqueous layer adjusted to pH 2 with 10% hydrochloric acid and twice with extracted 200 ml of ethyl acetate each time. The extracts are combined with saturated aqueous sodium chloride solution washed and dried. The solvent is then distilled off, with 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid (syn-isomeres) is obtained in the form of crystals with a melting point of 170-171 ° C.

Elemental analysis for CgHgNgO ^ SC £ Calculated: C 34.60; H 2.90; N 15.13

Found: · C 34.97; H 3.03; N 14.74

809845/0792

₆ : δ 5.95 (3H, s, = ^ 7.57 (IH, s, thiazole 5-H)

5) 1.5 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetic acid (syn isomer) are dissolved in 60 ml of dry tetrahydrofuran. 0.55 g of triethylamine are added to the solution with stirring. The mixture is cooled to -10 ⁰ C, followed by 0.74 g of isobutyl chloroformate are added dropwise. The mixture is stirred at this temperature for 2 hours. To the resulting solution of mixed acid anhydrides, an ice-cold solution of 0.55 g of triethylamine and 1.5 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 60 ml of 50% aqueous tetrahydrofuran is added. The mixture is stirred for 1 hour while cooling with ice and then for 2 hours at room temperature. A larger part of the tetrahydrofuran is distilled off under reduced pressure, whereupon 600 ml of water and then 120 ml of ethyl acetate are added. The mixture is adjusted to a pH of about 2 with 1N hydrochloric acid and separated into two phases. The aqueous layer is extracted three times with 150 ml of ethyl acetate each time. The ethyl acetate layers are combined, washed with water, dried and concentrated, whereby 1.75 g of 7- / 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamide 7-3-carbamoyloxymethyl-3-cephem-4-car - Bonsäure can be obtained. The entire amount of this product is dissolved in 45 ml of tetrahydrofuran. After adding 0.6 g of thiourea and 1 g of sodium acetate trihydrate, the mixture is stirred for 4 hours at room temperature. The precipitate is filtered off, dissolved in 30 ral water and adjusted to a pH of about 7.0 with sodium hydrogen carbonate. It is then purified by passing it through a column of "Amberlite XAD-2" ion exchange resin. 100 mg sodium / 2- (2-aminothiazol-4-yl) -

809845/0782

Z-methoxyiminoacetamido T-S-carbamoyloxymethyl-S-cephem-4-carboxylate (syn isomer) obtained in the form of a white powder.

NME Spectrum (E ₂ O): 6 3.48 (2H, q, 2-CH ₂ ), 3.92 (3H, s, OCH ₅ ), 4.16 (2H, q, 3-CH ₂ ), 5.? 7 (1H , d, 6-H), 5.7O (1H, d, 7-H), 6.95 (1H, s, thiazole 5-H)

809845/0782

Claims (10)

Claims 1) Process for the preparation of cephem compounds of formula J- N ^^ - CHpOCNH ₂ o Tp- COOE ^ in which R is hydrogen or an Es'cer radical _s or their salts _s characterized in that a compound of the formula E ¹ CONH _Ί s % ο CH ₂ OCM ₂ COOR ² 1 2 in which R CO is an acyl radical and R has the meaning given above, or a salt of this compound with a silylating agent and thereby a compound silylated on the carbamoyl group of the 3-position forms, the silylated compound reacts with a halogenating agent and thereby the corresponding Iminohalide compound forms the iminohalide compound with a lower aliphatic Alcohol converts to the corresponding imino ether compound and the imino ether compound of solvolysis subject. 2) Method according to claim 1, characterized in that R ² What:
formula R is hydrogen and the acyl radical is a group of HOOCCH (CH ₂ ) ^ CO- is where R is a protected amino group. 3) Method according to claim 1 and 2, characterized in that the acyl radical is a 5-p-t-butylbenzamido-5- 809845/0782 2-318025 carboxyvaleryl group is » 4) Method according to claim 1 and 2, characterized in that the acyl radical is a D-5 ~ p-t-butylbenzamido-5— is carboxyvaleryl group, 5) Method according to claim 1 and 2, characterized in that the acyl radical is an S-phthalimido-S-carboxyvaleryl group is, 6) Method according to claim 1 and 2, characterized in that the acyl radical is a D-5-phthalimido-5 ~ carboxyvaleryl group is. 7) Process according to claim 1 to 6, characterized in that the silylating agent is dimethyldichlorosilane used 8) Process according to claim 1 to 7, characterized in that there is methanol as the lower aliphatic alcohol used. 9) Process according to claim 1 to 6, characterized in that the halogenating agent used is phosphorus pentachloride used. 10) Method according to claim 1, characterized in that R CO- a D-5-p-t-butylbenzamino-5-carboxyvaleryl- or D-S-phthalimido-S-carboxyvaleryl group, as Silylating agent dimethyldichlorosilane, as halogenating agent phosphorus pentachloride and as lower Alcohol methanol is used. 809845/0782