FI64941C - 0-SUBSTITUTES 7BETA-AMINO-3-CEFEM-3-OL-4-CARBOXYLSYRAFOERENINGAR - Google Patents

Description

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lBJ (11) UTLÄGGNINGSSKRIFT 6 4 941? SjS c (45); - ID ·; ι 1-: 21 ^ ^ (51) Kv.ik.3 / int.a.3 C 07 D 501/59, 501/18 FINLAND —FINLAND (M) IWaltokemu · - P «Mnt« M6lt » ln (792008 (22) HtktmltpUvi - Ara & Vninpdaf 10.09.79 (23) AlkupUvt — GI (tlth «odif 30.05-73 (41) Tullut | ulktMksl - Bllvlt offantH | 10.09.79

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Patent · och regietaratyrelMn 'Amftkan uttafd och utUkrHten publicerad 31.10.83 (32) (33) (31) Pjrr1 · *** «uollwut —Bugtrd priority 29.06.72 17.08.72, 22.12.72, 23.02.73 Swiss Switzerland ( CH) 9788/72, 12195/72, 18722/72, 2655/73 (71) Ciba-Geigy AG, CH- ^ 002 Basel, Switzerland-Switzerland (CH) (72) Riccardo Scartazzini, Allschwil, Hans Bickel, Binningen, Switzerland-Schweiz (CH) (7 ^) Oy Jalo Ant-Wuorinen Ab (5U) O-substituted 7§-amino-3-cephem-3-ol-U-carboxylic acid compounds -O-substituent 7-amino-3-cephem The present invention relates to O-substituted 7β-amino-3-cephem-3-o-O-substituted 7β-amino-3-cephem-3-o Intermediates for the preparation of 1-4-carboxylic acid compounds of the formula

RrN1 \ · - · · 0 = · —άχ / i-0-R3 (A) 0 = 4-r2

A

wherein R1 represents an acyl group of formula

O

R - (X) m - CH - C - (B) d Iu 1

R b wherein R represents phenyl, hydroxyphenyl, 1,4-cyclohexadienyl or thienyl, X represents oxygen, m represents 0 or 1, and R 1 represents hydrogen, or when m represents 0, also hydroxy or hydroxy, R 2 represents hydroxy. and R 1 lower alkyl or phenyl lower alkyl and are known to be O-substituted 76-amino-3-cephem-3-ol-4-carbo- ____ - τ _______ 2 64941 carboxylic acid compounds of the formula NH 2 N___ ol -, i -O-R 3 (I) 0-1 -R 2 wherein R 2 represents hydroxy or a radical forming a carboxyl group protected in esterified form with a carbonyl group -C (= O) and lower alkyl or phenyl-lower alkyl, or salts thereof.

The enol derivatives of this invention are ethers of 3-cephem-3-ol compounds that can be used to prepare pharmacologically effective 3-cephem compounds.

In the protected carboxyl group of the formula -C (= O) -R2, R2 primarily represents an etherified hydroxy group R2 »which forms a esterified carboxyl group which can be cleaved under mild conditions, wherein any functional groups present in the carboxyl protecting group R2 can be protected in a manner known per se.

The group R2 is, for example, in particular a halogen-substituted lower alkoxy group, such as α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, in which halogen denotes, for example, chlorine, bromine or iodine, in particular 2.2, 2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy, or an optionally substituted, such as lower alkoxy, e.g. methoxy or nitro-containing 1-phenyl-lower alkoxy group, such as optionally substituted benzyloxy or diphenylmethoxy, e.g. benzyloxy, as mentioned above, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, further an organic silyloxy or stanynyloxy group such as tri-lower alkylsilyloxy, e.g. trimethylsilyloxy.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl.

Phenyl-lower alkyl is, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl.

/ ». , 3 64941

The salts are, in particular, salts of the compounds of the formula I having a free carboxy group and are preferably metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, and ammonium salts, including amine. or with suitable organic amines, and in the case of salt formation are preferably aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary polyhydric, di- or polyamines, as well as heterocyclic bases, such as lower alkylamines, lower alkylamines, trialkylamines, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-amino-benzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. bicyclohexylamine, or benzylamines, e.g. Ν, Ν '-dibenzyl-ethylenediamine, in addition to pyridine-type bases, e.g. pyridine, collidine or quinoline. The compounds of formula I may also form acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. trifluoroacetic acid or 4-methylenephenylsulfonic acid. Compounds of formula I having a free carboxy group may also exist as internal salts, i.e. as "double ions".

The novel compounds according to the invention are valuable intermediates in the preparation of compounds having pharmacological effects and can be converted into such compounds, for example, according to the method disclosed in patent publication FI 59 602.

The invention relates primarily to 3-cephem compounds of formula I.

J

4,64941 compounds wherein R 2 represents hydroxy, diphenylmethoxy or p-nitrobenzyloxy and lower alkyl or 1-phenyl-lower alkyl or salts of these compounds.

The compounds of formula I can be obtained, for example, by reacting a cefem-3-one compound of formula

H2 \ A

• - · ·

o = A — άΝ / i = o (ID

; O = C-R 2 or an equivalent enol having a double bond in the 2,3- or 3,4-position is converted to an enol derivative having a functionally modified group of the formula -OR 4 in the 3-position, and in the resulting compound of formula I of the formula -C ( = O) -R2-protected carboxyl group in esterified form is optionally converted to a free or another ester-protected carboxyl group and / or the resulting salt-forming compound is optionally converted to a salt or salt to the free compound or to another salt, and / or the resulting mixture of isomers is desired. separated into individual isomers.

The cefem-3-one starting materials of formula II may be in keto and / or enol form. The starting materials of formula II are generally converted from the enol form to the enol derivatives of formula I. In addition, a mixture of a compound of the formula II and the corresponding 1-oxide can also be used, for example, as a starting material, whereby a mixture of a compound of the formula I and the corresponding 1-oxide is obtained. In this case, the compound of the formula II can be used in pure form or in the form of a crude reaction mixture obtained during their preparation.

The conversion of the compounds of the formula II into enol derivatives can take place in a manner known per se.

Enol ethers, i.e. compounds of formula I in which R 1 is lower alkyl or phenyl-lower alkyl, are obtained according to a suitable method for etherification of enol groups. The etherification reagent used is preferably a diazo compound of the formula R 1 -N 2 (III) corresponding to the optionally substituted hydrocarbon residue R 1, preferably a phenyl-substituted diazo lower alkane, e.g. diazomethane, diazoethane, diazo-n-butane. a diazoalkoxy alkane such as 1-phenyldiazoalkanalkane, e.g. phenyldiazomethane. These reagents can be used in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon such as methylene chloride, lower alkanol or ethanol, e.g. methanol, e.g. such as in the presence of a dialkyl alkyl ether, e.g. diethyl ether, or a cyclic ether, e.g. tetrahydrofuran or dioxane, or a mixture of solvents and always depending on the diazo reagent while cooling, at room temperature or with little heating, in addition in a sealed vessel and / or inert gas, e.g.

In addition, enol ethers of formula I can be formed by treating an alcohol of formula R 1 -OH (IV) with a reactive ester. Suitable esters are preferably those obtained from strong inorganic or organic acids, such as mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acids, further sulfuric acid or halogenated sulfuric acids, e.g. fluorosulphuric acid, or strong organic sulphonic acids. such as optionally, e.g. halogen, such as fluorine-substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as e.g. optionally, e.g. lower alkyl, such as methyl, halogen, such as bromine, and / or nitro-substituted benzenesulfonic acids, e.g. - or with p-toluenesulfonic acid. These reagents, in particular lower alkyl alkyl sulphates, such as dimethyl sulphate, in addition to lower alkyl fluorosulphates, e.g. methyl fluorosulphate, or optionally halogen-substituted methanesulphonic acid lower alkyl esters, or in the presence of a hydrocarbon, e.g. methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a mixture. In this case, suitable condensing agents are preferably used, such as alkali metal carbonates or bicarbonates, e.g. sodium or potassium carbonate or bicarbonate (usually in combination with sulphate), or organic bases, such as generally sterically hindered trial leaving alkylamines, e.g. N, -diisopropyl-N-ethylamine (preferably in combination with lower alkyl halosulphates or optionally halogen-substituted methanesulphonic acid lower alkyl esters) while working under cooling, at room temperature or under heating, e.g. at a temperature of about -20 to about 50 ° C, if necessary in a closed and / or in an inert gas atmosphere, e.g. nitrogen.

Enol ethers can also be prepared by treating on the same carbon atom of an aliphatic nature with two or three etherified hydroxy groups of formula R 1 -O- (V), i.e. the corresponding acetal or orthoester, in the presence of an acidic substance. Thus, for example, gem-lower alkoxy-lower alkanes, such as 2,2-dimethoxypropane, a strong organic sulfonic acid, such as toluenesulfonic acid, and a suitable solvent, such as lower alkanol, e.g. methanol, or di-lower alkyl or dimethylsulfoxynulfoxysulfine, can be used as the etherifying agent. or in the presence of an orthomuric acid trialempkyl alkyl ester, e.g. in the presence of dioxane to give compounds of formula I in which R3 represents lower alkyl, e.g. methyl or ethyl.

The enol ethers of the formula I can also be obtained by treating the compounds of the formula II with the tri-R-oxonium salts of the formula (1 * 3) 3 OA (VI) (so-called Meerwin salts) and the formula (RO) ) With di-R-10-carbenium salts of CHCH A (VII) or

J ^ 0 Θ J

van (R -) - Hal with di-R - halonium salts according to A (VIII), wherein

Θ J ^ 0 J

A represents an acid anion and Hal a halonium, especially bromonium ion. Suitable are, in particular, trialemalkyloxonium salts, as well as dialeralkoxycarbenium or dialempkylhalonium salts, in particular the corresponding salts with complex fluorinated acids, such as the corresponding tetrafluoroborates, hexafluoroantimonates or hexachloroantimonates. Such 64941 reagents include, for example, trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate, or dimethyl bromonium hexafluorothiamide. These etherifying agents are preferably used in an inert solvent such as ether or a halogenated hydrocarbon, e.g. diethyl ether, tetrahydrofuran or methylene chloride, or mixtures thereof, optionally with a base such as an organic base, e.g. preferably a sterically hindered trialminalkylamine. in the presence of -isopropyl-N-ethylamine, and under cooling, at room temperature or with little heating, e.g. at about -20 to about 50 ° C, if necessary in a sealed vessel and / or in an inert gas, e.g. under a nitrogen atmosphere.

The enol ethers of formula I can also be prepared by treating the starting materials of formula II with a 3-substituted 1R, N-triazene compound (IX) (i.e. a compound of formula -N = N-NH-R 1), wherein the substituent of the 3-nitrogen atom means via a carbon atom a bonded organic residue, preferably a carbocyclic eryl residue, such as an optionally substituted phenyl residue, e.g. lower alkylphenyl, e.g. 4-methylphenyl. Such triatene compounds include 3-aryl-1-lower alkyl triazenes, e.g. 3- (4-methylphenyl) -1-methyltriazene, 3- (4-methylphenyl) -1-ethyltriazene, 3- (4-methylphenyl) -1-n-propyl-triazene or 3- (4-methylphenyl) -1-isopropyl-triazene, or 3-aryl-1-phenyl-lower alkyl-triazenes, e.g. 3- (4-methylphenyl) -1-benzyl- triazine. These reagents are usually used in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, e.g. benzene, or mixtures of solvents, and under cooling, at room temperature or preferably at elevated temperature, e.g. about 20 to about 100 ° C, if necessary in a sealed vessel, and / or in an inert gas atmosphere, e.g. nitrogen.

64941

In the above-mentioned etherification reaction, depending on the starting materials and the reaction conditions, compounds of the formula I or mixtures thereof with the corresponding 2-cephem compounds are obtained in each case. The latter compounds are obtained, for example, by using compounds of the formula II containing impurities of heavy metals, such as chromium II, or, if they are not isolated from the compounds of the formula XII, by using the impure compounds of the formula XII or by carrying out the reaction under basic conditions; this results in an increasing amount of 2-cephem. The mixtures obtained can be separated in a manner known per se, e.g. by suitable separation methods, e.g. in etc.

In the compound of the formula I thus obtained, in which the group of the formula -C (= O) -R 2 is a carboxyl group protected in the esterified form of the formula -C (= O) -1R, and / or the amino group is protected, these can be known in a manner known per se, e.g. as described below, is converted to a free carboxyl group or to another protected carboxyl group in esterified form.

The compounds of formula II used in the above process for the preparation of the starting materials of formula I can be prepared, for example, by reacting in a 3-cephem compound of formula

rf

H- ^ \ _ / K

Γ 0 XI

^ CH2 "0 c * CH3 0 - c - r2

(I

64941 wherein R 4 represents hydrogen or preferably an amino protecting group such as acyl R 1, and wherein R 2 preferably represents hydroxy but also an etherified hydroxy group R 1, the acetyloxymethyl rhythm is converted to a hydroxymethyl group, e.g. by hydrolysis in a weakly basic sodium pH solution such as aqueous sodium 9-10, or by treatment with a suitable esterase, such as an enzyme obtained from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, the free carboxyl group of formula -C (= O) -R2 is functionally modified in a suitable manner, e.g. -treated by treatment with a diazo compound such as diphenyldiazomethane and a hydroxymethyl group, e.g. by treatment with a halogenating agent such as a chlorinating agent, e.g. chloromethyl or iodomethyl group. The chloromethyl group is converted to the methylene group either directly, e.g. by treatment with a suitable chromium II compound such as an inorganic or organic salt thereof, e.g. chromium II chloride or chromium II acetate in a suitable solvent such as dimethyl sulfoxide, or indirectly via an iodomethyl group for example by treating the chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone) and converting the iodomethyl group to a methylene group by treatment with a suitable reducing agent such as zinc in the presence of acetic acid.

In the compound of the formula thus obtained

f XII

O 2 CH 2 o = c - r 2 obtained from compounds of formula XI, e.g. also by electrochemical reduction or reduction with chromium-II salts or aluminum amalgam, oxidatively cleaves the methylene group after the amino group in the 7-position has been liberated from the optionally protected amino group, and the compound is converted to the desired compound of formula II.

In the compound of formula XII, the protected amino group in 7-a4en) can be converted into a free amino group in a manner known per se.

10 64941

A

The amino protecting group, especially the easily cleavable acyl group, can be cleaved, e.g., an α-polybranched lower alkoxycarbonyl group such as a tert-butyloxycarbonyl group can be cleaved by treatment with trifluoroacetic acid, and a 2-halo-lower alkoxycarbonyloxy-2-trichloroethoxy or 2-trichloroethoxy; -sicarbonyl or phenenyloxycarbonyl group, e.g. by treatment with a suitable reducing metal or similar metal compound, e.g. zinc or a chloro-II compound such as chloride or acetate, preferably together with the metal or metal compound to form a hydrogen-forming substance, especially an aqueous carrier in the presence of acid.

In addition, in a compound of formula XII in which the carboxyl group of formula -C (= O) -R 2 is preferably present, e.g. by esterification, also by silylation, e.g. by reaction with a suitable organic halosilicon or halotin-IV compound such as trimethylchlorosilane or tri-n-butyl protected carboxyl group with tin chloride, acyl

A

the group R 1 in which the free functional groups optionally present are optionally protected is liberated by treatment with an imide halide-forming agent, reacting the formed imide halide with an alcohol and cleaving the imino ether formed, whereby the carboxyl group protected by an organic silyl residue can be liberated already during the reaction.

Imide halide-forming substances in which halogen is attached to an electrophilic central atom are, above all, acid halides, such as acid bromides and especially acid chlorides. Such substances are primarily acid halides of inorganic acids, in particular phosphorus-containing acids, such as phosphorus oxy, phosphorite and especially phosphorus pentahalides, e.g. phosphorus oxychloride, phosphorus trichloride and primarily phosphorus pentachloride, and , such as thionyl chloride, phosgene or oxalyl chloride.

The reaction with one of the abovementioned imide halide-forming agents is preferably carried out with a suitable, in particular organic base, preferably a tertiary amine, e.g. a tertiary aliphatic mono- or diamine, such as a trialkylalkylamine, e.g. trimethyl, triethyl or N, N-di- isopropyl-N-ethylamine, in addition to N, N, N ', N'-tetra-lower alkyl-lower alkylenediamine, e.g. N, N, N', N'-tetramethyl-1,5-pentylenediamine or N, N, N ', N1-tetramethyl-1,6-hexylenediamine, a mono- or bicyclic mono- or diamine, such as 11,64941 N-substituted, e.g. N-lower alkylated alkylene, azaalkylene or oxaalkylene amine, e.g. N-methyl -piperidine or N-methylmorpholine, in addition to 2,3,4,6,7,8-hexahydro-pyrrolo (1,2-a) pyrimidine (diazabicyclononene; DBN) or a tertiary aromatic amine such as dialkylalkylaniline, e.g. N, N-dimethylaniline or a primarily tertiary heterocyclic, mono- or bicyclic base such as quinoline, or a large in the presence of a quinoline, especially pyridine, preferably using a solvent such as an optionally halogenated, e.g. chlorinated, aliphatic or aromatic hydrocarbon, e.g. methylene chloride. In this case, approximately equimolar amounts of the imide halide-forming substance and the base are used? however, the latter may also be used in excess or undercut, e.g. about 0.2 to about 1-fold, or up to 10-fold, especially about 3-5-fold excess.

The reaction with the imide halide-forming agent is preferably carried out under cooling, e.g. at a temperature of about -50 to + 10 ° C, however higher temperatures, i.e. up to 75 ° C, may also be used if the stability of the starting materials and products allows the use of a higher temperature.

The imide halide product, which is usually further used without isolation, is reacted according to the invention with an alcohol, preferably in the presence of one of the abovementioned bases, to give the imino ether. Suitable alcohols are, for example, aliphatic and araliphatic alcohols, preferably optionally substituted, such as halogenated, e.g. chlorinated or lower hydroxy-containing lower alkanols, e.g. ethanol, propanol, or butanol, in particular methanol, in addition to 2-halo-lower alkanols, e.g. 2.2 , 2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl lower alkanols such as benzyl alcohol. Usually, for example, up to 100 times the excess alcohol is used and it is preferred to work with cooling, e.g. at a temperature of about -50 to + 10 ° C.

The iminoether product is most preferably cleaved without isolation. Cleavage of the iminoether can be accomplished by treatment with a suitable hydroxy compound, preferably by hydrolysis, in addition to alcoholization, whereby the latter, using an excess of alcohol, can be performed immediately after iminoether formation. In this case, water or an alcohol, in particular a lower alkanol, e.g. methanol or an aqueous mixture of an organic solvent, such as alcohol, is preferably used.

____ Τ 'Τ ~ 64941

Certain acyl residues of the acylamino group in a compound of formula XII, such as a 5-amino-5-carboxyvaleryl residue, in which the carboxyl is optionally protected, e.g. by esterification, in particular with diphenylmethyl, and / or the amino group is protected, e.g. by acylation, in particular , such as dichloroacetyl or phthaloyl, may also be cleaved by treatment with a nitrosating agent such as nitrosyl chloride, a carbocyclic arenediazonium salt such as benzenediazonium chloride, or a positive halogen-releasing solvent such as N-haloamide or imide, e.g. in a mixture such as formic acid, together with a nitro- or cyano-lower alkane and adding to the reaction product a hydroxyl-containing substance such as water or a lower alkanol, e.g. methanol, or

A

if the amino group in the 5-amino-5-carboxy-valeryl residue is unsubstituted and the carboxy group is protected, e.g. by esterification, it can be cleaved by standing in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. methylene chloride and, if necessary, amino compound in a manner known per se.

a

The formyl group R 1 can also be cleaved by treatment with an acidic substance, e.g. p-toluenesulfonic or hydrochloric acid, a weakly basic substance, e.g. dilute ammonia, or a decarbonylating agent, e.g. tris- (triphenylphosphine) rhodium chloride.

a

The triarylmethyl, such as the trityl group R 1, can also be cleaved, e.g., by treatment with an acidic substance, such as a mineral acid, e.g. hydrochloric acid.

Oxidative cleavage of the methylene group in compounds of formula XII with the formation of an oxo group at the 3-position of the kefam ring structure preferably takes place by formation of the ozone compound by treatment with ozone. In this case, ozone is preferably used in the presence of a solvent such as an alcohol, e.g. a lower alkanol such as methanol or ethanol, a ketone, e.g. a lower alkanone such as acetone, optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. , also in the presence of an aqueous mixture, while cooling or weakly heating, e.g. at temperatures of about -90 to about + 40 ° C.

The intermediate ozonide is reduced cleavage, using catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst such as nickel, palladium catalyst, preferably with a suitable support such as calcium carbonate or carbonate, or carbonate. reducing heavy metals, also heavy metal alloys or amalgams, e.g. zinc in the presence of a hydrogen donating agent such as an acid, e.g. acetic acid, or an alcohol, e.g. lower alkanol, reducing inorganic salts such as alkali metal iodides, e.g. sodium iodide such as sodium iodide in the presence of an acid, e.g. acetic acid, or reducing organic compounds such as formic acid, a reducing sulphide compound such as dialemial alkyl sulphide, e.g. dimethyl sulphide, a reducing organic phosphorus compound such as phosphine which may be optionally substituted by substituents. or aromatic hydrocarbon radicals, such as trialempkylphosphines, e.g. tri-n-butylphosphine or triarylphosphine, e.g. triphenylphosphine, in addition to phosphites which may be substituted with optionally substituted aliphatic hydrocarbon radicals, e.g. in the form of, for example, trimethylphosphite, or phosphoric acid triamides which may contain as substituents optionally substituted aliphatic hydrocarbon radicals, such as hexa-lower alkyl-phosphoric acid tretriamides, e.g. Usually, the cleavage of non-isolated ozonide normally takes place under the conditions used to prepare it, i.e. in the presence of a suitable solvent or solvent mixture, as well as under cooling or weak heating.

In each case, depending on how the oxidation reaction is carried out, a compound of the formula II or a corresponding 1-oxide or a mixture of both compounds is obtained. Such a mixture can be separated into a compound of formula II and the corresponding 1-oxide, e.g. by fractional crystallization or chromatography (e.g. column chromatography, thin layer chromatography).

When converting compounds of formula II to enol derivatives of formula I, they do not need to be isolated after their preparation; they can preferably be converted in the form of a crude reaction mixture, after their preparation from the compounds of the formula XII directly into the corresponding enol derivatives of the formula I.

__ - τ ~ 14 64941

The compounds of formula I may also be prepared in such a way that the compound of formula

RA

V

v N. / 'S.

Rb / ^ -r ^

o I XIII

O J-R 3 o = c - r 2 wherein R 2 and R 2 are as defined above, wherein -C (= O) -R 2 is preferably a carboxy group protected in esterified form, and RA is an amino protecting group and Rq is hydrogen or an acyl residue, or Rq and Rq together denote a bivalent amino protecting group, the amino group in the 7-position is liberated, and additional steps are performed if desired.

----- »

The amino-protecting group Rq is a hydrogen-substitutable group, preferably an acyl group Ac, in addition to a triarylmethyl group, especially a triethyl group, and an organic silyl and organic stanyl group. The group Ac which may also be a residue Rq is preferably an organic carboxylic acid, preferably a carboxylic acid having up to 18 carbon atoms, in particular an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic-carboxylic, heterocyclic or heterocyclic including the acyl residue of formic acid), and the acyl residue of a carbonic acid half-derivative.

A b The bivalent amino protecting group formed by the radicals Rq and Rq is in particular a bivalent acyl residue of an organic dicarboxylic acid, preferably a dicarboxylic acid having up to 18 carbon atoms, preferably a diacyl residue of an aliphatic or aromatic dicarboxylic acid.

A b

Groups R ^ resp. R 1 can be cleaved in a manner known per se, e.g. as described above for compounds of formula XII.

a

Thus, it is possible to start from compounds of the formula XIII in which Rq denotes, for example, the 5-amino-5-carboxy-valeryl residue generally present in the enzymatically obtainable 3-cephem compounds, in which case the amino group can be protected, for example, by an acyl residue, such as optionally halogen-substituted lower alkanoyl, e.g. dichloroacetyl, benzoyl or phthaloyl, and / or a carboxy group, e.g. an esterifying residue, e.g. diphenylmethyl, and Rq represents hydrogen, in such compounds in which the carboxyl in the 4-position is optionally protected, e.g. esterified, also silylated, the 5-amino-5-carboxy-valerylamino group (possibly having protected amino and / or carboxy groups) can be cleaved at the 7-position in a manner known per se, e.g. by treatment with an imide halide-forming agent, by modification imide halide to the imino ether and cleavage of the latter by hydrolysis or alcoholization (e.g. according to the method described), and in the compound of formula I thus obtained, if desired, the optionally protected carboxyl group in the 4-position can be liberated in a manner known per se.

Compounds of formula XIII may be obtained, for example, by reacting a cefem-3-one compound of formula

R ° X "1-XIV

/ VT

o = c to r 2 or an equivalent enol having a double bond at the 2,3- or 3,4-position is converted to enol derivatives having a functionally modified hydroxy group of the formula -OR 2 at the 3-position and -C (= O) The protected carboxy group according to -R2 is, if desired, converted into a free or another carboxyl group. The enol derivatives can be prepared according to the method described above.

In a compound of the formula I obtained according to the invention having a protected, in particular esterified, carboxyl group of the formula -C (= O) -R2, this can be converted into a free carboxyl group in a manner known per se, e.g. always depending on the nature of the group R2. The carboxyl group esterified, e.g., esterified with a lower alkyl residue, especially methyl or ethyl, can be converted to the free carboxyl group by hydrolysis in a weakly basic medium, e.g., by treatment with an aqueous metal hydroxide or carbonate, e.g. 10 and optionally in the presence of a lower alkanol. The carboxyl group esterified with a suitable 2-halo-lower alkyl or arylcarbonylmethyl group may be cleaved, e.g., by treatment with a chemical reducing agent such as a metal, e.g. which together with the metal is capable of forming the resulting hydrogen, such as in the presence of an acid, preferably acetic acid, and formic acid, or an alcohol to which water is preferably added, the arylcarbonylmethyl esterified carboxyl group also by treatment with a nucleophilic, preferably salt-forming, a carboxyl group esterified with sodium iodide, a suitable arylmethyl grouping, e.g. by irradiation, preferably with ultraviolet light, e.g. less than 290 μm, when the arylmethyl group means e.g. optionally in the 3-, 4- and / or 5-position, e.g. lower alkoxy and / or nitro with a substituted benzyl residue, or with longer wavelength ultraviolet light, e.g. more than 290 my, when the arylmethyl group represents a benzyl residue substituted in the 2-position by a nitro group, with an appropriately substituted methyl group such as a tert-butyl or diphenylmethyl group, an ester group. such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. by treatment with hydrogen in the presence of a noble metal, e.g. palladium catalyst.

In the resulting compound having an esterified grouping of the formula -O (= O) -1, this can be converted to another esterified carboxy group of this formula, e.g., 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl can be converted to 2-iodoethoxycarbonyl by treatment with an iodine salt. , such as sodium iodide, in the presence of a suitable solvent such as acetone.

Salts of the compounds of the formula I can be prepared in a manner known per se. Thus, salts of such acid-containing compounds may be formed by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of α-ethyl-caproic acid, or ammonia or a suitable organic amine, preferably using a stoichiometric amount or only a small excess of salt. The acid addition salts of the compounds of formula I are obtained in a conventional manner, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I containing a salt-forming amino group and a free carboxyl group may be formed, e.g., by neutralizing salts, such as acid addition salts, to an isoelectric point, e.g., with weak bases, or by treatment with liquid ion exchangers.

The salts can be converted into the free compounds in a conventional manner, the metal or ammonium salts, e.g. by treatment with suitable acids.

Da acid addition salts, e.g. by treatment with suitable bases.

17 64941

The resulting mixtures of isomers can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or using another suitable separation method. The racemates obtained can be separated into the antipodes in a conventional manner, optionally after the addition of suitable salt-forming groups, e.g. by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into diastereoisomeric salts and converting the separated salts into free compounds or fractionally active crystals.

Such starting materials are preferably used and the reaction conditions are chosen so as to obtain compounds which are initially preferred.

In this specification, "lower" organic residues, unless otherwise specified, contain up to 7, preferably up to 4 carbon atoms; acyl residues contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

The following examples illustrate the invention, temperatures are given in degrees Celsius. In the examples, the term "carboxylic acid" is used in the tennis "carboxylic acid".

Example 1:

To a solution of 0.50 g of 76-amino-cefam-3-one-4C-carboxylic acid diphenylmethyl ester as the 4-methylphenylsulfonate, which is mainly in the enol form, i.e. 7β-amino-3-cephem-3-ol-4-carboxylic acid diphenyl as the 4-methylphenyl sulfonate of the methyl methyl ester, in 25 ml of methanol a solution of diazomethane in diethyl ether is added at 0 ° until a permanent yellow coloration. Stir for 10 minutes in an ice bath and evaporate. The residue is chromatographed on silica gel. A 2: 1 mixture of toluene and acetic acid methyl ester elutes an oily 7g-dimethylamino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel, evolution of iodine vapor): Rf ^ 0.39 (system: ethyl acetate): (in ethanol): max = 265 mu (e = 6100); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.33y, 5.63p, 5.81y, and 6.23y.

Further elution with ethyl acetate gives an oily 7R-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel, evolution on iodine vapor), Rf ^ 0.20 18 64941 (system: acetic acid ethyl ester); ultraviolet absorption spectrum (in ethanol): = 265 my (ε = 5900), infrared absorption spectrum (in methylene chloride): characteristic lines at 2.98y, 3.33y, 5.62y, 5.81y and 6.24y.

Instead of diazomethane, dimethyl sulfate can be used in the presence of anhydrous potassium carbonate, 1-methyl-3- (4-methylphenyl) triazene, trimethyloxonium tetrafluoroborate in the presence of diisopropylethylamine, or trifluoromethanesulfonic acid diisopropyl ester methylmethylamine in the presence of, to give the desired 7,8-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester.

In a similar manner, starting from the 4-methylphenylsulfonate of 7-amino-cepham-3-one-4-carboxylic acid diphenylmethyl ester with diazo-n-butane, 78-amino-3-n-butoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained; ultraviolet absorption spectrum (in ethanol): \ naks = ^ (ε = 6700) 'infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96y, 5.62y, 5.80y and 6.25y, with diazoethane 7 (3-amino-3 -ethoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (in ethanol): λmax = 265 my (ε = 6500), infrared absorption spectrum (in methylene chloride): characteristic lines at 2.99y, 3.35y , 5.64y, 6.83y and 6.27y and with phenyldiazomethane 76-amino-3-benzyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester, infrared spectrum (in methylene chloride): characteristic lines at 2.99y, 3.35y, 5.63y, 5.82y and 6.25y.

The starting material used in the previous example can be prepared, for example, as follows:

To a solution of 11.82 g of crude sodium salt of 3-hydroxymethyl-78-phenylacetylamino-3-cephem-4-carboxylic acid (prepared by enzymatic deacetylation of 3-acetyloxymethyl-76-phenylacetylamino-3-cephem-4-carboxylic acid sodium salt with a purified enzyme extract from Bacillus subtilis strain ATCC 6633 followed by lyophilization of the reaction solution) in 200 ml of water, poured into 400 ml of ethyl acetate and acidified to pH 2 with concentrated aqueous phosphoric acid. The aqueous phase is separated off and the residue is extracted twice with 150 ml of ethyl acetate each time. The combined organic extracts are washed four times with 50 ml of water each time and dried over magnesium sulphate, then evaporated to about 400 ml. Excess diphenyldiazomethane is added to the solution, allowed to stand for 3 hours at room temperature, after which the granular precipitate is filtered off. The filtrate is evaporated to a volume of about 200 ml, cyclohexane is added at room temperature and, after cooling to room temperature, it is allowed to stand for a short time at about 4 °. The precipitate is filtered off and crystallized from a mixture of acetone and cyclohexane. The 3-hydroxymethyl-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester thus obtained melts at 176-176.5 ° (uncorrected); (α) D = -6 ° (c = 1.231% in chloroform); thin layer chromatogram (silica gel, development with iodine or ultraviolet light λ254 m), Rf = 0.42 (system: chloroform / acetone 4: 1); Rf = 0.43 (system: toluene / acetone 2: 1), and Rf = 0.41 (system: methylene chloride / acetone 6: 1).

1.03 g of 3-hydroxymethyl-7- (3-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimide iodide are dissolved in 25 ml under a nitrogen atmosphere. absolute tetrahydrofuran and heated for 1 hour at 35 [deg.] C. 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimide iodide in 15 ml of absolute tetrahydrofuran are then added again and the mixture is left to stand for 17 hours at room temperature under a nitrogen atmosphere. The solvent is removed from the reaction mixture on a rotary evaporator under reduced pressure, the residue is dissolved in methylene chloride and filtered through a column of 50 g of silica gel (10% distilled water is added), washed in four portions with 100 ml of methylene chloride each time; by adding 10% dripping water). A total of 900 ml of a 3: 7 mixture of toluene and methylene chloride are eluted off the non-polar impurities. Eluting with two portions of 200 ml each of methylene chloride gives 3-iodomethyl-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester; thin layer chromatographically uniform fractions are lyophilized from benzene, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00y, 5.62y, 5.82y, 5.95y, 7.32y and 8.16y.

The iodination reagent used above can be prepared as follows: In a 250 ml round-bottomed flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen sphere, 42 g of freshly distilled N, N'-dicyclohexylcarbodiimide are dissolved in 90 ml of methyl ________9-Ή under a nitrogen atmosphere at room temperature and the colorless reaction mixture is stirred for 72 hours at a bath temperature of 70 °. After this reaction time, the excess methyl iodide is distilled off from the red-brown solution under reduced pressure, and the viscous red-brown residue is dissolved in 150 ml of abs. toluene at 40 °. Within a few hours, the spontaneously crystallizing crystalline mass is separated from the mother liquor by means of a glass filter to which a nitrogen sphere is connected while shielding from air, the reaction mixture being rinsed three times with 25 ml of abs. ice-cold toluene and the same toluene are used to wash the slightly yellowish crystalline mass colorless with a glass filter. Dry for 20 hours at 0.1 mm Hg and room temperature to give N-methyl-N, N'-dicyclohexylcarbodiimidium iodide as colorless crystals, m.p. 111-113 °, infrared absorption spectrum (in chloroform): characteristic bands at 4.72μ and 6.00μ.

A solution of 0.400 g of 3-iodomethyl-78-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 15 ml of 90% aqueous acetic acid is cooled to 0 ° with an ice bath and 2.0 g is added portionwise with careful stirring. of zinc dust. Allow to react for 30 minutes at 0 °, after which the unreacted zinc dust is filtered off through a diatomaceous earth filter; the filter residue is suspended several times in fresh methylene chloride and filtered again. The combined filtrates are concentrated under reduced pressure, abs. toluene and evaporated to dryness under reduced pressure. The residue is added with stirring to 50 ml of methylene chloride and 30 ml of 0.5 molar aqueous dipotassium hydrogen phosphate solution; the aqueous phase is separated, extracted with two portions of 30 ml of methylene chloride and discarded. The organic extracts are washed several times with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on a column containing 22 g of silica gel (10% water is added). 3-Methylene-78-phenyl-acetylamino-cefam-4a-carboxylic acid diphenylmethyl ester is eluted with methylene chloride and methylene chloride containing 2% acetic acid methyl ester and recrystallized from a mixture of methylene chloride and hexame, m.p. 144-147 °, (α = 18 ° -1 ° (c = 0.715 in chloroform), uitraviolet absorption spectrum (in 95% aqueous ethanol): Amajcs = 254 my (ε = 1540) and 260 my (e = 1550); infra-red absorption spectrum (in methylene chloride): characteristic bands at 21,64941 at 2.94μ, 5.65μ, 5.74μ, 5.94y, 6.26y and 6.67μ.

To a solution cooled to -15 ° with 2.0 g of 3-methylene-78-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 80 ml of abs. methylene chloride, 3.2 ml of abs. pyridine and 32 ml of an 8% solution of phosphorus pentachloride in methylene chloride and stirred for 1 hour under a nitrogen atmosphere at -10 to -5 °. The reaction mixture is then cooled to -25 °, 25 ml of abs. methanol and stirred for 1 hour at -10 °, then for 1.5 hours at room temperature. 80 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate are then added, the pH is adjusted to 2 with 20% aqueous phosphoric acid and the mixture is stirred for 30 minutes at room temperature.

The organic phase is separated, the aqueous phase is extracted twice with 150 ml of methylene chloride each time and the organic solutions are combined, dried over sodium sulfate and evaporated. the oily residue is dissolved in 25 ml of ethyl acetate and at 0 ° a solution of 1.14 g of 4-methylphenylsulfonic acid monohydrate in 25 ml of ethyl acetate is added. A fluffy precipitate precipitates which is filtered, washed with cold ethyl acetate and diethyl ether, dried and recrystallized from a mixture of methylene chloride and diethyl ether. There is thus obtained 78-amino-3-methylene-cefam-4a-carboxylic acid diphenylmethyl ester 4-methylphenylsulfonate in the form of colorless needles, m.p. 153-155 °, (<*) D = -14 ° - 1 ° (c = 0.97 in methanol), ultraviolet absorption spectrum (in ethanol): λ ^ = 257 my (e = 1500), infrared absorption spectrum ( in methylene chloride): characteristic bands at 3.5y, 5.60y, 5.73y, 8.50y, 9.68y, and 9.92y.

A stream of oxygen and ozone (containing 0.35 g) is passed through a solution cooled to -60 ° containing 0.553 g of 78-amino-3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester 4-methylphenylsulphonate in 50 ml of methanol. mmol of ozone per minute). After 5 minutes, 0.3 ml of dimethyl sulphide is added to the light blue-colored solution. The mixture is stirred for 15 minutes at -70 °, 1 hour at -12 ° and 1 hour in an ice bath and then evaporated. The residue is dissolved in a small amount of methylene chloride, diethyl ether is added until cloudy and the mixture is allowed to stand. The microcrystalline red-colored powdery precipitate is filtered to give 4-methylphenylsulfonate of 78-amino-cefam-3-one-4ζ-carboxylic acid diphenylmethyl ester, which is mainly the enol form of 22B 4 4 9 41 sa 7B-amino-3-cephem-3 -ole-4-carboxylic acid diphenylmethyl ester as 4-methylphenylsulfonate, m.p. 143-145 ° (dec.); thin layer chromatogram (silica gel) Rf ^ 0.28 (system: acetic acid ethyl ester / pyridine / water 85: 10: 5); ultraviolet absorption spectrum (in ethanol):? max = ray (e = 3050) and 282 my (ε = 3020), infrared absorption spectrum (in methylene chloride): characteristic lines at 5.58y, 5f77y (shoulder), 6.02y and 6, 22y.

Example 2:

A solution of 0.514 g of 3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 30 ml of methylene chloride is cooled to -10 ° and 0.8 ml of abs. pyridine and 8.0 ml of 8% methylene chloride solution of phosphorus pentachloride. The reaction mixture is stirred for 1 hour at -10 to 5 °, then cooled to -30 ° and 5 ml of methanol are added. Stir for 1 hour at -10 to -5 °, 1 hour at 0 ° and 1 hour at room temperature. 20 ml of 0.5 molar aqueous potassium dihydrogen phosphate solution are added, the mixture is stirred at pH 2.4 for 30 minutes, diluted with methylene chloride, the aqueous phase is separated and extracted with methylene chloride. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is extracted with diethyl ether and allowed to stand for 16 hours at 0 °, the precipitate is filtered off, washed with diethyl ether and dried. 78-Amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a pale yellow powder, thin layer chromatogram (silica gel: evolution on iodine vapor); Rf ^ 0.17 (system: ethyl acetate), ultraviolet absorption spectrum (in 95% aqueous ethanol): Amaks = 258 my (ε = 5250) and 264 my (ε = 5300), and = 290 my (ε = 5200), infrared absorption spectrum (in dioxane): characteristic bands at 2.87y (broad), 5.62y, 5.85y and 6.26y.

Example 3:

A solution of 0.263 g of 7- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 13 ml of methylene chloride is cooled to -10 °: 0.132 ml of pyridine and 3.52 ml of 8% methylene chloride solution of phosphorus pentachloride are added. Stir for 1 hour at -10 °, then cool to -30 °, quickly add 2.2 ml of methanol cooled to -30 ° and stir for 30 minutes at -10 ° and -5 ° respectively. 6.5 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate are then added to the reaction mixture, stirred for 5 minutes at room temperature and the phases are separated. The aqueous phase is washed with methylene chloride; the combined methylene chloride phases are washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in methanol and diethyl ether is added to the solution until slightly cloudy. This gives 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester as an amorphous precipitate, thin layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate; evolution on iodine): ultraviolet absorption spectrum (95 absorption spectrum) in% aqueous ethanol): = 258 my (ε = 5700), infrared absorption spectrum (in dioxane): characteristic bands at 2.87μ, 5.62μ, 5.85μ and 6.26μ.

The starting material can be prepared, for example, as follows:

A solution of 50 g of the sodium salt of cephalosporin C in 1500 ml of 10% aqueous dipotassium hydrogen phosphate is diluted with 1200 ml of acetone and 21 g of benzoyl chloride are added at 0 °. Stir for 30 minutes at 0 ° and 45 minutes at 20 °, keeping the pH constant at 8.5 by adding 50% aqueous tricalcium phosphate solution. Evaporate under reduced pressure to about half volume, wash with ethyl acetate, acidify to pH 2.0 with 20% aqueous phosphoric acid and extract with ethyl acetate. The organic phase is dried and evaporated under reduced pressure; the residue is recrystallized from acetone to give N-benzoyl-cephalosporin C, m.p. 117-119 °; dangerous layer chromatogram (silica gel); Rf = 0.37 (system: n-butanol / acetic acid / water 75: 7.5: 21) and Rf = 0.08 (system: acetic acid ethyl ester / pyridine / acetic acid / water 62: 21: 6: 11).

A solution of 4.7 g of N-benzoyl-cephalosporin C in 85 ml of a 0.5 molar aqueous solution of dipotassium hydrogen phosphate and 9 ml of dimethylformamide is stirred with 4.7 g of aluminum amalgam for 45 minutes at pH 6. , 0 and 45 °, keeping the pH constant by adding 20% aqueous phosphoric acid. Add 100 ml of ice, pour in cold ethyl acetate and adjust to pH 2.0 with concentrated phosphoric acid. The mixture is saturated with sodium chloride, the organic layer is separated, and the aqueous phase is washed twice with ethyl acetate. After evaporation under reduced pressure, the combined organic extracts, which have been washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, give a residue which is crystallized from ethyl acetate. Slowly dilute to 15 ml with a 2: 3 mixture of ethyl acetate and hexane, filter after standing at -5 ° for 2 hours and after crystallization from a 1: 4 mixture of ethyl acetate and diethyl ether to give 78- (5-benzoylamino). -5-carboxy-valerylamino) -3-methylene-cefam-4a-carboxylic acid, m.p. 82-89 ° (dec.); Thin layer chromatogram (silica gel):

Rf = 0.53 (system: n-butanol / acetic acid / water 75: 7.5: 21), and Rf = 0.08 (system: acetic acid ethyl ester / pyridine / acetic acid / water 62: 21: 6: 11).

The aluminum amalgam used above can be prepared as follows:

The mixture of 3.3 g of aluminum powder and 100 ml of 50% aqueous sodium hydroxide solution is shaken for 30 seconds and the supernatant is poured off and washed three times with 300 ml of water each time. The residue is treated for 3 minutes with 130 ml of 0.3% aqueous mercuric chloride solution and washed three times with 300 ml of water each time. The whole treatment is repeated once and the aluminum amalgam is finally washed three times with tetrahydrofuran. About 15 ml of ethyl acetate is used to transfer the product to the reaction vessel.

To a solution of 2.3 g of 7β- (5-benzoylamino-5-carboxy-valerylamino) -3-methylene-cepham-4a-carboxylic acid in 25 ml of dioxane is added dropwise over 10 minutes a solution of 2 5 g of diphenyldiazomethane in 10 ml of n-pentane. Stir for 30 minutes at room temperature, decompose the excess diphenyldiazomethane by adding a few drops of acetic acid (glacial acetic acid) and evaporate the solution under reduced pressure. The residue is chromatographed on 80 g of silica gel, eluting with a 3: 1 mixture of toluene and ethyl acetate: 7β- (5-benzoylamino-5-diphenylmethoxycarbonyl-valerylamino) -3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester then crystallized from a mixture of acetic acid methyl ester and cyclohexane, m.p. 180-181 °, thin layer chromatogram (silica gel): Rf = 0.24 (system: toluene / ethyl acetate 2: 1), ultraviolet absorption spectrum (in 95% aqueous ethanol): no cracked bands, infrared absorption spectrum (methylene absorption spectrum) (methylene absorption spectrum) : characteristic lines at 5.66μ, 5.76μ, 5.95μ, 6.03μ, 6.64μ and 6.70μ.

A solution of 1.59 g of 7 - (5-benzoylamino-5-diphenylmethoxy)

II

25 6 4 9 41 Carbonyl-valeryl-amino) -3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester in 150 ml of methylene chloride, cooled to -70 ° and treated with a mixture of ozone and oxygen for 12 minutes 43 seconds with vigorous stirring. , 2 mmol of ozone per minute, followed by 1 ml of dimethyl sulfide. Stir for 5 minutes at -70 °, 30 minutes at room temperature and evaporate under reduced pressure. The residue containing 78- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -cepham-3-one-4C-carboxylic acid diphenylmethyl ester is dissolved in 40 ml of methanol, cooled in an ice bath and added to a constant yellow color until . The reaction mixture is evaporated under reduced pressure and the residue is chromatographed on 100 g of silica gel.

7β- (5-Benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 1: 1 mixture of toluene and ethyl acetate and obtained as an amorphous product, thin layer chromatogram: Rf: , 45 (system: toluene / ethyl acetate 1: 1), ultraviolet absorption spectrum (in 95% aqueous ethanol): = 258 πιμ (ε = 7450), 264 my (ε = 7050) and 268 my (ε = 6700), infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65y, 5.78y, 6.03y and 6.64y.

Example 4:

To a suspension of 1.65 g of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole are added 20 ml of precooled trifluoroacetic acid and stirred for 15 minutes in an ice bath. Dilute with 100 ml of cold toluene and evaporate the reaction mixture under reduced pressure. The dark brown residue is dried under high vacuum and stirred with diethyl ether; the precipitate is filtered off, washed with acetone and diethyl ether and dried. The trifluoroacetic acid salt of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid thus obtained is slurried in 10 ml of water; the aqueous solution is washed twice with 10 ml of ethyl acetate each time, and the pH is adjusted to 4.5 by adding 10% methanolic solution of triethylamine. Dilute with 10 ml of acetone; the mixture is stirred for 1 hour at 0 °. The precipitate is filtered, washed with a 1: 2 mixture of acetone and diethyl ether and dried under high vacuum to give 78-amino-3-methoxy-3-cephem-4-carboxylic acid as an internal salt, thin layer chromatogram (silica gel): Rf ^ 0.16 (system: n-butanol / acetic acid / water 67:10:23); ultraviolet thiabsorption spectrum (0.1 in hydrochloric acid):? max = 261 my (ε = 5400).

26 64941

In the 7B-amino-3-methoxy-3-cephem-4-carboxylic acid prepared according to the above method, by treating the carboxyl group with trimethylchlorosilane, and using an excess of silylating agent, the amino group can also be converted to a trimethylsilyl-protected carboxylic and possibly similarly protected amino in amino-3-methoxy-3-cephem-4-carboxylic acid, the amino group is acylated by treatment with phenylacetyl chloride and 3-methoxy-7B-phenylacetylamino-3-cephem-4-carboxylic acid is obtained by further treatment in a conventional manner in the presence of water.

Example 5; To a stirred suspension of 445 mg of p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride in 35 ml of dry tetrahydrofuran is stirred one equivalent of triethylamine, followed by the addition of 10 ml of additional diazo. -methane ether solution. After 30 minutes, the solvent and excess diazomethane are evaporated off. The residue is dissolved in a mixture of water and ethyl acetate. The organic phase is separated, washed with water and dried. The dried ethyl acetate solution is evaporated to dryness to give p-nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate. Treatment with diethyl ether gives a crystalline product. Infrared absorption spectrum (nujol): absorption bands at 2.99u, 5.75y and 5.98y. Ultraviolet absorption spectrum (ethanol): * mafcs = 268 my (ε = 14600).

The starting material can be prepared as follows:

To a solution of 965 mg (2 mmol) of p-nitrobenzyl 7-phenoxyacetamido-3-methylene cefam-4-carboxylate in 10 ml of methylene chloride are added 175 mg of dry pyridine and 460 mg of phosphorus pentachloride, followed by stirring. hours at room temperature. To the mixture thus obtained is added 1 ml of isobutanol and allowed to stir overnight at 0 °. In this case, p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate t-hydrochloride precipitating as a crystalline precipitate is filtered off.

Using the ozonation procedure described in Example 1, 3.85 g of p-nitrobenzyl 7-amino-3-methylene-cefam-4-carboxylate hydrochloride in methanol are ozonated, followed by decomposition of 3.5 ml of the intermediate ozonide at 0 °. with trime-style phosphite. The reaction mixture is evaporated and the residue is dissolved in 27,64941 of 100 ml of 0.1N hydrochloric acid in methylene chloride. The resulting solution is evaporated and the residue is recrystallized from acetone to give p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride.

Example 6;

A solution of 730 mg of p-nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate, 20 ml of water and 20 ml of acetonitrile is made rapidly with concentrated hydrochloric acid to acidify to pH 1. Immediately afterwards, titrate the resulting solution. Back to pH 2.5 with 1n sodium hydroxide. The solution is then evaporated to dryness and the residue is dissolved in a mixture of 40 ml of tetrahydrofuran, 80 ml of methanol and 6 ml of water. The solution is hydrogenated for 2 hours at a pressure of 3.5 kg / cm 3 at room temperature in the presence of 730 mg of 5% palladium-on-carbon (pre-reduced in ethanol). The catalyst is then filtered off and washed with tetrahydrofuran and water. The filtrate and washings are combined and evaporated, after which the aqueous residue is slurried with ethyl acetate. The pH of the slurry is adjusted to 3.5, the aqueous layer is separated and washed with ethyl acetate. The aqueous layer is evaporated to a volume of 4 ml, cooled to give 7-amino-3-methoxy-3-cephem-4-carboxylic acid as a crystalline solid. Infrared spectrum (nujol): absorption band at 5.61y, N.M.R. (DMSO-d 6): signals at 6.35 (s, 2H, 6.20 (s, 3H, C 1 methoxyl), 5.30 (d, 1H, C 7 H) and 4.94 (d, 1H, C 7 H) t. Ultraviolet absorption spectra (pH 7 buffer): \ naks = πψ ^ ε = 6500) ·

Claims (4)

64941 n ο Claims; Intermediates for the preparation of O-substituted 7β-acylamino-3-cephem-3-ol-4 * carboxylic acid compounds of the formula RrNHN A · - · · 0 = · - ^ A-O-R3 (A) o * 6-r2 7V wherein represents an acyl group of the formula OR = - (X) -CH - C - (B) am, Rb wherein R is phenyl, hydroxyphenyl, 1,4-cyclohexadienyl or thienyl, X is oxygen, m is 0 or 1 and represents hydrogen or, if m is 0, also amino or hydroxy, R 2 is hydroxy and R 1 is lower alkyl or phenyl-lower alkyl, characterized in that they are O-substituted by 7β-amino-3-cephem-3-ol. 4-carboxylic acid compounds of the formula NH2X ^ - - · · O * · - / «- O-Rj (I) 0 = 6 -r2 wherein R2 represents hydroxy or together with the carbonyl group -C (= O) in esterified form a residue forming a protected carboxyl group, and R 1 represents lower alkyl or phenyl-lower alkyl, or salts of such compounds. The 3-cephem compounds of the formula I for use according to Claim 1, in which R 2 represents hydroxy, diphenylmethoxy or p-nitrobenzyloxy and R 1 is lower alkyl or 1-phenyl-lower alkyl, or salts of such compounds. 76-Amino-3-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester for use according to claim 1. 7β-Amino-3-methoxy-3-cephem-4-carboxylic acid for use according to claim 1. <5