PL104396B1 - METHOD OF MAKING O-SUBSTITUTED ACID DERIVATIVES 7-BETA-AMINO-3-HYDROXY-CEFEMO-3-CARBOXYL-4 - Google Patents

Description

The invention relates to a manufacturing process Q-substituted acid derivatives 7 / α - amino- -3-hydroxy-cephem-3-carboxylic-4 of the formula E1, wherein R2 is hydroxy or the radical R £ to form with the moiety carbonyl -C (= O) -protected carboxy group and R3 is optionally substitute a converted hydrocarbyl or acyl radical or salt such relationships with groups having the ability to the ability to create salt. According to the invention, derivatives enols are the ethers and esters of 3-hydro xy-cephem-3.

Protected carboxyl group of formula -C [= Q] -R £ is primarily esterified carboxyl group but may also be included customarily a mixed anhydride group or possibly a mixed anhydride group a optionally substituted carbamoyl or hy- drazinocarbonyl.

The group R ^ may be a hydroxyl group of organic radical, in which the organic radical may preferably contain up to 18 carbon atoms to form together with the moiety -C (= 0) - nitrified carboxyl group. This The types of organic radicals are for example aliphatic, cycloaliphatic, cycloaliphatic radicals tic-aliphatic, aromatic or arylalipha- tic and especially optionally substituted such hydrocarbon radicals and radicals heterocyclic or heterocyclic aliphatic.

The R 2 group may also be an organic rhodium a silyloxy group and a hydroxyl group, organometallic radical, as per example organic stannyloxy group a w in particular a silyloxy or stannyloxy group I, substituted with 1-3, optionally substituted with hydrogenated hydrocarbon radicals (containing horse preferably up to 18 carbon atoms for example aliphatic hydrocarbon radicals) and, optionally by halogen, such as chlorine.

The group R ^, forming with the group -C (= 0) - mainly a mixed anhydride group, is in particular an acyloxy radical in which This acyl radical is a suitable radical organic carboxylic acid, including preferably up to 18 carbon atoms for example aliphatic, cycloaliphatic, cycloaliphatic * -aliphatic, aromatic or arylaliphatic- a carboxylic acid or a semi-derivative of the acid carbonic acid, such as a half ester of carbonic acid wego.

The group R2 »forming with the group -C (= 0) - a carbamoyl group is optionally substituted an amino group in which the substituents are possibly optionally substituted monovalent or bivalent hydrocarbon radicals containing preferably do 18 carbon atoms, such as for example possibly substituted monovalent or bivalent, alipha tic, cycloaliphatic, cycloaliphatic-aliphatic 104 396 104 396 tic, aromatic or araliphatic radicals hydrocarbon containing up to 18 carbon atoms followed by the corresponding heterocyclic radicals or heterocyclic aliphatic of up to 18 atoms say carbon and / or> function grips like for example Possibly functionally transformed into detail Generality ^ free hydroxyl group and then I-etherified / uh-nitrified hydroxy group new, "" w kt ^ re3 * - «Ethering or esterifying minics have the meaning given above and include up to the age of 18 carbon atoms as well as acyl radicals, especially all organic carboxylic acids and carbonic acid semi-derivatives, preferably including containing up to 18 carbon atoms.

In a substituted hydrazinecarbonyl group of formula -C (= C) -R 1 or both atoms nitrogen can be substituted, with substitution fictitious, they may be primarily possibly substituted mono- or bivalent radicals hydrocarbon, preferably up to 18 atoms say carbon, for example, possibly to base smoked, monovalent or bivalent, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aro matte or arylaliphatic hydrocarbon radicals bicycles with up to 18 carbon atoms and then recovered the corresponding heterocyclic or heterocycle radicals numerous-aliphatic containing up to 18 carbon atoms and / or functional groups such as radicals acyl mainly organic acids carboxylic acid or carboxylic acid derivatives wego; preferably containing up to 18 atoms coal.

An optionally substituted carbon radical Codium R3 may preferably be suitable cycloaliphatic or cycloaliphatic-aliphatic a hydrocarbon radical, but in particular an optionally substituted aliphatic radical and na stepwise corresponding arylaliphatic radical, Radical acyl R3 is primarily a radical acyl compounds of an organic carboxylic acid including formic acid such as for example cycloaliphatic or cycloaliphatic-aliphatic arylaliphatic, heterocyclic, heterocyclic cyclic aliphatic carboxylic acid or aromatic carboxylic acid as well also a half-derivative of carbonic acid.

The general terms may be used above and below for example the following meaning: radical alipha¬ tic, including an aliphatic radical corresponding to a suitable organic carboxylic acid, as well as the corresponding ilidene radical is optionally substituted with one or two layers a quantitative, aliphatic hydrocarbon radical especially with a lower alkyl radical as well as with a lower alkenyl radical or a lower alkynyl radical or a lower radical is the most suitable alkylidene radical that may contain for example up to 7, preferably up to 4 carbon atoms.

These kinds of radicals can possibly be mono- or bi- or multi-substituted with groups functional, for example by free, veteran or esterified hydroxyl or mer- captain. This could be: lower alkoxy- low radical alkenyloxy lower radical alkylene dioxy, optionally substituted phenyloxy radical or phenyl lower alkoxy- higher, lower alkylthio or optionally substituted phenylthio or lower phenyl-alkyl- lotiol, heterocyclothiol or lower hetero cycloalkylthio, optionally substituted with low lower alkoxycarbonyloxy radical or lower an alkanoyloxy radical or also a halogen. Moga be then substituted by a ketone group, nitro, optionally substituted amino, for example, an alkylamino group, lower dials- amine, lower alkylene amine, lower oxal- kilenoamine or lower azaalkyleneamine like also an acylamino group as well as a lower alkanoyl group amine, lower alkoxycarbonylamino, lower haloalkoxycarbonylamino, optionally substituted phenylalkoxycarbpnyl- lower group amino, optionally substituted carbohydrate moylamino, ureidocarbonylamino, or gua- nidynocarbonylamino, then being possibly in the form of a salt, for example a metal salt alkali sulfoamino, azide, acy- for example low alkanoyl or benzoyl, possibly a functionally transformed card group a carboxyl group, such as a carboxyl group salt esterified carbohydrate group xyl for example lower alkoxy carbohydrate nylon, optionally substituted carbamo- quantitative for example N, lower alkyl or N, N-di- alkylcarbamoyl, then optionally substituted ureidocarbonyl or gu- anidinocarbonyl or cyano, optionally a functionally converted sulfone group to for example sulfamoyl or sulfone being v salt form or optionally O-mono- or 0.0- - a bisubstituted phosphono group in which the actors are, for example, possibly a substitute a lower alkyl, phenyl or lower radical phenylalkyl wherein unsubstituted in O-position or O-monosubstituted phosphono group 40 can also be in the form of salt, such as a mate alkaline thallium.

A bivalent aliphatic radical, including the appropriate divalent radical of the aliphatic carboxylic acid is na For example a lower alkylene radical or a lower radical alkenylene, which possibly for example yes as the above-mentioned aliphatic radical may be mono-, double or multi-substituted and / or in which the chain enters heteroatoms, as for example oxygen, nitrogen or sulfur. . A cycloaliphatic or cycloaliphatic radical tic-aliphatic, including cycloaliphatic or with a cycloaliphatic-aliphatic radical a suitable carboxylic acid or the appropriate cycloaliphatic or cycloaliphatic-aliphatic any ilidene radical is optionally sub a set, monovalent or bivalent cycloaliphate a tic or cycloaliphatic-aliphatic radical hydrocarbon. It can be, for example, one A bi- or multicyclic cycloalkyl radical or cycloalkenyl, then cycloalkylide- new or lower cycloalkylalkyl, lower cyclo- alkenylalkyl, lower cycloalkylalkenyl, lower cycloalkenylalkenyl as well as lower 65 cycloalkylalkylidene or lower cycloalkenyl- 5G 555 104 396 6 alkylidene where the radical is cycloalkyl and cycloalkylidene contains up to 12 for example 3 to 8 and preferably 3 to 6 carbon atoms in the ring, connection 3 when the cycloalkenyl radical contains up to 12 for example 5-8, preferably 5 or 6 atoms 5 carbon in the ring and 1 or 2 double bonds ne, and the aliphatic part of the cycloaiiratic-ali- for example, it can include up to 7, and ko preferably up to 4 carbon atoms. The above radicals cy cloaliphatic or cycloaliphatic-aliphatic may 10 optionally be mono-, bi- or multi-substituted for example by optionally substituted aliphate tic hydrocarbon radicals as for example by the above mentioned, optionally substituted by the lower ones alkyl radicals or, for example, as above 15 the mentioned aliphatic hydrocarbon radicals by functional groups.

An aromatic radical, including a radical aromatic acid of the corresponding carboxylic acid is optionally substituted with aromatic a hydrocarbon radical, such as a mono-, a bi- or multicyclic aromatic radical hydrocarbon radical, in particular the pheny low, as well as biphenyl or naphthyl, which possibly as, for example, listed above Nanate aliphatic and cycloaliphatic carbon radicals hydrogen can be single, double or multi-base blown.

A divalent aromatic radical on an example of an aromatic carboxylic acid is primarily the 1,2-arylene radical (a v in particular 1,2-phenylene) which possibly, such as, for example, the aliphatic and cyclo-compounds mentioned aliphatic hydrocarbon radicals can be mono-, bi- or multi-substituted.

An arylaliphatic radical, including aryl- an aliphatic radical of the corresponding caracid a carboxylic acid and an arylaliphatic radical for example, ilidene is optionally substituted an arylaliphatic hydrocarbon radical like 40 for example optionally substituted for example up to three aliphatic hydrocarbon radical, including optionally substituted mono-, or multicyclic aromatic carbon radicals dorowe. It can be, above all, shorter phenylalkyl or lower phenylalkenyl radical, as well as lower phenylalkynyl and lower phenylalkylidene being such radicals for example they contain from 1 to 3 phenyl groups and possibly for example as mentioned above 50 aliphatic and cycloaliphatic radicals in part aro mathematical and / or aliphatic can be one-, two- or multi-substituted.

Heterocyclic groups, including groups, occurring in heterocyclic-aliphatic radicals and heterocyclic or heterocyclic groups locycyclic-aliphatic in the corresponding acids carboxylic acid, are in particular one, two, or multi-cyclic aza-, thia-, oxa-, thiaza- radicals, tiadiaza-, oxase, diaza-, triaza-, or tetraza- 60 cyclical of an aromatic nature and further suitable partially or fully saturated heterocyclic radicals of this kind, such being such radicals may possibly be, for example such as the above-mentioned cycloaliphatic radicals 65 single, double or multi-substituted. Hello alifa¬ tic in heterocyclic-aliphatic radicals different meanings are given, for example, for the rich of cycloaliphatic-aliphatic radicals or arylaliphatic.

The acyl radical of a halfhydrocarbyl acid is preferably native: acyl, suitable it is half-ester in which the organic part of the group the ester is an optionally substituted aliphase tic, cycloaliphatic, aromatic or aryl- an aliphatic hydrocarbon radical or a he- terocykiiczino-aiiphatic, and above all rhodium an optionally substituted acyl nickel (e.g. clade in the a or /? position of the lower alkyl half carbonic acid ester as well as optionally substituted in the organic part of a lower nyl-, cycloalkyl-, phenyl- or lower phenyl- carbonic acid alkyl half ester. Radicals carbonic acid half esters can be followed by the corresponding lower alkyl radicals carbonic acid half esters, in which part lower alkyl contains a heterocyclic group na for example one of the aforementioned hetero groups rocyclic of an aromatic nature with which both the lower alkyl part as well as the heterocyclic group may optionally be sub staked. The acyl radical of the semi-derivative of the acid coal suction can also possibly be an N-sub- the former carbamoyl group, for example optionally halogenated N-lower alkyl group -carbamoyl.

The etherified hydroxyl group is primarily all optionally substituted lower radical alkoxy in which the substituents are mainly free functionally transformed, for example etherified or esterified hydroxyl groups a new and especially a lower alkoxy radical or halogen followed by the lower alkenyl radical xyl, cycloalkyloxy or optionally substituted phenoxy as well as heterocyclyl- xyl or lower heterocyclylalkoxy a w in particular also optionally substituted lower phenylalkoxy radical.

An optionally substituted amino group is for example, an amino group, a lower alkyl radical amines, lower dialkylamino, lower radical alkyleneamine, lower aksaalkyleneamine, lower thiaalkyleneamine, lower azaalkyleneamine- new, hydroxyamine, lower alkoxy radical amino, lower alkanoyloxyamine radical, a lower alkoxycarbonylamino or a lower radical alkanoylamino.

Optionally substituted hydrazino group for example there is a hydrazino group, lower 2-alkylhydrazine, lower 2,2-dialkylhydrazine- Sine, 2-lower alkoxycarbonylhydrazine or 2-lower alkanoylhydrazine.

A lower alkyl radical may be on example methyl, ethyl, n-propyl- isopropyl, n-butyl, isobutyl ,. II-row. butyl, 3rd order butyl as well as n-pen- back, isopentyl, N-hexyl-isohexyl you or n-heptyl, while a lower radical alkenyl can be, for example, a guilt radical low, allyl, isopropanyl, 2-methylallyl 37 104 396 8 3-methylcallyl, or 3-butenyl for; lower an alkynyl radical is, for example, a radical propargyl or 2-butinyl and a lower rhodium the alkylidene can be, for example, a radical isopropylidene or isobutylidene.

A lower alkylene radical is, for example, 1,2-ethylene, 1,2- or 1,3-propylene radical, 1,4-butylene, 1,5-pentylene or 1,6-hexyl- new, however, with a lower alkenyl radical there is, for example, the 1,2-ethenylene or 2-bu- ten-1.4-ylene. A lower alkylene radical whose chain is interrupted by heteroatoms is for example, the lower oxaalkylene radical for example 3-oxa-1,5-pentylene clone, lower thiaalkylene such as for example 3-thia-1,5-penty, ene or lower azralkylene such as lower 3-alkyl-3- -aza-1,5-pentylenes and in particular 3-methyl- -3-aza-1,5-pentyl.

A cycloalkyl radical is, for example cyclopropyl, cyclobutyl, cyclopen- rear, cyclohexyl or cycloheptyl like also an adamantyl radical cycloalke- for example is the cyclopropene radical lowe, 1-, 2-. or 3-cyclopentinyl, 1-, 2- or • 3-cyclohexenyl, 3-cycloheptenyl or 1,4- -cyclohexadienyl and the cycloalkylide- radical a new one may be, for example, the cyclopenty radical lidene or cyclohexylidene.

A lower alkylene radical is, for example, lower cycloalkylalkenyl is for example cyclopropyl-, cyclopentyl-, cyclohexyl- radical or cycloheptylmethyl, cyclopropyl-1,1, or 1,2-ethyl, cyclopentyl-1,1, 1- or 1,2-ethyl, cyclohexyl-1, 1- or 1,2-ethyl, cycloheptyl-1, 1- or -1,2-ethyl, cyclopropyl-1, 1-, -1,2- or ^ 1,3-propyl, cyclopentyl-1,1-, -1,2- or -1,3- propyl, cyclohexyl-1,1-, -1,2- or -1,3-pro dust, cycloheptyl-1,1-, -1,2- or 1,3-propyl, cycloheptyl-1,1-, -1,2- or 1,3-propyl, cyclo propylvinyl, cyclopentylvinyl, cyclo- bexylvinyl, cycloheptylvinyl or cyclo- propylallyl, cyclopentylallyl, cyclohexa- loallyl or cycloheptyl allyl. While a lower cycloalkenylalkyl radical or or a cyclic-lower alkenylalkanyl may be for example the -1, 2- or 3-cyclopentenyl- radical, 1-, 2-, 3-cyclohexynyl- or 1-, 2-, 3-cyclohepte- nylmethyl, 1,1, or -1,2-ethyl, -1,1-, -1,2 or 1,3-propyl, -vinyl or -allyl. Lower a cycloalkylalkylidene radical is, for example, cyclohexylmethylene radical class a lower a cycloalkenylalkylidene radical, for example 3-cyclohexynylmethylene.

The naphthyl radical is a 1- or 2-naphthyl radical the rear biphenyl radical may be on example 4-biphenyl radical.

As a phenylalkyl or phenyl lower radical alkenyl should be replaced, for example, the radical benzyl, 1- or 2-phenylethyl, 1-, 2-, or 3-phe- nylpropyl, diphenylmethyl, triphenyl- methyl, styryl or cinnamyl, and as a lower naphthylalkyl radical, for example a radical 1- or 2-naphthylmethyl a. As a lower radical phenylalkylidene, for example the benzylide- new.

Heterocyclic radicals are primarily which optionally substituted heterocycle radicals numerous of an aromatic nature, for example corresponding monocyclic radicals, monoaza-; monothia- or monooxacyclic such as for example a pyrrolyl radical, for example 2-pyrryl or 3-pi- ethyl, pyridyl, for example 2-, 3- or 4-pi- ridyl, pyridinium, thienyl, for example 2- or 3-thienyl or furyl, for example and 2-furyl.

They are then two-cyclic mono- aza, monooxy-, or monothiacyclic as in for example an indolyl radical for example 2- or 3-indolyl, quinolinyl. for example 2- or 4-quinolinyl, isoquinolinyl, for example 1-isoquinolinyl, benzofuranyl, for example 2- or 3-benzofuranyl, benzothienyl, na example • 2- or 3-benzothienyl and single-cycle numerous radicals diaza-, triaza, tetraza, oxase-, thiaz- or thiadiazacyclic, for example the radical imi- dazolyl, e.g. 2-imidazolyl, pyrim- dyinyl, for example 2- or 4-pyrimidinyl, triazolyl, e.g. 1,2,4-triazol-3-yl, te- trazolyl, e.g. 1- or 5-tetrazolyl, ox- solyl, e.g. 2-Oxazolyl, isoxazolyl low, for example 3- or 4-isoxazolyl, thiazo- lyl for example 2-thiazolyl isothiazolyl, na for example 3- or 4-isothiazolyl, or 1,2,4-or L3,4-thiadiazolyl, e.g. 1,2,4-thiadiazol- -3-yl or 1,3,4-thiadiazol-2-yl and also di cyclic diaza-, oxase-, or thiazacyclic radicals such as for example benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl or benzothiazolyl as per example 2-benzothiazolyl. Suitable families with stones fully or partially saturated are on for example, a tetrahydro-thienyl radical as in example 2-tetrahydro-thienyl, tetrahydro furyl, such as for example 2-tetrahydrofuryl 40 or piperidyl, such as 2- or 4-piper- dylic, heterocyclic-aliphatic radicals Heterocyclic groups in particular above listed containing a lower alkyl radical or a lower alkenyl radical. 4g The above-mentioned heterocyclic radicals may be substituted with functional groups as in for example by optionally substituted alipha tic or aromatic hydrocarbon radicals and in particular lower alkyl radicals, for example clade via a methyl radical or optionally na for example by halogen, for example chlorine, substituted phenylic radical, for example phenyl- or 4-chlorophenyl, or aliphatic radicals hydrocarbon.

A lower alkoxy radical may be on example methoxy, ethoxy, n-pro radical poxyl, isopropoxy, n-butoxy, iso- butoxy, 2nd order -butoxy, IIT-row but- xyl, n-peotoxic or IJI-order. pentoxy- Iowa. These radicals can be substituted for example class as in the lower radical haloalkoxy- in particular the lower 2-haloalkox xyl, for example 2,2,2-trichloro, 2-chloro, 2-bromo or 2-iodoethoxy. A lower radical An alkenyloxy radical is, for example, a Wi-L04396 radical * 9 10 nyloxy or allyloxy, but of a lower grade An alkylene dioxy group is, for example, rhodium ethylene dioxy nickel or i-propylidenedioxy or cycloackoxy for example, cyclopentyloxy, cyclo- hexyloxy or adamantyloxy.

The lower phenylalkoxy radical is na for example benzoxy radical, 1- or 2-phenyl, oetho- xyl, diphenylmethoxy or 4,4'-dimene- diphenyl methoxy or heterocyclyloxy- a low or lower heterocyclylalkoxy as per for example pyridyl lower alkoxy, for example 2-pyridyl; r. Ethoxy, lower furylalkoxy, for example furfuryloxy or lower thienyl- alkoxy such as for example 2-thienyloxy.

The lower alkylthio radical, for example Clade v radical methylthiol, ethylthiol or n-bu- tylthiol with the lower alkenylthiol radical it is called the alliiothiol for example, and the lower rhodium a phenylalkylthio radical, for example a radical benzylthiol, while mercaptan- with dimethyl heterocyclic radicals or hetero-caliphatic are in particular carriers; ¥ © driitel pyridylthiols, for example 4-pyridines- dilthiolFWy, imidazolylthio, e.g. 2-imi- dazolylthiol, thiazolylthiol, e.g. 2-thia- zolylthiol, 1,2,4- or 1,3,4-thiadiazolylthio, na example 1,2,4-thiadiazolyl-3-thio or 1,3,4-thia- diazolyl-2-thiol or tetrazolyl; iol, e.g. 1-methyl-5-tetrazolylthio track.

Esterified hydroxyl groups are mainly halogens, for example fluorine, chlorine, bromine or iodine, lower alkene and oxy- for example acetyloxy or propionyl xyl, lower alkoxycarbonyloxy radicals, for example, methoxycarbonyloxy, ethoxycar- bonyloxy or tertiary butoxycarbonyloxy- low, lower 2-haloalkoxycarbonyloxy. for example 2,2,2-trichlorethoxycarbonyloxy, 2-bromomethoxycarbonyloxy or 2-iodoetho- xycarbonyloxy or arylcarbonylmethoxy- carbonyloxy, e.g. cycloxycarbony- loxylic.

It is a lower alkoxycarbonyl radical for example, methoxycarbonyl, ethoxy- carbonyl, n-propyloxycarbonyl, isoprop- loxycarbonyl, III-order. butoxycarbonyl or 3rd row. pentoxycarbonyl.

The lower radical N-alkyl or N, N-dialkyl- carbamoyl is, for example, the N-methyl radical locarbamoyl, N-ethylcarbamoyl, N, N-two- methylcarbamoyl, or N, N-diethylcarbamoyl alkyl, while the lower radical N-alkylsulfa- moilowyin is, for example, N-methylsulfamoyl or N, N-dimethylsulfamoyl.

A carboxyl or sulfone group may have alkali metal salt form for example group carboxylic! or the sulfone salt may be in the form of a salt sodium or potassium.

Lower alkylammonium or lower radical The dialkylamino radical is, for example, a tyloamine, ethylamine, diethylamine or diethylamine and lower alkyleneamine 50 55 65 there is, for example, a pyrrolidine or a piper- Dyncwy and the lower radical oxaalkyleneamino- for example, the morpholino radical, while with a lower thiaalkenamino radical, for example the thiomorpholine glacier and the lower azaalkyl clade a noamine for example the piperazine radical or 4-methylopiperazine. The acylamine radical it is in particular the carbamoylamino radical you, lower c: lyilcarbamoylamino, for example finish okarba.r.oylamino, ureidocarbonylamino- you (guanicincarbonylarrine, lower alkoxy- carbonylamino, for example methoxycarbonyl- amino, etcksycarbonylamino, or tertiary. butyloxycarbonylamino, lower halogenal xycarbonylamino, e.g. 2,2,2-trichloro roethoxycarbonylamino, lower phenylalkoxy- carbonylamino, for example 4-methoxybeazyl- xycarbonylamino, the lower alkanoyl lower radical amine, for example acetylamine or prcpio nylamine followed by phthalimide or possibly alternatively the sulfoamine radical in the form of a salt, na example, sodium or ammonium salt.

The lower alkanoyl radical is, for example, clade formyl, acetyl and propionyl radicals or pivaloyl.

The O-lower alkylphosphonic radical is na example 0-methyl, * or 0-ethylphosphonic and 0.0'- - a lower dialkylphosphate for example a radical O, O'-dimethylphosphonic or O, O'-diethylphosphonic a new lower radical 0-phenylalkylphosphono- for example 0-benzylphosphonic and lower O-alkyl-C-phenylalkylphosphonic for example O-benzyl-O'-methylphosphine radical.

With a lower alkenyloxycarbonyl radical is for example vinyloxycarbonyl, while cycloalkoxycarbonyl and lower phenylalkoxycarbonyl is, for example, rhodium adamantyloxycarbonyl nickel, benzyloxycarbonyl nylon, 4-methoxybenzyloxycarbonyl, dife- nylmethoxycarbonyl or α-4-biphenyl-methyl- loethoxycarbonyl.

With a lower alkoxycarbonyl radical, v which the lower alkyl radical contains, for example, clade monocyclic, monoaza-, monooxy- or monothiacyclic, it is for example a lower rhodium furylalkoxycarbonyl nickel for example furfu- ryloxycarbonyl or lower thienyl alkoxy car- bonyl, for example furfuryloxycarbonyl or thienyl lower alkoxycarbonyl, for example 2-thienyloxycarbonyl radical.

The lower radical 2-alkyl and 2,2-dialkylohy- for example the 2-methylhydratin radical drazine or 2,2-dimethylhydrazine salt the lower radical 2-alkoxycarbonylhydrazine- for example 2-methoxycarbonylhydrazines, 2-ethoxycarbonylhydrazine or 2-third-order-bu- tyloxycarbonylhydrazinium and a lower radical an alkanoyl hydrazine is, for example, a radical 2-acetylhydrazine.

A etherified hydroxyl group R forms together with the carbonyl group is an esterified group carboxyl, preferably easily cleavable or easily transformable into another, functionally an altered carboxyl group, such as, for example, 104 396 11 12 carbamoyl or hydrazinecarbonyl. This for example, the group R ^ is lower an alkoxy radical, for example, methoxy, xyl n-propoxy or isopropoxy, which together with the carbonyl group forms an estriflate a carbonated carboxyl group which is particularly suitable for in 2-cephemic compounds easily transformed lead to a free carboxyl group or v another functionally altered carboxyl group.

Veterated hydroxy group K, two throws together with group -C (= 0) esterified group carboxylic acid, especially easily cleavable solid new, for example, the lower radical 2-haloal xyl in which the halogen preferably has a shadow Zero atomic above 19. Such radical forms together with a carbonyl group, when treated with che- abrasive reducing agents in the environment neutral or slightly acidic, such as tin in the presence of an aqueous solution of acetic acid an easily cleavable esterified group carboxyl or esterified carboxy group I can easily move to the above replaced. It could be, for example, a radical 2,2,2-trichlorethoxy or 2-iodoethoxy like also 2-chloroethoxy or 2-bromoethoxy- you, who can easily be moved higher changed. Etherized hydroxyl group R 2> which, together with the carbonyl group, is treatment with chemical reducing agents in an inert or slightly acidic environment like for example zinc in the presence of an aqueous solution acetic acid or after treatment with acetic acid with a suitable nucleophilic reagent as for example clade sodium thiophenolate, easily cleavable the esterified carboxyl group is a radical arylcarbonylmethoxy, wherein the aryl radical in particular, it is optionally substituted a phenyl radical, preferably phenacyl xylic.

The R £ group may also be an aryl- methoxy, wherein the aryl radical is in particular monocyclic, preferably substituted aromatic hydrocarbon radical. This kind of radical together with the carbonyl group forms esterified carboxyl group, feasible easy to detach when irradiated, advantageously ultraviolet rays, in an environment near you jetnym or acidic. The aryl radical in ta which arylmethoxy radical is in particular it carries the lower alkoxyphenyl radical as, for example, methoxyphenyl clade (where the radical the accountant is primarily in the position 3-, 4- and / or 5- and / or above all nitrophenyl preferably the nitro group in position 2-. They are especially such radicals lower alkoxybenzyloxy radicals, for example methoxy and / or non-trobenzyloxy and above all all 3- or 4-methoxybenzyl oxyl, 3,5- dimethoxybenzyloxy, 2-nitiphthenzyloxy or 4,5-dimethoxy-2,2-nitrpbenzyloxy.

The etherified hydroxyl group R 2 may become is also a radical which, together with the carbonyl group under acidic conditions, for example after half treatment with trifluoroacetic acid or form it forms an easily cleavable esterified carboxyl group. Such a radical is primarily all a methoxy radical in which the radical methyl is multi-substituted or optionally substituted r. with hydrocarbon radicals and w in particular aliphatic or aromatic like for example with lower alkyl radicals, e.g. for example methyl and / or phenyl or is monosubstituted with donating substituents electrons with a carbocyclic aryl radical or an aro heterocyclic group matte having oxygen or sulfur as a component ring or a ring member in a multi a cycloaliphatic hydrocarbon radical or a ring member in the radical oxa- or thiacyclo- aliphatic, which is in the position a relative demo of the oxygen atom ring member or sulfur.

With preferred multisubstituted metabolic radicals of this kind are the following radicals: lower III-row. alkyl, e.g., tertiary. butoxy- low or third row. pentoxy, optionally sub substituted diphenylmethoxy, for example diphenylmethoxy phenylmethoxy or 4,4'-dimethoxy diphenyl- methoxy, then 2- (4-biphenyl) -2-propo- the xyl group and the methoxy radical, i.e. containing the above-mentioned substituted radical aryl or heterocyclic group, for example, lower clade a-alkoxy phenylene low alkoxy you such as, for example, 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy or furfuryloxy- low, for example 2-furfuryloxy. Multicycle an aliphatic hydrocarbon radical in which This is the methyl radical of the methoxy group preferably a threefold branched ring member nia, there is, for example, the adamantyl radical na the 1-adamantyl example is mentioned above an oxo- or thiacycloaliphatic radical in which the methyl radical of the methoxy group is a member the ring taking its position in relation to the atom oxygen or sulfur means, for example, the radical 2-ox- or 2-lower alkylene or lower 2-oxa or 2-thiaalkenylene with 5-7 ring atoms such as the 2-tetrahydrofuryl radical, 2-tetrahydro-pyranyl or 2,3-dihydro-2- -pyranyl or equivalent sulfur compounds.

The radical R 2 can also be etherified a hydroxyl group which, together with the carbo- 50 nylon forms hydrolytically in, for example, sro slightly alkaline or slightly acidic water graftable esterified carboxyl group.

This type of radical is a etherified group hydroxyl group formed preferably with a carbohydrate group nylon activated ester group. It could be for example, the nitrophenyloxy radical, for example clade 4-nitrophenyloxy or 2,4-dinitrophenyl- xyl, nitrophenyl low alkoxy, for example 4-nitrobenzyloxy, for example 4-hydroxy- 60 3-5-III-row butylbenzyloxy polyhalogen- phenyloxy, for example 2,4,6-trichlorophenyl- xyl or 2,3,4,5,6-pentachlorophenyloxy. and then cyanomethoxy as well as acy- loaminomethoxy, such as phthalimine- 65 toxic or succinyliminomethoxy. 13 104 396 14 The group R2 may also be a etherified group hydroxide vapor forming together with the carbohydrate group nylow? with the formula -C (= 0) - esterified group carboxylic acid cleavable under hydro genolytic. Such a group could be, for example, 5 optionally, via a lower alkoxy radical or nitro group, substitution of the radical a-phenylene- alkoxy, for example benzyloxy, 4-me- toxybenzyloxy or 4-nitrobenzyloxy.

Group R \ may also be a veteran group 10 hydroxyl, forming together with the carbony- half that is cleavable under physiological conditions an esterified carboxyl group, a primarily an acyloxy group in which an acyl radical is, for example, an organic radical acidic carboxylic acid, and above all kim of an optionally substituted lower acid alkanecarboxylic acid or in which the aryl- xymethyl forms the lactone radical. So zestryph- the hydroxyl groups are the lower rhodium-20 alkanoyloxymethoxy resins, for example acetyl loxymethyloxy or pivaloyloxymethoxy lower aminoalkanoyloxymethoxy, and in particular Generally lower α-aminoalkanoyloxymethoxy such as for example glycyloxymethoxy, L-valyl- 25 xymethoxy, L-leucyloxymethoxy and na stepphthalidyloxy.

R 2 silyloxy or stannyloxy group, preferably optionally, as substituents substituted aliphatic, 'cycloaliphatic, aromatic tic or araliphatic hydrocarbon radicals such as lower alkyl radicals, lower haloalkyl, cycloalkyl, phenyl or lower phenylalkyl or optionally transformations functional groups such as etched 25 hydroxyl groups, for example lower radicals alkoxy or halogen atoms for example chlorine and is primarily a lower radical trialkylsilyloxy for example trimethylsilyl- loxyl, haloalkoxy-loweralkylsilyl-40 Iowa, for example chloromethoxymethylsilyl or lower trialkylstannyloxy as for example tri-n-butylstannyloxy.

R * acyloxy radical, forming with the group one carbonyl one is cleavable, preferably 45 hydrolytically mixed anhydride group, e.g. For example, it has an acyl radical from one of the above the mentioned organic carboxylic acids carbonic acid and is for example, possibly by halogen at ¦ • e.g. fluorine or chlorine, preferably in position a substituted with the lower alkanoyloxy- for example, acetyloxy, pivalyloxy- or trichloroacetyloxy or less an alkoxycarbonyloxy radical, for example 55 methoxycarfoonyloxy or ethoxycarbonyl- xylic.

The radical R £ forming together with the carbon group nyl optionally substituted with carbamo alkyl or hydrazinocarbonyl, is for example amino, lower alkylamino, or lower dialkylamino, for example methylamino, ethylamine, diethylamine or dimethyl- amine, lower alkylene amine, e.g. pyrrolidine or piperidine, lower oxaalkyl- noamine, for example morpholine, hydroxy amine, hydrazine, lower 2-alkylhydrazine or 2,2-dialkyl cyclrazine lower, for example 2-methylhydrazine or 2,2-dimethylhydrazine new.

Optionally substituted with an aliphatic rhodium the hydrocarbon Rj is in particular lower alkyl radical of up to 7 and preferably up to 4 carbon atoms, such as a methyl radical poly, ethyl, n-propyl, isopropyl, n-shoes- low, isobutyl, or tertiary. butyl and na¬ stepwise lower alkenyl radical, for example allylic, lower third order. aminoalkyl where The tertiary amino group is separated from an oxygen atom with at least two carbon atoms, as 2- or 3-dialkylaminoalkyl-lower example 2-dimethylaminoethyl, 2-dimethyl- aminoethyl or 3-dimethylaminopropyl or etherified lower hydroxyalkyl radical, in which the etherated hydroxyl group a w in particular the lower alkoxy radical separated is from an oxygen atom at least two atoms carbon such as lower 2- or 3-alkoxy kilo, for example 2-methoxyethyl or 2-etho- xyethyl. An optionally substituted arylalipha- The tic hydrocarbon radical R3 is a trans de all optionally substituted lower phenylalkylovvTy semiconductor, in particular, lower l-phenylacyl with 1-3 optionally substituted phenyl radicals, for example benzyl or diphenylmethyl wherein the substituent is mi can be esterified or tethered, for example hydrogenated hydroxyl groups, halogens, for example clade fluorine, chlorine or bromine or lower alcohol radicals xylic, for example methoxy.

R3 acyl radical of an aliphatic acid carboxyl is first of all optionally a substituted lower alkanoyl radical, for example acetyl, propionyl or pivaloyl clade. such radicals may be substituted for example esterified or etherified a hydroxyl group, a halogen for example fluorine or chlorine or a lower radical xyl, for example methoxy or ethoxy lowe. An aromatic acyl radical R3 carboxylic acid is, for example, optional an optionally substituted benzoyl radical, for example a benzoyl clade or a benzoyl radical esterified or etherified hydro group oxygenated, halogen, for example fluorine or chlorine or a lower alkoxy radical na for example methoxy or ethoxy or a lower alkyl radical, such as, for example methyl. The acyl radical R3 of a semi-derivative carbonic acid in particular is lower an alkoxycarbonyl radical, such as, for example, a xycarbonyl or ethoxycarbonyl.

The salts are in particular the salts of the compounds of the formula 1 bearing a free carboxyl group. Those are mainly metal or ammonium salts, for example, alkali metal and metal salts alkaline earths, for example sodium, potassium, owls, magnesium or calcium as well as salts15 104396 16 ammonium with ammonia or appropriate amines organic, but they can be mainly all aliphatic, cycloaliphatic, cycloaliphatic tic-aliphatic and aryioaliphatic, primary, secondary or tertiary single, double or multi amines as well as heterocyclic bases as per example with lower alkylamines, for example triethylamine, lower hydroxyalkylamines, na example 2-hydroxyethylamine, di-2-hydroxy- ethylamine or tr- (2-hydroxyethyl) amine, ex with aliphatic acid esters of carboxylic acids for example with 2-diethylammoethyl ester 4-aminobenzoic acid, lower alkyl lenoamines, for example 1-ethylpiperidine, cy- with cloalkylamines, for example dicycohexylamines amine or benzylamines, for example N, N-di- benzylethylenediamine and then bases pyridine type such as, for example, pyridine, co- lidin or quinoline. Compounds of formula 1 may they also form acid addition salts, for example a clade with inorganic acids, for example with hydrochloric, sulfuric or phosphoric acid or with the appropriate organic carboxylic acids low or sulfonic acid, for example with acid trifluoroacetic acid or 4-methylphenylsulfon- dim. Compounds of formula 1 having a free group the carboxylic acid may also exist in the form of a salt internal, that is, in amphoteric form.

The new compounds that are the subject of the invention are used as manufacturing intermediates compounds with valuable pharmacological properties gic.

The invention relates in particular to 3-cephem compounds of formula I, wherein R:> denotes a hydroxyl group or optionally a co- preferably in position a, for example by possibly a substituted aryloxy radical as, for example lower alkoxyphenyloxy, for example 4-metho- xyphenyloxy, lower alkanoyloxy, na for example acetoxylic or pivaloyloxy lower α-aminoalkanoyloxy, for example glycyloxy- a-valyloxy or a-leucyloxy, aryl locarbonyl, for example benzoyl or possibly A optionally substituted aryl radical, for example a phenylic, lower alkoxyphenyl radical, for example 4-methoxyphenyl, nitrophenyl clade, e.g. 4-nitrophenyl or biphenyl clade, for example 4-biphenyl or in position /? by halogen, na for example chlorine, bromine or iodine mono- or poly- a substituted lower alkoxy radical, for example methoxy, ethoxy, n-propoxy, isopropoxy xylic, n-butoxy, III-order butoxy or 3rd row. pentoxy, possibly lower with an alkoxy radical substituted bis- -phenyloxymethoxy, e.g. bis-4-metho- xyphenyloxymethoxy, the lower alkanoyl lower radical xymethoxy, for example acetoxymethoxy or pivaloyloxymeioxy, lower α-aminoalkyl- noyloxymethoxy, for example- | licyloxymeth- xyl, phenacyloxy, optionally substituted a new phenylene alkoxy radical in particular 1-phenylene alkoxy, for example phenylmeth- toxic, and such radicals can include 1-3 optionally, (e.g. lower an alkoxy radical, for example, methoxy (e.g., nitro or phenyl) substituted with rhodium phenyl radicals, for example, benzyloxy, 4-me- toxybenzyloxy, 2-biphenyl-2-propoxy. 4-nitrobenzyloxy, diphenylmethoxy. 4,4'-dimethoxy diphenylmethoxy, or tri- phenylmethoxy or lower 2-haloalkox xyl, e.g. 2,2,2-trichlorethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodo ethoxy, then the 2-phthalidyloxy radical io as well as an acyloxy radical, for example alkoxycarbonyloxy, for example mecoxy- carbonyloxy or ethoxycarbonyloxy or a lower alkanoyloxy radical, for example aceto xyl or pivaloyloxy, a lower radical tri alkylsiloxy, for example trimethylsilyloxy- low, or possibly, for example, of a lower range an alkyl such as, for example, methyl or hydroxyl group substituted with amino group or hydrazine, for example amine, lower alkylamino or lower dialkylamino, na example methylamine or diethylamine, hydrazine, lower 2-alkyl or lower 2,2-di- alkylhydrazine, e.g. 2-methylhydrazine new or 2,2-dimethylhydrazine or hygrom xyaminowa while the symbol R3 can stand for lower alkyl radical, for example methyl, ethyl, n-propyl, isopropyl, or n-but- a low alkenyl radical, for example alli a low, optionally substituted phe- lower radical nylalkyl and in particular lower 1-phenyl- alkyl with 1 or 2, possibly lower, for example a lower alkoxy radical, such as, for example methoxy substituted phenyl radicals for example benzyl or diphenylmethane rear, then lower alkanoyl radical, na for example acetyl or propionyl or lower alkoxycarbonyl, for example methoxycarbony- as well as possibly, for example, low a lower allyl radical, for example a methyl With a higher or lower alkoxy radical, na for example, methoxy or halogen, for example clade with fluorine or chlorine substituted benzene radical zoil.

The invention also relates to the salts of these 45 compounds with salt-forming groups. In relation with 3-cephem of the formula I or in a salt of the compound with salt-forming groups, the symbol R2 denotes a group hydroxyl, lower alkoxy radical a w in particular the α-multi-branched lower radical Alkoxy, for example tertiary-butoxy then methoxy or ethoxy, lower 2-haloalkoxy, for example 2,2,2-tri chloroethoxy, 2-iodoethoxy or easily the latter, transformable 2-chloroethoxy- 55 Iowa or 2-bromoethoxy, phenacyloxy, 1-phenyl lower alkoxy with 1-3 optionally a lower alkoxy radical or a nitro group with substituted phenyl radicals as in example 4-methoxybenzyloxy, 4-nitrobenzylp- xyl, diphenylmethoxy, 4,4'-dimetpxy diphenyl methoxy or triphenyl methoxy, lower alkanoyloxymethoxy, for example ace Toxymethoxy or pivaloyloxymethoxy. lower α-aminoalkanoyloxymethoxy, for example 65 glycyloxymethoxy clade, 2-phthalidyloxymeto-17 104 396 18 xyl, lower alkoxycarbonyloxy, e.g. the ethoxycarbonyloxy or lower alkanoyl clade xyl, for example acetoxy, then lower trialkylsilyloxy, e.g. tylsilyloxy. \ The symbol R3 primarily means lower an alkyl radical, for example, methyl, ethyl or ii-butyl followed by the lower alkenes- low, for example allyl and lower 1-phenyl- alkyl, for example benzyl or diphenyl methyl as well as the lower alkanoyl radical na for example acetyl or propionyl, lower rhodium an alkoxycarbonyl nickel, for example a methoxycarbonyl bonyl or benzoyl.

The subject of the invention are primarily 3-cephem compounds of formula I, wherein R2 it primarily represents a hydroxyl group then the lower alkoxy radical and the lower alkoxy radical In general, the α-multi-branched lower alkoxy radical low, for example M-order ^ -butoxy, lower 2-chloro rcoalkoxy, e.g. 2A2-trichloroeto- xylic, 2 ^ j or possibly, for example, a lower radical alkoxy, such as methoxy, a substituted diphenyl methoxy radical, na example diphenylmethoxy or 4,4'-dimene- diphenylmethoxy toxoid, then lower trimethylsilyloxy, for example trimethylsilyl loxyl and R3 is lower alkyl, na for example methyl, ethyl or n-butyl like also a lower alkenyl radical, for example allyl or lower phenylalkyl, for example benzyl followed by lower alkanoyl, for example acetyl or propionyl or a lower radical alkoxycarbonyl, for example methoxycarbonyl nylon or also salts, for example alkali metal salts numerous, for example sodium or earth metals alkali, for example calcium or ammonium salts new compounds including amine salts of compounds, wherein R2 is hydroxy.

In the 3-cephem compounds of formula I as eq not in salts, R2 is primarily a group hydroxyl and further optionally substituted in position 2 with a halogen, for example chlorine, bromine or iodine, a lower alkoxy radical, and in particular the α-multi-branched lower radical alkoxy, e.g., tert-butoxy or 2-chloro lower alkoxy, for example 2, 1, 2 < 6 > chloroethoxy, 2-} odoethoxy or • 2-bromoethoxy or possibly lower rhodium alkoxy, for example methoxy a substituted diphenyl methoxy radical, na example diphenylmethoxy or 4,4'-dimethoxy xydiphenylmethoxy followed by a lower tri alkylsilyloxy, for example trimethylsilyl- xyl, and R3 is a lower alkyl radical, na pExample methyl, ethyl, or n-butyl, like also a lower alkenyl radical, for example allyl or lower ferrilalkyl, for example benzyl.

The subject of the invention are primarily lower acids 7 ^ -amino-3-alkoxy-cephemo ^ 3-icarbo- xyl © we-4, wherein the lower alkoxy radical contains up to 4 carbon atoms and means, for example an ethoxy or n-butoxy radical, and above all all methoxy, and their diphenyl- methyl and in the first row 7 /? - amino- -3-methoxycefem-3-carboxylic-4 and corresponding biphenylnaryn e -ter.

Compounds of formula 1 can be obtained if v a compound of formula 2, wherein R2 and R3 are above the given meaning, where R2 preferably is the carboxylic protecting group has R% and R is as combines the acyl group, the acyl group is released at position 7 and the resulting compound of formula I iso luje in salt or free form.

The acyl group R * may be primarily acyl radical Ac of organic carboxylic acid preferably containing up to 13 atoms carbon and in particular the acyl radical, possibly an alternately substituted aliphatic, cycloaliphatic cycloaliphatic-aliphatic, aromatic arylaliphatic, heterocyclic or he- terocyclic aliphatic carboxylic acid including formic acid as well as rhodium acyl nickel of the carbonic acid semi-derivative.

Group R q can be split off in a known manner.

The compounds of formula I can be obtained by starting from compounds of formula II, in which clade, in the fermentationally obtained 3-ce- by famic means obtained by a known method the remainder is 5-amino-5-carboxyvaleryl where the amino group may be protected against a clade by an acyl residue, possibly also by a halogen-substituted lower alkanoyl group na example, a dichloroacetyl, benzoyl residue or a phthaloyl and / or carboxyl group preferably it may be protected by an esterified residue for example biphenyls; methyl or where R * is phenylacetyl or phenoxyacetyl.

In such compounds of formula II the carboxy group The head of R2 in position 4 can "be secured by esterification including stabilization or M where R < 4 > is a phenylacetyl moiety or phenoxyacetyl, in a known manner, for example by treatment with an imidohalogene-forming agent nek, carrying out the imide halide in the imide ether, cleavage of the latter by hydrolysis 45 or alcoholized with imide halide-forming agents and in which the halogen is bonded to the electrophilic a meaningful central atom, they are above all acid halides such as bromides, especially acid chlorophylls. These are acid halides, especially non-acid acids organic compounds such as phosphorus-containing acids like oxy-phosphorus, three-, especially five-halo- phosphorus genes, such as phosphorus oxychloride, phosphorus trichloride, and above all 55 phosphorus compounds, then phosphorus-pyrocate- trichloride china, as well as acid halides, especially chlorides. acids containing sulfur or acids carboxyl groups such as thionyl chloride, phosgene or oxalyl chloride. 60 Reacts with said forming agent The imide halide is carried out in the usual way in the presence of an appropriate, especially organic bases, primarily a tertiary amine such as, for example, an aliphatic mono- or An amine, such as a tri-alkyl amine at -10 104 396 19 20 trimethyl-, triethyl- or N, N-diisopropyl clade pyl-N-ethyl-amine, N, N, N ', N'-tetrapole alkyl- low-alkylene diamine, e.g. N, N, N ', N' - - tetromethyl - 1,5 - pentylene - diamine solder N, N, NSN'-tetramethyl-1,6-hexylenediamine mo no- or bicyclo- mono- or diamines like N-substituted e.g. N-low alkyl alkyl leno-, azaalkylene- or oxaalkyleneamines, e.g. N-methyl-piperidine or N-methylmorphine clade. then 2,3,4,6,7,8-hexahydrrolo [1,2-a] pyrrole midins (dibasic cyclononene) or tertiary aromatic amine, such as diankoalkyl-an- a rope for example N, N-dimethylaniline or above all tertiary heterocyclic mo no- or bicyclic base like quinoline, or isoquinoline, especially pyridine, preferably w the presence of a solvent such as, possibly, chlorine grooved, for example chlorinated aliphatic dub an aromatic hydrocarbon such as chloride methylene. You can use approximations equimolar amounts of an imidohalo-forming agent genek and rules, the latter can also be stacked an excess or an underflow, for example in an amount of 0.2-1 or about 10 times, especially 3-5 fold excess.

Reacts with the imide halide forming agent is carried out preferably using cooling on for example at a temperature of about —50 ° to about + 10 ° C, but you can also work at higher temperatures for example * up to approx 75 ° C, as the stability of the substrate allows it and product.

The resulting imide halide, which can be converted working further in the usual way without insulating, soc itself, according to the invention, is carried out after alcohol strength in the iminoester preferably in the presence of one of the principles mentioned above. The right ones alcohols are, for example, aliphatic, arylalipha- The tic alcohols are especially optionally substituted such as hydrochloric e.g. chlorinated or having additional hydroxyl groups lower alkanols for example ethanol, propanol or butanol and in particular methanol, then 2-chloro cyclic-lower-alkanols, e.g. 2,2,2-trichlor- roethanol or 2-bromoethanol as optionally sub- a substituted phenyl-lower-alkanol such as an alcohol benzyl. Usually an excess of 1-100- -times alcohol and works favorably with cooling for example at -50 ° C + 10 ° C.

The resulting iminoether can preferably be iso-free treatment, cleavage, cleavage by are carried out with the use of an appropriate hydro xy, preferably by hydrolysis, then alcoholysis, the last one being carried out with an excess of alcohol immediately after the formation The use of the iminoether is preferably used here water or alcohol, especially lower alkanol na for example methanol or an aqueous organic mixture solvent like alcohol.

The acyl residues R5 of the acylamino- one compound of formula 2, such as the rest -amino-5-carboxy valeryl in which the group carboxyl is optionally protected by esterification in particular with diphenylmethyl and / or the amino group is acylated protected an acyl residue of an organic carboxylic acid such as halogenonisalkanoyl, such as di- chloroacetyl or phthaloyl, may be foamed also by treatment with a nitros- with a salt such as nitrosyl chloride, carbocyclic aryldiazonium salt, such as dibenzene chloride azonium or a positive chlorinating agent such as N-halo-amide or -imide for and the N-bromosuccinimide clade, preferably correspondingly with the solvent or mixing the solvent such as formic acid together with nitro- or cy- ion-low alkane and the reaction products are queried with an agent containing a hydroxyl group like water or a lower alkanol such as methanol, or in the case of a 5-amino-5-carboxy-wa- The leryl Rq amino group is not substituted, the group carboxylic acid protects by esterification, by standing in an inert solvent like dioxane or a halogenated aliphatic hydrocarbon na example methylene chloride and optionally work up free or monosacylated amine compound, i.e. methods.

The R * group can also be split off by treatment with an acidic agent, for example acid sem toluenesulfonate, hydrochloric or with weak principles, such as diluted ammonia or a decarbonylating agent like chloride tri (triphenylphosphine) product.

In connection with formula I obtained by the method according to the invention with a protected, in particular carries an esterified carboxyl group of the formula -C (= 0) -R \ f you can group these known method on example, depending on the type of group R \ convert to the free carboxyl group. Ze¬ a esterified carboxyl group, for example a lower alkyl radical and in particular methyl or ethyl can be transformed into free carboxyl group by hydrolysis in sro 40 a slightly alkaline junction such as by treatment with an aqueous hydroxide solution or alkali metal or alkaline earth carbonate numerous, for example sodium hydroxide or potassium, preferably at a pH of approx 9 clo 10 and possibly in the presence of a lower alkaline nolu.

Carboxyl group, esterified suitable. 2-haloalkyl lower or arylcarbohydrate group ^ n nylmethyl, can be split for example 50 by treatment with a chemical reducing agent a metal such as tin, for example salt or a metal reducing salt such as salt chromium, for example chromium chloride usually in the presence of a hydrogen donating agent, 55 which together with the metal can generate hydrogen in statu nascendi as, for example, acid above all acetic acid, as well as formic acid alcohol or alcohol, and preferably 60 give water.

Carbonyl group esterified with a radical arylcarbonylmethyl can also be cleaved by treatment with a nucleophilic reagent, preferably salt-forming, such as, for example, thiophene 65 with sodium lumen or sodium iodide in group 21 104 396 22 carboxylic acid esterified with a suitable radical the arylmethyl element can be cleaved into e.g. clone by irradiation, preferably with rays . ultraviolet light, for example with a wavelength of less than 290 m 3 when the arylmethyl radical is for example, a benzyl radical, or alternatively placed in position 3, 4 and / or 5, for example low lower alkoxy radicals and / or groups nitrous or ultraviolet rays o greater wave length, for example over 290 mtu, when the arylmethyl radical is for example a benzyl radical, substituted in the 2-position nitro.

Carbonyl group esterified appropriately with a substituted methyl radical as for example 3rd class butyl or diphenylmethyl- can be cleaved, for example, by the action of od a suitable acid agent such as acid formic or trifluoroacetic acid optionally in the presence of a nucleophilic compound as for example phenol or anisole clade. Activated and esterified the important carboxyl group followed by the carboxyl group The carboxylic acid in the form of an anhydride can be dissolved graft by hydrolysis, for example, works with an aqueous solution of an acid agent or slightly basic, such as hydrochloric acid or an aqueous solution of sodium bicarbonate or an aqueous potassium phosphate buffer solution with a pH of about 7 to about pH 9, while hydro- genolytically cleavable esterified group carboxyl can be cleaved by hydrogen lize, for example, by the action of hydrogen in the present carrying a noble metal catalyst for example palladium catalyst clade.

A carboxyl group, protected for example by silylation or stannylation it is possible to release in the usual way, for example, treat no water or alcohol.

In the resulting compound to be esterified on a group of formula -C (= O) -R2, this group may transform into a different, esterified group of cards box with the same formula. You can for example clade 2-chloroethoxycarbonyl or 2-bromo group moethoxycarbonyl convert into a 2-io group doethoxycarbonyl by the action of iodine salt (na example of sodium iodide in the presence of the answer a solvent such as acetone.

Salts of the compounds of formula I can be prepared known way. You can make salts of these compounds with acid groups, for example by treating them with metal compounds, for example alkali metal salts of the corresponding acids for example, the sodium salt of the acid a-ethylpropane or ammonia either. answer a suitable organic amine, preferably is to use stoichiometric amounts or only not great excess of salt-forming agent. Sour addition salts of compounds of formula I with groups the basic ones are usually used by treatment with acid, for example or a suitable anion exchanger. Salts internal compounds of formula 1, including a salt-forming amino group and a free carbohydrate group xyl, can be produced, for example, by evil salt scavenging for example in addition salts to isoelectric point for example with weak bases or by treatment with liquids ion exchangers.

The salts can be transformed into a simple six> yourself free compounds, i.e., for example, a metallic salt and ammonium, for example by treatment with with suitable acids and acid addition salts na example by treated? with an appropriate measure alkaline. The resulting isomer mixtures can be known by methods to separate into individual isomers. Have The mixtures of diastereoisomers are separated for example clade by T of fractionated crystallization, chr adsorption matography, column- and thin-film or other suitable metal separation method. The resulting racemates can be the usual way, possibly after entering appropriate salt-forming groups in the distribution on optical antipodes, for example by creation mixtures of diastereoisomerite salts with optically active salt-forming agents, then separating the mixture into diastereomeric salts ne and the transformation of separated salts into free compounds either by fractionated crystallization from optically active solvents.

The invention also includes such variations according to which as starting substances compounds obtained as intermediates are used and with their help, the remaining steps are carried out the way or the way it breaks up on any stage. The starting substances can take the form of derivatives or form during the reaction.

Preference is given to using such starting materials In any case, the reaction conditions are selected to achieve Z5 compounds previously mentioned as specifically valuable.

Compounds of formula 2 can be obtained, for example if the 3-cephem compound of formula III or corresponds to giving enol with a double bond in position The 2,3- or 3,4- will be converted to the enol derivative with a functionally converted hydroxyl group of formula -O-R3 in position 3 and optionally protected a linked carboxyl group of the formula -C (= O) -R * transform into free or other carboxy group- 45 Iowa.

Compounds of formula 2 are obtained, for example thus, with a 3-hydroxy-cephem compound of formula III or the corresponding enol with a cross-linkage the bipolar at the 2,3 or 3,4 position is performed into an enol derivative with functional transformation a hydroxyl group of formula -O-R3 at position 3 and an optionally protected carboxyl group of formula -C (= O) -R6 is converted free or to another protected carboxyl group.

The 3-hydroxy-cephem compounds of formula III may exist in the ketone form and / or in the enol form • in. Usually compounds of formula 3 transform from the enol form to the enol derivatives of formula 2. 60 You can then, for example, as a sub as a starting point, use a mixture of fr formula 3 and the corresponding 1-oxide and as a result to obtain as a product a mixture of the compound of formula 2 and the corresponding 1-oxide. Compound with formula 65 3 can be used in its pure form or23 1 * 4896 AT was obtained in the form of a crude reaction mixture important during its manufacture.

The compounds of formula III may be used in a known manner form enol derivatives.

Ether derivatives of enols, that is, compounds with 5 Formula II, wherein R3 is optionally sub- the substituted hydrocarbon radical is obtained. any method useful for remarking enol groups. Preferably as an etherifying agent the corresponding base-10 applies the net hydrocarbon radical R3, compound diazo of formula R: -N2, preferably possibly a optionally substituted lower diazoalkane as in example diazomethane, diazoethane or diazot -n-butane, then optionally substituted lower phenyldiazoalkane as for example lower 1-phenyldiazoalkane, for example phenyldiazoalkane methane or diphenyldiazoethane. These compounds are here suje 'in the presence of a suitable indifferent for example an aliphatic hydrocarbon tic, cycloaliphatic or aromatic like for example, hexane, cyclohexane, benzene or tobacco luen or a halogenated aliphatic hydrocarbon lower alkali methylene chloride (for example nol), for example methanol, ethanol or tertiary -butanol or ether, such as lower dialkyl ether or a cyclic ether (e.g. tetrahydro furan or dioxane) or a mixture of solvents nodes and (depending on the diazo relationship) at low, room or light temperature increased and, if necessary, in the order knocked vessel and / or inert gas atmosphere, for example, under a nitrogen atmosphere.

Ether derivatives of the enols of formula II may be followed not obtain the action of the alcohol ester of the formula R3-OH, corresponding to the optionally substituted one hydrocarbon radical R <. Respond esters suitable for this purpose are above all esters of strong organic acids or not organic such as mineral acids for example, hydrohalic acids for example hydrochloric acid, hydrobromic acid or hydroiodic acid, followed by sulfuric acid or halosulfuric acids for example fluorosulfuric acid or strong organic sulfonic acids as optionally, for example halogen, for example, substituted by fluorine lower alkali or aromatic acids tic sulfonic acids such as, for example possibly, for example, with a lower alkyl radical with a methyl, for example, a halogen na for example, bromine and / or the nitro group are substituted other benzenesulfonic acids as, for example, methanesulfonic acid clade, trifluoromethane- sulfonic acid or p-toluenesulfonic acid.

The above reagents, especially the lower dialkyl sulfates such as dimethyl sulfate and then low alkyl fluorosulphates such as fluoro methyl orosulphate or, optionally, a halogen substituted lower alkyl esters of methane- for example sulfonic acid methyl ester trifluoromethanesulfonic acid is usually used in the presence of a solvent such as, for example, or halogenated, for example, chlorinated aliphatic hydrocarbon, cycloaliphatic or aromatic, for example, methyl chloride or an ether, for example a dioxane or four rhodofuran or a lower alkanol for example methanol or mixtures of solvents.

Preference is given to using the appropriate ones condensing agents such as carbon or hydrogen alkali metal carbonates for example carbonate or sodium or potassium bicarbonate (usually together with with sulfate) or also organic bases such as the habit of spherically disturbing lower triples- amines such as, for example, N, N-diisopropyl-N- -ethylamine (preferably together with halosulfate- us low alkyl or possibly halogen substituted lower alkyl esters of the acid methanesulfonic acid). The reactions are carried out at including at low, room or sub-temperature temperatures higher, for example, at a temperature of approx —20 ° C to about 50 ° C and in a vessel if necessary closed and / or in an inert gas atmosphere for example, under a nitrogen atmosphere.

Ether derivatives of enols can also be prepared rule by acting with a relationship at the same time the carbon atom itself of an aliphatic nature two or three etherified hydroxyl groups of formula R3-O-, that is, a suitable acetal or with an orthoester in the presence of an acid agent. As an etherifying agent can be used, for example, gem- -lower alkoxyalkanes for example 2,2-dimene- toxypropane in the presence of strong organic sulfonic acid, for example p-toluenesulfonate as low as possible and suitable solvent an alkanol, for example methanol or lower two an alkyl or lower alkylenesulfatide for example a clade of dimethylsulfoxide or a lower tricycle orthoformic acid low ester, for example Triethyl orthoformate in the presence of a strong acid inorganic, for example sulfur or silicon dioxide organic sulfonic acid, for example p-toluenesulfonic acid and the corresponding a solvent such as a lower alkanol for example ethanol or an ether for example a dioxane and so method to obtain compounds of formula 2, wherein Ri represents a lower alkyl radical as for example methyl or ethyl.

Ethers of enols of formula II can also be used get when the compounds of formula 3 works with tri-R3-oxonium salts of formula: (Rj) 3 O © AO (so-called Meerwein salts) as well no two-R3Q-carbonate salts of the formula: (R30) 2 CH © A0 or di-Ra-halonium salts having the formula: (Ra) 2 Hal © A0, wherein A0 is acid anion a Hal © foalonium ion for example bromonium ion. First of all, it is about lower trialkyloxonate as well as lower dialkoxycarbonate or dialkylohalonio- in particular, suitable salts with additives containing fluorine complex acids as per- eo clade suitable ozterofLuoroborates, hexafluo- phosphates, hexafluoroantimonates or six- chloroanthimoniain. These kinds of relationships are on example, trimethylphosphate hexafluoroantimonate nium or triethyloxone, hexachloroanth- G5 trimethyl- or triethyloxonium monate, six- \ 25 trimethyl- or triethyloxy-sciofluorophosphate dimethoxycarbohydrate hexafluorophosphate diethylbromate or hexafluoroantimonate monior / s.

The foregoing ethers are preferably used in an inert solvent such as ether or chloride grooved hydrocarbon for example diethyl ether tetrahydrofuran or methylene chloride either in a mixture of them and, if necessary, in their presence an organic base, for example preferably a spherical base disruptive lower trialkylamine for example N, N-diisopropyl-N-ethylamine and at a low, room or slightly elevated (for example at a temperature of from -20 ° C to 50 ° C) and optionally in a sealed vessel contaminated and / or inert gas atmospheres, example of nitrogen.

Obtain the ether derivatives of enols of formula II you can also act on compounds of formula 3 A 3-substituted 1-R; -triazene compound (i.e. means a compound of formula: subst- -N = N-N-NH-R)) wherein the nitrogen substituent 3 is an organic radical bound by a carbon atom preferably a carbocyclic aryl radical such as for example, an optionally substituted phe- low for example low alkyl phenyl, for example 4-methylphenyl clade.

Such triazene compounds are the lower 3-ary- 1-1-alkyltriazenes, such as, for example, 3- (4-methylphe- nyl) -1-methyl-triazene, 3- (4-methylphenyl) -1-ethyl- triazene 3- (4-methylphenyl) -1-n-propyl> triaze or 3- (4-methylphenyl) -1-isopropyltriazene and then lower 3-aryl-1-1-alkenyltriazenes, for example 3- (4-methylphenyl) -allyltriazene, and lower 3-ary- 1-1-phenylalkyltriazenes, such as, for example, 3- (4-me- tylophenyl) -1-benzyltrriazene. He uses these substances usually in the presence of inert solvents such as optionally halogenated carbons hydrogens or ethers, for example benzene or mixtures of solvents and at reduced temperature room, preferably elevated (na for example at a temperature of about 20 ° C to approx 100 ° C) and, if necessary, closed in the vessel including and / or in an inert gas atmosphere for example nitrogen clade.

Ether derivatives of enols, that is, compounds of o Formula 2, wherein R3 is an acyl radical, any method useful for esterifying the enol groups, wherein w of the compound of formula III the amino group at position 7 preferably she should be secured if she wants avoid simultaneous free acylation amino group. So it is used favorably the acyl acids corresponding to the acyl radical hydroxyls of formula Ra-OH or their reactive compounds acid derivatives and in particular suitable anhydrides and between them also internal anhydrides carboxylic acid hydrides, i.e., ketones or carbamic acids or thiocarbamino- ie, isocyanates or thioisocyanates or mixed anhydrides, that is, those that can be formed, for example, with chlorinated 04 396 26 hydrocarbons such as hydrofluoric acid or Lolny with hydrocyanic acid with lower alkyl esters of haloformic acid such as, for example, with ethyl ester or isobuty- formic acid or with chloride trichloroacetic acid, that is, suitable halides, for example fluorides or chlorides, and na¬ steppes of pseudohalides, by which it should be understood compounds corresponding to carboxylic acids cyariocartonyl as well as lower alkoxycarbones- loxycarbonyl, such as ethoxycarbony- loxycarbonyl or isobutoxycarbonyloxycar- bonyl or activated esters, for example esters with alcohols of the vinyl series (so-called enols), for example, lower alkane carbohydrate esters xyls with lower alkanols of the vinyl series for example acetic acid isopropenyl ester and, if necessary, the reaction takes place carried out in the presence of appropriate measures condensing using acids, for example compounds carbodiimides, for example dicyclohexy- locarbodimide or rcarbonyl compounds na an example of a diimidazolylcarbonyl using re active acid derivatives, for example, agents basic as well as lower trialkylamines, for example triethylamine clade or heterocyclic bases for example, pyridines and the use of alcohol esters vinyl series in the presence of an acid agent like mineral acid, for example sulfuric acid or strong sulfonic acid, for example p-toluenesulfonic acid. Acylation reactions can be carried out without or in the presence of dissolving solvent or solvent mixture at reduced, peaceful or increased conditions C5 and possibly in a closed vessel and / or in an inert gas atmosphere, such as nitrogen.

Suitable solvents are, for example optionally substituted, especially optionally substituted aliphatic chlorinated hydrocarbons, cyclo- 4D aliphatic or aromatic such as benzene or toluene, whereby, as diluents, suitable esterification agents can also be used for example acetic anhydride.

In the above reactions of etheration or esters- fiction can be, depending on the substance of the output and the reaction conditions to obtain a uniform compound of the formula II or mixtures thereof with the corresponding 2-cephemic compounds. The latter occur, for example when using compounds rl of formula III, contaminated with e.g. with heavy metals, for example with compounds or in case they have not been extracted rebound during their manufacture from compounds formula 5 and compounds of formula 5 are respectively contaminated when running a reaction in an alkaline environment. In that case the share of 2-union unions increases. Received The mixtures can be separated in a known manner such as by using the appropriate 'methods what to separate, that is, for example, by ad- sorption and fractionated elution, including chromium columnar, blotting paper or plate graphics using appropriate adsorbent agents for example, silica gel or oxide 65 of aluminum and eluting and then through the tailcoat-87 ionized crystallization, solvent separation and other.

In the thus obtained compound of formula I, wherein In this respect, the group of formula -C (= O) -R2 is a protection a linked carboxyl group of the formula -C (= O) -R2 and / or the amino group is protected, they may be known by a different method (for example, described below) by transform into a free carboxyl group or else protected carboxyl group.

Compounds of formula III used in the above method day for the production of starting substances of formula 2, can be prepared, for example, then when in the 3-cephem compound of formula IV (in which when R4 is hydrogen, or preferably is an amino protecting group R f for example acyl and in which R2 is preferably a group hydroxide but also the R £ group (ace group toxicimetric by environmental hydrolysis slightly alkaline, for example with water sodium hydroxide solution at pH 9-10 or by the action of a suitable esterase, for example a clade of the corresponding enzyme from Rhizobium tritolli, Rhizobium lupinii, Rhizobium jasponicum or Ba- cillus subtillia will transform into a group of hydroc the xymethyl group and the free carboxyl group o The formula -C (= O) -R2 will change functionally, resp the right way, for example, to act in a relationship diazo gas (such as, for example, diphenyl diazomethane), esterifies a hydroxy group for example by the action of a halogen agent a detergent, such as a chlorinating agent (e.g. clade of thionyl chloride) or an iodinating agent (na example N-methyl-N4-dicyclohexyl iodide carbodiimide) transformed into a group halomethyl such as a chlorine group romethyl or iodomethyl, The chloromethyl group is converted into a methylene group or directly (for example the action of the corresponding chromium compound such as, for example, an inorganic or organic salt of this compound, for example, chromium chloride or chromium acetate) in a suitable solvent for example dimethylsyphoxide or indirectly through the iodomethyl group, which can be produced, for example, by acting on a compound chloromethyl ether with metal iodide as for example clade sodium iodide in a suitable solvent In a JRC dish, for example, acetone, with w in this case, the iodomethyl compound is affected with a suitable reducing agent, for example zinc in the presence of acetic acid.

In the thus obtained compound of formula 5, which can be obtained from compounds of formula 4, for example also by electrochemical or reductions chromium salts or aluminum amalgam, transformed by forms when the amino group is released in the position 7 from an optionally protected amine group the methylene group is rebuilt by oxidation and compound of formula 5 and proceeds to the target the compound of formula 3.

In connection with formula 5 can be found in position 7, protected amino group by a known 306 2 * himself, as for the example described, transform into the free amino group.

The amine protecting group Rf a in particular it carries an easily cleavable acyl radical as per example -multi-branched lower radical alcohol- 'xycarbonyl for example III-row. butoxycar- Bonylowa can be split off, for example, running with trifluoroacetic acid and a lower radical 2-haloalkoxycarbonyl for example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxy- carbonyl or phenacyloxycarbonyl for example due to the action of a suitable reducing metal of a suitable or suitable metal compound, e.g. zinc clade or a chromium compound (e.g. chromium chloride or acetate), preferably a surface standing in the presence of a metal or metal compound with hydrogen in statu nascendi, preferably in the present carry an aqueous acetic acid solution.

Oxadative cleavage of the methylene group in the compounds of formula V to form an oxo group in position 3 of the cepham ring skeleton are preferably carried out by the action of ozone in the formation ozone compound. Ozone is used for including usually in the presence of a solvent as per alcohol for example lower alkanol for example (for example methanol or ethanol) ketone as per example of a lower alkanol (for example acetone), optionally halogenated aliphatic hydrocarbon tic, cycloaliphatic or aromatic as for example the lower haloalkane na example methylene or carbon tetrachloride or mixtures of solvents including mixing water pump when using cooling or light heating, for example at a temperature of approx _9o ° C to about 40 ° C.

Ozone, formed as an intermediate, splits off reductive, but catalysts may be used tically activated hydrogen, for example hydrogen in the presence of heavy metal as a catalyst for example a nickel catalyst or palladium, preferably on a suitable nose . nickel such as calcium carbonate or carbon, or chemical Heavy metal reducing agents including table memory or amalgams of heavy metals, for example zinc clade in the presence of a hydrogen donor as per acid for example, for example acetic acid or alcohol, for example lower alkanol, reducing as inorganic salts such as alkali metal iodides for example sodium iodide in the presence of a burrow of hydrogen as, for example, acid, for example acetic acid or organic reducing compounds like for example lower dialkyl sulfide for example dimethyl sulfide clade. 55 It is also possible to use the reducing compound moat organophosphine as for example phosphine, which as substituents may optionally contain a substituent substituted aliphatic or aromatic carbon radicals hydrogen as for example lower trialkylphosphines 60 for example tri-n-butylphosphine or triarylphosphine fines, for example, triphenylphosphine followed by phosphorus forins containing as substituents optionally substituted aliphatic hydrocarbon radicals like the lower trialkylphosphites, usually in the form 65 suitable alcohol adducts, 104 396 29 30 such as trimethylphosphite or phosphorus triamides fora, containing as substituents optionally aliphatic hydrocarbon radicals such as the lower six-alkyl tri-amides phosphoric acid, for example hexamethyltria- phosphoric acid amide, the latter preferably in the form of a metabolic additive tannol or tetra-cyanoethyl. The cleavage of the the custom of un-isolated ozone is normal under the conditions used for its production cooling, that is, in the presence of a suitable solution a solvent or solvent mixture, such as also using cooling or light heating.

Depending on the oxidation reaction a compound of formula III is obtained or equivalent to what 1-oxide or a mixture of both. This kind of mixture can be broken down into compound of formula III and the corresponding 1-oxide, for example by fractionated crystallization or by chromatography column or thin-layer matography.

In the reaction of transformation of compounds of formula 3 into the enol derivatives of the formula II, the latter after the present invention creation need not be isolated. You can eat preferably in the form of a crude reaction mixture after being prepared from the compounds of formula 5 without indirectly transform into the corresponding derivatives enol compounds of formula 2.

Organic radicals defined in this specification themselves, as "lower", include (if ina¬ or more) up to 7, preferably up to 4, carbon atoms and acyl radicals contain up to 20, preferably not up to 12, but most importantly up to 7 carbon atoms.

The following examples are intended to explain the exclusion of invention. The temperature is given in degrees Celsius.

Example I. Solution 0.514 g of diphenyl ester 3-methoxy-7 / α-phenylethylmethyl- amino-3-cephem-4-carboxylic acid in 30 ml of chloride methylene is cooled to -10 ° and for a long time it contains 0.8 ml of absolute pyridine and 8.0 ml 8% solution of phosphorus pentachloride in chlorine towards methylene. The reaction mixture is stirred in within one hour at -10 ° to -5 ° and then cooled to -30 ° and for a long time 5 ml of methanol are consumed. Then it mixes up over and over one hour at a temperature of -10 ° to -5 °, for one hour at 0 ° and within one hour at room temperature peace. 20 ml of 0.5 M aqueous is added potassium dihydrogen phosphate solution, after the mixture is stirred for 30 minutes at pH = 2.4 diluted with methylene chloride, the aqueous phase is separated and extracted with the aid of methylene chloride. The combined organic phases were transferred to the washed with a saturated aqueous solution of chloride sodium chloride, dried over sodium sulfate and evaporated grooves under reduced pressure.

The residue is extracted warm with ether ethyl acetate and allowed to stand for 16 hours and then the precipitate is filtered off, washed with ether diethyl and dried. A bi-ester is obtained phenylmethyl acid 7 /? - amino-3-methoxy-3-ce- femocarboxylic acid-4 in the form of a colored powder light brown. Thin layer chromatogram (silica gel, iodine vapor deposition): Rf R -0.17 (ethyl acetate system). Absorption spectrum w ultraviolet (in a 95% aqueous solution of eta nolu): X max = 258 m ^ (s = 5250) and 264 mp (s = 5300) and ^ max inflection = 290 m in {e = 5200).

Infrared absorption spectrum (in dioxane): characteristic bands at 2.87 here (wide), , 62 µl, 5.85 µl and 6.26 µm.

The starting material used in the above the following example can be prepared for example as follows: solution of 11.82 g of crude sodium salt 3-hydroxymethyl-7'-phenylacetylamino-3- -cephemocarboxylic-4 (prepared by enzymes matic deacetylation of 3-ace acid sodium salt « toxymethyl-7'-phenylacetylamino-3-cephemocarbo- xylowy-4 with a purified extract enzyme enzyme from Bacillus subtilis, ATCC strain 6633 and the subsequent lyophilization of the re stock) in 200 ml of water is poured (mixed) 400 mL of ethyl acetate and concentrated aqueous solution acidifies phosphoric acid until obtained pH = 2.

The water phase is separated and twice additionally it is extracted with 150 ml of ethyl acetate each. Pola The combined organic extracts are washed four times no water (50 ml each), dried over sulfate with magnesium and concentrate it to a volume of about 400 ml.

The solution is treated with an excess of diphenyl of azomethane, allowed to stand on the draft 3 hours at room temperature and then a grainy, crystalline precipitate. Skip the button thesis up to a volume of about 200 ml, treats on heat with cyclohexine and after cooling to temperature room temperature is left for some time standing time at about 4 °. Precipitate is filtered off and recrystallized from the ace mixture tone and cyclohexane. The thus obtained biphery ester 3-hydroxymethyl-7 acid nylmethyl? - phenyl- acetylamino-3-cephem carboxylic-4 has a temperature of melting perature 176 ° -176.5 ° (uncorrected) and (a)% = -6 ° ± 1 ° (C = 1.231% in chlorophore me). Thin-layer chromatogram (silicon gel) muon, identified by iodine vapor or light ultraviolet X = 254 m ^): Rf = 0.42 (system: chloroform) acetone 4: 1), Rf = 0.43 (system: toluene) acetone 2: 1) and Rf = 0.4l / system: methyl chloride flax (acetone 6: 1). 1.03 g diphenylmethyl acid 3-hydroxy- methyl-7 /? - phenylacetylamino-3-cephem carboxyl- wego-4 and 1.05 g of N-methyl-N, N'-bicyclo- of hexylcarbodiimidium is dissolved in at in a nitrogen atmosphere in 25 ml of absolute tetrahydro furan and heated for 1 hour at temperature at 35 °. Then 1.05 g of iodide is added again N-methyl-N, N'-dicyclohexylcarbodiumidium- it in 15 ml of absolute tetrahydrofuran and it is allowed to stand for 17 hours room temperature X under a nitrogen atmosphere. Chap the solvent to remove gTsie from the reaction fluid under reduced volatilization by means of a rotary evaporator ction. The residue is dissolved in methyl chloride and filter through a 50 g silica gel column (1Q% addition of distilled water) and na¬ the steps are washed with additional methyl chloride flax (4 portions of 100 ml). The leakage escapes to 40 45 50 55 60 104 396 180-181 °. Thin layer chromatogram (zel silica): Pd = - = 0.24 (system: toluene / acetate ethyl 2: 1).

Ultraviolet absorption spectrum (95% aqueous ethanol): no bands of character ristic. Spectrum of ab: infrared orb (in methylene chloride): characteristic band at 5.66 (x, 5.76 µ, 5.95 µ, 6.03 µ, 6.64 µ, and 6.70 µ.

A solution of 1.59 g of diphenyl ethyl ester 7 / M5-benzoylamino-5-diphenylmethoxy acid carbonylvalerylamino) - 3 -ir ethylene cepemocarbo- of xyl-4a in 150 ml of methylene chloride is cooled to -70 ° and stirring vigorously it takes 12 minutes and 43 seconds a mixture of ozone and oxygen (containing 0.2 mmol ozone / minute) then treated with 1 ml of sulfide dimethyl. Then it is mixed for 5 mi notes at -70 ° and within 30 minutes at room temperature and evaporated under reduced pressure. The remainder, containing 7? - (5-benzoylami-) acid diphenylmethyl ester no-5-diphenylmethoxy carbonylvalerylamino) - cepham-3-carboxylic-4a, dissolved in 40 ml of methanol, cooled in an ice bath and a trowel with a solution of diazomethane in diethyl ether wash until a persistent yellow color is obtained nia. The reaction mixture was evaporated under reduced pressure and the chromatographic residue it graphs on 1C0 g of silica gel. Two- phenylmethyl acid 7 /? - (5-benzoylamino-5-di- phenylmethoxycarbonylvalerylamino) -3-methoxy- The mixture is eluted from 3-cephamocarboxylic-4 1: 1 toluene and ethyl acetate and obtained as pro amorphous product. Thin layer chromatogram white (silica gel) Rf = 0.45 (system: toluene / ethyl acetate 1: 1).

Absorption spectrum in ultraviolet (95% aq ethanol solution): k bend "= 25 & m (f = 7450), 264 m // (s = 7050) and 268 mtu (s = 6700).

Infrared absorption spectrum (in methyl chloride) lene): characteristic bands at 5.65 u, 5.78 u, 6.03 [i and 6.64 p.

Example III. a suspension of 1.65 g of bifenal ester nylmethyl acid 7 /? - amino-3-methoxy-3-ce- famocarboxylate-4 and 2 ml of anisole are treated ml of pre-cooled trifluoro acid of vinegar and stirred in an ice bath for 15 minutes music notes. It is then diluted with 100 ml of cold toluene and the reaction mixture was evaporated under reduced pressure high pressure. Dark-colored residue brown is dried under very reduced pressure and mixed with diethyl ether. Precipitate filtered, washed with diethyl acetone and subject to drying. The salt thus obtained 7 / α-amino-3-methoxy-3-cephem carboxylic acid go-4 and trifluoroacetic acid dissolve in 10 ml of water. The aqueous solution is washed twice times with ethyl acetate (10 ml each time) and added with a 10% solution of triethylamine in methanol brings the pH down to 4.5. Next it is diluted with 10 ml of acetone and the mixture is stirred within one hour at 0 °. Precipitate filtered, washed with 1: 2 acetone and diethyl ether and dried very well reduced pressure. It is acid 7 /? - amino-3-methoxy-3-cephem-4-carboxylic in the form of inner salt form. Thinner Chromatogram joint (silica gel): Rf = 0.16 (d: n-butants / acetic acid / water 67: 10: 23). Spectrum ultraviolet absorption (in 0.1 N hydrochloric acid): A max = - "261 m ^ (e = 5400). io W produced according to the above method 7'-amino-3-methoxy-3-cephem carboxylic acid dim-4 can be treated with trimethylchlorosilane, a carboxyl group and (when using nad measure of the silylating agent) also the amino group convert to a protected carboxyl group trimethylsilyl group and possibly the same protected amino group and in a three- 7 / α-amino-3-methoxy-3- methylsilylated acid -cephemocarboxylic-4 amino acylate the action of phenylacetyl chloride. After the knitting of the usual applied further processing in the presence of water gives 3-methoxy-7 acid /? - -phenylacetylamino-3-cephemocarboxylic-4.

P r z y k l a d IV. For a suspension of 2.55 g (7 mmol) 7 /? - phenoxyacetamido-3-methoxy-3-cefemo- -carboxylic acid-4 and 2.9 ml (22.4 mmol) N, N-di- methylaniline in 11 ml of absolute methyl chloride in a nitrogen atmosphere at a temperature of 20 ° C gives 0.7 ml (5.7 mmol) dimethyl-dichloro silane and stirred at this temperature continuously minutes. The resulting clear solution is cooled down to -20 °, deals 1.6 g (7.7 mmol) of a solid five phosphorus chloride and stirred for 30 minutes. In that same temperature is added over 2 to 3 minutes pre-cooled (-20 ° C) mixture 0.9 ml (7 mmol) of • N, N-dimethylaniline and 0.9 ml n-butanol, finally quickly 10 ml previously chilled (-20 ° C) n-butanol5 then stirred minutes at -20 °, then 10 minutes without chlorine making. At about -10 °, 0.4 ml of water is added, for about 10 minutes mixed with ice (0 ° C) in the bath 11 ml of dioxane are added stepwise, and after a further 10 ml mixing notes at around 0 ° added in portions 4.5 ml of tri-n-butylamine until diluted the sample water will not exhibit a constant value pH 3.5. After 1 hour stirring at 0 ° the precipitate is filtered off, washed with dioxane and recrystallized from glass high water / dioxane. Dioxane compound was obtained with acid hydrochloride 7 / α-amino-3-methoxy-3- -cephemocarboxylic-4 melting point above 300 °. Thin film chromatogram out: Rf = 0.17 (silica gel: n-buta- system nol / carbon tetrachloride / methanol / formic acid 55 wy / water 30: 40: 20: 5: 5).

Example 5 Suspension 11.75 g of 93% strength (equiv. 10.93 g 100% acid) 7 /? - phenoxyacet- tamido-3-methoxy-3-cephem-carboxylic-4] 00 13.4 ml (12.73 g) of N, N-dimethylaniline in 47 ml absolute methylene chloride (distilled with over P2O5) is chosen at a temperature of 20 ° C in a nitrogen atmosphere 3.6 ml (3.87 g) dimethyl dihydrogen rosilan, then stirred at the same temperature 65th round in 30 minutes. The clear solution cools 40 45 5037 104 396 38 down to -18-19 ° C and treated with 7.8 g of solid pentachloride phosphorus, with the temperature inside rising Aug to -10 °. After stirring for 30 minutes, it was added dropwise clear solution in 7 minutes to cool to -20 ° a mixture of 47 ml of n-butanol (anhydrous, dried over silica (and 4.4 ml / 4.18 g) dimethyl aniline. The internal temperature rises to —8 °. Stirs for 30 minutes, initially on Baths with a temperature of -20 °, then in the bathhouse with ice (0 °) so that the final indoor temperature is The net surface is -10 °. At this temperature A mixture of 47 ml of dioxane and 1.6 ml is added dropwise water (about 5 minutes). The product slowly crystallizes.

After a further 10 minutes of mixing, the mixture was allowed to stand ice baths are treated in portions of 9.5 ml of three n-butylamine in about 1 hour (the first ml is added in the first 5 minutes (positive It amounts to a pH of 2.2-2.4 and maintains it.

Finally, it drips off, washed approximately in portions • 0 ml of dioxane, then 15 ml of methylene chloride and gives the crystalline compound of dioxane with chlorine 7 / α-amino-3-methoxy-3-cephe acid hydride mo-carboxyl-4. Melting point after more than 300 °.

Ultraviolet spectrum (in 0.1 N acid carbon not sodium): Amax = 270 m ^ (s = 7600). The spectrum in infrared (nujol): characteristic bands at: 5.62 m / u, 5.80 m / *, 5.83 m / u, 6.26 mu, 6.55 mu, 7.03 m, 7.45 m, 7.72 mu, 7.96 rau, 8.14 m /, s, 3.26 m, 8.45 m ^ a, 8.64 m ^ a, 8.97 m, 9.29 m, 10.40 m, 11.47 mjw [a] D ° = + 134 ° ± 1 ° (C = 1; 0.5N solution acidic sodium carbonate).

From the obtained compound of dioxane with chlorine doric by treating its 20% dilution with 2N sodium hydroxide to a pH value of 4.1 (isoelectric point) one can obtain a di-ion polar acid 7 /? - amino-3-methoxy-3-cefemo- -carboxylic-4 which is filtered off and dried It has a melting point above 300 °.

Ultraviolet spectrum (in 0.1 m acidic solution sodium carbonate): X max = 270 m ^ (e = 7,600). Chro- thin layer matogram; the value of Rf is identical na with its hydrochloride (silica gel, ten system itself) [a] ™ ± 232 ° + 1 ° (C = 1.5N solution acidic sodium carbonate).

Claims (7)

Patent claims 1. The method for the preparation of O-substituted acid derivatives 7 (# - ammo-3-hydroxy-cephem-3-carboxyl-4) of the general formula (I), in which R1 represents a hydroxyl group or the radical R1 formed together with a carbonyl group C (= O) - a protected carboxyl group, while R3 is an optionally substituted hydrocarbyl or acyl radical or a salt of such compounds with groups having a salt-forming ability, characterized in that in a compound of formula II, in which R2 and R3 have the above given the meaning given, and R 0 is an acyl group, the amino group at position 7 is released by treatment with an imidolialogen-forming agent, and the resulting imide halide is reacted with an alcohol and the formed iminoether is cleaved, and the resulting compound of formula 1 is isolated as a salt or in the free substitute. 2. The method according to claim A compound according to claim 1, characterized in that the compound of formula II is used, wherein R "is an acyl residue of a carboxylic acid, preferably containing up to 18 carbon atoms, and R2, R3 is as defined in claim 1, 1. 3. The method according to p. A compound according to claim 1, characterized in that the compound of formula 2 is used, wherein R 20 is a 5-amino-5-carboxy valeric residue, in which the amino group is protected by a benzoyl group and the 5-carboxyl group is protected by a diphenylmethyl group , or Rq is a phenylacetyl or phenoxyacetyl residue, and R ', Rj are as defined in claim 1, 1. 4. The method according to p. A compound according to claim 1, characterized in that the compound of formula II is used in which the group -C (R 2) -R 2 represents an esterified carboxyl group, preferably diphenylmethoxycarbonyl. And R o, Rs are as defined in claim 1. 5. The method according to p. The process of claim 1, wherein phosphorus pentoxide is used as the imido halide forming agent and the formed imide halide is cleaved by treatment with an alcohol such as ethanol. 6. The method according to p. The process of claim 1, characterized in that in the obtained compound of formula (I), an esterified carboxyl group is converted by saponification to the free carboxyl group. 7. The method according to p. A compound according to claim 1, characterized in that the compound of formula 2 is used, in which Rz represents lower alkoxy, 2-halo-lower-alkoxy, in particular 2,2,2-trichloroethoxy, phenacyloxy, 1-phenyl-lower alkoxy. 1 to 3 phenyl residues optionally substituted with lower alkoxy or nitro group, then is a lower alkanoyloxymethoxy group, a-aminonisalkanoloxymethoxy trisylsilyloxy or optionally substituted amino or hydrazine, R3 is optionally lower alkylene and lower alkylene group, preferably lower alkylene group, - alkyl, in particular benzyl, lower alkanoyl, lower alkoxycarbonyl or benzoyl, and Rq is as defined in claim 1; 1.104 396 R 0 \, N in yn 0 = LN ^ 0-R 0 = C-R2 Formula 2 RH ': no ^ - | SL 0 = CR, Formula 3 OAO CHj-OC- CH3 0 = C-Rz Formula A OZGraf. Z.P. Dz-wo, 'z. 798 (95 + 20) 12.79 Price PLN 45