CA1106358A - Process for the manufacture of penicillins and cephalosporins - Google Patents

Abstract

Abstract Process for acylating 6-amino-penam and 7-amino-cephem derivatives by activating the acylating component with an optionally substituted 1-hydroxybenzotriazole and then reacting the activated derivative with the 6-amino-penam or 7-amino-cepham derivative.

Description

35~
_ 2 -One oP the greatest difficulties when manufacturing cephalosporins and penicillins lies in finding conditions which are as gentle as possible for the coupling of the cephem or penam body with an acid component at the 7- or, respectively, 6-amino group. For example, slight rises in the temperature during the reaction, or alkaline or acid reaction media result in a rapid degradation of the ~-lactam or effect profound changes in the acid component to be coupled.
The prior necessary activation of the acid component is also freguently associated with not inconsiderable stresses on the molecule, and for this reason it is fre-quently neces~ary to make even greater efforts to find optimum, gentle reaction conditions: thus, German Offen-legungsschrift 2,265,235 indicates a specific process by means of which 2-alkoximinoaryl-acetic acids are converted to the acid chlorides without the undesired isomerization of the syn- to the anti-alkoximino compound, which proceeds very easily in acids, taking place.
Because of their instability, the active intermediate stages can also present problems.
Thus, in German Offenlegungsschrift 2,540,37~, a process for the manu~acture of cefazolin is described in which tetrazolylacetic acid is converted to the acid chloride, which, because of its low stability, is appropriately immediately reacted in situ. In a case of this type, control over the extent of activation is made more difficult.

: :
: , . ~:, , ~ : , : , , . ,: :

~63 s As is generally krlown from peptide chemistry, but ! especially from the investigations on the preparation of, for example, ampicillin (Doyle et al. J Chem. Soc. 1962, 0), cephaloglycin (Kurita et al. J. Antibiot. 19, 243 (1966), Spencer et al. 3. Med. (,hem. 9, 746 (1966)), or I cephalexin (Ryan et al~ J. Med. Chem. 12, 310 (1969)), the ¦ problem o~ racemi~ation at the ~-C atom always arises when linklng the activated and N-prot;ected phenylglycine with the ! corresponding ~-lactam (in this context compare Flynn, l 10 Cephalosporins and Penicillins, Academic Press, New York, ¦ 1972, page ~6).
In the abovementioned cases, and also in many other cases, efforts must be made to obtain highly reactive inter-mediate stages, such as acid anhydrides or acid chlorides, for activation. Under certain circumstances, it is therefore necessary to protect any reactive groups which may be present in the acid molecule before activating the said molecule, in order to excIùde undesired intra- or inter-molecular adverse reaction.
The activation of a number of 2-aminothiazolylacetic acids and the subsequent coupling thereof with 7-amino-cephem derivatives is described in German Offenlegungsschrift

2,556,736, the 2-amino group being blocked by easily detach-able protective groups, using processes which in some cases are involved, prior to the activation and being set free agaîn only after coupling has taken place. Considerable losses arise with this process.
~

.
'"' ~ ' : ~ ' " ' ' ~ ~' ' . :, , . .

6~5~ ' , In French Patent Specification 7,601,~3~, a process E
is described which links 2-tritylaminothiazolylacetic acid derivatives with 7-aminocephalosporanic acid and subsequently detaches the protective group, as tritylcarbinol, under acid conditions.
The introduction of such prot0ctive groups, and the detaching thereof after the coupling reaction has ended, is generally associated with not inconsiderable substance losses (see above), further stress on the acylating component and on the acylation product and also a not inconsiderable expenditure of time and effort.
In many cases it is also necessary to bring the product into which the protective group is converted on detaching, after isolation of the said product, into a form in which it can be used again as a protective group reagent and thus can be fed back into the process.
However, detaching of the protective group is fre-quently associated with the irreversible loss thereof.
The purity of the desired substance in general suffers so greatly during the manipulations carried out to introduce and detach any protective groups that increased efforts have to be made to purify the product.
It has now been found that the difficulties des-cribed can be avoided, and cephalosporins and penicillins can be obtained in high yield and purity by acylation of 6_ amino-penam and 7-amino-cephem derivatives, by converting the acyla~ing component to an active derivative using an option-. , ............................... .' ' ' 35~3 ; - 5 -ally substituted l-hydroxybenzotriazole and then reacting ! the said derivative with a 6-amino-penam or 7-amino-cephem derivative.
The invention relates espeeially to a process for the acylation of 6-amino-penam and 7-amino-eephem deriva-tives, which eomprises using, as the acylating component, a carboxylic acid of the formula I

Rl in which Rl represents alkyl having 1 to 4 carbon atoms, an optionally substituted, saturated or mono- or poly-unsaturated carbocyelie ring, optionally substituted aryl or lS aralkyl or optionally substituted heteroaryl or heteroaryl-thio and R and R3, whiCh ean be identieal or different, represent hydrogen, alkyl having 1 - 4 C atoms in the optionally substituted aeyloxy having 1 - 4 C atoms in the acyl part, optionally substituted alkoxy having 1 - 4 C
atoms in the alkyl part, optionally substituted alkylamino, ; optionally substituted acylamino, alkoxycarbonyl having 1 -4 C atoms in the alkyl part, sulfoxy or aminosulfonyl, or together ean be oxygen or, espeeially, a group of the formula VIII
= N - X VIII
in which X preferably has the syn configuration and repres-ents hydroxyl, optionally substituted, saturated or unsatu-rated alkoxy, optionally substituted aryloxy or optionally substituted aeyloxy, reaeting this with a l-hydroxybenzo-~iazole of the general formula II

:: - ' , ~ . . : :
: . : ' , :
-. ,, ' , . . . .. .
-" ' '' . '' ' ~

.. . . : .

~ ~63s~
: 6 : R

R
7 /~\ N
R OH

` in which R6, R7, R~ and R9, whic:h can be identical or different, can represent hydrog~n, optionally ~ubstituted alkyl having 1 - ~ C atoms, optionally substituted alkoxy having 1 - ~ C atom~, halogeng cyano, nitro~ aminocarboxy, alkylaminocarboxy having 1 - 4 alkyl C atoms, aminosulfonyl, alkylaminosulfonyl having 1 - 4 alkyl C atoms or dialkyl-;~ aminosulfonyl having 1 - ~ C atoms per alkyl group, in the presence of a dehydrating agent, especially of a carbodi-imide, to give an sctivated derivative of the formula XI a or XI b R

R~ ~1 XI a R6 o - CO - C - R3 .,' R2 CO-ClR
R~ ' R2 XI b R7~\N D
~3 , , .
~ `

. , :. .

. . . . . , ~ .

~ 3 ! - 7 -or a mixture thereof, isolating this product if desired and subsequently reacting it with a 6-amino-penam dérivative of the formula III
()n Y-NH ,~ ~Cc~3 I I I
N -- ~
O COOA
in which n can represent O, 1 or 2 and A can denote hydro-gen, a cation or an ester group and Y represent~ hydrogen or a trialkylsilyl group, or wlth a 7-amino-cephem derivative of the formula IV ()n y-N~ ~ s ~ IV
N ~

15 in which n, A and Y are as defined above and B represents chlorine, bromine, hydroxyl, methoxy or a group of the formula IX
- CH2-B' IX
in which B' can denote hydrogen, hydroxyl, optionally sub-stituted acyloxy having 1 - 4 C atoms, optionally substitu-ted acylthio having 1 - 4 C atoms, optionally substituted aminocarbonyloxy, l-pyridinium or S-Hetj in which Het represents an optionally substituted, 5-membered or 6-membered heterocyclic ring, which optionally can also be fused to a carbocyclic or heterocyclic ring, to giv8 a com-pound of the formula V

.

.

.

3S~

Rl ( I)n R2 _ C - CONH V

R O ~02A

or a compound of the formula VI

.~ Rl (I~n R2 _ C - CONH--I~ S'~ VI
5R3 ~ N ~ B
~: C02A
in which formulae Rl, R , R3, A~ B and n can have the mean-ings defined.
Compounds which can be used for the reaction accord-ing to the invention are in particular those in which thesubstituents have tna following meanings.
R can represent alkyl having 1 4 carbon atoms, preferably methyl or ethyl, an optionally substituted, saturated or mono- or poly-unsaturated, 5-membered to 7-; 15 membered carbocyclic ring, such as cycloalkyl, preferably cyclohexyl, cycloalkenyl, preferably cyclohexenyl, or cyclo-alkadienyl, preferably cyclohexadienyl, otpionally sub-stituted aryl, preferably phenyl or m-methylsulfonylamido_ phenyl, optionally substituted aralkyl, preferably benzyl, optionally substituted 5-membered to 6-membered heteroaryl, which can contain, as hetero-atoms, nitrogen, sulfur or s~
_ 9 _ oxygen, such as, for exampl~, 2-pyridon-1-yl, 4-pyridon-1-yl, 3,5-dichloro-4-pyridon-1-yl, 2-thienyl or l-tetrazolyl, but preferably a 2-furyl or a thiazolyl Or the formula YII

R4 ~f R5 VII
in which R4 preferably represents amino or represents option-ally substituted acylamino, such as, in particular, formamido, acetamido, chloroacetamido, bromoacetamido, trifluoroacet-amido, phenoxyacetamido, (5-methyl-1,3,4-thiazol-2-yl)-thio-acetamido or (5-amino 1,3,~-thiadiazol-2-yl)-thioacetamido, optionally substituted alkyl- or dialkyl-amino having 1 - 4 C atoms per alkyl group, such as, preferably, methylamino, dimethylamino and ethylamino, optionally substituted alkenylamino having 2 - 4 C atoms, such as, preferably, allylamino, or hydroxyl, alkoxy having 1 to 4 C atoms, such as, preferably, methoxy, ethoxy or propoxy, acyloxy, such as, preferably, ~ormyloxy, acetoxy or propionyloxy, halogen, such as, preferably, chlorine or bromine, or alkylthio, such as, preferably, methylthio, ethylthio, propylthio or butyl-thio, and R preferably represents hydrogen or represents halogen, such as, preferably, fluorine, chlorine or bromine, cyano, thiocyano, hyd~oxyl, alkoxycarbonyl having 1 - 4 C
atoms in the slkyl radical, such as, preferably, methoxy- c carbonyl or ethoxycarbonyl, acyloxy, such as, preferably, formyloxy, acetoxy or propionyloxy, acylthio, such as, preferably, acetylthio, alkoxy, such as, preferably, methoxy, ethoxy or propoxy, or alkylthio, such as, preferably, methyl-: thio or ethylthio, or Rl can represent an optionally sub-~._ . ~,, ~.

:

.

~lg~635B
,. -- 10 --stituted heteroarylthio radical, such as, preferably, 2-methyl-1,3,4-thiadiazol-5-yl-thlo or 2_amino-1,3,4-thla-diazol-5-yl-thio .
R and R , which can be identical or different, can ` 5 denote hydrogen, alkyl having 1 - 4 C atoms, preferably -- methyl, or hydroxyl, optionally substituted acyloxy having `~ 1 to ~ C atoms in the acyl part, such as, for example, ; formyloxy, acetoxy or propionyloxy, optionally substituted alkoxy having 1 to ~ C atoms in the alkyl part, such as, for example, methoxy, ethoxy or propoxy, optionally subst~tuted alkylamino, such as, preferably, tert.-butylamino or tert.-amylamino, benzylamino, p-methoxybenzylamino, benzhydryl-amino, tritylamino, phenylethylamino, optionally substitu~
ted acylamino, such as, for example, formamido, acetylamino, ~- 15 chloroacetylamino, bromoacetylamino, benzoylamino, tert.-butoxycarbonylamino, 2,2,2_trichloroethoxycarbonylamino, ~-hydroxy-1,5-naphthyridine-3-carbonylamino, 3-hydroxy-pyrida-zine-4-carbonylamino, imidazolidin-2-on-1-yl-carbonylamino, (3-methyl-sulfonyl-imidazolidin-2-on-1-yl)-carbonylamino, (4-ethyl-piperazin-~,3-dion-1-yl)-carbonylamino, or alkoxy-carbonyl having 1 to 4 C atoms in the alkyl part~ such as, for example, methoxycarbonyl or ethoxycarbonyl, or sulfoxy or aminosulfonyl, or together denote oxygen or, preferably, a group of the formula VIII
: 25 : = N - X VIII
in which X preferably has the syn configuration and prefer-ably represents hydroxyl or represents optionally substitu-ted, saturated or unsaturated alkoxy, such as, preferably, "' , ) , .. ,, ~

,.~ . ...

' 635~

methoxy, ethoxy, propoxy or butoxy, benzyloxy, p-chloro-! benzyloxy, triphenylmethoxy, aminocarbonylmethoxy, tert.-butoxycarbonylmethoxy, methoxycarbonylmekhoxy, ethoxy-carbonylmethoxy, cyanomethoxy, allyloxy or bromoallyloxy, or optionally substituted aryloxy, such as, preferably, phenoxy, or optionally substituted acyloxy having 1 to 4 C
atoms, such as, preferably, acetoxy, chloroacetoxy or bromo-acetoxy.
6 7 ~ 9 R , R , R and R can be identical or different and ~enote hydrogen, optionally substituted alkyl having 1 - 4 C atoms, preferably methyl or ethyl, which can carry, as substituents, in particular halogen, preferably fluorine or chlorine, or cyano, or optionally substituted alkoxy having 1 - 4 C atoms, preferably methoxy or ethoxy, which in par-ticular can be substituted by halogen, such as fluorine or chlorine, or halogen, such asl for example, bromine, chlorine or ~luorine, cyano9 nitro, aminocarboxy, alkylaminocarboxy having 1 - 4 alkyl C atoms, such as, preferably,` methylamino-carboxy or ethylaminocarboxy, aminosulfonyl, alkylamino-sulfonyl having 1 - 4 alkyl C atoms, preferably methylamino-- sulfonyl, or dialkylaminosul~onyl having 1 - 4 alkyl C
atoms per alkyl group, preferably dimethylaminosulfonyl or diethylam~nosulfonyl.
Particularly preferred compounds of the formula VI
are: l-hydroxybenzotriazole, 1-hydroxy-4-methyl-benzo-triazole, l-hydroxy-5-methyl-benzotriazole, 1-hydroxy_6_ methyl-benzotriazole, l-hydroxy-5,6-dimethyl-benzotriazole, 1-hydroxy-5-methoxy-benzotriazole, 1-hydroxy-6-methoxy-b~nzotriazole, l-hydroxy-6-trifluoromethyl-benzotriazole, 5-., ~ ..

~, .
.
, ' - 12 _ chloro-l-hydroxy-benzotriazole, 5,S-dichloro-l-hydroxy_ benzotriazole, 6-bromo_l_hydroxy_benzotriazole, ~ 7 5,6~7_ tetrachloro-l-hydroxy-benzotria~ole, 6-chloro-1-hydroxy-5_ methyl-benzotriazole, 6-chloro-1-hydroxy-5-~sopropyl-benzo-triazole, 4-chloro-6-nitro-1-hydroxy-7-methyl-benzotriazole, 6-nitro-4-methyl-1-hydroxy-benzotriazole, 6_nitro-1-hydroxy-benzotriazole, l-hydroxy-6-meth~yl-5-cyano-benzotriazole, 1-hydroxy-benzotria~ole-carboxylic acid-~6) amide, l-hydroxy-;~ 6-methylaminosulfonyl-benzotriazole, 1-hydroxy-6-amino-sulfonyl-benzotriazole or 1-hydroxy-6_diethylaminosulfonyl-benzotriazole.
A can represen~ hydrogen, a metal cation, for example an alkali metal cation or alkaline earth metal cation, especially sodium,potassium or calcium, a cation of an organic base, such as, for example, a trialkyl-ammonium ion, preferably tr~methyl-ammonium, triethyl-ammonium or tri-n-butyl-ammonium, or an ester group, prefer-ably an easily removable ester group, such as, in particular, methyl, benzyl, benzhydryl, pivaloyloxymethyl, 2,2,2-tri-chloroethyl, tert.-butyl or trimethylsilyl.
B can represent, in particular, chlorine, bromine, . hydroxyl, methoxy or a group of the formula IX
-CH -B' IX
in which Br can denote hydrogen, hydroxyl, opttonally sub-~ 25 stituted acyloxy having 1 - 4 C atoms, such as, preferably, : acetoxy, optionally substituted acylthio having 1 - 4 C

,.

~ .
, .

atom~, such as, preferably, acetylthio, optionally sub-stituted aminocarbonyloxy, preferably unsubst~tuted amino-carbonyloxy, l-pyridinium or -S-Het, in which Het can be an optionally substituted 5-membered heterocycllc radical con-taining nitrogen, sul~ur and/or oxygen, especially pyrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazo~yl, isothiazolyl, thiadiazolyl, oxazolyl, lsoxazolyl or oxa-diazolyl, which can also carry one or more substituents, such as, for example, alkoxy having 1 to 4 C atoms, prefer-lo ably methoxy or ethoxy, halogen, preferably chlorine, 5-membered or 6-membered heteroaryl, especially furyl, thienyl or pyridyl, amino or optionally substituted alkyl having 1 - 4 C atoms, preferably methyl, in which the alkyl substituent can be yet furthar substituted, preferably by halogen, such as, ~or example, fluorine or chlorine, hydroxyl, carboxyl, sulfonyl, aminocarbonyl or amino-sulfonyl. Particularly preferred radical~ of this type which may be mentioned are, for exampIe: l-methyltetrazolyl, l-phenyltetrazolyl, l-hydroxyethyl-tetrazolyl, l-carboxy-: 20 methyl-tetrazolyl, l-amino-carbonylmethyl-tetrazolyl, 1-sulfonylmethyl-tetrazolyl, l-aminosulfonylmethyl-tetr3zolyl, 5-amino-1,3,4-triazolyl, 5-methyl-1,3,4-triazolyl, 5-tri-fluoromethyl-1,3,~-triazolyl, 5-(2-thienyl)-1,3,~-triazolyl, - 5_(2-furyl)-1,3,~_triazolyl9 5-trifluoromethyl-1-methyl-1,3,~-triazolyl, 5-(2-thienyl)-1-methyl-1,3,4-triazolyl, ; l-carboxymethyl-1,39~-triazolyl, 1-carboxymethyl-5~methyl_1,3,4_ triazolyl, 5-methyl-1,3~4-thiadiazolyl, 5-amino-1,3,4-thiadiazolyl, 5-methyl~1,3,4-thiadia~olyl, ~-methylthiazolyl, ~-carboxymethyl-thiazolyl, 5-aminothiazolyl, 3-methyl-1,2,~-thiadiazolyl, .~,5-dimethyl-hexazolyl or 4,5-dimethyl-thiazolyl.

', ~ .' .

' ;

~ ~ ' In the abovementioned radical -CH2-S-Het, Het can also be an optionally substituted 6-membered heterocyclic radical which contains one or more nitrogen atoms, optionally together with sulfur or oxygen~ Examples which may be mentioned are, in particular, pyridyl, pyrim~dinyl, pyrazinyl and pyridazinyl, and these 6-membered hetero-cyclic radicals can also carry one or more substituents, such as, for example, alkyl having 1 - 4 C atoms, preferably methyl, alkoxy having 1 - 4 C atoms, preferably methoxy or ethoxy, halogen, such as, for example, chlorine or bromine, amino, hydroxyl, mercapto, carboxyl or carboxymethyl.
Particularly preferred radicals which may be mentioned are, for example, ~,6-diamino-pyrimidin-2-yl, 6-hydroxy-4-amino-pyrimidin-2-yl, 4,5-diamino-6-hydroxy-pyrimidin-2-yl and 5-carboxy-methyl-~-hydroxy-6-methyl-pyrimidin-2-yl.
The carbocyclic or hetarocyclic ring which can be fused to the heterocyclic structure can be, in particular, a benzo, furo, thieno or pyrido ring. A preferred example of this which may be mentioned is 5,6-benzo-1,1 dioxo-1,~,~-thiadiazin-3-yl.
Y can represent hydrogen or a trialkylsilyl group, especially trimethylsilyl.
The carbodiimides which can be used as the carbodi-imide employed as the dehydrating agent for the reaction of the acylating component with the hydroxybenzotriazole are - the carbodiimides suitable for reactions of this type, especially those of the general formula X

R - N = C = N - Rll X

.

~J6~5 in which R and R can have the following meaning.
R10 and R can be identical or dlfferent and represent alkyl hav~ng 1 to 4 C atoms, such as; preferably, methyl, ethyl, propyl, isopropyl or butyl, an optionally substituted am~noalkyl having 1 to 4 C atoms per alkyl group, such as~
preferably, 3-dimethylamino-propyl, 3-triethylamino-propyl, 2-N-morpholino-ethyl or 2-pyrroJidino-ethyl, and also the metho-iodides and metho-p-toluene-sulfonates thereof, or an optionally substituted cycloalkyl radical, such as, prefer-ably, cyclohexyl, or an optionally substituted aromatic radical, such as, preferably, phenyl, p-chlorophenyl, p-tolyl, m-chlorophenyl or m-tolyl.
The starting materials for the reaction according to the invention are known from the literature or can be manu-factured by processes known from the literature.
The reaction of the carboxylic acid of the formula I
with an optionally substituted l-hydroxy-benzotriazole of the formula II can take place under variable experimental conditions.
Thus, for example, it is possible to combine a mix-ture of the carboxylic acid I, dissolved or suspended in a suitable sol~ent, and an optionally substituted l-hydroxy-benzotriazole II within a relatively wide temperature range with a carbodiimide, dissol~ed in a suitable solvent or in bulk.
The benzotriazole of the formula II can be employed in approximately equivalent amounts, but preferably in an ' ' " ' ' .

- -. ~ :
- : .
~ :

excess of, for example, about 0.2 to 1 mole or more.
The progress of ~he reaction can be followed in a manner which is in itself known, thus, for example, by thin layer chromatography or high pressure liquid chromatography or by nuclear magnetic resonance or infrared spectroscopy.
The activated carboxylic acids of the formula XI
can, if desired, be isolated by methods which in themselves are generally known, such as extraction, precipitation or fractional crystallization. In many cases, the reaction solutions obtained from the manufacture of these acids can also be reacted furtHer direct in the sense of the process according to the invention, if necessary after removal of the urea formed as the reaction product.
The activated carboxylic acids can be in two forms, that of the "activated ester" of the general formula XI a and that of the "activated amide" of the general formula XI b, which in solution obviously are in equilibrium.
In the solid state, it is generally the l'activated ester" of the general formula XI a which is present.
Depending on the substance, however, the "activated ester"
and the "activated amide" can also be isolated separately.
The isolation of the "activated ester" and of the "activated amide" from the reaction medium and their separa-tion can be carried out by methods which are in themselves known and which are based, for example, on the differing solubilities of the two products or on the differing polarities or crystallinities of the two products:

~"' ~

5~
. . ~

Thus, for example, the activated ester of ~-syn-methoximino~ 2-amino-thiazol-4-yl)-acetic acid can be separated from the corresponding amide by fractlonal precipitation from dimethylformamide solution by the addi-s tion of water. Separation by chromatography, such as,for example, on silica gel, can also prove expedient.
If an amine, such as, for example, compounds of the formula III or IV, is reacted w~th the "activated ester" of the formula XI a or with the "activated amide" of the formula XI b, the products obtained in both cases are iden--tical.
As a rule, however, neither the isolation of the activated carboxylic acid nor separation into the "acti~ated ester" and the "activated amide" is necessary for the pro-cess according to the invention.
In the present text, therefore, an "activatedcarboxylic acid" is understood as meaning the product, in the sense of the process according to;the invention, of the reaction between a carboxylic acid of the formula I and an : 20 optionally substituted l-hydroxy-ben~otria~ole of the formula II~ independently of whether the said product is in one o~
the two pure forms - "activated ester" XI a or "activated amide" XI b - or is a mixture of the two.
Suitable solvents are the solvents or solvent mix-tures customary in penicillin and cephalosporin chemistry,such as, for example, dimethylformamide, dimethylacetamide, diethyl ether, di-isopropyl ether, tetrahydro~uran, dioxane, carbon tetrachloride, chloroform, methylene chloride, aceto-,~

, ,' '' ' .. . : .

3~

nitrile, ethyl acetate, acetone or butanone.
Preferred solvents are dimethylformamide, tetra-hydrofuran, methylene chloride, acetoni~rile and ethyl ace-tate, and also mixtures thereof.
The only factor which must be taken into account is that the solvent does not enter into reaction with the reactanks, as is the case, for example, with solvents con-taining hydroxyl groups, such as, for example, H20.
However, activations have already also successfully been carried out employing acids which contained lower alkanols~ such as methanol or ethanol, bonded in the form of ; adducts and/or contained an alcoholic hydroxyl group in the : molecule.
In this case it is necessary merely to ensure that no bases are present which result in a reaction, which is undesired in the sense of the process according to the invention, between the activated acid and the alcohol (in this context compare Ikoh et al., Synthesis 1975, 456~.
The reaction temperature ~or the rsaction of the carboxylic acid with the optionally substituted l-hydroxy-ben~otr~a~ole is advantageously between about -20 and about +60C, preferably from -10 to ~40 and especially between 0 and 25 C.
The reaction time is in general between about 10 minutes and about 24 hours and preferably in the range of 1 to 4 hours.

' ~.. ~i ,.~.., The carbodiimides known from peptide chemistry and from penicillin and cephalosporin chemistry, especially N,N'-dicyclohexylcarbodiimide and N,N~-diisopropylcarbodiimide, are particularly suitable for use as the carbodiimides which are preferably employed as dehydrating agents.
The urea formed from the carbodiimide during the activation can be separated off, particularly if it is intended subsequently to isolate the activated carboxylic acid. However, it is also possible, without disad~antage, to dispense with the separation and to carry out the sub-sequent reaction with the 6-amino-penam derivative or 7-amino-cephem derivative in the presence of this urea.
The reaction of the activated carboxylic acid with 6-amino-penam or 7-amino-cephem derivatives can be carried out under variable experimental conditions. Thus, for example, it is possible to add the activated carboxylic acid either in bulk or, after isolation thereof, as a solution or suspension in a suitable solvent to a solution of the 6-amino-penam or 7-amino-cephem derivative. However, it is also possible to combine either the solution of the activa-ted carboxylic acid which has been freed from the urea formed from the carbodiimide or the solution of the activa-ted carboxylic acid which still contains this urea with a solution of the 6-amino-penam or 7-amino-cephem derivative.
Suitable sol~ents for the acylation reaction are, above all, the solvents or solvent mixtures customary in penicillin and cephalosporin chemistry.
Thus, t;he reaction can, for example, be carried out L
j .~c...~`
.'' in amides, such as, preferably, dime~hylformamide or dimethylacetamide, in ether~, such as, preferably, di-iso-:
propyl ether, diethyl ether, tetrahydrofuran and dioxane, in chlorinated hydrocarbons, such as, preferably, carbon tetrachloride, chloroform and CH Cl , in nitriles, such as, preferably, acetonitrile, in esters, such as, preferably, ethyl acetate, or in ketones, such as, pre~erably, acetone and butanone.
However, it is also poss~ble to use mixtures of these solvents.
Particularly preferred solvents are dimethylform~
amide, tetrahydrofuran, methylene chloride, acetonitrile and ethyl acetate, as well as mixtures thereof.
The finding that it is not necessary to take any special meaSures in order to carry out the reaction under completely anhydrous conditions was surprising. The slight water content of the commercially available solvents does not have an adverse effect on the reaction. The presence of impurities o~ other solvents containing hydroxyl groups, such as low-molecular alkanols, Por example methanol or ethanol, also does not impair the reàction If the reaction is to proceed well, lt is approp-riate to employ the 6-amino-penam or 7-amino-cephem deriva-tives in solution. An addition of organic bases, especially of tertiary amines, such as, for example, tri-` methylamine, triethylamine, tri-n-butylamine, N,N-dimethyl-aniline or N-methylmorpholine, has proved suitable for effecting dissolution of the derivatives in the above-. .

.'', ~.
, . ~

,~ .

6~58 mentioned solvents and solvent mixtures. The bases are generally added in at least stoichiometric amounts. An "
excess of base of, for example, about 0.1 to about 2.0 and especially 0.2 to 0.~ mole can be advantageous for the : . .
reaction.
Esters Or 6-amino-penam and 7-amino-cephem acids can also be employed in the reaction. Easily detachable esters are preferably used, such as, for example, the benzyl, methyl, pi~aloyloxymethyl, benzhydryl, 2,2,2_trichloroethyl or tert.-butyl esters or a tri-alkylsilyl ester, especially the trimethylsilyl ester. The advantage, above all of the last-mentioned trialkylsilyl esters, such as, for example, of the trimethylsilyl ester, lies in the fact that it is detached easily, detaching frequently already taking place during working up of the rsaction product.
In order to obtain high yields, the acti~ated car-- boxylic acids are employed in at least stoichiometric amounts. An excess of about 5 to 25% can prove approp-riate.
The time taken for the reaction between the activa-ted carboxylic acid and the 6-amino-penam or 7-amino-cephem derivative is in general between about ~ hour and 25 hours, preferably between 2 and 16 hours. a The reaction can be carried out in a wide tempera-ture range, for example between about -20 and +60C, but appropriately a temperature of 40C should not be exceeded.
The reaction temperature is preferably between 0 and ~25C.
', .
- `~ 7 s ''':

. .
, . ~ ~ ` , ~1~635~

The compounds of th~ formulae V or VI can be iso-lated from the reaction medium by method~ which are in them-selves known and which depend on the solubilities of the resulting compounds.
; 5 Thus, for example, the reaction products can be taken up in water9 after evaporating off the organic solvent if necessary, and, after appropriate purification operations, such as, for example, filtering or centrifuging, precipitated -~ by adding acids. In order to remove the hydroxybenzo-triazole formed during the reaction, the product is approp-riately stirred in a suitable solvent, such as, ~or example, ~ methanol, ethanol, propanol, butanol or acetone. I
; If desired, the hydroxybenzotriazole can also be extracted at a pH between about 5.O and 3.5 from the aqueous solution of the reaction product in a water-immiscible organic solvent, for example ethyl acetate or methyl iso-butyl ketone. The hydroxybenzotriazole employed in the reaction is recovered by evaporating off the solvent.
Subsequent further acidification precipitates the products of the formula Y or VI in the form of their free acids.
They can be obtained by filtration,or, if desired, extracted in water-immiscible organic solvents, such as, for example, ethyl acetate or methyl isobutyl ketone.
The resulting products of the formula V or VI can be obtained from the extracts, for example by evaporating off the solvent and grinding with ether.
.

:

' ~ ' ' .. .. . . . .

3S~

Preparative separation by chromatography can also be expedient.
Esters which are obtained from the reaction accord-ing to the lnvention and in which the ester group has protective group for the carboxyl group, such as, for - example, p-methoxybenzyl, p-nitrobenzyl or tert.-butyl, can be separated off from optionally substituted l-hydroxy-benzo-triazole by conventional experilmental methods which depend on the solubility, the crystallinity or the extractability of the esters. If desired, they can then be converted to the free carboxylic acids or to salts thereof in a manner known from the literature.
; The process according to the invention is thus dis-~inguished by the fact that it leads, under very mild reac-tion conditions, to extremely reactive carboxylic acid derivatives, and it is thus possible to convert both highly sensitive carboxylic acids and also carboxylic acids which - are difficult to activate because of steric or electronic effects into highly reactive acylating reagents.
Thus, surprisingly, with some of the active carboxylic acid derivatives manufactured by the process according to the invention, for example with the reaction product of 1-hydroxy-benzotriazoleand ~-(2-aminothiazol-~-yl)-~-syn-methoximino-acetic acid, the transfer of the acyl component to 6-amino-penam or 7-amino-cephem derivatives proceeds successfully; this transfer does not take place whèn the ;.
carboxylic acid which has been activated with the N-hydroxy-succinimide customary in cephalosporin chemistry and is in ~; the form of the N-acyloxysuccinimide, for example N-[~-(2-, .............................. . .
,' ."`'1 . ~,.
. ~:

.
. .

: . , ~63~
_ 24 -amino-thiaæol-4-yl)~ syn-methoximino-acetoxy]-succinimide, is used, even when more vigorous reaction condltions are employed, such as a prolonged reaction time and ele~ated temperature.
The finding tha~, when the activation is carried out in the sense of the process according to the invention, an amino protective group is not required in the case of those amino-substituted carboxylic acids in which the amino group has a PKS value of less than 6.o was also surprising: khe lo abovementioned negative aspects of the use of a protective group, such as additional synthesis steps, additional stress on the molecule, the reduction in yield, the longer time expended, the higher expenditure on purification and the - reactivation of the protective group reagent are therefore eliminated completely with the process according to the invention.
; Hydroxyl groups are also surprisingly not attacked by the carboxylic acids activated with optionally substituted l-hydroxybenzotriazoles, although according to Mc Carthy et al., J. Chem. Soc. Perkin II 1977, 224 the reactivity of the ~aid acids can be compared with that of anhydrides.
This also applies in the case of alcoholic hydroxyl ,~.
groups: It is, therefore, surprisingly also possible successfully to activate, in the sense of the process according to the invention, those carboxylic acids which con-tain alkanols bonded in an adduct-type manner in the crystal or which are otherwise contaminated with these alkanols.
French Patent Specification 7,601,~34 describes a process in which ~-[2-tritylamino-thiazol-4-yl]-~-syn-methoximino-acetic acid is converted to its symmetrical .
~,~. J
;,~ ~.. .. ..
.' .: : , : ' .
~: , ~ . : - -.
: ' - ' . . -: ' :
: :
:

. ' -: . :

-6;3~3 - 25 _ anhydride and coupled with 7-amlno-cephalosporanic acid utilizing theoretically only at.most half of the carboxylic acid employed.
Compared with this process, the process according to the invention is distinguished, on the one hand, by the fact that, as stated above, an amino protective group is not required for the acid and, on the other hand; by the fact that the unavoidable loss of ha:Lf of the carboxylic acid is avoided.
The activated derivatives XI a and/or XI b obtained from the reaction of optionally substituted l-hydroxybenzo-triazoles of the formula II w~th a carboxylic acid of the : formula I are very valuable for the syntheses of penicillins . and cephalosporins because, as stated in de~ail above, they are formed, inter alia, as highly reactive compounds under very mild conditions, because their manufacture, handling and reaction is extremely problem-free, because they react with penicillins and cephalosporins in the des~red manner under very mild conditlons and because they render a protec-tive group superfluous in the case Or weakly basic aminogroups and in the case of hydroxyl groups.
The following Examples illustrate the invention, without, however, restricting it thereto.
Example 1:
7~ s~n-Methoximino-~-(2-amino-thiazol-4-yl)-acetamido]__ cephalosporanic acid Variant A
: lst Sta~e:

. ~
. .
" , ,. - : ' ' , . , - .

:

'. ' ' :

60.3 g of ~-(2-amino-thiazol-4-yl)-a~syn-methox-imino-acetic acid are dl~solved in 540 ml of DMF, and 40.5 K
of hydroxybenzotriazole dis~olved in 240 ml of DMF are added.
61.~9 g of dicyclohexylcarbodiimide are added, whilst stirring. After 2 hours, the dicyclohexylurea which has precipitated out is filtered off and the filter residue is washed with 20 ml of DMF. The filtrate is cooled to 10C and 500 ml of H20 are added dropwise, whilst stirring. The precipitate whic~h forms is filtered off, washed with H20 and dried over P205 in vacuo:
This gives 77.1 g of a mixture of l-[~-syn-methox-imino-~-(2-amino-thia~ol-~-yl)-acetoxy]-benzotriazole and l-[~-syn-methoximino-~-(2-amino-thiazol-~-yl]-acetyl)-benzo-triazole 3-oxide with a melting point of 145 - 147.
2nd Sta~e:
6~.o~ g of 7-aminoceph~losporanic acid are stirred - up in 600 ml of methylene chlor~de and 75.75 g of triethyl-amine are added. The mixture is stirred until a clear solution is obtained and 79.5~ g of the mixture obtained in stage 1, suspended in 600 ml of tetrahydrofuran, are added in portions. The solution ls stirred overnight, after which the acti~e ester has been converted.
The reaction solution is evapora~ed and the residue is taken up in a mixture of 350 ml of formic acid (100%~ and 100 ml of H20. This solution is added slowly dropwise to a solution of ~75 g of ammonium sulfate in 1,750 ml of H 0, whilst stirring~

.
.'~

:
. . ~.
. . ' ' ' .

: `, ' ' ~

~ 6~S~3 _ 27 -After stirring for 1 hour, the light granular preci-pitate is filtered off, washed with H 0, dried and stirred in 500 ml of ethanol for ~ hour at 50 C and for 1 hour at room temp~rature~ It is filtered off and washed a furkher twice with, in each case, 50 ml of ethanol. After drying over P2s, 7~- 5 g of the title compound result.
IR (KBr~: 1770 cm~~ lactam) NMR (DMSO-d6~: S= 2.05 ppm (s, 3H, OCOCH3 = 3.~5 ppm (s) 3H, OCH ~

~ = 6.75 ppm (s, lH, thiazole-H) Variant B:
1.0 g of ~-(2-amino-thiazol-4-yl)-a-syn-methoximino-acetic acid are suspended in 25 ml of tetrahydrofuran and 0.676 g of hydroxybenzotriazole and then 1003 g of dicyclo-hexylcarbodiimlde are added. The mixture is stirred for2 hours, the dicyclohexylurea formed is filtered off and a solution of 1.36 g of 7-aminocephalosporanic acid and 1.5 g of triethylamine in 25 ml of methylene chloride is added dropwise at room temperature to the solution obtained after filtering. The mixture is stirred for 16 hours at room temperature, undissolved material is filtered o~f and the filtrate is eYaporated. The residue is taken up in 25 ml of water and the solution is three times extracted by shak-ing with, in each case, 10 ml of ethyl acetate, at pH ~.5.

The aqueous phase is acidified to pH 2.5 with 2 N hydro-chloric acid at O C. The acid solution is filtered and the product is dried over P205 in vacuo and 1.07 g of 7-[~-, , ~ ~r.r, ~, ~~

~, ~ ` ' , ' `' ' .`
, , .

s~
- 2~ _ syn-methoximino~ ~(2-aminothiazo~ -yl)-acetam~do]-cepha sporanic acid are obtained~ The NMR spectrum of this product (recorded in DMSO_d6) is identical to that of the compound prepared according to Example 1.
-! 5 Variant C
.
Sta~e 1 l-[~-syn-Methoximino-~-(2-amino-thia ~ tXYl-benzotriazole and 3-~-syn-methoximino-~-(2-amino-thia ol-4-i yl)-acetyl]-benzotriazole l-oxide !
5,~ g of l-hydroxybenzotriazole, dissolved in ~0 ml of dimethylformamide, and then ~.9 g Or solid N,N-dicyclo-hexylcarbodiimide were added, at O , to ~.6 g of ~-syn-methoximino-~-(2-amino-thiazol-4-yl)-acetic acid, dissolved in ~0 ml o~ dimethylformamide. After stirring for 5 hours in an ice bath, the dicyclohexylurea formed was filtered off.
60 ml of H20 were added droFwise, at 0C, to the mother liquor. After 10 minutes, 7.14 g of l-[~-syn-- methoximino-~-(2~amino-thiazol-4-yl)-acetoxy]-benzotriazole were isolated.
Melting point: 153 - 155 (decomposition) Rf: 0.5~ (chloroform/acetone = 2/3) IR (~Br): 1~05 cm (ester) NMR (DMSO-d6): ~ = 4.07 ppm (s, 3H, OCH ) ~ = 7.23 ppm (s, lH, thiazole-H) ~ = 7.0 - ~.5 ppm (m, 7H, NH , benzo-H, thiazole-H) ; After 40 minutes at O C, 3.9~ g of 3-[~-syn-methox-imino-~-(2-amino-thiazol-~-yl¦-acetyl]-benzotriazole l-oxide x 1~ H20 crystallized out from the mother liquor.

~ ...... .... .s, i~
.
` `' . , ` . : :

.
. . , , ~
.

635~
,~
- 29 _ 3 Melting point: 151 - 1S3 (decomposition) ¦ Mixed melting point of the two products : 1~ - 149 (decom-positionJ
Rf: 0.52 (chloroform/acetone = 2/3) IR tXBr): 1725 cm (amide) NMR (DMS0-d~ = 3.~7 ppm (s, 3H, OCH3) = 7.15 ppm (s, lH, thiazole-H) , ~ = 7.22 ppm (s, 2H, NH2) ~= 7.5 ~ ~.55 ppm (m, 4H, benzo-H) ~ = 3.25 ppm (s, 3H, H20) ~
, Sta~e ? a:
1~593 g of 1-[~-syn-methoximino-~-(2-amino-thiazol-~-yl)-acetoxy]-benzotriazole, suspended in 20 ml of tetra-hydrofuran, are added to a solution, which is stirred at room temperature, of 1.365 g-of 7-amino-cephalosporanlc acid and 1.515 g of triethylamine in 20 ml of methylene chloride.
After a short time, a clear solution forms and th~s is stirred overnight at room temperature. After filtering, ~ the reaction solution is evaporated and the residue is taken `~ 20 up in a-mixture of 7 ml of formic acid (100%) and 2 ml of H 0.

- The solution is added slowly dropwise to a solution of 17.5 g Or (NH4)2S0 in 35 ml of H20. The precipitate - is filtered off and stirred in 30 ml of ethanol for ~ hour at 55 and for 1 hour at room temperature. The product is filtered off and stirred in 30 ml of ethanol for ~ hour at 55 and for 1 hour at room temperature. The product is filtered off and dried over P20s in vacuo. This gives 7-~-[~-syn-methoximino-~-t2-amino-thiazol-4-yl)-acetamido]-, .
:

.

cephalosporanic acid, which according to thin layer chromato-graphy and IR and NMR spectroscopy is identical to the pro-duct obtained in Variant A.
Sta~e 2_b:
If 1.593 g of 3-[~-syn-methoximino-~-(2-amino-thiazol-4-yl)-acetyl~-benzotriazole l-oxide are used in stage 2 a of variant C, this likewise gives 7-~-[~-syn methoximino-a-(2-amino-thiazol-4-yl)-acetamidoJ-cephalo-sporanic acid, which according to thin layer chromatography and IR and NMR spectroscopy is identical to the product obtained from stage 2 a of variant C.
1 Example 2:
¦ 7-B-[~-syn-Ethoximino-~-(?-amino-thiazol-4-yl)-acetamido]
cephalosporanic acid In accordance with Example lB, using 1.07 g of ~-(2-amino-thiazol-4-yl)-~-syn-ethoximino-acetic acid. 0.9~ g of the title compound is isolated.
Melting point: 125 - 135 (decomposition) - IR (KBr): 1770 cm (~-lactam) 1720 cm~l (acetate) NMR (DMS0-d6) ~ = 2.0 ppm (s, 3H, OCOCH3) = 1.27 ppm (t, 3H, CCH3) = 4.13 ppm (q, 2H, OCH2-~
~ = 6.~ ppm ~s, lH, thiazole-H) E_ample 3:
7-~-[~-s~n-Propoximino-~-~2-amino-thiazol-4=~1)-acetamido]-ce~halosporanic acid In accordance with Example lB, using 1.15 g of ~-(2-amino-thiazol-4-yl)-~-syn-propoximino-acetic acid. 0.~ g ~-,the title compound is isolated.
~:'' . ' .

;8 .,~.~

Melting polnt = 120 - 130 (decomposition) IR (KBr): 1775 cm~l (~-lactam) 1720 cm 1 (acetate) NMR (DMSO-d6): ~ = 1.23 ppm (t, 3H, CH3~
~ = 2.05 ppm (c;, 3H, COCH3) = 4.00 ppm (t, 2H, O-CH2) ~= 6.70 ppm (s, lH, thiazole-H) Example 4:
7-~-[ a-syn-I sopropoximino- a_ (2-amino-thiazol~ 1)-acet-~o amido~-cephalo~poranic acid_ ; In accordance with Example lB, using 1.15 g of a-(2-amino-thiazol-~-yl)-~syn-isopropoximino-acekic acid.
1.03 g of the title compound are isolated.
Melting point: lgO - 190 tdecomposition) IR (KBr): 1770 cm~l (~-lactam) 1725 cm~l ~acetate) NMR (DMSO-d6): ~ = 1.2 ppm (d, 6H, CH(CH3)2) - ~ = 2.0 ppm (s, 3H, CO ~ ) = 6-75 ppm (s, lH, thiazole-H) Example 5:
7-~-~ a - sYn -n - But oximin o-a - ( 2 -am~ _ ~ e =
cephalosporanic acid In accordance with Example lB, using 1.22 g Or a-(2~
amino-thiazol-~-yl)-a-syn-n-butoximino-acetic acid.
0.~2 g of the title compound is isolated.
Melting point: 250 (decompositi OR ) IR (KBr). 1770 cm~l (~-lactam) 1715 cm~l (acetate) NMR (DMSO-d6): ~ = 007 - 1.~ ppm (m, 7H, CH2 - CH2 - I ) ~ = 2.05 ppm Is, 3H, COCH~) S = 6.75 ppm (s, lH, thiazole-H) .__ .. _ .... .. ... . . . ... .. ~ ,,. __ _ .. _. .. . .. . . . ~

- 32 _ I Exam~e 6:
7-~ -s~n-Methoxim~no-~-(2-amino-thiazol-4-Yl)-acetamidol-.
3-(2_amino~ -thiadiazol_~-yl_thiomethyl)-~_cephem-~-_rboxylic acid 3.34 g of the mixture obtained in stage 1 of Example lA are added to a solution of 3.55 g of 7-amino-3-(2-amino-1,3,~-thiadiazol-5-yl-thiomethyl)-3-cephem-~-carboxylic acid and 4.0 ml of triethylamine in 40 ml of dry methylene chloride. After adding 30 ml of tetrahydrofuran, the - 10 mixture is stirred overnight at room temperature. It is e~aporated, the residue is taken up in 60 ml of H20, the undissolved material is filtered off and the filtrate is covered with a layer of ethyl acetate and acidified to pH

4.5 with 1 n HCl, with ice-cooling. The phases are separated, a further extraction with ethyl acetate is carried ~- out at pH 4.5 and the aqueous phase is acidified to pH 2.5 in an ice bath.
After filtering off and drying over P205, 3.1 g of the title compound are obtained.
Melting point: 190 - 200 (decomposition) IR (KBr): 1760 cm (~-lactam) NMR (DMSO-d6): ~ = 3.~ ppm (s, 3H, OCH3) S= 5.7 ppm (q, lH, 7-CH) S= 6.73 ppm (s, lH, thiazole H) ~= 7.4 ppm (broad signal, 2H, NH2) Example 7:
7-~-[~-syn-Met;hoximino-~-(2-allylamino-thiazol-~ acet-amido]-ceE~halosporanic acid ;

' ' ' : ' ' . ,., , :

.

1.6~ g (7 mmoles) of ~-syn-methoximino-~-(2-allyl-! amino-thiazol-~-yl)-acetic acid are dissolved in 50 ml of ~ anhydrous tetrahydrofuran and O.95 g (7 mmoles) of hydroxy-., benzotriazole is added. The mix~ure is warmed to 45C, 1.45 g (7 mmoles) of dicyclohexylcarbodiimide are added and ~-! the resulting mixture is stirred for 5 hours at this tem-perature. After cooling, the dicyclohexylurea which has .
precipitated out is filtered off. The solution of the activated ester which is thus obtained is added dropwise at room temperature to a solution of 1.91 g (7 ~oles) of 7-- aminocephalosporanic acid and 3.36 ml of triethylamine in 30 ml of anhydrous methylene chloride. The mixture is stirred overnight at room temperature, the undissolved material is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water and the solu-tion is washed several times with ethyl acetate at pH 5~
` The pH is then adjusted to 2.9 with 1 N hydrochloric acid.
The product precipitates out and is filtered off, washed well with water and dried over potassium hydroxide. This gives 1.75 g of 7-~-[~-syn-methoximino-~-(2-allylamino-thiazol-4-yl)-acetamido]-cephalosporanic acid~
` Melting point: 155 - 170 (decomposition~
IR (KBr): 1775 cm~l (~-lactam) ; 1730 cm (OCOCH3) NMR (DMSO-d6): ~ = 2.05 ppm (s, 3H, OCO ~ ) = 3.~ ppm (s, 3H, OCH3) ~= b.~ ppm (s, lH, thiazole-H) ~' ., .

~ . . . ~ . .
., , -'' . ~

6;~8 ¦ 7-~-[a-s~n-Methoximin~ 2_chloroacetamino thlazo1-~-yl)-acetamido]-cephalosp ranic acid ~ . .
In accordance with Example 7, using 1.9~ g of a(2-chloroacetylamino-thiazol-4-yl)-a-syn-methoximino-acetic acid.
2.4 g o~ the title compound are obtained.
- Melting point: 200 (decomposition) IR (KBr): 1770 cm~l (~-lactam) 1725 cm (acetate) NMR (DMSO-d6): ~ = 2.05 ppm (s, 3H, COCH3) = 3.9 ppm (s, 3H, OCH3) S = 4.~ ppm (s, 2H, COCH2 Cl) ~= 7.45 ppm (s, lH, thiazole H) Example 9:
.' 15 7-~-[a-s~n-Methoximino-(2-(5-amino-1,3,4-thiadiazol-2_yl=
mercapto-acetamido)-thiazol-4-~l)-acetamido]-cephalosp-oranic acid ' In accordance with ~xample 7, using 2.6 g of a-syn-~ methoximino-[2-(5-amino-1,3,4-thiadiazol-2-yl-mercaptoacet-- 2~ amido)-thiazol-4-yl]-acetic acid. 2.3 g of the title compound are obtained.
Melting point: 250 (decomposition) IR (KBr): 1770 cm (~-lactam) NMR (DMSO-d6): ~ = 2.05 ppm (s~ 3N, COCH3) ~= 3.95 ppm (s, 3H, OCH3) = 7.4 ppm (s, lH, thiazole-H) 3 = 7.2 ppm (broad 9i gnal, 2H, NH2) Example 10:
7-~-ra-syn--Methoxi-m-i-n-o--(2--l5---m-ethy~ 4-thiadiazo-l--2-yl-mercaptoacetamido)-thiazol-4-~1)-.acetamidol-cephalosporanic ~acid ~" ~ .
- . . ~ . .

.
. . .
., ' .

:
. . . .

3S~
.~

In accordance with Example 7, using 2.6 g of ~-syn-methoximino-[2-(5-methyl-1~3,4-thiadiazol-2-yl-mercapto-acetamido)-thiazol-4-yl]-acetic acid. 2.1 g of the t1tle compound are obtained.
S Melting point: l90 ~ 200 (decomposition) IR IKBr~: 1775 cm l ( ~-lactam) NMR (DMSO-d6): ~ = 2.05 ppm (s, 3H, COCH3) S= 2.7 ppm ~s, 3H, CH3) ~ = 3.95 ppm (s, 3H, OCH3) ~ = 7.3 ppm (s, lH, thiazole-H) Example ll:
7-~i-[~-s~n-Methoximino-~-(2-amino-5-bromo-thiazol-~-yl)-acet-amido~-cephalo ~_anic acid 750 mg of a-s~n-methoximino-~-(2-amino-5-bromo-thiazol-4-yl)-acetic acid, containing ~ mole of ethanol, are dissolved in 7 ml of DMF, 30 ml of carbon tetrachloride are added and the mixture is e~aporated to 7 ml. 0.373 g of hydroxybenzotriazole in 5 ml of DMF and then 0.5 g of di-cyclohexylcarbodiimide are added at room temperature, whilst stirring.
After stirring for 2 hours at room temperature, a solution of 6~0 mg of 7-aminocephalosporanic acid and 750 mg of triethylamine in 25 ml of methylene chloride is added to the mixture and the resulting mixture is stirred for a further 16 hours.
The dicyclohexylurea is filtered off, the methylene chloride is evaporated off in vacuo and the residual solu-tion is diluted with water to 70 mlO The pH ~s ad~usted ~i~
'`'`'```' .

~` - 36 _ ~ to 7.5 with saturated NaHC03 solution and the result$ng solu-i tion is extracted 3 times with 20 ml bf ethyl acetate and filtered again and the pH is ad~usted to 2.0 with 2 N HCl at ~ 0C. After stirring for one hour in an ice bath7 750 mg 1 5 of 7-[~-syn-methoximino~ 2_amino-5-bromo-thiazol-~-ylJ-! acetamido]-cephalosporanic acid can be filtered off.
Melting point = 140 - 150 (delomposition) IR ~KBr): 1770 cm ( ~-lactam) 1720 cm 1 (acetate) NMR: S = 2.0 ppm (s, 3H, OC0 ~ ) . I .
l ~ = 3.9 ppm 23~ Hz (s, 3H, =N - 0 ~ ) . ~ = 9.5 ppm (d, lH, - NH - C0 _ ) Example 12:
, 7- B -J~-syn-Methoximino-~-(2-amino-5-chloro-thiazol-~-yl) 15 acetamido]-cephalosporanic acid 1.42 g of ~-(2-amino-5-chloro-thiazol-~-yl3--syn-methoximino-acetic acid, containing 1 mole of methanol, were dlssol~ed in 20 ml of tetrahydrofuran, 30 ml of carbon tetra-chloride were added and the mixture was evaporated to dry-ness. The residue is dissolved in ? ml of.~tetrahydro-furan and after adding 670 mg of hydroxybenzotriazole the :-~ mixture is warmed to 50~. 1.03 g of dicyclohexylcarbo-diimide are added, whilst stirring, and about 1 minute later dicyclohexylurea starts to precipitate out.
. 25 A~ter stirring for ~ hours, the urea which has . formed is filtered off and the mother liquor is added drop-I wise to 1.36 g of 7-aminocephalosporanic acid and 2.0 ml of ' ' .

.

' ' triethylamine, dissolved in 20 ml of methylene chloride.
The mixture is left to stand overnight at room temperature and is evaporated to dryness, the residue is taken up in 30 ml of H20 and the solution is covered with a layer of ethyl acetate and acidified to pH 4.5 with 2 N HCl, with ice-cooling. The phases are separated, the extraction with ethyl acetate i5 repeated and the aqueous phase is acidified to pH 2.2 in an ice bath. After filtering off and drying the product over P205, 0.9g g of 7-[~ syn-methox-imino-~-(2-amino-~-chloro_thiazol_~-yl)_acetamido]_cephalo_ sporanic acid is obtained.
Melting point = 135 - 145 (decomposition) IR ~KBr): 1770 cm (~-lactam) 1720 cm~l (acetate band) NMR (DMSO-d6): S = 2.0 ppm (s, 3H, OCOCH3) = 3.~5 ppm [231 Hz] (s, 3H, = NOCH3) ~ = 9.5 ppm (d~ lH, NHCO) Example 13:
7-~ -syn-Methoximino-~-~2-amino-5-chloro-thiazol-4-yl)-acetamido]-cephalosPoranic acid 1.42 g of ~-(2-amino-5-chloro-thiazol-4-yl)-~-syn-methoximino-acetic acid~ containing 1 mole of methanol, are dissolved in 20 ml of tetrahydrofuran and, after adding 670 mg of hydroxybenzotriazole, 1.03 g of dicyclohexylcarbo-diimide are added, whilst stirring. Dicyclohexylurea starts to precipitate out after about 3 minutes.
The further react~on and working up are carried out ' ' .

.

6~
. .
- 3~ -as described in Example 12. This gi~es 1.2 g of the title ¦ compound, the physical constants of which, according to thin layer chromatography and NMR and IR spectroscopy, are iden-tical to those of the product obtained according to Example 12.
Example 14:
?~ yn-Methoximino-~-(2-amino-5-thioc~anato-thiazol-4-yl)-acetamidol-cephalosporanic acid 645 mg of ~-(2_amino_5 thiocyanato-thiazol-4-yl)-~-syn-methoximino-acetic acid are suspended in a mixture of 2 ml Or dimethylformamide and 15 ml of methylene chloride.
350 mg of hydroxybenzotriazole are added, the mixture is heated to the reflux temperature and 500 mg of dicyclohexyl-carbodiimide are now added. The reaction mixture is stirred at room temperature for 1~ hours, the urea is separated off by filtration and a solution of 6~o mg of 7-aminocephalosporanlc acid and l.O g of triethylamine in 20 ml of methylene chloride is`added dropwise to the filtrate.
The mixture is stirred for 5 hours at room tempera-ture, 20 ml of H20 are added, the phases are separated and the organic layer is again extracted with 10 ml of H20.
The pH of the comblned aqueous phases is adjusted to 5 and the solution is three times extracted by shaking with ethyl acetate and then acidified to pH 2.3 with 2 N HCl. The .
solution is extracted 3 times with ethyl acetate, the organic phases are combined, a layer of 20 ml Or H20 is introduced below these combined phases and the pH is ad~us-ted to 7 with saturated NaHC0 solution.

~' .

. ' , ~6~ ;3 ~, The aqueous phase is separated off and freeze-dried.
This gives 700 mg of 7-[~-syn-methoximlno-~-(2-amino-5-thio-cyanato-thiazol-~-yl)-acetamido]-cephalosporanic acid.
Melting point = 210 IR (XBr): 1760 cm~l (~-lactam band) NMR (DMS0-d6): ~ = 2.0 ppm (s, 3H, OCOCH3) = 3.9 ppm [236 Hz] (s, 3HI = N0 ~ ) ~ = 9.5 ppm (d, lH, -NHC0-) Example 15:
10 7-~-[~-syn-M,ethoximino-~-~2-hydroxy-thiazol-4-yl~-acetamido]-cephalosE~
1.01 g (5 mmoles) of ~-syn-methoximino-a-(2-hydr thiazol-~-yl~-acetic acid are dissolved in 30 ml of tetra-hydrofuran. 0.67~ g (5 mmoles) of hydroxybenzotriazole are added to this solution, the resulting mixture is warmed to about 40 C and 1.03 g (5 mmoles) of dicyclohexylcarbodiimide are added. The mixture is stirred for 4 hours, the urea which has formed is filtered orf and the clear yellow solu-tion is added dropwise to 1.36 g (5 mmoles) of 7-amino-cephalosporanic acid and 2.4 ml of triethylamine dissolvedin 25 ml of methylene chloride. The mixture is stirred for 13 hours at room temperature, the undissolved material is filtered off and the filtrate is evaporated. The residue is taken up in water and washed at pH 5 with ethyl acetate.
The pH value is adjusted to 3 with 1 N hydrochloric acid and the product is extracted with ethyl acetate. After evaporating off the solvent, 1.22 g of crude product, which still contains hydrox~zotriazole3 are obtained. For ';I f.
:lj,, ~j~ j . .
. ' ' ' " ' ' ' ' o -purification, the product is dissol~ed in 30 ml of acetone, the undissolved mater~al is filtered of r and the filtrate is concentrated to half its volume. This concentrate is left to ~tand for several hours at ice-bath temperature and the product which has crystall:ized out is then filtered orf This gives o.6 g of 7-~-[~-syn-methoximino-a-(2-hydroxy-thiazol-4-yl~-acetamido]-cephalosporanic acid.
Melting point = 15~ - 160 (decomposition~
IR (KBr): 1775 cm (~-lactam) 1725 cm (OCOCH3) NMR (DMSO-d6): ~ - 2.05 ppm (s, 3H, OCO ~ ) ; ~ - 3.9 ppm (s, 3H, OCH3) = 6.53 ppm (s, lH, thiazole-H) Example 16:
`:
~ _ ]_ cephalosporanic acid Sta~e 1:
27.1 g of a-syn-ethoximino-a-(2-amino-thiazol-4-yl)-acetic acid were dissolved in 145 ml~of DMF and, successively, :.
12.1 g of l-hydroxy-benzotriazole and 1~.~ g of dicyclohexyl-carbodiimide were added at room temperature.
After 2 hours, the urea was filtered off.
H20 was added to the filtrate, with ice-cooling and ; whilst stirring, until no further precipitate formed.
The precipitate was filtered off and dried. This gave 19.~ g of l_[a~ n_ethoximino-a-(2-amino-thiazol_4-yl)~
acetoxy]-benzotriazole. Melting point~ 120 ` (decomposition) Sta~e 2:
, ~ ' '.': 5~'l :.
. . . .

.. . .

, . . ~

j35~

1~1 i 2.72 g of 7-aminocephalosporanic acid were made to dissolve in 40 ml of methylene chloride with 3.5 ml of tri-ethylamine, and 3 g of the ester obtained in Stage 1 were added to the solution. A clear solution had formed after 10 minutes. This solution was stirred for a further 5-~
hours. After the dropwise addition of 25 ml of 1 N HCl, the precipitate was filtered off and ground in alcohol.
After filtering off and dr~ing, it was possible to collect 1.9 g of the title compound, which according to th~n layer chromatography and IR and NMR spectroscopy was identical to the product obtained in Example 2.
Example 17:
7~ syn-Methoximino-~-(2-amino-5-c~loro-thiazol-4-yl)-acetamido]-deacetoxyceE~halosporanic acid 26~ ~g of ~-syn-methoximino-~-(2-amino-5-chloro-thiazol-4-yl)-acetic acid, containing 1 mole of methanol, were dissolved in 10 ml of THF, and 135 mg of l-hydroxy-benzotriazole and 216 mg of dicyclohexylurea were added.
After 1 hour the urea was filtered off. A solution of 214 mg of 7-amino-deacetoxycephalosporanic acid and 303 mg of triethylamine in 10 ml of acetone~2 ml of H20 was added to the mother liquor and the resulting mixture was stirred overnight at room temperature. 30 ml of ethyl acetate were added to the reaction solution and the solu~ion was ~ 25 acidified to pH 2.0, whilst stirring. The residue which - remained after concentrating the ethyl acetate phase was dissolved in 2.5 ml of ~0% formic acid and this solution was .
. . . ' ' ~ :
.

' ~ . ' - 42 _ added dropwise to a solution of 5.25 g of ammonium sulfate in 11.25 ml of H20, whilst stirring vigorously. It was possible in this way to isolate 120 mg Or the title compound in the form of the formate.

- 5 Melting point: ~ 200 (decomposition) IR (KBr): 1760 cm 1 (~-lactam) NM~ (DMSO_d6): ~ = 1.9~ ppm ~s, 3H, CH3) = 3.~3 ppm [230 Hz] (S, 3H, OCH3, syn) - ~= 9.43 ppm (d, lH, NHCO) Exam~le lB:
7~ s~yn-Ethox-imino--a-(2-amino-5-chloro-thiazo~ acet amido?-cephalosp-o-ranic acid ; In accordance with Example 12, using 1.25 g of a-syn-ethoximino-a-(2-amino-5-chloro-thiazol-4-yl)-acetic acid.
1.45 g of the title compound are obtained.
Melting point: 140 - 150 (decomposition) ` IR (KBr): 1775 cm~l t~-lactam) 1725 cm (O-acetate) NMR (DMSO-d6)- ~ = 1.25 ppm (t, 3H, OCH2 CH3) . ~ 20 S= 2.0 ppm (s, 3H, OCOCH3) ~ = 4.1 ppm t251 Hz] (q, 2H, ~ CH3 ; ~ = 9.7 ppm (d, lH, NHCO) Example 19:
7-~-(a-syn-Ethoximino-~-(2-amino-s-chloro-thiazol-~-yl) acetamidol-deacetoxy-cephalosporanic acid 1.~7 g of a-syn-ethoximino-~-(2_amino-5-chloro-thiazol-4-yl)-acetic acid together with 1.35 g of l-hydroxy-- benzotriazole were dissolved in 50 ml of THF at 50, and 2.06 g Or dicyclohexylGarbodiimide were added. After 1 hourJ the precipitate was filtered off and a solution of -. - .

:
' : ' ' ,.
' - ~3 -2.14 g of 7~amino-deacetoxy-cephalosporanic acid and 3 g of triethylamine in 50 ml of THF!10 ml of H O was added to the filtrate. The mixture was stirred overnight. After diluting with 60 ml of water, the organic solvents were removed in vacuo. The residue was shaksn with twice 30 ml of ethyl acetate and the aqueous phase was then care-fully acidified to pH 4.5. After extracting five tlmes with, in each case, 30 ml of ethyl acetate, the solution was further acidified to pH 2.5 and the product was filtered off and dried.
This gave 1.1 g of the title compound.
Melting point: 130 (decomposition) IR (KBr): 1775 cm-l ( ~-lactam) NMR (DMSO-d6): ~ = 1.3 ppm ~tr. 3H, CH2CH3) ~ = 2.0 ppm (s, 3H, CH3) = 3.3 ppm (broad, 2H, C-2-H) 3 = 4.10 ppm (q, 2H, N-O-CH2CH3, syn) = 5.10 ppm (d, lH, C-6-H) ~ = 5.70 ppm (q, lH, C-7_H~
~ = 7.35 ppm (broad, 2H, NH2) = 9.5 ppm (d, lH, CONH) ; Example 20:
7-[~-syn-Ethoxycarbonyl-methoximino~ 2-amino-5_chloro_ thiazol-4-yl)-acetamido~-cephalosporanic acid 2.75 g o~ ~-syn-ethoxycarbonylmethoximino-~-(2-tritylamino-5-chloro-thiazol-4-yl)-acetic acid together with 0.675 g Or l-hydroxybenzotriazole were dissolved in 50 ml of dry THF, and 1.0~ g of dicyclohexylcarbodiimide were added. After stirring for one hour at room temperature, ~J

.. , . ... .. . ..... . . .
.. . .
.. . . . .
.

0.~3 g of dlcyclohexylurea was filtered off. A solution of 1.36 g of 7-ACA and 1.52 g of triethylamine in 30 ml of acetone/5 ml of H20 was added to the mother liquor, whilst Il stirring. After stirring o~ernight, the solution was I s concentrated, the concentrate was taken up in 50 ml of ethyl acetate and the solution extracted with H20 at pH 1.~.
After evaporating the ethyl acetate phase, 4.4 g of a brown-colored residue remained. This residue was stirred in 12 ml Or 75% HC02H for 1 hour at 50 and the solu-tion was twice extracted with toluene and decolorized with 1 g of active charcoal. The light colored formic acid solution was added dropwise to a stirred solution of 26 g of (NH432 S04 in 56 ml of water. This gave 0.~ g of 7~
~ syn-ethoxycarbonyl-methoximino-~-(2-amino-5-chloro-thiazol-; 15 4-yl)-acetamidol-cephalosporanic acid with a melting point of 175 - 1~0 (decomposition) IR (KBr): 1765 cm (~-lactam) ; 1725 cm (OCOCH3 and -C02C2Hs) NMR (DMSO-d6~: ~ = 9.5 ppm (d, lH, CONH) ~ = 7.22 ppm (s, broad, NH2) = 5.7 ppm ~q, 7-H) ~ = 5.1 ppm (d, 6-H) S = ~.~2 ppm (A B, 2H, CH20) ~= 4.65 ppm [279 Hz syn]
! 25 (s, 2H, CH2 C02) = 4.13 ppm ( q, 2H, OCH2 CH3) = 3.5 ppm (d, 2, 2-H) = 2.0 ppm (s, 3H, COCH3) = 1.2 ppm (t, 3H, OCH2 ~ ) ~i ' .. . ..... _ _ _ .... . _ _ . . .... . .. .

6;~5~
- ~5 -Example 21:

7-[a -sYn-EthoxycarbonYl-me~hoximino-~12-amino-5-chloro-` thiazol~ yl)-acetamido]-deacetoxAy---ce~halosporanic acid ;~ Analogously to Example 17, using 310 mg of ~-syn-ethoxycarbonylmethoximino-~-(2-amino-5-chloro-thiazol-4-yl)-acetic acid. In this way, 210 mg of the title compound are isolated in the form of the formate.
Melting point: about 150 (decomposition~
IR (KBr~: 1750 cm (~-lactam) NMR (DMSO-d6):S = 1.19 ppm (t, 3H, CH2 ~ ) = 2.0 ppm (s, 3H, CH~) = 4.67 ppm [2~0 Hz] (s, 2H, O-CH2-) ~ = 9.~ ppm (d, lH, NHCO) Example 22:
7-_[~-syn-Methoximino-~-~?-?mino-thiazol-4-yl)-acetamidol-3-[2-(2 thienyl)-lH-1,3,4-triazol-5-yl-thiometh~ -3-ceph-em 4-carboxylic acid In accordance with Example 6, using 4.15 g of 7_ amino-3-[2-(2-thienyl)-lH-1,3,4-triazol-5-yl-thiomethyl]-3-cephem-4-carboxylic acid. 3.77 g of the title compound are isolated.
IR (KBr): 1765 cm (~-lactam~
NMR (DMSO-d6): ~ = 3.Bl ppm (5, 3H, N_OCH3j S = 5.06 ppm (d, lH, C_6-H) ~ = 5.70 ppm (q, lH, C-7-H) = 6.6B ppm (s, lH~ thiazole-H) = 7.14 ppm (t, 3H, NH2 + ~ H

:H S
= 7.62 ppm (d, 2H, = 9.5 ppm (d, lH, CONH) :

, , ` ' : ' :
:. , ,:
: ..... ; .

- ~6 -pl~ 23:
7_r~-s~n-Methoximino~ -(2-amino-thiazol-4-yl)-acetamido]-.~
~-(4,6 diamino-Pyrimidin-2-yl~thiometl~Ll~ ce carboxYlic acid In accordance with Example 6, using 3.7 g of 7-amino-' 3-(~,6-diamlno-pyrimidin-2-yl-thiomethyl)-3-cephem-~-carboxylic acid. 5.2 g of the title compound are isolatsd.
IR (KBr): 1755 cm (~-lactam) NMR (DMSO_d6): ~ = 3.79 ppm (s, 3H, NOCH3) ~ H
10~ = 5.07 ppm (m, 2H, C_6_H + ~ J
N
= 5.65 ppm ~q, lH, C-7-H~
= 6.~ ppm (s, lH, thiazole-H) ~ = 9.5 ppm (d, lH, CONH) Example 24:
7-~-[~-syn-Methoximino-~-(2-amino_thia~ol-~-yl)-acetamido]-; 3-(5- ~
__ cephem-4-carboxyl acid In accordance with Example 6, using ~.2 g of 7-~-;~ amino-3-(5-carboxymethyl-4-methyl l ! 3-thiazol-2-yl-thio-` 20 methyl)-3-cephem-4-carboxylic acid. 5.2 g of the title compound are isolated.
IR (KBr~: 1770 cm (~-lactam) NMR (D~SO-d6): d= 2.25 ppm (s, 3H, =C-CH3) ~= 3.75 ppm (s, 2H, ~CH2-C02H~
~ = 3.~5 ppm (s, 3H, NOCH~, syn) = 6.75 ppm (5~ lH, thiazole-H) = 9.50 ppm (d, lH, CONH) .

3S~
~7 Example_2~
7 ~ do]-3-(6-hydroxy-~-meth~1-5-oxo-1,2,4-triazin-3-yl-thiometh ~ be~ l s~g~ylic acid In accordance with Example 6, using 3.9 g of 7-amino-3-(6-hydroxy-~-methyl-5-oxo-1,2,4-triazin-3-yl-thiomethyl)-~-cephem-4-carboxylic acid. 4.73 g of the title compound are isolated.
IR (KBr): 1760 cm (~-lactam) ~- 10 NMR (DMSO_d6): ~ = 3 2g ppm (s, 3H, N- ~ ) : ~= 3.~? ppm (s, 3H, N-O-CH3) - 5-75 ppm (q, lH, C-7-H) = 6.72 ppm (s, lH, thiazole-H, syn) ~ = 9.54 ppm (d, lH, CONH) Example 26:
7-~-syn-Methoximino-~-(2-amino-thiazol-4-y _-acetami~
3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-~-carboxylic acid In accordance with Example 6, using 3.3 g of 7-amino-3-(1-methyl-lH-tetrazol-5 yl)-thiomethyl-3-cephem-4-carboxylic acid. 4.32 g o~ the title compound are isolated.
IR (KBr): 1760 cm (~-lactam~
NMR (~MSO-d6): ~ = 3.9 ppm (s, 3H, N-CH ) CS = 3.~2 ppm (s, 3H, N-O- ~ ) ~ = 5.62 ppm (q, lH, C-7-H) = 6.71 ppm (s, lH, thiazole-H) = 9.5 ppm (d, lH, NHCO) , ' .. ~.
~ -.~ i ......

; ' '' . , , ' ' .
:
, ~ .

35~3 ~ , ` 4~ -Example_27 ?--L~-sy~Methoximino~ ( 2~midol ~3-., ~5-methyl-1,3,~-thiadiazol-2~ thiomethyl-3-cephem-4-_ . carboxylic acid In accordance with Example 6, using 3.5 g of 7-amino-3-(5-methyl-1,3,~-thiadiazol-2-yl)-thiomethyl-3-cephem-~-carboxylic acid. 4.2 g of the t1tle compound are isolated.
IR (KBr~: 1765 cm 1 (~-lactam) NMR (DMSO-d6): ~ = 2.6g ppm (s, 3H, CH3) S = 3.~2 ppm (s, 3H, N-O-CH3) = 5.7g ppm (q, lH, C-7-H) = 6.74 ppm (s, lH, thiazole-H) = 9.5 ppm (d, lH, CONH) ' '' ,~

, .

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the acylation of a 6-amino-penam or 7-amino-cephem derivative, in which the acylating component is converted to an active derivative using l-hydroxybenzotriazole or a substituted l-hydroxybenzotriazole and the derivative is then reacted with a 6-amino-penam or 7-amino-cephem derivative.

2. A process as claimed in claim 1 wherein the acylating component is a carboxylic acid of the formula I

I

wherein R1 represents alkyl having 1 to 4 carbon atoms, an optionally substituted, saturated or mono- or poly-unsaturated 5-membered to 7-membered carbocyclic ring, optionally sub-stituted aryl or aralkyl or optionally substituted hetero-aryl or heteroarylthio and R2 and R3, which can be identical or different, represent hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyl, optionally substituted acyloxy having 1 to 4 carbon atoms in the acyl part, optionally substituted alkoxy having 1 to 4 carbon atoms in the alkyl part, optionally substituted alkylamino, optionally substituted acylamino, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part, sulfoxy or amino-sulfonyl, or together can be oxygen or a group of the formula VIII

= N - X VIII

wherein X represents hydroxyl, optionally substituted, saturated or unsaturated alkoxy, optionally substituted aryloxy or optionally substituted acyloxy.

3. A process as claimed in claim 1 wherein X has the syn configuration.

4. A process as claimed in claim 1, which comprises using, as the 6-amino-penam derivative, a compound of the formula III.

III

wherein n can represent 0, 1 or 2, A can represent hydrogen, a cation or an ester group and Y can represent hydrogen or a trialkylsilyl group.

5. A process as claimed in claim 4 in which the 6-amino-penam derivative is 6-aminopenicillanic acid or an ester or salt thereof.

6. A process as claimed in claim 1, which comprises using, as the 7-amino-cephem derivative, a compound of the formula IV

IV

wherein n can represent 0, 1 or 2, A can represent hydrogen a cation or an ester group, Y can represent hydrogen or a trialkylsilyl group and B represents chlorine, bromine, hydroxyl, methoxy or a group of the formula IX

- CH2 - B' IX

wherein B' can represent hydrogen, hydroxyl, optionally sub-stituted acyloxy having 1 to 4 carbon atoms, otpionally substituted acylthio having 1 to 4 carbon atoms, optionally substituted aminocarbonyloxy, 1-pyridinium or -S-Het, in which Het represents an optionally substituted 5-membered or 6-membered heterocyclic ring, which can optionally also be fused to a carbocyclic or heterocyclic ring.

7. A process as claimed in claim 1 which comprises converting the acylating component and the 1-hydroxybenzotriazole or substituted 1-hydroxybenzotriazole to an active derivative with the aid of a dehydrating agent.

8. A process as claimed in claim 7 in which the dehydrating agent is a carbodiimide.

9. A process as claimed in claim 1 which comprises using a 1-hydroxybenzotriazole of the general formula II

II

wherein R6, R7, R8 and R9, which can be identical or different, can denote hydrogen, optionally substituted alkyl having 1 to 4 carbon atoms, optionally substituted alkoxy having 1 to 4 carbon atoms, halogen, cyano, nitro, aminocarboxy, alkylamino-carboxy having 1 to 4 alkyl carbon atoms, aminosulfonyl, alkyl-aminosulfonyl having 1 to 4 alkyl carbon atoms or di-alkylamino-sulfonyl having 1 to 4 alkyl carbon atoms.

10. A process as claimed in claim 9, which comprises using l-hydroxybenzotriazole.