CA1060434A - Process for producing amino compounds - Google Patents

Abstract

Abstract of Disclosure A derivative of 6-aminopenicillanic acid or 7-amino-cephalosporanic acid is produced by a process which comprises disulfidizing a 6-thioacylaminopenicillanic acid or 7-thio-acylaminocephalosporanic acid compound to obtain a corres-ponding disulfide compound, and then solvolyzing the disul-fide compound. The process is novel and industrially feasible one for producing the amino compound, which is not accompanied with "reconversion reaction".

Description

~ - ~

1~6Q434 PROCESS FOR PRODUCING AMINO COMPOUNDS
The present invention relates to a process for producing amino compounds, more particularly relates to a novel and industrially feasible process for producing derivatives of 6-aminopenicillanic acid or 7-aminocephalosporanic acid of the following general formula (I), which are useful as intermediates for the synthesis of varieties of synthetic penicillins and cephalosporins;

H2N - A (I) ~ -~

wherein A is the residue of a 3-cephem or penam compound.

m e process of the present invention, by which the above object amino compound (I) can be produced, comprises reacting a compound of the general formula (III) S
R -C-NH-A (III) wherein R is an organic residue and A has the same meaning as above with a disulfidizing agent, to obtain an unsymmet-rical disulfide compound of the general formula (II) S-R
R ~¢=N-A ~II) wherein R represents substituted mercapto group and, R
and A have the same meaning as above, and then, solvolyzing the compound (II~o me reactions involved in the present process are shown in the following sche~e;

1061~)434 S Step (A) s_R2 Step (B) R -C-NH-A ~R -C=N-A > 2 (III) disulfi- (II) solvolyza_ (I) dization tion wherein A, Rl and R2 have the same meaning as above.
Heretofore, 6-aminopenicillanic and 7-aminocephalos-poranic acid compounds (I) have been produced, for example, by the method comprising halogenating penicillin G or cephalosporin C to obtain the corresponding iminohalide, then reacting the imino-halide further with an alcohol to obtain an imino-ether compound and finally solvolyzing the imino-ether compound (Japanese Patent Publications No. 13862/
1966, No.27391/1969, No.40899/1970~ etc.). However, known also is the fact that a "reconversion" reaction, which reproduce the starting acylamido compound from the imino-ether compound, takes place as a side reaction in the course of said solvoly9i9. Further in these methods the imino-etherification reaction thereof must be carried out at an extremely low temperature or some specific alcohols must be employed as solvents for said solvolysis in order to obtain the object compound in good yield.
Previously, as a means for cleavage of the acyl group of 7-acylam~nocephalosporanic acid derivatives, which is not accompanied with such reconversion reaction as above, some of the present inventors developed a process involving the route via the thioacylamido-compound. However, this ~060434 process is also accompanied with such drawback as trouble-some handling of intermediates, because in this process the intermediate thioacylamido compound must be isolated or separated prior to next reaction step thereof, and in this process so-called one-batch procedure starting from the corresponding acylamido compound can not be applied. Thus, these known methods for the production of the amino compound (I) are not so satisfactory from an industrial point of view such as yield, handling of inter-mediates, reaction temperature and kind of solvents used for said solvolysis.
Under these circumstances, the present inventors have made extensive studies for developing novel and advant-ageous route for the production of the amino compound (I)o As the result of the studies, the present inventors have quite unexpectedly found out that a thioacylamido compound (III) is disulfidized with a disulfidizing agent to give a corresponding novel unsymmetrical disulfide compound (II), and the disulfide compound (II) is easily solvolized even by readily available alcohol from an industrial point of view such as methanol to give an amino compound (I3 at not so low temperature in good yield and without any substantial reconversion reactionO Further, it has been also found out that the compound (III) is employable as a starting compound of the reaction of Step (h) without prior isolation or purification thereof. As the result of above, the object amino compound (I) is produced in a good yield ,, . , . ~ .. . .

in this process.
The present invention has been accomplished on the basis of these findings. Thus, according to the present process, the object amino compound ~I) can be easily produced in good yield by simple procedure and therefore the p:resent process is remarkably feasible, effective and advantageous from an industrial point of view.
The present invention therefore provides a process for producing an amino compound of the general formula:

wherein A is a penicillin moiety represented by the formula " N COOH
wherein the carboxy group is unprotected or protected by a conventional pro-tecting group, or A is a cephalosporin moiety represented by the formula OOH
wherein the carboxy group is unprotected or protected by a conventional protecting group and R3 is a group which does not take part in the reaction described below and is a member selected from the group consisting of l. lower alkyl

2. lower alkoxymethyl,

3. lower alkanoyloxymethyl,

4. a group represented b~ the formula wherein R4 is lower alkyl or a 5 or 6 membered nitrogen-containing hetero-cyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or sub-stituted by Ca) lower alkyl, (b) trifluoromethyl, Cc) lower alkoxy, (d) halogen, ~e) amino, Cf) mercapto, (g) hydroxy, Ch) carbamoyl, (i) carboxy, (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbony~ having 2 to 13 carbon atoms, mono- or di-~ ~.
~ -4-lower alkylcarbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di- lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atons, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, or (1) amino mono- or di- substituted by carboxy, carbamoyl, lower alkyl, alkoxycar-bonyl having 2 to 13 carbon atoms, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di- lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkyl-sulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and

5. an iminomethyl group of the formula -CH NoR5 wherein R5 is alkyl having 1 to 6 carbon atoms or cycloalkyl having up to 6 carbon atoms, which alkyl and cycloalkyl groups are unsubstituted or substituted by (a) allyl, (b) phenyl, (c) an unsubstituted 5 or 6 membered heterocyclic group having 1 or 2 hetero atoms selected from the group consisting of nitro-gen, oxygen and sulfer, ~d) carboxy or ~e) pyridinium, which comprises solv-olyzing a compound of the general formula:
s_R2 R -C=N-A

~herein Rl is an organic residue derived from an acylamido group in the 6 -position of a penicillin or the 7-position of a cephalosporin by eliminating the -COM~- moiety of the acylamido group, which organic residue is capable ~ ` ~ -4a-1~60434 of combination with a thiocarbonyl group to form a thioacyl group, R
represents a member selected from the group consisting of (1) lower alkoxy-carbonylthio, (2) halocarbonylthio wherein the halo is chloro or bromo, (3) lower alkylthio, (4~ mono-, di- or tri-halo lower alkylthio wherein the halo is chloro or bromo, (5) mono- or di-lower alkylaminothio, ~6) mercapto substituted by an unsubstituted nitrogen-containing 5 or 6 membered hetero-cyclic group, (7) halothio wherein the halo is chloro or bromo and ~8) halodithio wherein the halo is chloro or bromo, and A has the same meaning as above.
The present invention also provides a process for producing an amino compound of the general formula:

wherein A is a penicillin moiety represented by the formula ~ CH3 O~ N COOH
wherein the carboxy group is unprotected or protected by a conventional protecting group, or A is a cephalosporin moiety represented by the formula ~ ~ R3 COOH
wherein the carboxy group is unprotected or protected by a conventional protecting group and R3 is a group which does not take part in the reaction described below and is a member selected from the group consisting of 1. lower alkyl, 2. lower alkoxymethyl, 3. lower alkanoyloxymethyl, 4. a group represented by the formula wherein R is lower alkyl or a 5 or 6 membered nitrogen-containing hetero-c~c~ic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or sub-stituted by Ca) lower alkyl, Cb) trifluoromethyl, (c) lower aldoxy, (d) ,. ~, ~ ~ -4b-~060434 halogen, (e) amino, (f) mercapto, Cg) hydroxy, (h) carbamoyl~ (i) carboxy (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo~ carbamoyl alkoxy carbonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or substituted by hydroxy, mercapto, amino, morpholino, carboxy sulfo, car-bamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the `
group consisting of acetoxy, proionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, or ~1) amino mono-or di-substituted by carboxy, carbamoyl, lower alkyl, alkoxycarbonyl having 2 to 13 carbon atoms, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycar-bonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkysulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and 5. an iminomethyl group of the formula -CH:=NOR
wherein R5 is alkyl having 1 to 6 carbon atoms or cycloalkyl having up to 6 carbon atoms, which alkyl and cycloalkyl groups are unsubstituted or substi-tuted by ~a) allyl, ~b) phenyl, (c) an unsubstituted 5 or 6 membered hetero-cyclic group having 1 or 2 heterocyclic atoms selected from the group consist-ing of nitrogen, oxygen and sulfur, Cd) carboxy or ~e) pyridinium, which com-prises reacting a compound of the general formula 3Q If R -C-NH-A

-4c-iO6~;)434 wherein Rl is an organic residue derived from an acylamido group in the 6-position of a penicillin or the 7-position of a cephalosporin by eliminat-ing the -CONH- moiety of the acylamido group, which organic residue is cap- -able of combination with a thiocarbonyl group to form a thioacyl group and A
has the same meaning as the above with a disulfidizing agent, to obtain an unsymmetrical disulfide compound of the general formula:
,,~;_R2 Rl-~=N-A
wherein R2 represents a member selected from the group consisting of ~1) lower ~ :

C -4d-'.- ' -.' " , : ~ ' ,. ' ' '' , ' ' ' ' ,- ' . ' ' ~060434 propionyl), benzoyl, phenylacetyl, phenoxyacetyl, benzyloxycarbonyl, phthaloyl, isob~rnyloxycarbonyl, pivaloyl, p-(t-butyl)benzoyl, p-toluene-sulfonyl, p-(t-butyl)ben~enesulfonyl, camphorsulfonyl, etc.
Among the above, phthaloyl, isobornyloxycarbonyl, p-(t-butyl)-benzoyl or p-(t-butyl)benzenesulfonyl is preferable as the protective group for free amino group.
m e residue of penam compound which is represented by A is a penicillin moiety derived by el;m;nating the 6-acylamino group thereof, which is represented by the formula:

~ ~ (V) O COOH
or a group corresponding to (V) whose carboxy function has been previously protected. As the residue of 3-cephem compound, use is made of a cephalo-sporin moiety derived by eliminating the 7-acylamino group thereof, which is representéd by the general formula:

N ~ R3 (VI) COOH
wherein R3 is a group which does not take part in the present reaction or a group corresponding to ¦VI) whose carboxy function has been previously protected. me group which does not take part in the present reaction as mentioned hereinbefore is a group which is not affected by the reaction of this inventionO As typical examples of the group represented by R , there may be mentioned, among others, lower alkyl (e~g. methyl, ethyl, propyl), lower alkoxy methyl (e.g. methoxymethyl, ethoxymethyl, propoxy-methyl); lower acyloxy methyl (e.g. acetoxymethyl, propoxymethyl); a group represented by formula -GH2SR . In the formula~ R4 stands for lower alkyl (e.g. methyl, ethyl or propyl) or a nitrogen-containing heterocyclic group containing not less than one nitrogen atom which may be in the oxide form or, in addition to a nitrogen atom or nitrogen atoms, such other atoms as - 5 _ oxygen or/and sulfur atoms. m e nitrogen-containing heterocyclic group desirably has 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in its heterocyclic ring, and the ring may be 5 or 6 membered ones.
As such nitrogen-containing heterocyclic group, there may be mentioned, among others, pyridyl, N-oxido-pyridyl, pyr;midyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, thiazolyl, thiadiazolyl such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl, oxadiazolyl such as 1,2,3-oxadiazaIylj` 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl, triazolyl such as 1~2,3-triazolyl or 1,2,~ triazolyl, tetrazolyl such as lH-tetrazolyl or 2H-tetrazolyl and others. Each of these nitrogen-containing heterocyclic groups may be further substituted in its optional position by a substituent described hereinafter. As the substi-tuenks mentioned just above there may be mentioned, among others, monovalent group~ for example~ lower alkyls haring 1 to 4 carbon atoms such as methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, isobutyl, etc.; lower alkoxyls having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, etc.; halogens such as chlorine, bromine, etc.; amino;
mercapto; hydroxyl; carbamoyl; or carboxy group. As the substituents of the heterocyclic group, there may also be mentioned, among others, monoralent group, for example, a substituted lower aIkyl group whose alkyl moiety is a lower one such as methyl, ethyl, propyl, a substituted mercapto group or a mono- or di-substituted amino group. The substituents of the substi-tuted lower alkyl group may be hydroxyl, mercapto, aminoj morpholino, carboxy, sulfo, carbamoyl, aIkoxycarbonyl, mono- or di-lower alkylcarbamoyl, alkoxy alkylthio, alkylsulfonyl, acyloxy or morpholinocarbonyl group, etc.
In the substituents of the substituted lower alkyl group, the aIkyl group is exemplified by methyl, ethyl or isopropyl, the alkoxy group is exempli-fied by methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy or dodecyloxy; the acyloxy is exemplified by acetoxy, propionyloxy, ~aleryloxy, caproyloxy, benzoyloxy, phenylacetoxy. The substituents of the substituted mercapto group may be the same lower alkyl group or the

- 6 _ ~060434 same substituted lower aIkyl group as mentioned above. The substituents of such the mono- or di-substituted aminO group may be carboxy, carbamoyl, or the same lower alkyl, aIkoxycarbonyl, lower aIkylcarbamoyl or substituted lower alkyl group as mentioned aboveO As the substitutes of the hetero-cyclic group mentioned above specifically, use may be made of, for example, a substituted lower alkyl group such as carboxymethyl, an N-lower aIkyl-carbamoylmethyl (eOg. N,N-dimethylcarbamoylmethyl), a hydroxy-lower aIkyl (e.g. hydroxymethyl, 2-hydroxyethyl), an acyloxy-lower aIkyl (e.g. acetoxy-methyl, 2-acetoxyethyl), an aIkoxycarbonylmethyl (e.g. methoxycarbonylmethyl, hexyloxycarbonylmethyl, octyloxycarbonylmethyl), methylthiomethyl, methyl-sulfonylmethyl, an N-lower alkylamino_lower alkyl (e.g. N~N-~imethylamino-methyl, N,N-dimethylaminoethyl), morpholinomethoy, etc., mono- or di- -substituted amino groups such as a lower alkylamino (e.g. methylamino), a sulfo_lower alkylamino (e.g. 2-st~fo-ethylamino), a hydroxy-lower aIkylamino (e.g. hydroxyethylamino), a lower alkylamino_lower aIkylamino (e.g. 2-dimethylamino-ethylamino, a lower alkoxycarbonylamino(e.gO methoxycarbonyl-amino), etc., a substituted mercapto group such as methylthio, 2-hydroxy-ethylthio, 2-acyloxyethylthio (e.g. 2-acetoxyethylthio, 2-phenyl-acetoxy-ethylthio, 2-caproyloxyethylthio), carboxymethylthio, an alkoxycarbonyl_ methylthio (e.g. methoxycarbonyl-methylthio, hexyloxycarbonyl-methylthio), a N-lower alkylcarbamoyl_methylthio (e.g. N,N-dimethylcarbamoyl-methylthio), an N-lower aIkylamino-lower aIkylthio (e.g. 2-N,N-dimethylamino-ethylthio), morpholinocarbonyl-methylthio, 2-sulfo-ethylthio, etc.
The group represented by R3 also stands for an ;m;nomethyl group of the general formula (VIII) _C~=NoR5 (YII) wherein R is an unsubstituted or substituted alkyl group. As examples of the unsubstituted or substituted alkyl represented by symbol R , there may be mentioned, among others, straight-chain, branched or cyclic aIkyl groups having 1 to 6 carbon atoms (e.gO methyl, ethyl, propyl, isopropyl, n_butyl, i-butyl, sec_butyl, t-butyl, pentyl, heptyl, hexyl, cyclopentyl, cyclohexyl, etc.) and the said aIkyl groups having 1 to 6 carbon atoms as

- 7 -substituted by alkenyl, aryl, 5 to 6 membered heterocyclic group having 1 to 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atom, carboxy or primary to quaternary amino groups (e.g. benzyl, furfuryl, 2-thienylmethyl, 3-thienylmethyl, allyl, tetrahydrofurfuryl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridyl-ethyl, 4-pyridylethyl, carboxymethyl (-CH2COOH), ~-dimethylaminoethyl, ~-pyrroli~;noethyl, ~-piperidinoethyl, ~-cyanoethyl, pyridinium methyl, ~-morpholinoethyl,~ -morpholinopropyl, etc.) Among the groups represented by the formula -CH2SR ~ a group wherein R4 is an unsubstituted or substituted nitrogen-containing hetero-cyclic group is preferable. Further, among the unsubstituted or substituted ~-nitrogen-containing heterocyclic group, tetrazolyl, oxadiazolyl and thiadiazolyl groups are more preferable.
A~ the protective group for the carboxy group of said organic re9idue Rl or for the carboxy group of the residue of a 3-cephem or penam compound which is represented by A, there may be employed, among others, lower straight or branched aIkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl, tert_butyl, tert-amyl), araIkyl unsubstituted or substituted by nitro or lower alkoxy (e.g. benzyl~ p-nitro_benzyl~ p-methoxybenzyl)~
lower acyl (e.g. acetyl, propionyl)~ benzhydryl; l-indanyl, phenacyl, phenyl~
p_nitrophenyl, lower alkoxy aIkyl (eOg. methoxymethyl, ethoxymethyl), acyloxy lower alkyl (e~g. benzyloxymethyl, acetoxymethyl), pivaloyloxy-methyl, ~-methylsulfonylethy~, methylthiomethyl, trityl,~ -trichloroethyl, silyl groups (e.g. di or tri-lower aIkylsilyl group such as trimethylsilyl, dimethylsilyl~, phosphorus trichloride, etc. Further, said carboxy groups may each be employed in the form of an inorganic or organic salt with, for example, an alkali metal or alkaline earth metal e.g. sodium, potassium or magnesium or the like, or any of variou~ organic amines. As the said protective group for carboxy group, ~-methylsulfonylethyl, phosphorus trichloride and silyl groups are preferableO
As the substituted mercapto group represented by R , there may be mentioned, among others, lower alkoxycarbonylthio groups (eOg. methoxy_ carbonylthio, ethox~carbonylthio, propoxycarbonylthio), halogenocarbonylthio groups (e.g. chlorocarbonylthio, bromocarbonylthio), lower alkylthio groups (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.), mono-, di-or trihalogeno lower alkylthio groups (e.g.
monochloromethylthio, dichloromethylthio, trichloromethylthio, tribromo-methylthio7 etc.), substituted aminothio groups (e.g. mono- or di-lower alkylaminothio such as dimethylaminothio, diethylaminothio, dipropylamino-thio, methylaminothio, ethylaminothio), nitrogen-containing 5 to 6 membered heterocyclic group substituted mercapto such as morpholinothio, etc.), halogenothio or halogenodithio (eOg. chlorothio, chlorodithio, bromothio, bromodithio), etc.
The reaction of Step (A) is carried out b~ reacting a compound (III) with a disulfidizing agent. This disulfidizing reaction is effected by permitting the disulfidizing agent to act upon the compound (III).
The disulfidizing agent to be employed in this reaction is a reagent which is able to react with the compound (III) to give an inter-mediary unsymmetrical disulfide compound (II), said reagent typically including sulfenyl halide derivatives of the general formula:

R X ~VIII) wherein X is a halogen atom and R has the same meaning as above, isothiourea derivatives of the general formula:
N}~
R2-S-C (IX) wherein R has the same meaning as above and their acid addition salts, ;m;de derivatives of the formulas:

R N ~ (X) or o R N ~ (XI) _ g _ 1060~34 wherein R2 has the same meaning as above; Bunte salts of the general formula:
O ~ :
R -S_OMe (XII) O .
wherein R2 has the same meaning as above and Me represents alkali metal such as sodium, potassiumO In these formulas, X stands for a halogen atom such as chlorine, bromine or the like.
As specific examples of said disulfidizing agent, there may be mentioned, among others, C~3cScQ, CQCH2SCQ, CH30COSCQ, C~COSC~, CH3SC~, c.e3Css~J~, (C2H5)2NSCQ, o ~ ~SC~ S-methylthioisothiourea, S-isobutylthioisothio- ~ -urea, N-methylthiosuccinimide, N-isopropylthiosuccinimide, N-ethylthiophthal-imide, N-n-butylthiophthalimide, N-propyl_thiophthalimide, sulfur dichloride (SC92), sulfur nochloride (S2~2), etc. Since some of these disulfidizing agents are unstable compounds, they may each be caused to form in the reaction mixture and subjected to the contemplated reaction as it occurs therein. Among the disulfidizing agent, sulfur halide, especially, sulfur chloride such as sulfur monochloride, Cl3csc~(trichloromethanesulfen chloride) are preferableO
The reaction of thioacylamido compound (III) with disulfidizing agent may generally be carried out in an organic solvent and in the presence or absence of a base. As said organic solvent may be employed any of the solvent which will not react with the disulfidizing agent used in the reaction of Step (A). As typical examples of said solvent, there may be mentioned, among others, halogenated hydrocarbon (e.g. dichloromethane, chloroform, 1,2-dichloroethane), aromatic hydrocarbon (e.gO benzene, xylene, toluene), ester (eOgO ethyl acetate), dioxane, acetonitrileO

As the base to be used in the reaction of Step (A), inorganic or organic base may be employed. Typical examples of such inorganic base may be an aIkalimetal ~e.g. sodium or potassium) carbonate or bicarbonate -- 10 _ , , : .. . . . ... . . .

such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate. And typical example of such organic base may be pyri~;ne, picoline, quinoline, N,N-dimethylaniline triethylamine.
The amount of the disulfidizing agent to be used in the reaction of Step (A) is generally about 1 to 2 mole per mole of the starting compound (III).
The reaction is generally conducted at -30C to room temperature.
Some of thus-obtained unsymmetrical disulfide compounds (II) are comparatively stable and may therefore be isolated, but more generally it is preferable to subject them directly to the next solvolysis reaction of Step [B].
However, if desired, the compound (II) thus obtained may be isolated or separated by conventional means (e.g. evaporation of solvent used, column chromatography on silica gel .
The reaction of Step (B) is carried out by subjecting the result-ant novel intermediate compound (II) to solvolysis reaction. The solvolysis reaction comprises reacting compound (II) with solvolysis solvent. In the reaction, the intermediate compound (II) obtained in Step (A) is preferably directly subjected as merltioned as above, to the solvolysis reaction without prior isolation. As the solvent to be used for said solvolysis, there may be mentioned alcohols including lower aliphatic alcohols having 1 to 4 car-bon atoms such as methanol, ethanol, propanol, butanol, i-butanol, glycols such as ethylene glycol, propylene glycol , 1~3-buta~ediol~ triols such as glycerin, etc., organic carboxylic acids such as acetic acid, propionic acid, etc.; mercaptans such as methylmercaptan, ethyl mercaptan, etc., and water to name but a few. Par~icularly preferred of these solvents are the alcohols, and among the alcohols s~raight chained monohydric ones having 1 to 3 carbon atoms such as methanol or ethanol, espeeially methanol is most preferable. The amount of the solvent that is theoretically required for the solvolysis is 2 mole equivalents relative to compound (II), but better results are in many cases obtained when an excess of the solvent is employedO
This solvolysis is preferably conducted in the presence of an acid. As *he acid, there may be employed inorganic acids such as mineral -- 11 _ ... . .

106~)434 acid (e.g. hydrochloric acid, sulfuric acid); phosphoric acid, etc. and organic sulfonic acids such as camphorsulfonic acid, toluenesulfonic acid, benzenesulfonic acid, etc. The amount of the acid to be used is generally not less than one mole equivalent relative to compound (II). Such an acid need not be added to reaction system of Step (B) in cases where an acid is formed with the progress of the solvolysis reaction. While the solvolysis may be effected by producing the intermediate compound (II) beforehand and, then, adding a solvolysis solvent and an acid thereto, it may alternatively be carried out in such a manner that a solvolysis solvent and an acid are previously added prior to the production of intermediate compound (II), i.e.
the reaction of Step (A), so that the addition of a disulfidizing agent will give rise to intermediate compound (II) which will then be substantially simultaneously solvolyzedO
This solvolysis reaction may be generally conducted at about _30C to room temperature but, being an exothermic reaction, the reaction is desirably carried out under cool;ng.
The amino-compound (I) thus obtained may be isolatedin the con-ventional manner. Thus, when the product has separated out as an acid addition salt corresponding to the acid used or produced from the reaction system, it may be easily isolated by mere filtration. When the carboxy group thereof has been protected with a silylating agent or phosphorus trichloride, the object amino compound (I) may be easily isolated by decom-posing the protected portion of the group of the reaction product with water and adjusting the pH of the resultant to its isoelectric point.
m e process of this invention involving the route via the novel intermediate compound (II) is a commercially very profitable process in that, unlike the process via iminoether compound, it virtually does not entail a reconversion reaction and the reactions proceed in a single reaction vessel to give an amino_compound (I) in good yield even at mild temperatures.
m e object amino compounds (I) thus produced are useful as intermediates for the synthesis of varieties of synthetic penicillins and cephalosporins. For example, by acylating the compounds (I), the cephalo-~060434 sporin derivatives having anti-bacterial properties and useful as anti_ biotics are obtained as follows:

2 ~ >
~ N ~f ~R3 1 ) C~CH2COCH2COCQ
(I) COOH 2) NH2CSNH2 HN ~ ~

HN ~ S
-CH2CONH ~ ~ , COOH ~ :

wherein R3 has the meaning as above.
The compound (III) of this invention may be produced, for :
example, by the procedure set forth in Japanese Patent Application Laid Open No.34898/1973 from the corresponding acyla,mido compound (IV) as follows;

O S ~.
~; 10 R -C-NH-A > Rl-C-NH-A

(IV) thioacylation (III) :~ wherein R and A have the same meaning as aboveO

The starting compound (IV) of this reaction can be easily pro-duced by a fermentation process or can be easily derived from products of a fermentation process.
A compound (IV) wherein R is -CH2SR may be produced by reacting a compound (IV) wherein R is -CH20COCH3 with a corresponding mercaptan (R4SH3.
The thioacylation mentioned above comprises reacting compound _ 13 -.

(IV) with a sulfuri7ing agent such as phosphorus pentasulfide or, alterna-tively, by reacting firstly compound (IV) with a halogenating agent such as phosphorus pentachloride to obtain the corresponding iminohalide compound and then reacting the product with a sulfur compound such as hydrogen sulfide, thiocarboxylic acid, thioacetamide or a phosphorus compound of the formula:

R6~ "
R7 ~ P-SH (XIII) wherein R and R respectively represent an aIkoxy (e.g. methoxy, ethoxy, propoxy) or diaIkylamino group (e.g. dimethylamino)0 m e reaction of the compound (IV) with the sulfurizing agent is carried out in a solvent such as dichloromethane, chloroform, benzene, xylene, dioxane, ethyl acetate or carbon disulfide. m is reaction is pre-fera~ly conducted ~n the presence of a base, for example, pyridine, quinoline or N,N-dimethylaniline, generally at room temperature or under cooling with ice. The halogenating agent which is employed in the formation of the iminohalide compound may, for example, be phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride or thionyl chloride. m e reaction leading to an iminohalide is generally conducted advantageously in a solvent such as chloroform or dichloromethane. This reaction is preferably carried out in the concomitant presence of an organic base such as pyridine, quino-line, N,N-dimethylaniline, triethylamine or N-methylmorpholine. As the pro-portion of said base, it is sufficient to add 2 to 3 equivalents of the base per the halogenating agent. Relative to the compound (IV), generally 1 to 2 equivalents of a halogenating agent is employed. This reaction leading to the formation of an iminohalide is generally preferably conducted at a temperature of about _40 C to about 30 C and it is advantageous to arrange so that the reaction goes to completion generally in about 15 to 120 m;nutes.

Subsequently, to the thus-obtained reaction mixture containing the iminohalide compound, is added a sulfur compound such as hydrogen sulfide, thioacetic acid, thioacetamide or a phosphorus compound (XIII) such as 106(~434 dimethyl dithiophosphate, diethyl dithiophosphate, etc. m e reaction with the sulfur compound proceeds within the abovementioned temperature range to give the compound (III) in good yield. In adding the sulfur compound to the iminohalide compound, it is desirable to add simultaneously an acid acceptor such as an organic base, as mentioned in the preceding reaction. When suitable amount of hydrogen chloride and pyridine co-exists in the reaction system, the compound (III) precipitates as an adduct consist-ing of the compound, hydrogen chloride and pyridine (1:1:1).

In this invention said compound (III) may be subjected to the contemplated reaction of this invention either as it is contained in the reaction mixture of the above reaction for the production thereof or as it has been previously subjected to a suitable purification processO
However, the compound thus obtained is preferably subjected directly to the reaction of Step (A) without prior isolation or purification. Or the ¢ompound (III) may be subjected to the contemplated reaction in the form of an adduct to an equimolar amount each o~ hydrogen chloride and pyridineO
For further explanation of the present invention, the following Examples and References are given, wherein the word "part(s)" is based on weight unless otherwise noted and the relationship between "part(s)" and volume part(s)~ corresponds to that between "gram(s)" and "milliliter(s)".
And in the following respective Examples starting from an acylamido compound (IV), the production of the corresponding thioacylamido compound (III) was confirmed by thin layer chromatography.
Reference 1 ~ -methylsulfonylethyl 7-phenylacetamido-3-desacetoxycephalosporanate (13 parts) and pyridine (2.4 parts) were dissolved in dichloromethane (150 volume parts). At room temperature, phosphorus pentasulfide (15 parts) was added to the solution and the mixture was stirred for 5 hours.
The resultant insolubles are filtered off and the solution was washed with water, dried and concentratedO The resultant residue was chromatographed on silica gel by eluting with a mixture o~ dichloromethane and ether (1:4) to afford ~ methylsulfonylethyl 7_phenylthioacetamido_3-_ 15 -~060434 desacetoxycephalosporanate (9.2 parts). Pale yellow needles (recrystallized from ethylalcohol). Melting point: 142-144C.
Reference 2 Phosphorus pentachloride (6.5 parts) was suspended in dichloro-methane (45 volume parts), followed by the addition of pyridine (12 parts).
m e mixture was cooled to -10 C and ~-methylsulfonylethyl 7-phenylacetamido-3-desacetoxycephalosporanate (4.38 parts) was added. After the mixture was stirred for 2 hours at the same temperature, hydrogen sulfide was bubbled `
through the mixture at -5 to -10 C for 3 hours.
m e dichloromethane solution was poured into ice-water~ and the organic layer was washed with water, dried and concentratedO m e procedure yields ~-methylsulfonylethyl 7-phenylthioacetamido-3-desacetoxycephalos-poranate (4.26 parts). In IR and N~R spectra, the above product was in agreement with the product obtained in Reference 1.
Reference 3 In dichloromethane (2000 volume parts) was suspended phosphorus pentachloride (312 parts), and to the suspension was added pyridine (240 p~rts) under cooling at 0 to -5 C and stirring, followed by adding a solution of ~-methylsulfonylethyl 7-phenylacetamido-3-desacetoxycephalos-poranate (438 parts) dissolved in dichloromethane (2800 volume parts) over 30 minutes at the same temperatureO The mixture was stirred for 1.5 hour at 0 to _5 C~ and to the reaction mixture was added dimethyl dithiophos-phate (640 parts) while keeping the reaction temperature under 0C, followed by stirring for 3 hours. m e reaction mixture was filtered to collect the precipitates, which were washed with dichloromethane to give the crystals (461 parts) of an adduct consisting of ~-methylsulfonylethyl 7-phenylthio-acetamido-3-desacetoxycephalosporanat~ pyridine and hydrogen chloride (1:1:1). Melting point: 129 to 157 C (decomp.).
Example 1 (1) In dichloromethane (10 volume parts) were dissolved ~-methylsul-fonylethyl 7-phenylthioacetamido-3-desacetoxycephalosporanate (0.908 part) and N-ethylthiosuccinimide (0.48 part), and the solution was stirred :1060434 at room temperature for 20 hours. m e solvent was distilled off, and the residue was purified by column chromatography on silica gel, whereupon ~ -methylsulfonylethyl 7~ ethyldithiophenethylidene)amino-3-desacetoxy-cephalosporanate (0~91 part) was obtained as a principal product. Amorphous.
IR(KBr disc): 1768, 1719, 1611 cm (2) The ~-methylsulfonylethyl 7-(~-ethyldithiophenethylidene)amino-3-desacetoxycephalosporanate thus obtained (0.514 part) was dissolved in 1,2-dichloroethane ( 4 volume parts), and to the solution, under cooling with ice and stirring, 10 % methanolic hydrochloric acid (0.6 volume part) was added. The mixture was stirred for 2 hours, and the resultant precipitate was recovered by filtration and recrystallized from methanol-toluene. m e procedure yielded ~_methylsulfonylethyl 7-amino-3-desacetoxycephalosporanate hydrochloride (0.323 part)O Melting point: 187 C (decomp.). The IR
spectrum of this product was in complete agreement with an authentic samplc obtained by a different route of synthesisO
Example 2 (1) In dichloromethane (20 volume parts) were dissolved ~-methylsul-fonylethyl 7-phenylthioacetamido-3-desacetoxycephalosporanate (0.908 part) and dimethylaniline (0.363 part), and to the solution under cool;ng with ice and stirring, methoxycarbonylsulfenyl chloride (0.25 volume part) was added dropwise. After the drop-by-drop addition had been completed, the mixture was stirred for 10 minutes. m e solvent was distilled off, and the resultant residue was purified by column chromatography on silica gel. me procedure yielded ~-methylsulfonylethyl 7-~x-methoxycarbonyldithiophene-thylidene~amino_3-desacetoxycephalosporanate (0.632 part). AmorphousO
IR(K~r disc): 1766, 1724, 1625 cm (2) In 1,2 dichloroethane (4 volume parts) was dissolved the~ -methyl-sulfonylethyl 7-(~-methoxycarbonyldithiophenethylidene)amino_3_desacetoxy_ cephalosporanate thus obtained (0O544 part), and to the solution, under cooling with ice and stirring, 10 % methanolic hydrochloric acid (0.6 volume part) was added. The mixture was stirred for 2 hours, and the resultant crystals were recovered by filtration. The procedure yielded _ 17 -' , . ..

~-methylsulfonyleth~ 7_amino-3-desacetoxycephalosporanate hydrochloride (0.332 part). The infrared spectrum of this product was in complete agree- -ment with that of an authentic sampleO
Example 3 (1) In dichloromethane (10 volume parts) was dissolved ~-methylsul-fonylethyl 7-phenylthioacetamido-3-desacetoxy-cephalosporanate (0.454 part~, followed by the addition of pyridine (0.2 volume part). Under cooling with ice and stirring, to the solution trichloromethanesulfenyl chloride (0.1 volume part) was added~ followed by stirring for 30 minutes. m e reaction mixture was washed with water (10 volume parts)~ dried over anhydrous sodium sulfate and concentrated under reduced pressure. The procedure yielded ~_methylsulfonylethyl 7-(~-trichloromethyldithiophenethylidene)amino-3-desacetoxycephalosporanate (0.601 part).
IR(KBr disc): 1770~ 1722, 1626 cm (2) The thu9-obtained ~-methylsulfonylethyl 7-(o~trichloromethyldithio-phenethylidene)amino-3-desacetoxycephalosporanate (0.302 part) was dissolved in 1,2-dichloroethane (2 volume parts), and to the solution, under cooling with ice and stirring~ 10 % methanolic hydrochloric acid (0.3 volume part) was added. The mixture was further stirred for 2 hours. m e resultant crystals were recovered by filtration. m e procedure yielded ~_methylsulfonylethyl 7-amino-3-desacetoxycephalosporanate hydrochloride (0.130 part), the infrared spectrum of which was in complete agreement with that of an authentic sample.
ample 4 (1) In dichloromethane ( 5 volume parts) was dissolved ~ methylsul-fonylethyl 7-phenylthioacetamido-3-desacetoxycephalosporanate (0.454 part), and to the solution , under stirring, S-isobutylthioisothiourea hydrochloride (0.21 part~ and water (6 volume parts) were added.
Then, to the resultant sodium bicarbonate (0.184 part) was added, and the whole mixture was stirred for 3 hours. m e resultant organic layer was purified by chromatography on silica gel to obtain ~-methylsulfonylethyl 7-(~t_isobutyldithiophenethylidene)amino-3-desacetoxycephalosporanate _ 18 -:1060434 (0O35 part). AmorphousO IR(KBr disc): 1767, 1722, 1615 cm 1 (2) The thus-obtained ~-methylsulfonylethyl 7-(~-isobutyldithiophene-thylidene)amino_3_desacetoxycephalosporanate (0.29 part) was dissolved in 1,2-dichloroethane (5 volume parts), and to the solution, under cooling with ice and stirring~ 10% methanolic hydrochloric acid (1 volume part) was added and, the mixture was stirred for 2 hours. The resultant crystals were recovered by filtration and recrystallized from methanol-toluene. The pro-cedure yielded ~-methylsulfonylethyl 7-amino-3-desacetoxycephalosporanate hydrochloride (0.168 part).
In IR spectrum, this product was in complete agreement with the product according to Example 1.
Example 5 (1) In dichloromethane (5 volume parts) was dissolved ~-methylsul-fonylethyl 7-phenylthisacetamido-3-desacetoxycephalosporanate (0.454 part), followed by the addition of S-n-propylthioisothiourea hydrochloride (0028 part). Under cooling with ice and stirring, a mixture of triethylamine (0.21 volume part) and dichloromethane (1 volume part) was added to the solution sver a period of 10 minutes, and the mixture was stirred for an additional 15 minutes. m e reaction mixture was washed with ice-cooled water (5 volumelparts) and purified by chromatography on silica gel. The procedure yielded ~-methylsulfonylethyl 7-(e-n-propyldithiophenethyl_ idene)amino-3_desacetoxycephalosporanate (0.51 part). Amorphous.
IR(KBr disc): 1764, 1722, 1625 cm 1 (2) m is product was dissolved in 1~2-dichloroethane (6 volume parts) and under cooling with ice and stirring, to the solution lO~o methanolic hydrochloric acid (loO volume part) was added. m e mixture was stirred for 2 hours, after which time the resultant crystals were recovered by filtration.
The procedure yielded ~methylsulfonylethyl 7-amino-3-desacetoxycephalospor-anate hydrochloride (09282 part). The infrared spectrum of the product was in complete agreement with that of an authentic sample.
Bxample 6 In dichloromethane (5 volume parts) was dissolved ~-methylsulfony_ :1060434 lethyl 7-phenylthioacetamido-3-desacetoxycephalosporanate (0.454 part), and to the solution, under cooling with ice, methanol (1 volume part) and 27 % ethanolic hydrochloric acid (0.35 volume part) were added, followed by the addition of sulfur monochloride (0.1 volume part). ~he mixture was stirred for 30 minutes and, then, to the resultant dichloromethane was added. The resultant mixture was stirred under cooling with ice for an additional 30 minutes. m e resultant precipitate was recovered by filtra-tion to harvest crude crystals (0.361 part). mis product was recrystal-lized from methanol-toluene. m e procedure yielded ~-methylsulfonylethyl 7-amino-3-desacetoxycephalosporanate hydrochloride (0.32 part). m e infrared spectrum of the product was in complete agreement with that of an authentic sample. ~-Methylsulfonylethyl 7-phenylacetamido-3-desacetoxy-cephalosporanate (i.eO reconversion product) was not detected by thin layer chromatography and IR spectrum in resultant mother liquor nor crude cry~tal~ obtained.
Example 7 In a mixture of methanol (75 volume parts) and toluene (100 volume parts) was suspended an adduct consisting of ~-methylsulfonylethyl 7-phenylthioacetamido-3-desacetoxycephalosporanate, pyridine and hydrogen chloride (28.5 parts), and to the suspension under cooling with ice and stirring, sulfur monochloride (4,5 volume parts) was added over 5 minutes.
Then, toluene (300 volume parts) was added to the mixture over a period of 10 minutes, and the whole mixture was stirred for 1 hourO The resultant precipitate was recovered by filtration and washed with toluene-methanol (5~ he procedure yielded crude crystals (17.9 parts) of ~-methylsulfony-lethyl 7-amino-3-desacetoxycephalosporanate hydrochloride. After recrysta_ lization from methanol-toluene, there was obtained a pure product (16.9 parts). m e infrared spectrum of the product was in complete agreement with that of an authentic sample. ~-Methylsulfonylethyl 7-phenylacetamido-3-desacetoxycephalosporanate (i.e. reconversion product) was not detected by thin layer chromatography and IR spectrum in resultant mother liquor nor crude crystals obtained.

_ 20 -~:060434 Example~8 In toluene (57 volume parts) was suspended an adduct consisting of ~-methylsulfonylethyl 7-phenylthioacetamido-3-desacetoxyce-phalosporanate, pyridine and hydrogen chloride (5.70 parts), and under cooling with ice, to the suspension, 10 % methanolic hydrochloric acid (10 volume parts) was added. Then, to the resultant sulfur monochloride (1.0 volume part) was added under stirring, and the whole mixture was further stirred under cooling with ice for a period of 1 hour. The resultant precipitate was recovered by filtration and washed with toluene and acetone in this order. m e procedure yielded crude crystals (304 parts) of ~-methylsulfonylethyl 7-amino-3-desacetoxycephalosporanate hydro-chloride. After recrystallization from methanol-toluene, there was obtained a pure product (3.2 parts), The infrared spectrum of the product was in complete agreement with that of an authentic ~ample.
Example 9 In a mixture of 1~2-dichloroethane (40 volume parts) and 10 %
methanolic hydrochloric acid (6 volume parts was suspended an adduct con-sisting of ~ methylsulfonylethyl 7-phenylthioacetamido-3-desacetoxycephalos-poranate, pyridine and hydrogen chloride (5.70 parts), and to the suspen-sion, after cooling to -5 ~, one of the under-mentioned reagents, R SX, was addedO
After a reaction time of a few hours (e,g. 105 - 5 hours), the resultant crystals were recovered by filtration and recrystallized from methanol-toluene. The procedure yielded ~-methylsulfonylethyl 7-amino-3- `
desacetoxycephalosporanate hydrochlorideO The results are summarized below in the table. m e infrared spectrum of the product was in complete agreement with that of an authentic sample.

106~)434 , .
No~ of 8 Amount Reaction Yield Percent Examp. R SXadded time (part) yield(%) _ _ , .
9-(1) C~3GSC~ 1-5 pValrtse 2 hrs. 3.23 90.5 9-(2) cQ3CSSCQ 1.5 ~ 4 hrs. 2.35 65.8 9-(3) C~CH,oSC~ 2.0 " 5 hrs. 1.59 44.5 9-(4) CH30dSCQ 105 parts 5 hrs. 1.70 47.6 9-(5) S2C~21.0 pvalrutsme 2 hrs. 3.32 93.0 9-~6) 0 ~ N / 1.70 parts 1,$ hr~. 2.76 7-.3 Example 10 In dichloromethane (10 volume parts~ was suspended 7-phenyl-thioacetamido_3_desacetoxycephalosporanic acid (0.348 part)~ and to the suspension, under cooling with ice and stirring, trichloromethanesulfenyl chloride (0.1 volu~e parts) was added. The mixture was stirred for 10 minutes. Under cooling with ice, methanol (5 volume parts) and concen- -~
trated hydrochloric acid (0.3 volume part) were added to the reaction mixture, and the whole mixture was stirred for 30 minutes. Following the addition of water (10 volume parts), the mixture was adjusted to pH 3.8 with aqueous ammonia and stirred for 30 minutes. m e resultant precipi-tate was recovered by filtration, washed with dichloromethane, acetone and methanol in this order and finally dried.
The procedure yielded 7-amino-3-desacetoxycephalosporanic acid ~0.}95 part). In IR spectrum, this product was found in good agreement with an authentic sample obtained by a different route of synthesis.
Example 11 (1) In dichloromethane (5 volume parts) was suspended 7-phenylthio_ acetamido-3-desacetoxycephalosporanic acid (0.348 part) and, then~ N,N-dimethylaniline (0.2 volu~e part was added to the suspension. Under cooling with ice and stirring, a solution of morpholine-N-sulfenylchloride (0.154 i060434 part) in dichloromethane (1 volume part) was added dropwise to the mixture over a period of 5 minutes, and the whole mixture was further stirred for 10 minutes. The reaction mixture was then washed with water, dried and concentrated under reduced pressure. The procedure yielded 7-(~-morpholino-dithiophenethylidene)amino_3-desacetoxycephalosporanic acid (0.465 part)O
Amorphous.
IR(~Br disc): 2600 - 2100, 1772,1620 cm (2) The above product was suspended in dichloromethane (10 volume parts), and to the suspension, under cooling with ice and stirring, 10 %
methanolic hydrochloric acid (1 volume part) was added. The mixture was stirred for 30 minutes. Then, following the addition of water (10 volume parts)~ the whole mixture was adjusted to pH 3.8 with aqueous ammonia and stirred for 30 minutesO m e resultant precipitate was recovered by filtration, washed with dichloromethane~ acetone and methanol and driedO
The procedure yielded 7-amino-3-desacetoxycephalosporanic acid (0.20 part), the infrared spectrum of which was in complete agreement with that of an authentic sampleO
Example 12 In dichloromethane (30 volume parts) was suspended 7-phenylace-tamido-3-desacetoxycephalosporanic acid (1.66 parts), and to the suspension, under cooling with ice and stirring, triethylamine (0.51 part) was added.
Then, to the resultant N,N-dimethylaniline (1.33 volume parts) was added, followed by the addition of dimethyldichlorosilane (0.5 volume part). The mixture was stirred under cooling with ice for 30 minutes and, then, at room temperature for 30 minutes. The resultant mixture was chilled to -20 C, and to the mixture phosphorus pentachloride (1.2 parts) was addedO
The mixture was stirred at -20 to -10 C for about one hour, and to the resultant thioacetamide (0.75 part) was added at -20 C. The mixture was further stirred for 105 hours, after which time to the mixture, trichloromethanesulfenyl chloride (1.2 volume parts) was added dropwise.
The mixture was stirred for 40 minutes and, at -20 C, to the mixture metha_ nol (10 volume parts) was added. Then, to the resultant concentrated hydrochloric acid (1 volume part) was added, and the whole mixture was stirred for another one hour. Following the addition of water (10 volume parts), the mixture was adjusted to pH 308 with concentrated aqueous ammonia and, then, allowed to stand in the cold. The resultant precipitate was recovered by filtration, washed well with methanol, acetone and dichloro-methane and dried. The procedure yielded 7-amino-3-desacetoxycephalospor-anic acid (0.910 part), the infrared spectrum of which was in complete agreement with that of an authentic sample.

Example 13 In dichloromethane (20 volume parts) was suspended 7-phenylace~

tamido-3-desacetoxycephalosporanic acid (1.66 parts) and, then, to the suspension N,N-dimethylaniline (1.9 volume parts) was added. m e mixture was chilled to -20 C and, following the addition of phosphorus trichloride (0.262 volume part), the mixture was stirred for 20 minutes. To the mix-ture was added phosphorus pentachloride (1.3 parts), followed by stirring for 30 minutes, after which time, to the resultant thioacetamide (0.6 part) was added. The mixture was stirred for 45 minutes. At -20C, N,N-dimethyl-aniline (1.9 volume parts) was added to the reaction mixture and, then, to the resultant trichloromethanesulfenyl chloride (1.0 volume part) was addedO m e mixture was stirred for 30 minutes, after which time, methanol (8 volume parts) was added to the mixtureO The mixture was further stirred for 20 minutes and, with the addition of water (8 volume parts), from the mixture the resultant water layer was separated outO The water layer was adjusted to pH 3.8 with 6N sodium hydroxide and allowed to stand in the cold for 12 hours. m e resultant precipitate was recovered by filtration, washed with methanol and methanol-water (3:1) in this order and dried. The procedure yielded 7-amino-3-desacetoxycephalosporanic acid (0.902 part), the infrared spectrum of which was in complete agreement with that of an authentic sample.

Example 14 In dichloromethane (40 volume parts) was suspended N-phthaloyl-cephalosporin C (2.8 parts), and to the suspension, under cooling with ice and stirring, triethylamine (1.0 part), N,N-dimethylaniline (2.9 volume parts) and dimethyldichlorosilane (0.7 volume part) were addedO The mixture was stirred for 1 hour. m e reaction mixture was chilled to -20C, and to the resultant phosphorus pentachloride (104 parts) was addedO The mixture was stirred at the same temperature for 1.5 hours, after which time thioacetamide (0.75 parts) was added to the mixtureO The whole mix-ture was further stirred at -20 to -15C for 1 hour and to the resultant N,N-dimethylaniline (1.4 volume parts) was added. men, at -20C, trichloro-methanesulfenyl chloride (1.6 volume parts) was added dropwise to the mixture. After 40 minutes' stirring, to the mixture methanol (10 volume parts) and 10 % methanolic hydrochloric acid (2 volume parts) were added, followed by stirring for 30 minutes.
To the mixture was added water (10 volume parts) and the resultant was adjusted to pH 305 with concentrated aqueous ammoniaO
The mixture was then allowed to stand and cool. The resultant cry~tal~ were recovered by filtration and washed well with methanol and dichloromethane.
The procedure yielded 7-aminocephalosporanic acid (loO part), the infrared spectrum of which was in complete agreement with that of an authentic sample.
Example 15 N-phthaloyl-cephalosporin C (20728 parts) was suspended in dichloromethane (30 volume parts) at 0 C and, then triethylamine (1.4 volume parts) was added to the suspension. The mixture was stirred for 10 minutes, at the end of which time, to the mixture N,N-dimethylanil;ne (3.35 volume parts~ and dimethyldichlorosilane (007 volume part) were added in succession. The mixture was stirred for 1 hour. The resultant mixture was chilled to -20 C, and to the resultant phosphorus pentachloride ~~
(1.40 parts) was added. After 90 minutes' stirring, to the nn~ture thioace-tamide (1.0 part) was added and, the whole mixture was stirred at -10 C for 30 minutes. Then, methanol (10 volume parts3 was slowly added to the mixture, followed by t~e addition of sulfur monochloride (1.0 volume part)0 - 25 _ The mixture was stirred for 10 minutes, after which to the resultant water (7 rolume parts~ was addedO me mixture was adjusted to pH 7.5 with concentrated aqueous ammonia and, then, stirred at oC for 20 minutes.
m e resultant insolubles were filtered off and, the filtrate was adjusted to pH 3.5 with concentrated hydrochloric acid and, then, stirred at 0C for 1 howr.
The resultant crystals were recovered by filtration, washed with dichloromethane, methanol and 75 % methanol in this order and driedO m e procedure yielded 7-aminocephalosporanic acid (1.020 part), the infrared spectrum of which was in complete agreement with that of an authentic sample.
Example 16 In dichloromethane (40 volume parts) was dissolved N.N-dimethyl-aniline (5,32 volume parts) and, then, to the solution 7~(5-p-t-butyl-benzoylamido-5-carboxyvaleramido)-3-(2-morpholinoethoxy)iminomethyl-3-cephem-4-carboxylic acid (4.62 parts) was suspended. The suspension was chilled to -10 C and, under stirring, to the suspension phosphorus trichloride (1,575 volume parts) was added, The mixture was stirred at -10 C for 1 hour, after which time it was chilled to -20C, and to the mixture phos-phorus pentachloride (2.9 parts) was addedO m e resultant mixture was stirred at -15 to -20C for 2 hours, at the end of which time to the mixture thioacetamide (2.25 parts) was added, followed by stirring for one hour. To the resultant mixture methanol (20 volume parts) was slowly added dropwise at -20 C. After 30 minutes' stirring, to the resultant trichloromethanesulfenyl chloride (5.6 parts) was added and the mixture was stirred for 1 hour, Following~the addition of water (20 volume parts), the mixture was extracted three times with each of water (20 volume parts).
The extracts were pooled and concentrated and, the resultant concentrate was developed on a chromatographic column of XADL2 type resin with water as the eluent. The eluate was freeze-dried.
The procedure yielded 7-amino-3-(2-morpholinoethoxy)-iminomethyl-3-cephem-4-carboxylic acid (2.12 part).

IR(KBr): 1788 cm NMR(in D20): ~ 3.2-4.9(m, 14H), 5.20(d,J=5Hz,6-H), 5.56 (d,J=5Hz), 8057~s, -CH=N0-).
Example 17 In dichloromethane (25 volume parts) was suspended potassium salt of benzylpencillin (6.0 parts) and to the suspension, under stirring at -room temperature, N,N-dimethylaniline (5.2 volume parts) and dichlorodi-methylsilane (1.6 volume parts) were added in succession and, the mixture was stirred for 30 minutes. Then, the mixture was chilled to -30C and phosphorus pentachloride (3.6 parts) was added, followed by stirring for 2 hours at -30C. Then, to the resultant thioacetamide (105 parts) was added and the mixture was further stirred at -40 to -25C for 1.5 hours.
m en, under stirring at -40C, to the mixture methanol (20 volume parts) was added drop by drop in such a manner that the temperature of _30C was not exceeded, followed by the addition of trichloromethanesulfenyl chloride (2.3 volume parts), The mixture was stirred for 30 minutesO Under stirring at _30 C to the mixture water (5 volume parts) was added and, then~ to the mixture concentrated aqueous ammonia (20 volume parts) was slowly added `
dropwise. Then, on an ice-water bath, the resultant was adjusted to pH
4,1 with ammonia water, followed by stirring for 1 hourO The resultant precipitate was recovered by filtration, washed with 50% methanol and dichloromethane and dried. The procedure yielded 6_aminopenicillanic acid (2.2 part). In IR spectrum, this product was found in good agreement with an authentic sample.
Example 18 (1) In a mixture of water (500 volume parts) and acetone (150 volume parts) was dissolved monosodium salt of cephalosporin C ~47O4 parts), and the solution was adj-~ited to pH 9.0 with sodium carbonate. To the solution was added dropwise p-(t-butyl)benzoyl chloride (27.9 parts) over a period of 1.5 hours under cooling at 10 to 15 C and stirring, during which time the reaction system was kept at pH 9.0 with sodium carbonate.
After stirring for further 1.5 hours at the same temperature, the reaction ~ - -mixture was adjusted to pH 7.0 with phosphoric acid, and acetone was distilled off under reduced pressure. ~he residue was washed twice with ethyl acetate ~400 volume parts each), and the resultant water layer was adjusted to pH 2.5 with phosphoric acid.
The resultant was extracted three times with each of ethyl acetate (600 volume parts each), and the ethyl acetate layer was dried over sodium sulfate and concentrated to dryness under reduced pressureO
The procedure yielded N-rp-(t-butyl)benzoyl]cephalosporin C (40.1 parts)O
IR(KBr disc): 1778, 1730, 1708 cm NMR(in d6-DMSO): ~ 1.28(9H), 1.5 - 109(4H), 2001(3H), 2010 -2035(2H), 3.36 and 3.61(2H,ABq), 4.37(1H), 4.68 and ~-4.99(2H,ABq), 5.06(1H), 5067(1H), 7.46 and 7.82(4H, ABq), 8.41(1H), 8079(IH).
(2) In phosphate buffer solution of pH 6.4(60 volume parts) were dissol~ed N-(p-(t-butyl)benzo ~ cephalosporin C (5.75 parts), l-methyl-l H_tetrazol-5-thiol and sodium bicarbonate (2.52 parts), and the solution was adjusted to pH 6.4 with sodium bi~arbonate. The solution was heated at 60 C for 14 hours in nitrogen gas stream under stirring. After cool;ng, the reaction mixture was adjusted to pH 205 with phosphoric acid and the result&nt was extracted twice with each of ethyl acetate (80 volume parts).
The ethyl acetate layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The procedure yielded 7-(D~5-t-butylbenzoyl-amido-5-carboxy-valeramido)-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.82 parts).
(3) In dichloromethane (20 volume parts) was suspended 7-(DL5_p_t-butylbenzoylamido-5-carboxyvaleramido)-3-(1-methyltetrazol-S-yl) thio-methyl _3_cephem_4-carboxylic acid (3.16 parts), and to the suspension were added triethylamine (1.2 volume parts), N,N-dimethylaniline (4.0 volume parts) and dimethyldichlorosilane (1.0 volume part) in this order, followed by stirring at 30 C for one hour. To the reaction mixture, which was chilled to -25 C, was added phosphorus pentachloride and the whole mixture was stirred for 1.5 hours. To the resultant was added thioacetamide (1.2 parts) at -20C and the mixture was stirred at -10 to -15 C for one hour.
After which time, to the reaction ~;xture were added slowly methanol (10 volume parts) and sulfur monochloride (1.2 volume parts) in this order.
To the resultant mixture were further added water (10 volume parts) at ~`-_20 C and then the whole mixture was adjusted to p~ 3.3 with ammonium bicarbonate (3.0 parts), followed by cooling with ice under stirring.
The resultant crystals were recovered by filtration, washed with 50%
methanol, methanol and dichloromethane in this order and dried to give slightly yellow powder. In water (10 volume parts) was suspended the powder, and the suspension was adjusted to pH 7O5 with ammonium bicarbonate under cooling with ice, followed by stirring for one hour. ~he insolubles were filtered off, and to the filtrate was added methanol (20 volume parts).
m e mixture was adjusted to pH 3.3 with diluted hydrochloric acid under cooling with ice and the resultant was stirred for one hour. The resultant crystals were recovered by filtration, washed with 50 % methanol, methanol and dichloromethane in this order and dried. The procedure yielded 7_amino_3~ methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.85 part).
IR(KBr disc): 1795 cm NMR (in D20 + NaHC03): ~ 3061 and 3.98 (ABq,J=18Hz~2_CH2)~
4021(s,tetrazol -CH3), 5.21(d,J=4.5Hz,6_H), 5.60(d, J=4o5Hz~7H).
Example 19 According to a s;nnlar procedure to that of Example 18-(3), from the following 7-substituted amino_3_cephemr4-carboxylic acid derivatives (i.e. starting compounds) were obtained the corresponding 7_amino_3-eephem-4_carboxylic acid deri~atives (i.e. products) respectively, which are described in the following table3 - 2~ _ . . c, __ ~
~ ~ ~ ~ ~ ~C`l ~ ~
O C~:

_ ~ ~ N .~ .~ ~ d --~-- ~ t ~ N N N ~1 ~ ~1 ~ ~ J 1, ,~ 0 3~ o ,~
!~ ~ ~ 0 CJ~ 1 I ~ ~_ ~ t~
o N 1:~ N o m ~ o ~1 ~ ~ ~c ~ 13 c~ ~ 0 c ~ ~ N __ 1 ~ ~
~I ~ ~ ~ O ~ rl ~ 0 ~` ~ ~ o ~: ~ X ~ ~D N N ~ ~ O ~D ~ ~
rl ~ ~ ~ -- ~ O ~
~ eq m * ~ o ~ ~ ~7 ~ ~ ~
~--~s ~ ~ ~ ~ ~ ~ ~ o ~ ~q _ _ U) _ __ _ _ N b0 ~ ~ ~D _ ~ ~ 0 a~ 0 ~ 0 o c~ ~ O
00 ~ U~ o U~ ~ .
~`1 ~ ~t '~ 1~ ~ d- U) Il~ ~ C`l ~ d- ~) l~
C~ _ 7,~ ;~ cn 0~ ~0n ~.~ ~1 ~1 ~1 H~
__ ~ ~ J~ ~ J~

~ ~ o , $ ~ o u~$~ ~ o N~ ~ t~ I r 0 _ O O.~d O O I N O O O I
~ ~ rl ~ ~ ~ ~ ~, X
____ ._ A.. .. ..
~1 ~ ~q _ ~
NO h ~ h ~ ~ o ;~i ~ o ~ _ ~ ~ ~ ~ i ~ _ ¦ A ~ l O

d ~ d ~ ~ o ~
du~ d ' ~0~ ~"o, ~1 ~-rl , ho~ ~ ~0 , .. _ ._._ . ~ c~ ~
I _ . ~ ~ ............ ..

Example 20 (1) In a 10 % aqueous solution of dipotassium phosphate (200 volume parts) was dissolved sodium salt of cephalosporin C (20 parts), and the ~olution was adjusted to pH 9.1 with tribasic potassium phpsphateO To the solution were added acetone (80 volume parts) and then a solution of N-carboethoxyphthalimide (12 parts) in acetone (120 volume parts) under stirring at 22 C, followed by stirring at the same temperature for further one hour, during which time pH value of the reaction system was kept to 9.1 with tribasic potassium phosphate. m e resultant reaction mixture was adjusted to pH 7 with phosphoric acid, and then, acetone was distilled off under reduced pressureO The residue was washed with ethyl acetate, adjusted to pH 2.0 with phosphoric acid and then extracted with ethyl acetate (200 volume parts).
To the ethyl acetate layer was added water (200 volume parts), and the mixture was adjusted to pH 7.0 with sodium bicarbonate under stirringO m e water layer was separated out, and small amount of ethyl acetate remaining in the layer was distilled off under reduced pressure.
To the resultant water layer was added l-methyl-lH-tetrazol-5-thiol(5.0 parts), and the mixture was adjusted to pH 5.0 with dipotassium phosphate~
followed by stirring and heating at 65C on a steam-bath for 4 hours. After cool;ng the reaction mixture was adjusted to pH 2.0 with phosphoric acid and extracted with ethyl acetate (200 volume parts). The ethyl acetate layer was dried on sodium sulfate and concentrated. To the resultant residue was added toluene to give powdery product. The product was recovered by filtra-tion, dried and then dissolved in ethyl acetate. The resultant insolubles were filtered off and the filtrate was concentrated under reduced pressure.
To the resultant residue was added toluene to give powdery product. One more same purification procedure yielded 7-(DL5-phthalimido_ 5-carboxyvaleramido)-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxy-lic acid (13.0 parts).
IR(KBr disc): 1778, 1717 cm NMR(in d6 -DMSO): ~ 1.3-2.5(m,6H), 3063(ABq, 2-CH2), 3093 . -- ~sl--(s, tetrazol -CH3), 4030(3-CH25_), 4.73(t,=N-C,H-C00), 5.01(d,J=5Hz,6-H), 5.62(q,J=5 and 8 Hz,7-H), 7.85 o (s, ~ .,~ ), 7.78(d,J=~Hz) ~ ~ N_ (2) According to the similar procedure to that of Example 18-(3), from 7-(D~5-phthalimido-5-carboxyvalera~ido)-3-(1-methyltetra~ol-5-yl)-thiomethyl-3_cephem_4_carboxylic acid (3.0 parts) was obtained 7-amino-3-(l-methyltetrazol-5-yl)thiomethyl_3_cephem_4-carboxylic acid (0.92 part)O
This product was in complete agreement with the product of Example 18 in IR and NMR spectra.
Exam~le 21 (1) According to the similar procedure to that of Example 18-(1) except that p-(t-butyl)be~zoylchloride was replaced with p-(t-butyl)benzene-sulfonylchloride (29.4 parts) and the reaction was carried out at room temperature (about 20 C), N-(p-(t-butyl)benzenesulfonyl)cephalosporin C
was obtained from monosodium salt of cephalosporin C.

IR(KBr disc): 1770, 1728, 1710, 1660 cm NMR(in d6-DMS0): ~ 1.29(9H), 2.01(3H)~ 3.40 and 3.64(2H, ABq), 4.70 and 5.02(2H,ABq), 5.06(1H,d), 5.64(1H,q), 7.50 and 7.68(4H,ABq), 7.94(1H,d), 8072(1H,d).
(2) According to the similar procedure to that of Example 18-(2), 7_(D~5_t-butylbenzenesulfonam~do-5_carboxyvaleramido)-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.67 parts) was obtained from N-(p-(t-butyl)benzenesulfonyl]cephalosporin C (6.11 parts).
IR(KBr disc): 1783, 1731, 1158 cm NMR(in d6-DMSO): ~ 1027(s,9N), 1.51(4H), 2.08(2H), 3.66(2H, 2-CH2), 3.92(s,3H, tetrazol -CH3), 4.28(2H,3-CH2), 5.02 (d,J=5Hz,6-N)~ 5.60(dd,J=5 and 8Hz, 7-H), 7.51 and 7.69(4H,ABq), 7~94(d,J=8Hz,NHS02), 8.74(d,J=~8Hz,CONH).
(3) According to s;m;lar procedure to that of Example 18-(3), 7_amhno-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.91 part) ~060~34 was obtained from 7-(DLp-t-butylbenzenesulfonamide-5-carboxyvaleramido)-3-(l-methyl-tetrazol_5_yl)thiomethyl carboxylic acid (3.43 parts). This product was in good agreement with that of ~xample 18 in IR and NMR spectra.
Example 22 (1) According to the similar procedure to that of Example 18-(1) except that p-(t-butyl)benzoylchloride was replaced with-isobornyl chloro-carbonate (43.3 parts), and the reaction was carried out at 3 to 4C, N-isob~rnyloxycarbonyl-cephalosporin C ¦55.4 parts) was obtained from mono-sodium salt of cephalosporin C.
IR(KBr disc): 1790, 1720 cm 1 (2) According to the similar procedure to that of Example 18-(2), from N-isobor~yloxycarbonyl-cephalosporin C (5.95 parts) was obtained 7-(D-5-isobornyloxycarbonyl-5-carboxyvaleramido)-3-(1-methyltetrazol-5-yl) thiomethyl_3-cephem-4-carboxylic acid (3.28 parts)O
(3) According to the similar procedure to that of Example 18-(3)~
from 7-(D~5-isobornyloxycarbonyl-5-carboxyvaleramido)-3-(1-methyltetrazol-5_ yl)thiomethyl-3-cephem_4-carboxylic acid (3.25 parts) was obtained 7-amino-3-(1-methyltetrazol-5-yl)thiomethyl-3_cephem A -carboxylic acid (0.92 part).
This product was in good agreement with that of Example 18 in IR and NMR
spectra.
Example 23 (1) A solution of N-phthaloylcephalosporin C (5.46 parts), 2-(~-hydroxy ethylthio)-5-mercapto-1,3,4-thiadiazole(1.94 parts) and sodium bicarbonate (2.20parts) in water (60 volume parts) was heated at 65 ~ for 4 hoursO The reaction mixture was adjusted to pH 5O0 with 4N-hydrochloric acid~ followed by washing with ethyl acetate.
To the resultant were added ethyl acetate (30 volume parts) and tetrahydrofuran (20 volume parts), and the mixture was adjusted to pH 2.0 with 4N-hydrochloric acid.
The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and subjected to evaporation of the solvent under reduced pressure. To the resultant residue _ 33 -ethyl acetate (20 volume parts) and ether (30 volume parts) to give powdery substance The resultant powdery substance was collected by filtration to give 7-(D-5-phthalimido-5_carboxyvaleramido)-3-(5-(~-hydroxyethylthio)-1,3,4-thia~iazol-2-yl)thiomethyl-3_cephem_4_carboxylic acid (4.45 parts).
IR(Kl3r disc): (cm ), 1777, 1730, 1715 NMR(in d6-DMS0): ~ 1.30 to 2.40(m~6H), 3.20 to 3.8Q(m~6H)~
4.36(AB pattern, 2H,J--13cps), 4.75(t,1H,J=8cps), 5.05(d,1H~J=Scps)~ 5.64(q,1H~J=5, 9 cps), 7088(s,4H), 8O80(d~1H~J=9cps) (2) In dry dichloromethane (25 volume parts) was suspended 7-(D'5-phthal;m;do-5-carboxyvaleramido)-3-(5-( ~ hydroxyethylthio)-1,3,4-thiadiazol-Z-yl)thiomethyl-3-cephem-4-carboxylic acid (2.8 parts), and to the suspen-sion were added triethylamine (1.4 volume parts) N~N-dimethylaniline (5.0 volume parts) and dimethyldichlorosilane (l.S volume parts) in this order under cooling with ice water. Then, the mixture was stirred at 28C for Z hours and then chilled to _30 C, and to the resultant was added phosphorus pentachloride (1.8 parts), followed by stirring at -20 to -15 C for one hour.
To the resultant was added thioacetamide (1.0 part) and stirred at -10 to -15 C for one hour~ followed by addition of methanol (20 volume parts). And then sulfur monochloride (loO volume part) was added and stirred for ten minutes, and then, to the resultant water (10 volume parts) was added. me mixture was adjusted to pH 3.3 with ammorium bicarbonate, followed by cooling with ice for one hour. The resultant crystals were recovered by filtration, washed with 50 % methanol, methanol and dichloromethane in this order and dried to give 7-amino-3-(5- ~-hydroxyethylthio)_1,3,4-thiadia_ zol-2-yl)thiomethyl-3_cephem-4-carboxylic acid (1.3 parts).
IR (KBr disc): 1800 cm NMR(in D20and NaHC03): ~ 3.54(t~j=6Hz~SCH2CH2-)~ 3OS4 and 3.73 (q~J=16Hz~2-CH2-)~ 3.91(t~J-6Hz~CH20H)~ 4O07 and 4.38(q~
J=13Hz,3_CH2), 5.05(d,J=5Hz,6_H)~ 5.45(d,J=SHz,7-H).

Example 24 According to the similar procedure to that of Example 23-(2), _ 3~ -from the following 7-substituted amino-3-cephem-4-carboxylic acid derivatives (i.e. starting compounds) were obtained the corresponding 7-amino-3-cephem-4-carboxylic acid derivatives (iOe. products) respectively, which are described in the following table;

106043~

,~ ..

~I ~1 ô~ a ~ 7 ~ â
æ ~ " x~ , O ~
~j ~ o~ N z ~1. _ N X~
~ o ~ _ 0 ~ ,!, '`
æ ~ ~ N ~ ~ ~) _ ,~ X

8 ~ ;~X o ~ ^ XC`~
_ ~ _(~ _ I a :~ ,1 ~1,1 _ . ._ _ ~ ~
~ ~ X ~ ~ ~ ~ ~ T
~ ~o ~ r~ -.
... -.
,U~ ~

co~ ~ ~ h ~Z^~
~ ~ .~ o ~ ~to - ~ 1 - ~ ,~

~Q ~ O ~ O e~ N ~I

l ~ -- l ~ ~ ~ l ~
- -- ---

Claims (38)

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

1. A process for producing an amino compound of the general formula:

wherein A is a penicillin moiety represented by the formula wherein the carboxy group is unprotected or protected by a conventional pro-tecting group, or A is a cephalosporin moiety represented by the formula wherein the carboxy group is unprotected or protected by a conventional protecting group and R3 is a group which does not take part in the reaction described below and is a member selected from the group consisting of 1. lower alkyl 2. lower alkoxymethyl, 3. lower alkanoyloxymethyl, 4. a group represented by the formula wherein R4 is lower alkyl or a 5 or 6 membered nitrogen-containing hetero-cyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or sub-stituted by (a) lower alkyl, (b) trifluoromethyl, (c) lower alkoxy, (d) halogen, (e) amino, (f) mercapto, (g) hydroxy, (h) carbamoyl, (i) carboxy, (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono-or di-lower alkylcarbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di- lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, or (1) amino mono- or di- substituted by carboxy, carbamoyl, lower alkyl, alkoxycar-bonyl having 2 to 13 carbon atoms, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di- lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkyl-sulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and 5. an iminomethyl group of the formula -CH = NOR5 wherein R5 is alkyl having 1 to 6 carbon atoms or cycloalkyl having up to 6 carbon atoms, which alkyl and cycloalkyl groups are unsubstituted or substituted by (a) allyl, (b) phenyl, (c) an unsubstituted 5 or 6 membered heterocyclic group having 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfer, (d) carboxy or (e) pyridinium, which comprises solvolyzing a compound of the general formula:

wherein R1 is an organic residue derived from an acylamido group in the 6 -position of a penicillin or the 7 position of a cephalosporin by eliminating the -CONH- moiety of the acylamido group, which organic residue is capable of combination with a thiocarbonyl group to form a thioacyl group, R2 represents a member selected from the group consisting of (1) lower alkoxycarbonylthio, (2) halocarbonylthio wherein the halo is chloro or bromo, (3) lower alkylthio, (4) mono-, di- or tri-halo lower alkylthio wherein the halo is chloro or bromo, (5) mono- or di-lower alkylaminothio, (6) mercapto substituted by an unsubstituted nitrogen-containing 5 or 6 membered heterocyclic group, (7) halothio wherein the halo is chloro or bromo and (8) halodithio wherein the halo is chloro or bromo, and A has the same meaning as above.

2. A process for producing an amino compound of the general formula:

wherein A is a penicillin moiety represented by the formula wherein the carboxy group is unprotected or protected by a conventional protecting group, or A is a cephalosporin moiety represented by the formula wherein the carboxy group is unprotected or protected by a conventional protecting group and R3 is a group which does not take part in the reaction described below and is a member selected from the group consisting of

1. lower alkyl,

2. lower alkoxymethyl,

3. lower alkanoyloxymethyl, 4. a group represented by the formula wherein R4 is lower alkyl or a 5 or 6 membered nitrogen-containing heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen,oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or substituted by (a) lower alkyl, (b) trifluoromethyl, (c) lower alkoxy, (d) chlorine or bromine, (e) amino, (f) mercapto, (g) hydroxy, (h) carbamoyl, (i) carboxy, (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 car-bon atoms, alkysulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoy-loxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or sub-stituted by hydroxy, mercapto, amino, morpholino, carboxy sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkyl-sulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consist-ing of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and pheny-lacetoxy, morpholinocarbonyl or N-lower alkylamino, or (1) amino mono- or di-substituted by carboxy, carbamoyl, lower alkyl, alkoxycarbonyl having 2 to 13 carbon atoms, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 atoms, alkylthio having 1 to 3 carbon atoms, alkysulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propiony-loxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and 5. an iminomethyl group of the formula -CH=NOR5 wherein R5 is alkyl having 1 to 6 carbon atoms, or cycloalkyl having up to 6 carbon atoms, which alkyl and cycloalkyl groups are unsubstituted or substi-tuted by (a) allyl, (b) phenyl, (c) an unsubstituted 5 or 6 membered hetero-cyclic group having 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, (d) carboxy or (e) pyridinium, which comprises reacting a compound of the general formula wherein R1 is an organic residue derived from an acylamido group in the 6-position of a penicillin or the 7-position of a cephalosporin by eliminating the -CONH- moiety of the acylamido group, which organic residue is capable of combination with a thiocarbonyl group to form a thioacyl group and A has the same meaning as above with a disulfidizing agent, to obtain an unsymmetrical disulfide compound of the general formula:

wherein R2 represents a member selected from the group consisting of (1) lower alkoxycarbonylthio, (2) halocarbonylthio wherein the halo is chloro or bromo, (3) lower alkylthio, (4) mono-, di- or tri-halo lower alkylthio wherein the halo is chloro or bromo, (5) mono- or di-lower alkylaminothio, (6) mercapto substituted by an unsubstituted nitrogen-containing 5 or 6 membered hetero-cyclic group, (7) halothio wherein the halo is chloro or bromo and (8) halodithio wherein the halo is chloro or bromo, and R1 and A have the same meaning as above, and then solvolyzing the compound.

3, A process as claimed in claim 1, wherein an alcohol is used as a solvent of the solvolysis.

4. A process as claimed in Claim 3, wherein the alcohol is a lower aliphatic one.

5. A process as claimed in Claim 4, wherein the lower aliphatic alcohol is a straight chained one having 1 to 3 carbon atoms.

6. A process as claimed in Claim 5, wherein the straight chained alcohol is methanol.

7. A process as claimed in Claim 6, wherein the disulfidizing agent is a sulfenyl halide derivative of the general formula wherein R2 has the same meaning as claim 1 and X is a halogen atom, iso-thiourea of the general formula wherein R2 has the same meaning as above, imide compound of the general formula or wherein R2 has the same meaning as above, or Bunte salt of the general formula wherein R2 has the same meaning as above and Me represents alkali metal.

8. A process as claimed in Claim 7, wherein R2 represents a halogeno-thio or halogenodithio, lower alkoxycarbonylthio, halogenocarbonylthio, lower alkylthio, mono-, di- or trihalogenoloweralkylthio, mono- or diloweral-kylaminothio group or nitrogen-containing 5 to 6 membered heterocyclic group substituted mercapto group.

9. A process as claimed in Claim 8, wherein the halogenothio or halogenodithio is chlorothio or chlorodithio; the lower alkoxycarbonylthio is methoxycarbonylthio; the halogenocarbonylthio is chlorocarbonylthio;
the lower alkylthio is methylthio, ethylthio, propylthio, isopropylthio, butylthio or isobutylthio; the mono-, di- or trihalogeno - loweralkylthio is monochloromethylthio, dichloromethylthio, trichloromethylthio or tribromo-methylthio; the mono- or diloweralkylaminothio is methylaminothio, dimethylaminothio or diethylaminothio and the nitrogen-containing 5 to 6 membered heterocyclic group is morpholinothio.

10. A process as claimed in Claim 9, wherein the disulfidizing agent is C?3CSC?, C?CH2SC?, CH3OCOSC?, C?COSC?, CH3SC?, C?3CSSC?, (C2H5)2-NSC?, , S-methylthioisothiourea, S-isobutylthioisothiourea, N-methyl-thiosuccinimide, N-isopropylthiosuccinimide, N-ethylthiophthalimide, N-n-butylthiophthalimide, N-propylthiophthalimide, sulfur chloride or sulfur dichloride.

11. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-t-butylbenzoylamido-4-carboxybutyl, R2 is chlorodithio, R3 is (1-methyltetrazol-5-yl) thiomethyl and the carboxy group is protected with dimethylsilyl group.

12. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl, R2 is chlorodithio, R3 is (1-methyl-tetrazol-5-yl) thiomethyl and the carboxy group is protected with dimethylsilyl group.

13. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-t-butylbenzenesulfonamido-4-carboxybutyl, R2 is chlorodithio, R3 is (1-methyltetrazol-5-yl)thiomethyl and the carboxy group is protected with dimethylsilyl group.

14. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-benzoylamido-4-carboxybutyl, R2 is chlorodithio, R3 is (1-methyl-tetrazol-5-yl)thiomethyl and the carboxy group is protected with dimethyl-silyl group.

15. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-isobornyloxycarbonylamido-4-carboxybutyl, R2 is chlorodithio, R3 is (1-methyltetrazol-5-yl)thiomethyl and the carboxy group is protected with dimethylsilyl group.

16. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl, R2 is chlorodithio, R3 is (5-methyl-1,3, 4-thiadiazol-2-yl)thiomethyl and the carboxy group is protected with dimethylsilyl group.

17. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl, R2 is chlorodithio, R3 is (1,3,4-thia-diazol-2-yl)thiomethyl and the carboxy group is protected with dimethylsilyl group.

18. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl, R2 is chlorodithio, R3 is (5-methyl-1, 3,4-oxadiazol-2-yl)thiomethyl and the carboxy group is protected with dimethylsilyl group.

19. A process as claimed in Claim 1, wherein in the starting compound R1 is benzyl, R2 is chlorodithio, R3 is methyl and the carboxy group is protected with .beta.-methylsulfonylethyl group.

20. A process as claimed in Claim 1, wherein in the starting compound R1 is benzyl, R2 is trichloromethylthio, R3 is methyl and the carboxy group is protected with .beta.-methylsulfonylethyl group.

21. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl , R2 is chlorodithio, R3 is (5-(.beta.-hydroxy-ethylthio )-1,3,4-thiadiazol-2-yl)thiomethyl and the carboxy group is pro-tected with dimethylsilyl group.

22. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl, R2 is chlorodithio, R3 is (5-carboxy-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl and the carboxy group is protected with dimethylsilyl group.

23. A process as claimed in Claim 1, wherein in the starting compound R1 is 4-phthalimido-4-carboxybutyl, R2 is chlorodithio, R3 is (5-(N,N-dimethylcarbamoylmethyl )-1,3,4-thiadiazol-2 yl)thiomethyl and carboxy group is protected with dimethylsilyl group.

24. A process as claimed in Claim 1, wherein in the starting compound R1 is 4 phthalimido-4 carboxybutyl, R2 is trichloromethylthio, R3 is acetoxymethyl and the carboxy group is protected with dimethylsilyl group.

25. A process according to claim 2, wherein 7-amino-3-(1-methyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-p-t-butylbenzoylamido-5-carboxyvalerthioamido)-3-(1- methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected with dimethylsilyl, with sulfur monochloride,and reacting the resultant com-pound with methanol.

26. A process according to claim 2, wherein 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepham-4-carboxylic acid is produced by reacting 7-(D-5-phthalimido-5-carboxyvalerthioamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected with dimethylsilyl, with sulfur monochloride, and reacting the resultant compound with methanol.

27. A process according to claim 2, wherein 7-amino-3-(5-methyl-1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-phthalimido-5-carboxyvalerthiomadio)-3-(5-methyl-1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected with dimethylsilyl, with sulfur monochloride, and reacting the resultant compound with methanol.

28. A process according to claim 2, wherein 7-amino-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-phthalimido-5-carboxyvalerthiomado)-3-(1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected with dimethyl-silyl, with sulfur monochloride, and reacting the resultant compound with methanol.

29. A process according to claim 2, wherein 7-amino-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-isobornyloxycarbonylamido-5-carboxyvalerthioamido)-3-(1-methyltetrazol-5-y1) thiomethyl-3-cephem-4-carboxylic acid whose carboxy groups are protected by dimethyl-silyl, with sulfur monochloride, and reacting the resultant com-pound with methanol.

30. A process according to claim 2, wherein 7-amino-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-phthalimido-5-carboxyvalerthioamido)-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected with dimethy-silyl, with sulfur monochloride, and reacting the resultant compound with methanol.

31. A process according to claim 2, wherein 7-amino-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-p-t-butylbenzenesulfonamido)-5-carboxyvalerthioamido)-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with sulfur monochloride, and reacting the resultant compound with methanol.

32. A process according to claim 2, wherein 7-amino-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-ben-zoylamido-5-carboxyvalerthioamido)-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with sulfur monochloride, and reacting the resultant compound with methanol.

33. A process according to claim 2, wherein 7-amino-3-[5-(.beta. -hydroxyethyl-thio)-1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid is pro-duced by reacting 7-(D-5-phthalimido-5-carboxyvalerthioamido)-3-[5-(.beta.-hydroxye-thylthio)-1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with sulfur monochloride, and reacting the resultant compound with methanol.

34. A process according to claim 2, wherein 7-amino-3-(5-carboxymethyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-phthalimido-5-carboxyvalerthioamido)-3-(5-carboxymethyl-1, 3,4-thiadiazol-2yl) thiomethyl-3-cephem-4carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with sulfur monochloride, and reacting the re-sultant compound with methanol.

35. A process according to claim 2, wherein 7-amino-3-[5-(N,N-dimethyl-carbamoylmethyl)-1,3,4-thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid is produced by reacting 7-(D-5-phthalimido-5-carboxyvalerthioamido)-3-[5-(N,N-dimethylcarbamoylmethyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with sulfur mono-chloride, and reacting the resultant compound with methanol.

36. A process according to claim 2, wherein 7-aminocephalosporanic acid is produced by reacting 7(D-5-phthaloylimido-5carboxy valerthioamido)-3-acetox-ymethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with trichloromethanesulfenyl chloride, and reacting and result-ant compound with methanol.

37. A process according to claim 2, wherein 7-aminocephalosporanic acid is produced by reacting 7-(D-5-phthaloylimido-5-carboxy valerthioamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid, whose carboxy groups are protected by dimethylsilyl, with sulfur monochloride, and reacting the resultant compound with methanol.

38. A process according to claim 2, wherein .beta.-methylsulfonylethyl 7-amino-3-desacetoxycephalosporanate is produced by reacting an adduct consist-ing of .beta.-methylsulfonylethyl 7-phenylthioacetamido-3-desacetoxycephalosporanate, pyridine and hydrogen chloride with sulfur monochloride, and reacting the resultant compound with methanol.