CA1209577A - 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof - Google Patents
3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereofInfo
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- CA1209577A CA1209577A CA000477197A CA477197A CA1209577A CA 1209577 A CA1209577 A CA 1209577A CA 000477197 A CA000477197 A CA 000477197A CA 477197 A CA477197 A CA 477197A CA 1209577 A CA1209577 A CA 1209577A
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Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of the formula (III):
Compounds of the formula (III):
Description
The present invention relates to new intermediates for 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts.
This application is a division oE Canadian Patent Appli-cation Serial Number 273,202, filed March 4, 1977.
The 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof have antimicrobial activities, and thus may be used therapeutically in the treatment of infectious diseases in animals and human beings.
In accordance with one aspect of *he invention, there is provided a compound of ~he ormula (III):
Rl ~ ~ - Co-R5 (III) wherein Rl is amino, lower alkylamino, a protected amino, or a protected lower alkylamino, R4 is hydrogen or halogen, and R5 is carboxy or a protected carboxy, or a salt thereof.
In ano~her aspect of the invention, there is provided a process for preparing an intermediate of formula (III~, as defined above comprising:
~ a) reacting a compound of the formula:
Rl ~ ~ CO-Z ~IIIi~
wherein Rl is amino, or lower alkylamino, and Z is a protected carboxy, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, to give a compound of the for-mula:
~ .
5~7' R--~;~ CO-Z tIIIa) herein Rl is a prt)tected amino, or a protected loweT
alkylamino, and is as defined above " or (b) reacting a compound o the formula-Rl ~CO- COOH ( I I I Q) wherein Rl is as defined above, or i~s reactiYe derivative at the amino group or a salt ~hereof wil:h an amino-protecting agent, to give a compound of ~he formula:
Rl ~ CO-COGH (IIIb) S
wherein Rl is as defined above, or (c) oxidizing a compound o the formula:
lR. ~ ~H2-Z (~
S
wherein Rl and Z` aTe each as defined above, to give a compound of ~he formula:
}~l~CO-Z (IIIa) wherein Rl and Z are each as defined above, or ~d) subjecting a compound of ~he formula:
- la -7~
Rl ~ CO-Z (IIIa) S
wherein R~ and Z a~e each as def;ned above, to .
elimination ~eaction of ~he protectiv~ group of the ca~boxr -~o gi~e a compound of ~he fo~mula:
Rl ~ ~ CO-COOH (IIIb) S
, I
wherein R~. is as defined above, or (e~ subjecting a compound of ~he formula:
Rl _ ~ ~ CO-Z (IIIj) wherein Rl and ~ are each as defined abo~e, and R4 - is halogen, to elimination rea~tion of ~he p~.otecSi~e group of the ca~boxy, to gi~e a compound of the formula:
Rl ~ ~ CO-COOH (IIIk) S
wherein Rl and R4 aTe eaeh as defined above, or (f~ subjecting a compound of the formula:
Rl ~ CO-~ (IIIa) S
wherein Rl and Z are each as defined above, to elimination Teaction of the protectiYe gTOUp of the amino, to give a compound of the fsrmula:
- lb ~-z~
Rl ~ CO-Z (IIIi~
whel ein Rl and Z are each as defî7led absYe, or a sal'c thereof 9 or (g) Teacting a compound of the formula:
R ~ CO-Z tIIIa) wherein Rl and Z a~e each as def~ ned above ,, with a halogenati~g agen~c ~co ~iYe a compound of the formula:
ff~ ( I I I j ) wherein Rl " R4 an~ Z are eacil as defined above, or (h~ oxidizing a compound of *he foTmula:
H COOH ~I I Im) S OH
whe~ein Rl îs as defined above ~
to give a compound of the fo~mula:
Rl t~o COOH (IIIQ) - wherein Rl is as defined above, The 3,7-disubstituted-3-cephe~.-4-carboxylic acid co~pounds;
which can be prepared from the intermediates ~III), can be represented by the fQllowing general formula (I):
-- lc --R1 ~ ~ A-CONI~ _ ~ S~
S ~ N ~ CH2 . . R3 ~herein Rl is amino, lower alkylamino, a protected amino, a protected lower al~ylæmino, hydroxy or ~ower ~lko~y, R? i~ hydrogenD acyloxy, pyridinium or a heterocyclic-thio ~roup which mny have suitable su~stituent(~), R3 is car~oxy or its derivati~e~
A is carbonyl, hydro~y(lower)alkylene or a protectcd hydroxy(lower)alkylene and ~ i9 hyd~ogen or hzlogen, or R' and R~ are linked together to represent a group of the ~ormula: -CQO-, wherein ~ COO when R2 is pyridinium, pro~ided that R i~ not aceto~y or l-~ethyI~ tetrazol-5-ylthio wh~n the group of the formula : R4 R ~ A-CO-i8 2-hydroxy~2-(2-amino-1~3-thiazol-4-yl)acetyl or
This application is a division oE Canadian Patent Appli-cation Serial Number 273,202, filed March 4, 1977.
The 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof have antimicrobial activities, and thus may be used therapeutically in the treatment of infectious diseases in animals and human beings.
In accordance with one aspect of *he invention, there is provided a compound of ~he ormula (III):
Rl ~ ~ - Co-R5 (III) wherein Rl is amino, lower alkylamino, a protected amino, or a protected lower alkylamino, R4 is hydrogen or halogen, and R5 is carboxy or a protected carboxy, or a salt thereof.
In ano~her aspect of the invention, there is provided a process for preparing an intermediate of formula (III~, as defined above comprising:
~ a) reacting a compound of the formula:
Rl ~ ~ CO-Z ~IIIi~
wherein Rl is amino, or lower alkylamino, and Z is a protected carboxy, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, to give a compound of the for-mula:
~ .
5~7' R--~;~ CO-Z tIIIa) herein Rl is a prt)tected amino, or a protected loweT
alkylamino, and is as defined above " or (b) reacting a compound o the formula-Rl ~CO- COOH ( I I I Q) wherein Rl is as defined above, or i~s reactiYe derivative at the amino group or a salt ~hereof wil:h an amino-protecting agent, to give a compound of ~he formula:
Rl ~ CO-COGH (IIIb) S
wherein Rl is as defined above, or (c) oxidizing a compound o the formula:
lR. ~ ~H2-Z (~
S
wherein Rl and Z` aTe each as defined above, to give a compound of ~he formula:
}~l~CO-Z (IIIa) wherein Rl and Z are each as defined above, or ~d) subjecting a compound of ~he formula:
- la -7~
Rl ~ CO-Z (IIIa) S
wherein R~ and Z a~e each as def;ned above, to .
elimination ~eaction of ~he protectiv~ group of the ca~boxr -~o gi~e a compound of ~he fo~mula:
Rl ~ ~ CO-COOH (IIIb) S
, I
wherein R~. is as defined above, or (e~ subjecting a compound of ~he formula:
Rl _ ~ ~ CO-Z (IIIj) wherein Rl and ~ are each as defined abo~e, and R4 - is halogen, to elimination rea~tion of ~he p~.otecSi~e group of the ca~boxy, to gi~e a compound of the formula:
Rl ~ ~ CO-COOH (IIIk) S
wherein Rl and R4 aTe eaeh as defined above, or (f~ subjecting a compound of the formula:
Rl ~ CO-~ (IIIa) S
wherein Rl and Z are each as defined above, to elimination Teaction of the protectiYe gTOUp of the amino, to give a compound of the fsrmula:
- lb ~-z~
Rl ~ CO-Z (IIIi~
whel ein Rl and Z are each as defî7led absYe, or a sal'c thereof 9 or (g) Teacting a compound of the formula:
R ~ CO-Z tIIIa) wherein Rl and Z a~e each as def~ ned above ,, with a halogenati~g agen~c ~co ~iYe a compound of the formula:
ff~ ( I I I j ) wherein Rl " R4 an~ Z are eacil as defined above, or (h~ oxidizing a compound of *he foTmula:
H COOH ~I I Im) S OH
whe~ein Rl îs as defined above ~
to give a compound of the fo~mula:
Rl t~o COOH (IIIQ) - wherein Rl is as defined above, The 3,7-disubstituted-3-cephe~.-4-carboxylic acid co~pounds;
which can be prepared from the intermediates ~III), can be represented by the fQllowing general formula (I):
-- lc --R1 ~ ~ A-CONI~ _ ~ S~
S ~ N ~ CH2 . . R3 ~herein Rl is amino, lower alkylamino, a protected amino, a protected lower al~ylæmino, hydroxy or ~ower ~lko~y, R? i~ hydrogenD acyloxy, pyridinium or a heterocyclic-thio ~roup which mny have suitable su~stituent(~), R3 is car~oxy or its derivati~e~
A is carbonyl, hydro~y(lower)alkylene or a protectcd hydroxy(lower)alkylene and ~ i9 hyd~ogen or hzlogen, or R' and R~ are linked together to represent a group of the ~ormula: -CQO-, wherein ~ COO when R2 is pyridinium, pro~ided that R i~ not aceto~y or l-~ethyI~ tetrazol-5-ylthio wh~n the group of the formula : R4 R ~ A-CO-i8 2-hydroxy~2-(2-amino-1~3-thiazol-4-yl)acetyl or
2-hydroxy-2-[2-~2,2,2-trichlsroetho~y)carbonylamino-; 1,3-thiazol~4-yl]acetyl.
~ , '. .
.
~Z~ 7 According to -the presen-t invention, the
~ , '. .
.
~Z~ 7 According to -the presen-t invention, the
3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) can be prepared by conventional various processes which are illustrated by the following scheme, in which the process comprising step, (II) -~ (I) is a ~undamental process and the others are alternative processes.
Process 1. 4 R
1 N ~
R ~ ~ A-COOH(III) R4 H2N ~ S~ lN ~ S
~ N ~ CH -R or its reactive R ~ ~ A-CONH I ~ ~ 2 O r 2 derivative at S ~ N ~ CH2-R
3 the carboxy o ~3 R group ~II) ' (I) or its reactive derivative at the amino group Process 2.
H R2' (V) or its reactive R4 derivative at the ~4 N I mercapto Nt__ Rl ~ t ~ ~-CONH ~ S~ group Rl ~ ~ A-CONH ~ ~S~ 2' o N~l~ ~H2 Y ~ ~ CH2-R
R R
(IV) (Ia) .~'`, L2~ 7P~
P~ocess 3 Elimination of the
Process 1. 4 R
1 N ~
R ~ ~ A-COOH(III) R4 H2N ~ S~ lN ~ S
~ N ~ CH -R or its reactive R ~ ~ A-CONH I ~ ~ 2 O r 2 derivative at S ~ N ~ CH2-R
3 the carboxy o ~3 R group ~II) ' (I) or its reactive derivative at the amino group Process 2.
H R2' (V) or its reactive R4 derivative at the ~4 N I mercapto Nt__ Rl ~ t ~ ~-CONH ~ S~ group Rl ~ ~ A-CONH ~ ~S~ 2' o N~l~ ~H2 Y ~ ~ CH2-R
R R
(IV) (Ia) .~'`, L2~ 7P~
P~ocess 3 Elimination of the
4 protectlve group 4 of ~che amino R
R1~3-A CONH S R~ A-CO~ _~ S~ 2 S ~- N ~,J C~l 2 R
R.3 R
tI C) ~ Ib) Proc~ss 4 Elim~natlon of the R4 protect~ve group ~4 of the hydroxy CONH~S _ 2 ~ ~A'-CON~ 2 R~ 2 ~ R
(Ie) tId) ' Process 5 ~ R
Rl~--CO-CONII~ ~S~ 1 ~N ~L_CH2 R
tIg) tIf) wherein Rl, R2, R3, R4 and A are each &~ defined above, a pro~ected ~ino or a protected lower alkylamino, Rl i8 amino or lower alkyl~mino, R2 is a heterocyclic-t31io group which may have suitable substituent (s), A' is hydroxy(lower) alkylene~
A" is a protec'ced hy~lroxy(lower~alkylene and Y is a conlrentional group which is capable to be replaced by the residue t-R2; of a compound o~ the formula:
HT~2 in which R2 is as deined above.
\
~2~S~7 The starting compound~(III) and (IV) can be ~repared ~y th~ proces3es whlch are illustrated by the following scheme~
~1) Rl ~ CH2 Z ~ Rl ~ t--L
tVI ) / ~/ ( II I i ) or lts reac'cive derivati~Te / / ~-at the an~slo B,~
c:o Z -- Rl~ COCOOH~ Rl~ CG(~OGH
~IIIa~ R4~ (IXIb)(IIIl3 Rl~ CO Z
Rl~,~CH-Z ¦ R~ CIHCOOH ~R~
. ~IIId3 R4~ (IIIC) (I') R~-COCOOEI
- (IIIk) l Rl ~ - CH-Z ~ R1 ~ CHCOOH~ 1' ~ C~COGII
) (IIIf3 (III~) ~2) - .
H~3 -CH2- z ~ oH~ co- Z ~ COCOOH
(~III) ~IIIg) ~IIIh3 ~2~
~ ~ ~ A-COOH (III) or i-ts ractive derivative H2N ~ s~at the carboxy group N ~
H2-Y R ~$~ A ~ CH2 Y
(IX) (IV) or its reactive derivative at the amino group wherein Rl, Rl , Rl , R3, R , A and Y are such as defined above , 4, :R is halogen Y~ is a protected hydroxy and Z is a protected carboxy.
Regarding the object compounds (I) and (Ia)-(Ig) and the starting compounds (III), (IIIa)-(IIIm), (IV) and (VI~-(VIII), it is to be understood that they include tauto-meric isomers, 4that is, in the case that the group of the formula: 1 N ~
(provided that R- is amino, lower alkylamino, protected amino or hydroxy, and R4 is as defined above) in the formula of4 sa`d object and starting compounds take the formula~
(R and R are each as defined above), said group of the formula: 1 N~ ~
can be also a~t~natively represented by its tautomeric formula: Rla (Rla is imino, lower alkylimino, a protected imino or oxo~
and R4 is as defined above). That is, both of the said groups are in the state of equilibrium and such tautomerism can be represented by the following equilibrium. 4 Rl ~ ~la J ~
These types of tautomerism of the amino- and hydroxy-thiazole co~pounds as stated above have been well known in the liter-ature, and it is obvious to be any person skilled in the arts that y~
bo~h of the tautomeric isomers are easily convertible reciprocallyand are încluded within the same catego~y of ghe compound per se.
Accordingly, the both o the ~automerio forms of the object compounds (13 and (Ia~ - (Ig) and the starting compounGs (III), (IIIa) ~ ), (IV) and (VI) - tVIII) are clearly included within the scope of the present invention. In the present specifica~iong the object and star~ing compounds includi~g the group o such tautome~ic isomers are represented by us ng one o the expressions therefoT ~ ~hat is the formula ~ only for ~he convenient s a~e . R~s~
Suitable pharmaceu~ically accep~Lable sal~s of the ob ject 3"7-disubstitu~ced-3-cephem-4-carboxylic acid compounds (1) are conventional non-toxic salts and may inslude a metal sal~c such as an alkali metal sal~ ~e.g., sodium salt, potassium sal~ , etc . ) and an alkaline earth metal salt (e.g.. 9 calcium salt3 magnesium salt, e~c.) " aminonium sal~ o~ganic amine salt (e.g., trimethyl-amine s al t, tri e~hylamine s al t, pyr i dine s al t, pi col ine s al ~, dicyclohexylamine salt9 N9N'-dibenzylethylenediamine saltp etc.), an organic acid salt ~e. g., ace~ate, maleate, tartrate, methane-sulfonate D benzenesulfonate, toluenesulfonate, etc.~, an inorganic acid salt (e.g., hydrochloride, hydTobromide, sulfate 9 phosphate, etc.), o~ a salt with an amino acid (e.gO~ arginine, aspartic acid, glutamic acid, etc.~, and the like.
In the above and subsequent descriptions of the p~esent specificstion, suitable examples and illustrations of the various defini~ions which the present invention intend to include within the scope theTeof aTe explained ~n details as follows.
The 'cerm "lower" is in~ended to mean 1 to 6 carbon a~oms.
Suitable lower alkyl moiety in theterm~ "lowe~ alkyl-amino" and Ua protected lower alkyl~ o" may include met~yl7 ~hyl, '7 ~Z~9~
propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and -the like.
Suitable protective group in the terms "a protected amino" and "a protected lower alkylamino" may include an acyl and a conventional protective group other than the acyl group such as benzyl and the like.
Suitable protected hydroxy moiety in the term "a protected hydroxy(lower)alkylene" may include an acyloxy and hydroxy group substituted by a conventional protective group other than the acyl group such as tetrahydropyranyloxy and the like.
Suitable acyl and acyl moiety in the term "acyloxy"
as mentioned above may include carbamoyl, thiocarbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxy-carbonyl, proproxycarbonyl, l-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxyearbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g., mesyl, ethansulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl ~e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g~, benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.), and the like. The acyl moiety as stated above may have one to ten suitable substituent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), cyano, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.~, or the like, suitable examples of which may be mono(or di or tri)halo(lower)alkanoyl (e.g., trifluoroacetyl, ete.) Suitable lower alkoxy may inelude methoxy, e-thoxy, propoxy, isopropoxy, butoxy, pentyloxy and the like.
3~
Suitable heterocyclic group in the term "a he-tero-cyclicthio group which may have suitable substituent(s)" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be N-containing heterocyclic group such as unsatura-ted 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrro]inyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl,*riazolyl Ie.g-, 4H-1,2,~-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) (e.g., indolyl, isoindolyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzo-triazolyl, etc.); unsaturated 3-to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);
etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atoms(s) (e.g., morpholinyl, etc.); unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., benzoxazolyl, benzoxadiazolyl, etc.);
unsaturated 3 to 8-membered heteromonocyclic group con-taining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 :a2~ '7 sulfuT atom~s) and 1 to 3 nitrogen atom(s) (e.g., thiazolidinyl, etc.);
unsaturated condensed heterocyclic group con~aining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (~ . g., benzothiazolyl, benzothiadiazolyl, etc. ) and the like, wherein said heterocyclic group may have one to ~our suitable substituent(s~ such as lower alk~l (e.g., methyl, ethyl, propyl, isopropyl, butyl 9 isobutyl, pentyl~ cyclopentyl 9 hexyl, cyelohexyl, etc.); lower alkenyl ~e.g., vinyl, allyl~ butenyl, eto.);
aryl (e.g., phenyl, tolyl, etc.); halogen~ (e.g. J ch,orine, bromine, iodine or fluorine); amino and the like.
Suitable carboxy derivative may include -COO and a protected carboxy such ~9 carboxylic ester or the like.
Suitable examples of said ester may be the ones such as lower alkyl es~er (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester~ pentyl es~er, hexyl ester, l-cyclopropylethyl ester, etc.);
lower alkenyl ester (e.g., vinyl ester, allyl ester etc.);
lower alkynyl est~r ~e.g. 9 ethynyl ester, propynyl ester, etc.);
mono~or di or tri)-halo~lower)alkyl ester (e.g., 2-iodoethyl ester, 292,2-trichloroethyl ester~ etc.);
lower alkanoyloxy~lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester~ pivaloyloxymethyl es~er, 2-acetoxyethyl ester, 2-propionyl-oxyethyl ester, etc.);
lower alkanesulfonyi~lower~alkyl ester (e,g., 2-mesylethyl ester etc.); phenyl~lower~alkyl ester which may have one or more suitable substituent(s) te.g., benzyl ester) 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 57~
4-hydroxy-3,5-ditertiarybutylbenæyl ester~ etc.);
aryl ester which may have one or more suitable substituent~s) (e.g. 9 phenyl ester, tolyl ester, ter~iarybutylphenyl ester, xylyl ester, mesi~yl ester, cumenyl ester, et~c.), and the like.
Suitable lower alkylene moiety in the te~ns ;'hydroxy-(lower~alkyle;le~' and l'a protected hydroxy(lower)alkylene" may include, me~hylene, ethylene, trime~hylene, propylene~ ~etra- -methylene and the like; among which the preferable hydroxy(lower)-alkylene and protec~ed hydroxy(lower)alkylene may be hydToxy (C
2) alkylene and a protected hydroxy (Cl 2) alkylene~ and the most preferable ones are hydroxymethylene and a protected hydroxy methylene.
Suitable "a conventional group which is capable to be ~eplaced by the residue of a compound of the formula: H-R2 "
in ~he symbol Y may include a halogen atom (e.g., chlorine, bromine, etc.) 9 azido group7 ~n acyloxy group such as lo~er alkanoyloxy ~e.g~, formyloxy~ acetoxy, propionyloxy9 butyryloxy, etc.) and aroyloxy (e.g., benzoyloxy, toluoyloxy, etc.), and the like.
Suitable halo~en msy include the same one~ as ~forementioned.
Suitable "a protected carboxy" may include an ester as aforementioned.
The various processes or preparing the object compounds of the present invention arg explained in details in the following.
Process 1:
-The object compound (I~ or a salt thereof can be ~repared by reacting the compound (II) or it3 reactive derivative at the amino group or a salt thereof with the compou~d (III) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivative at the amino group of ~he compound (II) may include Schiff's base type imino or i~s tautomeric enamine type isomer formed by the reaction of the compound ~II) with a carbonyl compol~d; a silyl derivative formed by the reaction of the compound ~II) with z silyl compound such as bis~trimethylsilyl)acetamide or the like; a derivative fo~med by reac~ion of the compound (II) wi~h phosphorus trichloride or phosgene, and the like.
Sui~able salt of the compound (II) may include an acid addition salt such as an organic acid salt (e.g., acetate~
malea~el tartra~e, benzenesul~onate; ~oluenesulfonate, etc.) or an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate7 etc.); a metal salt (e.g., sodium salt;
potassium salt, calcium salt~ magnesium salt, etc.); ammonium salt; an organic amine sal~ (e.g.~ triethylamine sal~, dicyclo-hexylamine salt, etc.), and the like.
; Suitable ~eactive de~ivative at the carboxy group of the compound (III~ may in~lude an acid halide,an acid anhydride, an actlvated amide, an activated ester, and the like. The suitable example may be an acid chloride; an acid azide; a mixed acid anhydride wi~h an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid~ diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid~ etc.), dialkylphosphorous acid, sulfurous acid, thîosulfuric aoid, sulfuric acid, alkylc~rbonic acid, aliphatic carboxylic acid ~e. g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl-butyric acid or trichloroacetic acid, etc.) or aromatio carboxylic acid (e.g , benzoic acid, etc.); a symmetrical acid anhydride;
an ac~ivated amide with imidazole, 4-substi~uted imidazole 7 dimethylpyrazole, triazole or tetrazole; or an activated este (e.g.~ cyanomethyl ester, methoxymethyl ester, dimethylimino-methyl ~CH3)2N = CH-) ester,vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazo-phenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,~pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or an ester with N,N-dimethylhydroxylamine, l-hydroxy-2-(1~)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or l-hydroxy-6-chloro-lH-benzo~riazole, and ~he like. These reactive derivatives can be optionally selected from them according to ihe kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solven~ such as water, acetone~ dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethyl~formamide, pyridine or any other organic solvent which does not adversely influence to the reaction.
Among these solvents, hydrophilic solvents may be used in a mixture with water.
When the compound (III~ is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-oyclohexyl-N'-morpholinoethyl-carbodiimide, N-cyclohexyl-Nl~4-diethylaminocyclohexyl)carbodi-imide, N,N-diethylcarbodiimide, N,N-diisopropylcarbodiimide, N ethyl-N'-~3-dimethylaminopropyl)carbodiimide, N,N-carbonylbis-(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, l-alkoxy-l-chloroe~hylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride) phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)-. ~ 13 -
R1~3-A CONH S R~ A-CO~ _~ S~ 2 S ~- N ~,J C~l 2 R
R.3 R
tI C) ~ Ib) Proc~ss 4 Elim~natlon of the R4 protect~ve group ~4 of the hydroxy CONH~S _ 2 ~ ~A'-CON~ 2 R~ 2 ~ R
(Ie) tId) ' Process 5 ~ R
Rl~--CO-CONII~ ~S~ 1 ~N ~L_CH2 R
tIg) tIf) wherein Rl, R2, R3, R4 and A are each &~ defined above, a pro~ected ~ino or a protected lower alkylamino, Rl i8 amino or lower alkyl~mino, R2 is a heterocyclic-t31io group which may have suitable substituent (s), A' is hydroxy(lower) alkylene~
A" is a protec'ced hy~lroxy(lower~alkylene and Y is a conlrentional group which is capable to be replaced by the residue t-R2; of a compound o~ the formula:
HT~2 in which R2 is as deined above.
\
~2~S~7 The starting compound~(III) and (IV) can be ~repared ~y th~ proces3es whlch are illustrated by the following scheme~
~1) Rl ~ CH2 Z ~ Rl ~ t--L
tVI ) / ~/ ( II I i ) or lts reac'cive derivati~Te / / ~-at the an~slo B,~
c:o Z -- Rl~ COCOOH~ Rl~ CG(~OGH
~IIIa~ R4~ (IXIb)(IIIl3 Rl~ CO Z
Rl~,~CH-Z ¦ R~ CIHCOOH ~R~
. ~IIId3 R4~ (IIIC) (I') R~-COCOOEI
- (IIIk) l Rl ~ - CH-Z ~ R1 ~ CHCOOH~ 1' ~ C~COGII
) (IIIf3 (III~) ~2) - .
H~3 -CH2- z ~ oH~ co- Z ~ COCOOH
(~III) ~IIIg) ~IIIh3 ~2~
~ ~ ~ A-COOH (III) or i-ts ractive derivative H2N ~ s~at the carboxy group N ~
H2-Y R ~$~ A ~ CH2 Y
(IX) (IV) or its reactive derivative at the amino group wherein Rl, Rl , Rl , R3, R , A and Y are such as defined above , 4, :R is halogen Y~ is a protected hydroxy and Z is a protected carboxy.
Regarding the object compounds (I) and (Ia)-(Ig) and the starting compounds (III), (IIIa)-(IIIm), (IV) and (VI~-(VIII), it is to be understood that they include tauto-meric isomers, 4that is, in the case that the group of the formula: 1 N ~
(provided that R- is amino, lower alkylamino, protected amino or hydroxy, and R4 is as defined above) in the formula of4 sa`d object and starting compounds take the formula~
(R and R are each as defined above), said group of the formula: 1 N~ ~
can be also a~t~natively represented by its tautomeric formula: Rla (Rla is imino, lower alkylimino, a protected imino or oxo~
and R4 is as defined above). That is, both of the said groups are in the state of equilibrium and such tautomerism can be represented by the following equilibrium. 4 Rl ~ ~la J ~
These types of tautomerism of the amino- and hydroxy-thiazole co~pounds as stated above have been well known in the liter-ature, and it is obvious to be any person skilled in the arts that y~
bo~h of the tautomeric isomers are easily convertible reciprocallyand are încluded within the same catego~y of ghe compound per se.
Accordingly, the both o the ~automerio forms of the object compounds (13 and (Ia~ - (Ig) and the starting compounGs (III), (IIIa) ~ ), (IV) and (VI) - tVIII) are clearly included within the scope of the present invention. In the present specifica~iong the object and star~ing compounds includi~g the group o such tautome~ic isomers are represented by us ng one o the expressions therefoT ~ ~hat is the formula ~ only for ~he convenient s a~e . R~s~
Suitable pharmaceu~ically accep~Lable sal~s of the ob ject 3"7-disubstitu~ced-3-cephem-4-carboxylic acid compounds (1) are conventional non-toxic salts and may inslude a metal sal~c such as an alkali metal sal~ ~e.g., sodium salt, potassium sal~ , etc . ) and an alkaline earth metal salt (e.g.. 9 calcium salt3 magnesium salt, e~c.) " aminonium sal~ o~ganic amine salt (e.g., trimethyl-amine s al t, tri e~hylamine s al t, pyr i dine s al t, pi col ine s al ~, dicyclohexylamine salt9 N9N'-dibenzylethylenediamine saltp etc.), an organic acid salt ~e. g., ace~ate, maleate, tartrate, methane-sulfonate D benzenesulfonate, toluenesulfonate, etc.~, an inorganic acid salt (e.g., hydrochloride, hydTobromide, sulfate 9 phosphate, etc.), o~ a salt with an amino acid (e.gO~ arginine, aspartic acid, glutamic acid, etc.~, and the like.
In the above and subsequent descriptions of the p~esent specificstion, suitable examples and illustrations of the various defini~ions which the present invention intend to include within the scope theTeof aTe explained ~n details as follows.
The 'cerm "lower" is in~ended to mean 1 to 6 carbon a~oms.
Suitable lower alkyl moiety in theterm~ "lowe~ alkyl-amino" and Ua protected lower alkyl~ o" may include met~yl7 ~hyl, '7 ~Z~9~
propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and -the like.
Suitable protective group in the terms "a protected amino" and "a protected lower alkylamino" may include an acyl and a conventional protective group other than the acyl group such as benzyl and the like.
Suitable protected hydroxy moiety in the term "a protected hydroxy(lower)alkylene" may include an acyloxy and hydroxy group substituted by a conventional protective group other than the acyl group such as tetrahydropyranyloxy and the like.
Suitable acyl and acyl moiety in the term "acyloxy"
as mentioned above may include carbamoyl, thiocarbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxy-carbonyl, proproxycarbonyl, l-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxyearbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g., mesyl, ethansulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl ~e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g~, benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.), and the like. The acyl moiety as stated above may have one to ten suitable substituent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), cyano, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.~, or the like, suitable examples of which may be mono(or di or tri)halo(lower)alkanoyl (e.g., trifluoroacetyl, ete.) Suitable lower alkoxy may inelude methoxy, e-thoxy, propoxy, isopropoxy, butoxy, pentyloxy and the like.
3~
Suitable heterocyclic group in the term "a he-tero-cyclicthio group which may have suitable substituent(s)" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be N-containing heterocyclic group such as unsatura-ted 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrro]inyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl,*riazolyl Ie.g-, 4H-1,2,~-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) (e.g., indolyl, isoindolyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzo-triazolyl, etc.); unsaturated 3-to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);
etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atoms(s) (e.g., morpholinyl, etc.); unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., benzoxazolyl, benzoxadiazolyl, etc.);
unsaturated 3 to 8-membered heteromonocyclic group con-taining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 :a2~ '7 sulfuT atom~s) and 1 to 3 nitrogen atom(s) (e.g., thiazolidinyl, etc.);
unsaturated condensed heterocyclic group con~aining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (~ . g., benzothiazolyl, benzothiadiazolyl, etc. ) and the like, wherein said heterocyclic group may have one to ~our suitable substituent(s~ such as lower alk~l (e.g., methyl, ethyl, propyl, isopropyl, butyl 9 isobutyl, pentyl~ cyclopentyl 9 hexyl, cyelohexyl, etc.); lower alkenyl ~e.g., vinyl, allyl~ butenyl, eto.);
aryl (e.g., phenyl, tolyl, etc.); halogen~ (e.g. J ch,orine, bromine, iodine or fluorine); amino and the like.
Suitable carboxy derivative may include -COO and a protected carboxy such ~9 carboxylic ester or the like.
Suitable examples of said ester may be the ones such as lower alkyl es~er (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester~ pentyl es~er, hexyl ester, l-cyclopropylethyl ester, etc.);
lower alkenyl ester (e.g., vinyl ester, allyl ester etc.);
lower alkynyl est~r ~e.g. 9 ethynyl ester, propynyl ester, etc.);
mono~or di or tri)-halo~lower)alkyl ester (e.g., 2-iodoethyl ester, 292,2-trichloroethyl ester~ etc.);
lower alkanoyloxy~lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester~ pivaloyloxymethyl es~er, 2-acetoxyethyl ester, 2-propionyl-oxyethyl ester, etc.);
lower alkanesulfonyi~lower~alkyl ester (e,g., 2-mesylethyl ester etc.); phenyl~lower~alkyl ester which may have one or more suitable substituent(s) te.g., benzyl ester) 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 57~
4-hydroxy-3,5-ditertiarybutylbenæyl ester~ etc.);
aryl ester which may have one or more suitable substituent~s) (e.g. 9 phenyl ester, tolyl ester, ter~iarybutylphenyl ester, xylyl ester, mesi~yl ester, cumenyl ester, et~c.), and the like.
Suitable lower alkylene moiety in the te~ns ;'hydroxy-(lower~alkyle;le~' and l'a protected hydroxy(lower)alkylene" may include, me~hylene, ethylene, trime~hylene, propylene~ ~etra- -methylene and the like; among which the preferable hydroxy(lower)-alkylene and protec~ed hydroxy(lower)alkylene may be hydToxy (C
2) alkylene and a protected hydroxy (Cl 2) alkylene~ and the most preferable ones are hydroxymethylene and a protected hydroxy methylene.
Suitable "a conventional group which is capable to be ~eplaced by the residue of a compound of the formula: H-R2 "
in ~he symbol Y may include a halogen atom (e.g., chlorine, bromine, etc.) 9 azido group7 ~n acyloxy group such as lo~er alkanoyloxy ~e.g~, formyloxy~ acetoxy, propionyloxy9 butyryloxy, etc.) and aroyloxy (e.g., benzoyloxy, toluoyloxy, etc.), and the like.
Suitable halo~en msy include the same one~ as ~forementioned.
Suitable "a protected carboxy" may include an ester as aforementioned.
The various processes or preparing the object compounds of the present invention arg explained in details in the following.
Process 1:
-The object compound (I~ or a salt thereof can be ~repared by reacting the compound (II) or it3 reactive derivative at the amino group or a salt thereof with the compou~d (III) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivative at the amino group of ~he compound (II) may include Schiff's base type imino or i~s tautomeric enamine type isomer formed by the reaction of the compound ~II) with a carbonyl compol~d; a silyl derivative formed by the reaction of the compound ~II) with z silyl compound such as bis~trimethylsilyl)acetamide or the like; a derivative fo~med by reac~ion of the compound (II) wi~h phosphorus trichloride or phosgene, and the like.
Sui~able salt of the compound (II) may include an acid addition salt such as an organic acid salt (e.g., acetate~
malea~el tartra~e, benzenesul~onate; ~oluenesulfonate, etc.) or an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate7 etc.); a metal salt (e.g., sodium salt;
potassium salt, calcium salt~ magnesium salt, etc.); ammonium salt; an organic amine sal~ (e.g.~ triethylamine sal~, dicyclo-hexylamine salt, etc.), and the like.
; Suitable ~eactive de~ivative at the carboxy group of the compound (III~ may in~lude an acid halide,an acid anhydride, an actlvated amide, an activated ester, and the like. The suitable example may be an acid chloride; an acid azide; a mixed acid anhydride wi~h an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid~ diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid~ etc.), dialkylphosphorous acid, sulfurous acid, thîosulfuric aoid, sulfuric acid, alkylc~rbonic acid, aliphatic carboxylic acid ~e. g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl-butyric acid or trichloroacetic acid, etc.) or aromatio carboxylic acid (e.g , benzoic acid, etc.); a symmetrical acid anhydride;
an ac~ivated amide with imidazole, 4-substi~uted imidazole 7 dimethylpyrazole, triazole or tetrazole; or an activated este (e.g.~ cyanomethyl ester, methoxymethyl ester, dimethylimino-methyl ~CH3)2N = CH-) ester,vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazo-phenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,~pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or an ester with N,N-dimethylhydroxylamine, l-hydroxy-2-(1~)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or l-hydroxy-6-chloro-lH-benzo~riazole, and ~he like. These reactive derivatives can be optionally selected from them according to ihe kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solven~ such as water, acetone~ dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethyl~formamide, pyridine or any other organic solvent which does not adversely influence to the reaction.
Among these solvents, hydrophilic solvents may be used in a mixture with water.
When the compound (III~ is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-oyclohexyl-N'-morpholinoethyl-carbodiimide, N-cyclohexyl-Nl~4-diethylaminocyclohexyl)carbodi-imide, N,N-diethylcarbodiimide, N,N-diisopropylcarbodiimide, N ethyl-N'-~3-dimethylaminopropyl)carbodiimide, N,N-carbonylbis-(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, l-alkoxy-l-chloroe~hylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride) phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)-. ~ 13 -
5~7 isoxazolium hydroxide intramolecular salt, (chloromethylene)-dimethylammonium chloride, l-(P-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, or the like.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lowe-r)alkyl-morphorine, N,N-di(lower)alkylbenzylamine, or the like.
~he reaction temperature is not critical, and the reaction is usually carried out under cooling or at room temperature.
The present invention includes, within its scope, the case ~hat the free hydroxy group is transformed into the formyloxy group during the reaction.
Process 2 The object compound (Ia) or a salt thereof can be prepared by reacting the compound (IY) or a salt thereof with the compound (V) or its reactive derivative ~t the mereaI;to group.
The starting compound (IV) to be used in the present process can be prepared by reacting the compound ~IX) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group. Thc reaction condi~ions for preparing the star~ing compound ~IV~ are substantially same as those for preparing the compound (I) as stated in the explana~ion of Process 1, and therefore the details of the reaction condition is to be referred to the explanation of Process 1 by reading "the compound (II~ "
as "the compound (IX~" for the convenient sake. That is, suitable reactive derivative at the amino group of the compound ~IX) is the same as that of the compound (II), suitable salt of the compound (IX) is the same as that of the compound (II) ~Z~:I9S~7 And the reaction conditions, solvents, reaction temperature, etc. also are the same as those used in Process 1.
Suitable reactive derivative at the mercapto group of the compound (V) may include a metal salt such as an alkali me~al fialt (e.g.~ sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. 9 magnesium salf, etcr) or the like.
The reaction of the compound ( I~) or a salt thereo~ with the compouna ( V ) or its reactive derivative at the mercapto group may be preferably carried out in a solvent such as water, acetone, chloroform9 nitrobenz~ne~ dimethylfo~mamide, methanol, ethanol, dime~hyl-sulfoxide, or any o~her organic solvents which do not adversely influence to the reaction, preferably in a rather high polar solvent. Among these solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carri0d out in around neutral medium. ~hen the çompound (IV) or the compound (V) is used in a free from, the reaction is preferably conducted in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, trialkylamine, or the like. The reaction temperature is not critical, and the reaction is usually carried out at room temperature or s lightly elevated ~emperature.
The presen~ invention may include , within-its scope, the cases that the protected amino group and/or the protected hydroxy group and/or the carboxy derivative are *ransformed into the corresponding free amino group and/or hydroxy group and/or carboxy group during the reaction or post-treating in the present reaction.
s~
Process 3 The object compound (Ib) or a ~alt thereof can be prepared by ~ubjeotlng th~ compound ~Ic) o~ a salt ther~of to elimination reactio~ of th~ protective group of the amino~
The present elimina~ion reaction is carried out in accordance with a conventional method such as hydrolysis 9 reduction, or ~he like. The hydrolysis may include a method using an acid or base or hydrazine and the like.
These methods may be selected depending on the kind of the pro~ective groups t~ be eliminated.
Among these methods 3 hydrolysis using an acid is one of the most common ~nd preferable method fur eliminating the protective groups such as alko~ycarbonyl ~e.~.9 tert-pentyloxy-carbonyl9 etc.), substituted alko~ycarbonyl, aral'~oxycarbonyl (e.g., benzyloxycarbonyl, etcO), substituted aralkoxycarbor~yl, tritylz substituted phenylthio, substituted aralkylidene, substi-tu~ed alkylidene, subs~ituted cycloalkylidene or the like.
Sui~able acid may include, for example9 formic acid, trifluoro-acetic acid, benzenesulfonic acid, p-toluenesulfonic aicd and the like9 and the most suitable acid is an acid which can be easily removed from the reaction mixture by a conventional manner such as dis~illa~ion under reduced pressure, for example, formic acid, trifluoroacetic acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Sui~able solvent may include a hydrophilic oTganic solvent, water or a mixed solvent thereof. The hydrolysis using hydrazine is co~monly ap~,lieG
for eliminating the protective group, for example J phthaloyl.
5~?7 The reductive elimination is generally applied for eliminating the protective group, for example, trichloroethoxy-carbonyl~ benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycaTbonyl, etc. Suitable re~uction may nclude, for example, reduction wi~h an alkali metal borohydride ~e.g., sodium borohydride, etc~), reduction with a combination of a metal (e.g., tin, zinc7 iron~ etc.) or the said me,al together wi~h a metallic compound te.g. a chromous chloride, chromous ace~ate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid9 etc.); and ca~alytic reduction. Sui~able catalyst used for catalytic reduction may include, or example,Raney nickel, platinum oxide, palladium carbon and other conventional catalysts.
Among the protective groups,the acyl group can be generally eliminated by hydrolysis as mentioned above or by the other conventional hydrolysis. Especially, trifluoroacetyl group can be easily eliminated by ~reating with water in the presence or absence of the base; and halogen substituted-alkoxycarbonyl and 8-quinolyloxycarbunyl groups are usually eliminated by treating with a heavy metal such as copper, zinc, or ~he like.
The reaction temperature is not critical and may be suitably selected in accordance ~ith the kind of the protective group for the amino group and the elimination method as mentioned above 7 and the present reaction is preferably earried out under a mild condition such as under cooling or slightly elevated temperature.
The present invention includes, within its scope, the cases that the carboxy derivative is transformed into the free carboxy group and/ or the protected hydroxy group is transformed into the free hydroxy group during the reaction or post-treating in the present reaction.
~ Z~3 Process 4 The object compound (Id) or a ~alt the~eof can be pre~ared by ~ubjecting the compound (Ie) or a salt thereo~ to eli~3ination re~ction of the protecti~e group ~f the hydro~y.
The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like. The hydrolysis may include a method using an acid or base and the like. These methods may be selected depending on kind of the protective groups to be eliminated.
The hydrolysis using an acid is one of the most common and preferable methods for eliminating the protective groups such as tetrahydropyranyl, benzyloxycarbonyl, substituted benzyloxy-carbonyl~ alkoxycarbonyl, substituted alkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, ~ubstituted aralkylide~e, substituted alkylidene, substituted cycloalkylidene or the like. Suitable acid may include, for exampleS formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like.
The acid suitable for the reac~ion can be selected according to theprotective group to be eliminated and other factors.
The hydrolysis using an acid may be carried out in ~he presence of a solvent, such as a hydrophilic organic solvent, wa~er or a mixed sol~en'c thereo:E.
The hydrolysis with a base is preferably applied ~or elim;nating acyl g~oup. Suitable base may include, for example3 an inorganic base such as alkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereof or the like, and an organic base such as trialkylamine (e.g., trimethyl-s~
amine, ~riethylamine, etc.), picoline, N-methylpyrrolidïne, N-methyl~morpholine, l,5-diazabicyclo~4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2~oc~ane, 1,8-diazabicyclo~5,490]undecene-7 or the likeO The hydrolysis using a base ~is often carried ou~ in wa~er or a hydrophilic organic solven~ or a mixed solvent thereo .
The reduction is generally applied for eliminatlng, for example, trichloroethoxycarbonyl, benzyloxycarbonyl, sub-stituted benzyloxyca~bonyl3 2-pyridylmethoxycarbonyl, etc.
The reduction applicable for the elimination reaction of ~he p~esent inven~ion may inclu~e, for example 7 reduction using a metal ~e.gO, tin, zinc9 iron~ e~c.~ or a combination of metallic compound ~e.g., chromous chloride, chromous acetate7 etc.) and an organic or ino~ganic acid ~e.gD, acetic acidS
propionic acid, hydrochloric acid, etc.), and reduction in the presence of a metallic catalys~ for catalytic ~eduction.
Suitable metallic catalyst fo~ catalytic reduction may include, fo~ example, Raney-nickel, pla~inum oxide, palladium carbon and ~ther conventional catalysts.
When the protective group is acyl~ the acyl can be generally eliminated by hydrolysis as mentioned above or by other conventional hydrolysis.
Especially, tTifluoroacetyl can be usually eliminated by treating wi~h wa~er in the presence or absence of the base, and halogen substituted-alkoxycarbonyl and 8-quinolyloxycaTbonyl are usually eliminated by treating with a heavy metal such as coppe~, lead, zinc, etc.
The reaction temperature is not c~itical and may be suitably selected in accordance with the kind of the protective group and the elimina~ion me~hod, and the present reac~ion is ~Z~?~5;7~
prefe~ably carried out under a mlld condition such as under cooling or slightly warming~
The present invention includes 9 within its scope, the cases that the carboxy derivati~ç is transfor~med into the free carboxy group and/or the protected amino group is transformed in~o the free amino group during the reaction or post-tTea~ing in ~he present reaction.
Process S
-The object compound ~If~ or ~ salt thereof can be ~re~ared by reduoing the co~pound (Ig) or a ~alt thereof.
The present reduction is conducted by a conventional me~hod such as a method of using an alkali me~al borohydride (e.g., sodium borohydride, potassium borohydride, etc.) or the like.
The present reduction is usually carried out in a solvent which does not adversely influence to the reaction 9 for example, wa~er~ methanol, ethanol, tetrahydrofuran, dioxane and the like. The present reduction can be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal ~e . g.; magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereofJ tri~lower)alkylamine ~e.g., trim~hylamine , triethylamine, etc.), picoline, N-methylpyrrol-idine, N-methylmorpholine, 1,5-diazabicycloL4,3,0~none-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diaæabicyclo[5,4,0]undecene-7, or the like.
The reaction temperature is not critical and the present reaction is p~eferably carried out under a mild condition such as under cooling or slightly warming.
~Z~9~77 Processes for preparing ~he sta~ting compounds (III) are explained in de~ails as follows.
The star~îng compounds (IIIC) can be prepared by reducing the compound (III~) and the starting compound (IIId~
can be prepared by reducing the ~ompound (IIIa~ 9 respec~ively.
The reaction method, i.e. reduction and the reaction conditions, i.e. solvent, ~eaction temperature, etc. are the same as those used in the ~eac~ion o~ Process 5, and therefore th~ details therefor is ~o be ~eferred ~o the explana~ion for the Process 5.
~ he compound ~VII) can be prepared by reacting the compound (VI) or its reactive derivative at the amino group or a salt thereo~ with an amino-protecting agent, and the starting compound (IIIa) can be prepared by reacting the compound tIIIi) or its reacti~e deri~ative at the ~mino group or a salt thereof with an amino-protecting agent, and the starting compound (lIlb) can be prepared by reacting the compound (IIIl) or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, and the starting compound (IIIf) can be prepared by reacting the compound (IIIm) or its reactive derivative at the amino group or a salt thereo~ with an amino-protecting agent, respectively.
Suitable reactive derivative at the amino group of the compounds (VI) 9 (IIIi), (IIIl) and (IIIm) and suitable salt of the compounds (V~), (IIIi), (IIIl) and (IIIm) may include the same ones as illustrated in the explanations of reactive derivative at the amino group of the compound (II) or (IX) and salt of the compound (II) or (IX), respectively.
Suita~le amino-protecting agent may include acylating ~1 -~Z~77 agent which may include an aliphatic, aromatic and heterocyclic isoc~anate, and the corresponding i~othiocyanate, and an aliphatic, aromatic and heterocyclic carboxylic acid, and the corres~onding sulfonic acid, carbonic acid ester and carbamic acid, and the corresponding thic acid, and th~ reactive derivative o~ the above acids.
Suitable reactive derivative o~ the above ~cids m?y include the same ones as illustrated in the explanation of "reactive derivative at the carboxy group of the compound (I~I)".
The example o~ the protective group (e,g. ~cyl group) to ~e introduced into the amino group in the compounds (VI), (III1)9 (IIIl) and (IIIm) by the above amino-~rotecting agent (e.g.
ecylating agent) may be the same protective group (e.g. acyl group~ a~ illustr~ted in the explanation of the protective ~roup in the terms "a protected amino" and "a protected lower ~lkylamino".
The pre~ent reaction (e.g. acylating reaction) is carrjed out in the similar manner as illu~trated in the reaction of the compound (II) or its reactive deri~ative at the amino group or a salt thereof with the compound (III) or its reactive deriv~tive at the carboxy group.
The starting co~pound (IIIa~ can be prepared by oxidizing the compound tVII), and the starting compound ~IIIg) can be p~epared by oxidizin~ the compound ~VIII).
The present oxidation reaction is conducted by a conventional method which is applied or the transformation of so-called activated methylene group into carbonyl group. '~'hat is,the presenk oxidation is conducted by a con~rentional mcthod such as oxidation by using a conventional oxidizing agent such a~ ~elenium dioxide, trivalent manganese compound(e~g~ man~anous ;7~
acetate and potassium permanganate, etc.) or the like~ The present o~idation is usually carried out in a solvent which does not ad~ersely influence to the reaction, for examp~.e7 water, dioxane, tetrahydrofuran, and the like~
The reaction te~pe~ature is no~ criticai and the Teac~ion is preferably ca~ried out under warming to hea~ing.
The star~ing compound (IIIb) can be prepared by subjecting thc compound (IIIa) ~o elimination reac~ion of the pr~tective group of the carboxy, the starting compound (III~) can be prepared ~y subjccting the compound (III~ to elimination reaction of the p~otec~ive group o the carboxy 9 and the startin~
compound tIIIh) can be prcpared by subjecting the compound (IIIg) to elimination reaction of the protective group of the carboxy, and the starting compound (IIIk) can be prepared by subjecting the compound (IIIj) to elimination reaction of the protecti.ve group of the carbo~y, respectively.
-2~-~l2~S~7 In the present elimina~ion reaction, all conventional methods used in the elimination reaction of the protected carboxy, for example, hydrolysis, reduc~ion, etc. can be applicable.
When ~he prot~ctive gTOUp iS an es~er, i~ can be eliminated by hydrolysis. The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base such as an alkali metal ~e.g., sodium, potassium9 ets.), an alkaline earth metal (e.g., magnesium, calcium, e~c.), the hydroxide or carbonate or bicarbonate thereof, trial~ylamine (e.g., trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo~4,3,0Jnone-5-ene, 1,4-diazabicyclo-[2,2~2]octane, l,8-diazabicycloC5,4,0]undecene-77 or the like.
Suitable acid may include an organic acid (e.g., formic acid, acetic acid, propionic acid, etcO) and an inorganic acid (e.g., hydrochloric acid, hydTobromic acid, sulfuric acid, etc.).
The reduc~ion can be applicable for elimination of the protecti~e group such as ~-iodoethyl ester, 2,2,2-trichloroethyl es~er, or the like. The reduction applicable for the elimination ~eaction of ~he p~esent invention may include, for example~
rcduction using a combination o a metal (e,gO, zinc~ æinc amalgam, etc.) or a chrome salt compound (e~g., chromous chlo~ide, chromous acetate , e~c . ) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid, etc.), and reduc~ion in ~he presence of a metallic catalytic reduction.
The me~allic catalysts for ca*alytic reduction include, for example, platinum catalyst ~e.g., platinum wire, spongy pla~inum, platinum black, platinum colloid, etc.), palladium catalyst (e.g., palladium spongy, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel, palladium colloid, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, etc.), and the like.
The reaction temperature is not critical, and it may be suitably selected in accordance with the kind of -the protective group of the carboxy and the elimination method.
The starting compound (IIIe) can be prepared by re-acting the compound (IIId) with a hydroxy-protecting agent.
~s the hydroxy-pxotecting agent, there may be used a con-ventional hydroxy-protecting agent which is capable of intro-ducing a protective group as illustrated hereinabove into hydroxy to give a protected hydroxy. suitable hydroxy-protecting agent may include, for example, an acylating agent including the same as illustra-ted in the explanation of the acylating agent in the amino-protecting agent, an olefinic heterocyclic compound (e.g. 3,4-dihydro-2H-pyrane, etc.), and the like. The example of the acyl group to be introduced into the hydroxy group in the compound (IIId) by the above acylating a~ent may be the same as illustrated in the ex-planation of the acyl moiety in the term "acyloxy".
The present reaction using an olefinic heterocyclic compound is preferably carried out in the presence of an acidic catalyst such as p-toluenesulfonic acid, hydrochloric acid, phosphorus oxychloride, or the like. The present re-action is usually carried out in a solvent which does not ad-versely influence to the reaction, for example, ethyl acetate, tetrahydrofuran, dioxane, and the like under anhydrous con-dition .
't~
The reaction temperature is not critioal, and thepresen~ reaction proceeds sufficiently under cooling or a~
room temperature.
The starting compound (m i) and its salt can be prepared by subjecting the compound (D¢a) to elimination reaction of the pTotective group of the amino.
The present elimination reaction is carried out in the similar manner to that illus~rated in the elimination ~- reac~ion of Process 3.
~, The starting compound (m j) can be prepared by reac~ing the compound ~m a) wi~h a halogenating agent.
Suitable halogena~ing agen~ may include halogen ~e.g., chlorine, bromine, e~c.), ~rihaloisocyanuric acid ~e.g., trichloroisocyanuric acid, etc.), ~-halosuccinimide (e.g., N-chlorosuccinimide, N-bromosuccinimide7 etc.~ and the like.
The present reaction is usually ~arried out in a solvent which does not ad~ersely influence to ~he reaction, ~or example, dimethylformamide, dioxane, acetic acid and the like.
The reaction tempeTature is not critical and the reaction is preferably carried out at ambient temperature or under warming to heating.
The starting compound (m m) can be prepared by reacting the compound (IX) with glyoxylic acid.
The pr~sent reaction is usually carried out in a solvent which does not adversely influence to the Teaction, ~Z~57'7 for example, water~ acetone, dioxane, acetonitrile, methylene chloride, dime*hylformamide and the like.
The present reaction is preferably conducted in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbon~te and the like.
The reaction temperatureis no~ critical and the reaction is preferably carried out under warming to heating.
The starting compound tm Q) can be prepared by oxidizing ~he compound (m m).
, .
The presen~ oxidation reaction is conducted by a con~en~ional method which is applied for the transformation of hydroxymethylene group into carbonyl group. That is, the present oxidation is conducted by a conventional method such as oxidation by using a conventional oxidizing agent such as manganese dioxide o~ the like. The present oxidation is usually carried out in a solvent which does not adversely in1uence to the reaction, for example 9 water, dioxane, tetrahydrou~an and the ].ike.
The reaction tempeTature is not critical and the reaction is preferably car~ied out under warming to heating.
In the aforementioned Teac~ions and/or the post-treating of the reactions of ~he p~esent invention, the afore-mentioned tautomeric isomers may be oc~'asionally transformed into the other tautomeric isomers, and such cases are also included in the scope of the present invention.
In case that the object compound (I) is obtained in a form of ~he free acid at 4 position and/or in case that the object compound (I) has free amino group, it may be transformed into its pharmaceutically acceptable sal~ as aforementioned by ~L2~ S~7 a conventional method.
The object compounds ~I) of the presen~ invention exhibit high antibacterial zctivity and inhibit the growth of a number of mioroorganisms including Gram-positive and Gram-negati~e bacteria. Por therapeutic administration, the cephalosporin compounds according to the present invention are used in *he form of pharmaceutical preparation which contain said compounds in admixture with a pharmaceutically acceptable caTriers such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solidform such as capsules, tablet, dragees) ointments or suppositories, o~ in liquid form such as solutions~ suspens-ions 9 or emulsions. If desired, there may be included in the abo~e p~eparations auxiliary subs~ances, s~abilizing agents 7 wetting OT emulsifying agents, buffers and other commonly used additives.
While the dosage o the compounds will vary from and also depend upon the age and condition of the patient~ an average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. sf the compounds according to the present invention has proved to be ef~ectiYe in treating diseases caused by bacterial infection. In general amounts be~ween 1 mg. and about 1000 mg. or even more may be administered.
Now, in order to show the utility of the object compounds, test data on anti-microbial activity of some repre-sentative compounds of the present invention are shown below.
Tes~ compounds , - 2~ -~L2~5~
(l~ 3~ Methyl-lH-tetTazol-5-yl)thiomethyl-7-[2-(2-amino-1,~ thiazol-4-yl~glyoxylamido]-3-cephem-4-carboxylic acidg which can be represented as 3-(1-methyl-lH-te~ra~ol-5-yl)thiomethyl-7-[2-(2-imino-2J3-dihyd~o-1,3-thiazol-4-yl3glyoxylamido~-3-cephem-4-ca~boxylic acid.
(2) 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-c~rboxylic acid, which can be represented aæ ~ j4-thiadiazol-2-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro~ thia~ol-4-yl)glyoxyla~ido~-3-ce~hem-4-carboxyllo acid.
(33 3-(5-Methyl-1,3~4-thiadiazol-2-yl)thiomethyl-7-[2-~2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4 carboxylic acid, which can be represented ~s 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-~-[2-(2-imino-2,3-dihydro-1"3-thiazol-4-yl)glyoxyl-arllidol-3-cephem-4-carboxylic aci~
(4) 3-~5-Methyl-1,3,4-oxadiazol-2-yl~thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido~-3-cephem~4-carboxylic acid, which can be represented a.s 3-(5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7- [2- (2-imino-2 ~3-dihydro-1, 3-thiazol-4-yl)-glyoxylamido~-3-cephem-4-carboxylic acid.
(5) 3-(4-Methyl-aH-1s2,~-triazol-3-yl)Lniomethyl-7-[2 ;;mino-1,3-thiazol-4-yl)glyoxylamido]-3-c~phem-4-caTbo~ylic ~c~d, which can be represented as 3-(4-methyl-4H-1,2,4-trlazol-;~-yl)thiomethyl-7-l2-(2-imino-2,~-dihydro-1J3-thiazol-4-yl)-g'~voxylamido~-3-cephem-4-carboxylii; acid.
-29~
~IL2~577 Test Method In vitro antibacterial activity was determined ~y the two-fold agar-plate dilution method as described below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (108 viable cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhibitory concentration (MIC) was expressed in terms of ~g/ml. after incubation at 37. C for 2 0 hours ~
f Tes-t results . . _ . _ Test Bacteria MIC~g rl.) Test compounds (1~ (?) (~ (4) ~5) E Coli 324 0.05 O.OS 0.05 0.05 0.05 The following examples are given for the purpose of illustrating the presen~ in~ention:-~' -3~
5~7 Preparation of the starting compounds -(1) Preparation of 2-(2-tert-pentyloxyearbonylamino-1,3-thiazol-4-yl)ylyoxylic acid which can be represented as 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylic acid.
To a solution of ethyl 2-(2-amino-1,3-thiazol-4-yl)-acetate, which can be represented as ethyl 2-(2-amino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (14 g.) in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) was grad-ually added diethyl ether solution of tert-pentyl chloro-formate (70 ml.) containing 0.35 mole of tert-pentyl chloro-formate over 100 minutes at -20C with stirring, and the mix-ture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0C. After -the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2N hydro-chloric aeid, water, 5~ sodium biearbonate aqueous solution and water in turn and then dried over magnesium sulfate. The solvent was distilled off from the organie layer to give dark brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (12 g.).
I.R. Spectrum (liquid) 1667,1660 (CO) cm 1 N.M.~. Spectrum (CDC~3, ~) 3.75 (2H, s)
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lowe-r)alkyl-morphorine, N,N-di(lower)alkylbenzylamine, or the like.
~he reaction temperature is not critical, and the reaction is usually carried out under cooling or at room temperature.
The present invention includes, within its scope, the case ~hat the free hydroxy group is transformed into the formyloxy group during the reaction.
Process 2 The object compound (Ia) or a salt thereof can be prepared by reacting the compound (IY) or a salt thereof with the compound (V) or its reactive derivative ~t the mereaI;to group.
The starting compound (IV) to be used in the present process can be prepared by reacting the compound ~IX) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group. Thc reaction condi~ions for preparing the star~ing compound ~IV~ are substantially same as those for preparing the compound (I) as stated in the explana~ion of Process 1, and therefore the details of the reaction condition is to be referred to the explanation of Process 1 by reading "the compound (II~ "
as "the compound (IX~" for the convenient sake. That is, suitable reactive derivative at the amino group of the compound ~IX) is the same as that of the compound (II), suitable salt of the compound (IX) is the same as that of the compound (II) ~Z~:I9S~7 And the reaction conditions, solvents, reaction temperature, etc. also are the same as those used in Process 1.
Suitable reactive derivative at the mercapto group of the compound (V) may include a metal salt such as an alkali me~al fialt (e.g.~ sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. 9 magnesium salf, etcr) or the like.
The reaction of the compound ( I~) or a salt thereo~ with the compouna ( V ) or its reactive derivative at the mercapto group may be preferably carried out in a solvent such as water, acetone, chloroform9 nitrobenz~ne~ dimethylfo~mamide, methanol, ethanol, dime~hyl-sulfoxide, or any o~her organic solvents which do not adversely influence to the reaction, preferably in a rather high polar solvent. Among these solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carri0d out in around neutral medium. ~hen the çompound (IV) or the compound (V) is used in a free from, the reaction is preferably conducted in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, trialkylamine, or the like. The reaction temperature is not critical, and the reaction is usually carried out at room temperature or s lightly elevated ~emperature.
The presen~ invention may include , within-its scope, the cases that the protected amino group and/or the protected hydroxy group and/or the carboxy derivative are *ransformed into the corresponding free amino group and/or hydroxy group and/or carboxy group during the reaction or post-treating in the present reaction.
s~
Process 3 The object compound (Ib) or a ~alt thereof can be prepared by ~ubjeotlng th~ compound ~Ic) o~ a salt ther~of to elimination reactio~ of th~ protective group of the amino~
The present elimina~ion reaction is carried out in accordance with a conventional method such as hydrolysis 9 reduction, or ~he like. The hydrolysis may include a method using an acid or base or hydrazine and the like.
These methods may be selected depending on the kind of the pro~ective groups t~ be eliminated.
Among these methods 3 hydrolysis using an acid is one of the most common ~nd preferable method fur eliminating the protective groups such as alko~ycarbonyl ~e.~.9 tert-pentyloxy-carbonyl9 etc.), substituted alko~ycarbonyl, aral'~oxycarbonyl (e.g., benzyloxycarbonyl, etcO), substituted aralkoxycarbor~yl, tritylz substituted phenylthio, substituted aralkylidene, substi-tu~ed alkylidene, subs~ituted cycloalkylidene or the like.
Sui~able acid may include, for example9 formic acid, trifluoro-acetic acid, benzenesulfonic acid, p-toluenesulfonic aicd and the like9 and the most suitable acid is an acid which can be easily removed from the reaction mixture by a conventional manner such as dis~illa~ion under reduced pressure, for example, formic acid, trifluoroacetic acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Sui~able solvent may include a hydrophilic oTganic solvent, water or a mixed solvent thereof. The hydrolysis using hydrazine is co~monly ap~,lieG
for eliminating the protective group, for example J phthaloyl.
5~?7 The reductive elimination is generally applied for eliminating the protective group, for example, trichloroethoxy-carbonyl~ benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycaTbonyl, etc. Suitable re~uction may nclude, for example, reduction wi~h an alkali metal borohydride ~e.g., sodium borohydride, etc~), reduction with a combination of a metal (e.g., tin, zinc7 iron~ etc.) or the said me,al together wi~h a metallic compound te.g. a chromous chloride, chromous ace~ate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid9 etc.); and ca~alytic reduction. Sui~able catalyst used for catalytic reduction may include, or example,Raney nickel, platinum oxide, palladium carbon and other conventional catalysts.
Among the protective groups,the acyl group can be generally eliminated by hydrolysis as mentioned above or by the other conventional hydrolysis. Especially, trifluoroacetyl group can be easily eliminated by ~reating with water in the presence or absence of the base; and halogen substituted-alkoxycarbonyl and 8-quinolyloxycarbunyl groups are usually eliminated by treating with a heavy metal such as copper, zinc, or ~he like.
The reaction temperature is not critical and may be suitably selected in accordance ~ith the kind of the protective group for the amino group and the elimination method as mentioned above 7 and the present reaction is preferably earried out under a mild condition such as under cooling or slightly elevated temperature.
The present invention includes, within its scope, the cases that the carboxy derivative is transformed into the free carboxy group and/ or the protected hydroxy group is transformed into the free hydroxy group during the reaction or post-treating in the present reaction.
~ Z~3 Process 4 The object compound (Id) or a ~alt the~eof can be pre~ared by ~ubjecting the compound (Ie) or a salt thereo~ to eli~3ination re~ction of the protecti~e group ~f the hydro~y.
The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like. The hydrolysis may include a method using an acid or base and the like. These methods may be selected depending on kind of the protective groups to be eliminated.
The hydrolysis using an acid is one of the most common and preferable methods for eliminating the protective groups such as tetrahydropyranyl, benzyloxycarbonyl, substituted benzyloxy-carbonyl~ alkoxycarbonyl, substituted alkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, ~ubstituted aralkylide~e, substituted alkylidene, substituted cycloalkylidene or the like. Suitable acid may include, for exampleS formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like.
The acid suitable for the reac~ion can be selected according to theprotective group to be eliminated and other factors.
The hydrolysis using an acid may be carried out in ~he presence of a solvent, such as a hydrophilic organic solvent, wa~er or a mixed sol~en'c thereo:E.
The hydrolysis with a base is preferably applied ~or elim;nating acyl g~oup. Suitable base may include, for example3 an inorganic base such as alkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereof or the like, and an organic base such as trialkylamine (e.g., trimethyl-s~
amine, ~riethylamine, etc.), picoline, N-methylpyrrolidïne, N-methyl~morpholine, l,5-diazabicyclo~4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2~oc~ane, 1,8-diazabicyclo~5,490]undecene-7 or the likeO The hydrolysis using a base ~is often carried ou~ in wa~er or a hydrophilic organic solven~ or a mixed solvent thereo .
The reduction is generally applied for eliminatlng, for example, trichloroethoxycarbonyl, benzyloxycarbonyl, sub-stituted benzyloxyca~bonyl3 2-pyridylmethoxycarbonyl, etc.
The reduction applicable for the elimination reaction of ~he p~esent inven~ion may inclu~e, for example 7 reduction using a metal ~e.gO, tin, zinc9 iron~ e~c.~ or a combination of metallic compound ~e.g., chromous chloride, chromous acetate7 etc.) and an organic or ino~ganic acid ~e.gD, acetic acidS
propionic acid, hydrochloric acid, etc.), and reduction in the presence of a metallic catalys~ for catalytic ~eduction.
Suitable metallic catalyst fo~ catalytic reduction may include, fo~ example, Raney-nickel, pla~inum oxide, palladium carbon and ~ther conventional catalysts.
When the protective group is acyl~ the acyl can be generally eliminated by hydrolysis as mentioned above or by other conventional hydrolysis.
Especially, tTifluoroacetyl can be usually eliminated by treating wi~h wa~er in the presence or absence of the base, and halogen substituted-alkoxycarbonyl and 8-quinolyloxycaTbonyl are usually eliminated by treating with a heavy metal such as coppe~, lead, zinc, etc.
The reaction temperature is not c~itical and may be suitably selected in accordance with the kind of the protective group and the elimina~ion me~hod, and the present reac~ion is ~Z~?~5;7~
prefe~ably carried out under a mlld condition such as under cooling or slightly warming~
The present invention includes 9 within its scope, the cases that the carboxy derivati~ç is transfor~med into the free carboxy group and/or the protected amino group is transformed in~o the free amino group during the reaction or post-tTea~ing in ~he present reaction.
Process S
-The object compound ~If~ or ~ salt thereof can be ~re~ared by reduoing the co~pound (Ig) or a ~alt thereof.
The present reduction is conducted by a conventional me~hod such as a method of using an alkali me~al borohydride (e.g., sodium borohydride, potassium borohydride, etc.) or the like.
The present reduction is usually carried out in a solvent which does not adversely influence to the reaction 9 for example, wa~er~ methanol, ethanol, tetrahydrofuran, dioxane and the like. The present reduction can be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal ~e . g.; magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereofJ tri~lower)alkylamine ~e.g., trim~hylamine , triethylamine, etc.), picoline, N-methylpyrrol-idine, N-methylmorpholine, 1,5-diazabicycloL4,3,0~none-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diaæabicyclo[5,4,0]undecene-7, or the like.
The reaction temperature is not critical and the present reaction is p~eferably carried out under a mild condition such as under cooling or slightly warming.
~Z~9~77 Processes for preparing ~he sta~ting compounds (III) are explained in de~ails as follows.
The star~îng compounds (IIIC) can be prepared by reducing the compound (III~) and the starting compound (IIId~
can be prepared by reducing the ~ompound (IIIa~ 9 respec~ively.
The reaction method, i.e. reduction and the reaction conditions, i.e. solvent, ~eaction temperature, etc. are the same as those used in the ~eac~ion o~ Process 5, and therefore th~ details therefor is ~o be ~eferred ~o the explana~ion for the Process 5.
~ he compound ~VII) can be prepared by reacting the compound (VI) or its reactive derivative at the amino group or a salt thereo~ with an amino-protecting agent, and the starting compound (IIIa) can be prepared by reacting the compound tIIIi) or its reacti~e deri~ative at the ~mino group or a salt thereof with an amino-protecting agent, and the starting compound (lIlb) can be prepared by reacting the compound (IIIl) or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, and the starting compound (IIIf) can be prepared by reacting the compound (IIIm) or its reactive derivative at the amino group or a salt thereo~ with an amino-protecting agent, respectively.
Suitable reactive derivative at the amino group of the compounds (VI) 9 (IIIi), (IIIl) and (IIIm) and suitable salt of the compounds (V~), (IIIi), (IIIl) and (IIIm) may include the same ones as illustrated in the explanations of reactive derivative at the amino group of the compound (II) or (IX) and salt of the compound (II) or (IX), respectively.
Suita~le amino-protecting agent may include acylating ~1 -~Z~77 agent which may include an aliphatic, aromatic and heterocyclic isoc~anate, and the corresponding i~othiocyanate, and an aliphatic, aromatic and heterocyclic carboxylic acid, and the corres~onding sulfonic acid, carbonic acid ester and carbamic acid, and the corresponding thic acid, and th~ reactive derivative o~ the above acids.
Suitable reactive derivative o~ the above ~cids m?y include the same ones as illustrated in the explanation of "reactive derivative at the carboxy group of the compound (I~I)".
The example o~ the protective group (e,g. ~cyl group) to ~e introduced into the amino group in the compounds (VI), (III1)9 (IIIl) and (IIIm) by the above amino-~rotecting agent (e.g.
ecylating agent) may be the same protective group (e.g. acyl group~ a~ illustr~ted in the explanation of the protective ~roup in the terms "a protected amino" and "a protected lower ~lkylamino".
The pre~ent reaction (e.g. acylating reaction) is carrjed out in the similar manner as illu~trated in the reaction of the compound (II) or its reactive deri~ative at the amino group or a salt thereof with the compound (III) or its reactive deriv~tive at the carboxy group.
The starting co~pound (IIIa~ can be prepared by oxidizing the compound tVII), and the starting compound ~IIIg) can be p~epared by oxidizin~ the compound ~VIII).
The present oxidation reaction is conducted by a conventional method which is applied or the transformation of so-called activated methylene group into carbonyl group. '~'hat is,the presenk oxidation is conducted by a con~rentional mcthod such as oxidation by using a conventional oxidizing agent such a~ ~elenium dioxide, trivalent manganese compound(e~g~ man~anous ;7~
acetate and potassium permanganate, etc.) or the like~ The present o~idation is usually carried out in a solvent which does not ad~ersely influence to the reaction, for examp~.e7 water, dioxane, tetrahydrofuran, and the like~
The reaction te~pe~ature is no~ criticai and the Teac~ion is preferably ca~ried out under warming to hea~ing.
The star~ing compound (IIIb) can be prepared by subjecting thc compound (IIIa) ~o elimination reac~ion of the pr~tective group of the carboxy, the starting compound (III~) can be prepared ~y subjccting the compound (III~ to elimination reaction of the p~otec~ive group o the carboxy 9 and the startin~
compound tIIIh) can be prcpared by subjecting the compound (IIIg) to elimination reaction of the protective group of the carboxy, and the starting compound (IIIk) can be prepared by subjecting the compound (IIIj) to elimination reaction of the protecti.ve group of the carbo~y, respectively.
-2~-~l2~S~7 In the present elimina~ion reaction, all conventional methods used in the elimination reaction of the protected carboxy, for example, hydrolysis, reduc~ion, etc. can be applicable.
When ~he prot~ctive gTOUp iS an es~er, i~ can be eliminated by hydrolysis. The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base such as an alkali metal ~e.g., sodium, potassium9 ets.), an alkaline earth metal (e.g., magnesium, calcium, e~c.), the hydroxide or carbonate or bicarbonate thereof, trial~ylamine (e.g., trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo~4,3,0Jnone-5-ene, 1,4-diazabicyclo-[2,2~2]octane, l,8-diazabicycloC5,4,0]undecene-77 or the like.
Suitable acid may include an organic acid (e.g., formic acid, acetic acid, propionic acid, etcO) and an inorganic acid (e.g., hydrochloric acid, hydTobromic acid, sulfuric acid, etc.).
The reduc~ion can be applicable for elimination of the protecti~e group such as ~-iodoethyl ester, 2,2,2-trichloroethyl es~er, or the like. The reduction applicable for the elimination ~eaction of ~he p~esent invention may include, for example~
rcduction using a combination o a metal (e,gO, zinc~ æinc amalgam, etc.) or a chrome salt compound (e~g., chromous chlo~ide, chromous acetate , e~c . ) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid, etc.), and reduc~ion in ~he presence of a metallic catalytic reduction.
The me~allic catalysts for ca*alytic reduction include, for example, platinum catalyst ~e.g., platinum wire, spongy pla~inum, platinum black, platinum colloid, etc.), palladium catalyst (e.g., palladium spongy, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel, palladium colloid, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, etc.), and the like.
The reaction temperature is not critical, and it may be suitably selected in accordance with the kind of -the protective group of the carboxy and the elimination method.
The starting compound (IIIe) can be prepared by re-acting the compound (IIId) with a hydroxy-protecting agent.
~s the hydroxy-pxotecting agent, there may be used a con-ventional hydroxy-protecting agent which is capable of intro-ducing a protective group as illustrated hereinabove into hydroxy to give a protected hydroxy. suitable hydroxy-protecting agent may include, for example, an acylating agent including the same as illustra-ted in the explanation of the acylating agent in the amino-protecting agent, an olefinic heterocyclic compound (e.g. 3,4-dihydro-2H-pyrane, etc.), and the like. The example of the acyl group to be introduced into the hydroxy group in the compound (IIId) by the above acylating a~ent may be the same as illustrated in the ex-planation of the acyl moiety in the term "acyloxy".
The present reaction using an olefinic heterocyclic compound is preferably carried out in the presence of an acidic catalyst such as p-toluenesulfonic acid, hydrochloric acid, phosphorus oxychloride, or the like. The present re-action is usually carried out in a solvent which does not ad-versely influence to the reaction, for example, ethyl acetate, tetrahydrofuran, dioxane, and the like under anhydrous con-dition .
't~
The reaction temperature is not critioal, and thepresen~ reaction proceeds sufficiently under cooling or a~
room temperature.
The starting compound (m i) and its salt can be prepared by subjecting the compound (D¢a) to elimination reaction of the pTotective group of the amino.
The present elimination reaction is carried out in the similar manner to that illus~rated in the elimination ~- reac~ion of Process 3.
~, The starting compound (m j) can be prepared by reac~ing the compound ~m a) wi~h a halogenating agent.
Suitable halogena~ing agen~ may include halogen ~e.g., chlorine, bromine, e~c.), ~rihaloisocyanuric acid ~e.g., trichloroisocyanuric acid, etc.), ~-halosuccinimide (e.g., N-chlorosuccinimide, N-bromosuccinimide7 etc.~ and the like.
The present reaction is usually ~arried out in a solvent which does not ad~ersely influence to ~he reaction, ~or example, dimethylformamide, dioxane, acetic acid and the like.
The reaction tempeTature is not critical and the reaction is preferably carried out at ambient temperature or under warming to heating.
The starting compound (m m) can be prepared by reacting the compound (IX) with glyoxylic acid.
The pr~sent reaction is usually carried out in a solvent which does not adversely influence to the Teaction, ~Z~57'7 for example, water~ acetone, dioxane, acetonitrile, methylene chloride, dime*hylformamide and the like.
The present reaction is preferably conducted in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbon~te and the like.
The reaction temperatureis no~ critical and the reaction is preferably carried out under warming to heating.
The starting compound tm Q) can be prepared by oxidizing ~he compound (m m).
, .
The presen~ oxidation reaction is conducted by a con~en~ional method which is applied for the transformation of hydroxymethylene group into carbonyl group. That is, the present oxidation is conducted by a conventional method such as oxidation by using a conventional oxidizing agent such as manganese dioxide o~ the like. The present oxidation is usually carried out in a solvent which does not adversely in1uence to the reaction, for example 9 water, dioxane, tetrahydrou~an and the ].ike.
The reaction tempeTature is not critical and the reaction is preferably car~ied out under warming to heating.
In the aforementioned Teac~ions and/or the post-treating of the reactions of ~he p~esent invention, the afore-mentioned tautomeric isomers may be oc~'asionally transformed into the other tautomeric isomers, and such cases are also included in the scope of the present invention.
In case that the object compound (I) is obtained in a form of ~he free acid at 4 position and/or in case that the object compound (I) has free amino group, it may be transformed into its pharmaceutically acceptable sal~ as aforementioned by ~L2~ S~7 a conventional method.
The object compounds ~I) of the presen~ invention exhibit high antibacterial zctivity and inhibit the growth of a number of mioroorganisms including Gram-positive and Gram-negati~e bacteria. Por therapeutic administration, the cephalosporin compounds according to the present invention are used in *he form of pharmaceutical preparation which contain said compounds in admixture with a pharmaceutically acceptable caTriers such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solidform such as capsules, tablet, dragees) ointments or suppositories, o~ in liquid form such as solutions~ suspens-ions 9 or emulsions. If desired, there may be included in the abo~e p~eparations auxiliary subs~ances, s~abilizing agents 7 wetting OT emulsifying agents, buffers and other commonly used additives.
While the dosage o the compounds will vary from and also depend upon the age and condition of the patient~ an average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. sf the compounds according to the present invention has proved to be ef~ectiYe in treating diseases caused by bacterial infection. In general amounts be~ween 1 mg. and about 1000 mg. or even more may be administered.
Now, in order to show the utility of the object compounds, test data on anti-microbial activity of some repre-sentative compounds of the present invention are shown below.
Tes~ compounds , - 2~ -~L2~5~
(l~ 3~ Methyl-lH-tetTazol-5-yl)thiomethyl-7-[2-(2-amino-1,~ thiazol-4-yl~glyoxylamido]-3-cephem-4-carboxylic acidg which can be represented as 3-(1-methyl-lH-te~ra~ol-5-yl)thiomethyl-7-[2-(2-imino-2J3-dihyd~o-1,3-thiazol-4-yl3glyoxylamido~-3-cephem-4-ca~boxylic acid.
(2) 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-c~rboxylic acid, which can be represented aæ ~ j4-thiadiazol-2-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro~ thia~ol-4-yl)glyoxyla~ido~-3-ce~hem-4-carboxyllo acid.
(33 3-(5-Methyl-1,3~4-thiadiazol-2-yl)thiomethyl-7-[2-~2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4 carboxylic acid, which can be represented ~s 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-~-[2-(2-imino-2,3-dihydro-1"3-thiazol-4-yl)glyoxyl-arllidol-3-cephem-4-carboxylic aci~
(4) 3-~5-Methyl-1,3,4-oxadiazol-2-yl~thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido~-3-cephem~4-carboxylic acid, which can be represented a.s 3-(5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7- [2- (2-imino-2 ~3-dihydro-1, 3-thiazol-4-yl)-glyoxylamido~-3-cephem-4-carboxylic acid.
(5) 3-(4-Methyl-aH-1s2,~-triazol-3-yl)Lniomethyl-7-[2 ;;mino-1,3-thiazol-4-yl)glyoxylamido]-3-c~phem-4-caTbo~ylic ~c~d, which can be represented as 3-(4-methyl-4H-1,2,4-trlazol-;~-yl)thiomethyl-7-l2-(2-imino-2,~-dihydro-1J3-thiazol-4-yl)-g'~voxylamido~-3-cephem-4-carboxylii; acid.
-29~
~IL2~577 Test Method In vitro antibacterial activity was determined ~y the two-fold agar-plate dilution method as described below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (108 viable cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhibitory concentration (MIC) was expressed in terms of ~g/ml. after incubation at 37. C for 2 0 hours ~
f Tes-t results . . _ . _ Test Bacteria MIC~g rl.) Test compounds (1~ (?) (~ (4) ~5) E Coli 324 0.05 O.OS 0.05 0.05 0.05 The following examples are given for the purpose of illustrating the presen~ in~ention:-~' -3~
5~7 Preparation of the starting compounds -(1) Preparation of 2-(2-tert-pentyloxyearbonylamino-1,3-thiazol-4-yl)ylyoxylic acid which can be represented as 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylic acid.
To a solution of ethyl 2-(2-amino-1,3-thiazol-4-yl)-acetate, which can be represented as ethyl 2-(2-amino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (14 g.) in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) was grad-ually added diethyl ether solution of tert-pentyl chloro-formate (70 ml.) containing 0.35 mole of tert-pentyl chloro-formate over 100 minutes at -20C with stirring, and the mix-ture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0C. After -the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2N hydro-chloric aeid, water, 5~ sodium biearbonate aqueous solution and water in turn and then dried over magnesium sulfate. The solvent was distilled off from the organie layer to give dark brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (12 g.).
I.R. Spectrum (liquid) 1667,1660 (CO) cm 1 N.M.~. Spectrum (CDC~3, ~) 3.75 (2H, s)
6.75 (lH, s) To a solution of selenium dioxide (0.11 g.) in a mixture of dioxane (2.5 ml.) and water (0.1 ml.) was added S~7 ., .
mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4~yl)acetate9 which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, tO.3 ~.) and dioxane (2.5 ml.) at 110C with stirring. The mixture was stirred for 30 minutes a~ the same ~emperature, and selenium dioxide (0.055 g.) was further added there~o and then the mixture was stirred for 1.5 hours at the same temperature.
Ater the reaction, ths reaction liquid i5 separated by decanta~ion, and the residue was washed with a small amount of d~oxane. The ~eaction liquid and washing are combined ~ogether, and then the solvents were distilled off. The residue was dissol~ed in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil o ethyl-2-~2-tert-pentyloxycarbonylamino-lt3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-~tert-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)-glyoxyla~e, (0.22 g.).
I.R. Spectrum ~liquid) l~ 1720~ 1~90 (CO) cm 1 N.M.R. Spec~rum (COCR3,~
8.3 (lH, s) A mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate~ whic~ can be represen~ed as ethyl 2- t2-tert-pentyloxycarbollylimino-2,3-dihydro-1,3-thiazol-4-yl) -glyoxylate, (2.8 g.) and ethanol (lO ml.) was mixed with a solution of sodium hydroxide ~0.54 g.) in water t20 ml.~, and the mixture was stirred for 1 hour at room temperature.
After the reaction, a small amount of ethanol was distilled off.
The remaining reaction mixture was washed with diethyl ether and then the aqueous layer was separated therefrom. To the 95~
aqueous layer was added ethyl aceta~e, and *he mixture was ~djusted to pH 1 to 2 with 10~ hyd~ochloric acid and then the ethyl ~cetate layer was separa~ced therefrom. The ethyl acek~te layer was washed with a saturated aquc~us solut;on of sodium chloride3 dried oYer magnesium suïa~e and then treated with actiYated charcoal. The solvent was distilled off from the ethyl acetate layer ~o g;ve yellow brown powder of 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represen~ed as 2-t2-~ert-pentyloxycarbonyl-imino^2,3-dihydro-1,3-~hiazol-4-yl~glyoxylic acid, (1.75 g.).
I~R. Spectrum (Nujo~
1730, 1680 (CO) cm 1 N,M.R. Spectrum (d6-dime~hylsulfoxide, 8.4 (1~, 5) (2~ Preparation o 2 hydroxy-2-(2-ter~-pentyloxy-carbonYlamino~1,3-thiazol-4-Yl)acetic acid which can be ~epresen~ed as 2~hydroxy-2-(2-ter~-pentylo~ycarbon)rlimino-2,3-_ _ _ _ _ d;hydro-1,3-thiazol-4-yl~ace~cic acid .
To a mixture of 2-(2-ter~-pen~yloxycarbonylamino-1 J 3-thiazol-4-yl)glyoxylic acid9 which can be reprcsented as 2-(2-tert-~entyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic ~cid, (1.7 g.), sodium bicarbonate ~0.5 ~.), ethanol ~10 ml.~
and water (10 ml.) was added sodium borohydride (0.23 g~) under stirring and ice-cooling ~ and ~hen the mixtuTe was s~irred for ~ hour at the same ~emper~ure. After the reaction, ~he reaction mixture was concentrated slightly. To the remaining rea~tion mix~ure were added lN sodium hydroxidc aqueous solution (6 ml.) and diethyl ether (20 ml.)~ and then the aqueous layer was separated. To the aqueous layer was added ethyl acetate, ~and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric - trade mark . E - 3 --33~
~2~S~
acid and then the ethyl acetate layer was s~parated therefrom.
~he cthyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The s~olvent was distilled of from the ethyl acetate layer to give brown powder of 2-hydroxy-2-(2-tert-pentyloxycaTbonylamino-1,3-thiazol-4-yl)acetic acid3 which can be represented as 2-hydroxy-2-(2-tert pentyloxy-carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)ace~ic acid, (1.5 g~).
I,R~ Spectrum (Nujol) 1690-1740 (C0) cm 1 N.M.R. Spectrum ~d6-dimethylsulfoxide, ~) 5.0 (~H, s)
mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4~yl)acetate9 which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, tO.3 ~.) and dioxane (2.5 ml.) at 110C with stirring. The mixture was stirred for 30 minutes a~ the same ~emperature, and selenium dioxide (0.055 g.) was further added there~o and then the mixture was stirred for 1.5 hours at the same temperature.
Ater the reaction, ths reaction liquid i5 separated by decanta~ion, and the residue was washed with a small amount of d~oxane. The ~eaction liquid and washing are combined ~ogether, and then the solvents were distilled off. The residue was dissol~ed in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil o ethyl-2-~2-tert-pentyloxycarbonylamino-lt3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-~tert-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)-glyoxyla~e, (0.22 g.).
I.R. Spectrum ~liquid) l~ 1720~ 1~90 (CO) cm 1 N.M.R. Spec~rum (COCR3,~
8.3 (lH, s) A mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate~ whic~ can be represen~ed as ethyl 2- t2-tert-pentyloxycarbollylimino-2,3-dihydro-1,3-thiazol-4-yl) -glyoxylate, (2.8 g.) and ethanol (lO ml.) was mixed with a solution of sodium hydroxide ~0.54 g.) in water t20 ml.~, and the mixture was stirred for 1 hour at room temperature.
After the reaction, a small amount of ethanol was distilled off.
The remaining reaction mixture was washed with diethyl ether and then the aqueous layer was separated therefrom. To the 95~
aqueous layer was added ethyl aceta~e, and *he mixture was ~djusted to pH 1 to 2 with 10~ hyd~ochloric acid and then the ethyl ~cetate layer was separa~ced therefrom. The ethyl acek~te layer was washed with a saturated aquc~us solut;on of sodium chloride3 dried oYer magnesium suïa~e and then treated with actiYated charcoal. The solvent was distilled off from the ethyl acetate layer ~o g;ve yellow brown powder of 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represen~ed as 2-t2-~ert-pentyloxycarbonyl-imino^2,3-dihydro-1,3-~hiazol-4-yl~glyoxylic acid, (1.75 g.).
I~R. Spectrum (Nujo~
1730, 1680 (CO) cm 1 N,M.R. Spectrum (d6-dime~hylsulfoxide, 8.4 (1~, 5) (2~ Preparation o 2 hydroxy-2-(2-ter~-pentyloxy-carbonYlamino~1,3-thiazol-4-Yl)acetic acid which can be ~epresen~ed as 2~hydroxy-2-(2-ter~-pentylo~ycarbon)rlimino-2,3-_ _ _ _ _ d;hydro-1,3-thiazol-4-yl~ace~cic acid .
To a mixture of 2-(2-ter~-pen~yloxycarbonylamino-1 J 3-thiazol-4-yl)glyoxylic acid9 which can be reprcsented as 2-(2-tert-~entyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic ~cid, (1.7 g.), sodium bicarbonate ~0.5 ~.), ethanol ~10 ml.~
and water (10 ml.) was added sodium borohydride (0.23 g~) under stirring and ice-cooling ~ and ~hen the mixtuTe was s~irred for ~ hour at the same ~emper~ure. After the reaction, ~he reaction mixture was concentrated slightly. To the remaining rea~tion mix~ure were added lN sodium hydroxidc aqueous solution (6 ml.) and diethyl ether (20 ml.)~ and then the aqueous layer was separated. To the aqueous layer was added ethyl acetate, ~and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric - trade mark . E - 3 --33~
~2~S~
acid and then the ethyl acetate layer was s~parated therefrom.
~he cthyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The s~olvent was distilled of from the ethyl acetate layer to give brown powder of 2-hydroxy-2-(2-tert-pentyloxycaTbonylamino-1,3-thiazol-4-yl)acetic acid3 which can be represented as 2-hydroxy-2-(2-tert pentyloxy-carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)ace~ic acid, (1.5 g~).
I,R~ Spectrum (Nujol) 1690-1740 (C0) cm 1 N.M.R. Spectrum ~d6-dimethylsulfoxide, ~) 5.0 (~H, s)
7~5 (1ll, s) ~3) Pre aration of 2-(2-oxo-2,3-dih dro-l 3-thiazol-P _ . Y
4-yl)glyoxylie acid which can be represented as 2-(2-hydroxy-1 3-thiazol-4- l)glyoxylic acid J , , __ Y _ __ _ To a solution prepa~ed by hea~ing a mixture of selenium dloxide (0.33 g.), dioxane (15 ml.) and water ~0.3 ml.) at 110C
with sSirring was added ethyl 2-~2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl~acetate, (0.56 g.) without heating, and then the mixture was stirred for 30 minutes a~ 110C. After the ~eaction, ~he reaction liquid was separated and the ~esidue was washed with a small amount of dioxane. The Teac*ion liquid and the washings were combined together, and the sol~ents were distilled off. To-the residue was added cthyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was dis~illed off from the mixture to give a solid of ethyl Z-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, which can be represented as ethyl 2-(Z-hydroxy-1,3-thiazol~4-yl)glyoxy:Late, (0.55 g.) S 7 : I.R. Spec~rum (Nujol) 1720, 163~-1680 (CO) cm~
N.M.R. Spectrum (CDC~3,~) 7.96 (1l~; s~
A mixture of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, ~hich can be represented as ethyl 2-~2-hydroxy- 1, 3 - thiazol - 4 -yl) glyoxylate, (1.45 g.~ and lN sodium hydroxide aqueous solu~ion (21 ml.) was allowed ~o stand for 30 minutes at room ~empera~ure. After the reaction, the ~- reaction mixture was washed with diethyl ether and then adjus~d to pH 1 with 10~ hydrochloric acid. The ~recipitates were collected by filtration, washed with water and die~hyl ether and dried to give powder of 2-(2-oxo-293-dihydro-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (0.30 g ~. On the other hand, the filtra~ion was extracted with ethyl acetate, and the ethyl acetate was distilled off rom the extract to f~ give the same object compound (0.40 g.).
I.R. Spectrum (Nujol) 1740, 1660, 1620 ~CO) cm~l t4) Preparation of 2-(2-propanesulfonylamino-1,3-thiazol-4- 1) ~vox lic acid which can be re resell~ea as 2-(2-. ~ ~ . Y ~, Y _ P_ propanesulfonylimino-2~3-dihydro-l~3-thiazol-4-yl~glyoxylic acid A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate which can be represented as ethyl 2-t2-imino-2,3-dihydro-1,3-thia~ol-4-yl)acetate, (40 g.) and pyridine (200 ~1.) was stirred in a stream of nitrogen gas at 40C, and to the mixture was dropwise added a mixture of propanesulfonyl chloride (61.3 g.) and methylene chloride (100 ml.) over 2 hours~ and then the 7 ~
mixtu~e was stirred ~or 2 hours at the same temperature.
Af~er the reaction, pyridine and methylene chloride were distilled off rom the reac~ion mix~ure. The residue was dissolved in ethyl acetate, and the solution ~as washcd with water; 1/2 N hydrochloric acid and water in turn and then dTied The ethyl acetate was distilled of from the solution, and the residue was washed with a mixture of ethyl acetate and diethyl ether and then d~ied ~o give ethyl 2-(2-propanesulfonylamino-1, 3-thiazol-4-yl)acetate~ which can be represented as ethyl 2-(2-propanesulfonyli~ino-2,3-dihydro-1,3-~hiazol-4-yl)acetate, (16,4 g.), mp 140 to 142~C.
I.R. Spectrum (Nujol~
1740 (C0) cm~l N~M~Ro Spectrum ~d6-dimethylsulfoxide, ~) 3062 (2H, s) .56 (1~, s) To a solution prepared by stirring a mixture of selenium dioxide (6.2 g.), dioxane (3~0 ml.~ and water (6.4 ml.) at S0 to 60C was added ethyl 2-(2-propancsulfonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate~
tl6.3 g.), and the mixture was refluxed for 1 hour. To the mixture was added selenium dioxide (0.6 g.3, and the mixture was further refluxed for 30 minutes and selenium dioxide (0.3 g.) was added thereto, and then the mixture was further refluxed foT 30 minutes. After the reaction, the reaction mixture was filteredl and then dioxane was distilled off. The residue was dissolved in ethyl acetate under heating and then treated with activated cilarcoal. The solvent was distilled off, and the residue was washed with a small amount of ethyl acetate and i7~
diethyl ethe~ in turn and dried to give ethyl 2-(2-propane-sulfonylamino-1,3^thiazol-4-yl)glyoxyla~e, which can be representcd as ethyl 2-(2-propanesul~onylîmino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, (12.5 g.~, mp 132 to 134C.
I.R. Spectrum (Nujol~
1690, 1725 (CO) cm 1 N.M.R. Spectrum (d6-acetone, ~3
4-yl)glyoxylie acid which can be represented as 2-(2-hydroxy-1 3-thiazol-4- l)glyoxylic acid J , , __ Y _ __ _ To a solution prepa~ed by hea~ing a mixture of selenium dloxide (0.33 g.), dioxane (15 ml.) and water ~0.3 ml.) at 110C
with sSirring was added ethyl 2-~2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl~acetate, (0.56 g.) without heating, and then the mixture was stirred for 30 minutes a~ 110C. After the ~eaction, ~he reaction liquid was separated and the ~esidue was washed with a small amount of dioxane. The Teac*ion liquid and the washings were combined together, and the sol~ents were distilled off. To-the residue was added cthyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was dis~illed off from the mixture to give a solid of ethyl Z-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, which can be represented as ethyl 2-(Z-hydroxy-1,3-thiazol~4-yl)glyoxy:Late, (0.55 g.) S 7 : I.R. Spec~rum (Nujol) 1720, 163~-1680 (CO) cm~
N.M.R. Spectrum (CDC~3,~) 7.96 (1l~; s~
A mixture of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, ~hich can be represented as ethyl 2-~2-hydroxy- 1, 3 - thiazol - 4 -yl) glyoxylate, (1.45 g.~ and lN sodium hydroxide aqueous solu~ion (21 ml.) was allowed ~o stand for 30 minutes at room ~empera~ure. After the reaction, the ~- reaction mixture was washed with diethyl ether and then adjus~d to pH 1 with 10~ hydrochloric acid. The ~recipitates were collected by filtration, washed with water and die~hyl ether and dried to give powder of 2-(2-oxo-293-dihydro-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (0.30 g ~. On the other hand, the filtra~ion was extracted with ethyl acetate, and the ethyl acetate was distilled off rom the extract to f~ give the same object compound (0.40 g.).
I.R. Spectrum (Nujol) 1740, 1660, 1620 ~CO) cm~l t4) Preparation of 2-(2-propanesulfonylamino-1,3-thiazol-4- 1) ~vox lic acid which can be re resell~ea as 2-(2-. ~ ~ . Y ~, Y _ P_ propanesulfonylimino-2~3-dihydro-l~3-thiazol-4-yl~glyoxylic acid A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate which can be represented as ethyl 2-t2-imino-2,3-dihydro-1,3-thia~ol-4-yl)acetate, (40 g.) and pyridine (200 ~1.) was stirred in a stream of nitrogen gas at 40C, and to the mixture was dropwise added a mixture of propanesulfonyl chloride (61.3 g.) and methylene chloride (100 ml.) over 2 hours~ and then the 7 ~
mixtu~e was stirred ~or 2 hours at the same temperature.
Af~er the reaction, pyridine and methylene chloride were distilled off rom the reac~ion mix~ure. The residue was dissolved in ethyl acetate, and the solution ~as washcd with water; 1/2 N hydrochloric acid and water in turn and then dTied The ethyl acetate was distilled of from the solution, and the residue was washed with a mixture of ethyl acetate and diethyl ether and then d~ied ~o give ethyl 2-(2-propanesulfonylamino-1, 3-thiazol-4-yl)acetate~ which can be represented as ethyl 2-(2-propanesulfonyli~ino-2,3-dihydro-1,3-~hiazol-4-yl)acetate, (16,4 g.), mp 140 to 142~C.
I.R. Spectrum (Nujol~
1740 (C0) cm~l N~M~Ro Spectrum ~d6-dimethylsulfoxide, ~) 3062 (2H, s) .56 (1~, s) To a solution prepared by stirring a mixture of selenium dioxide (6.2 g.), dioxane (3~0 ml.~ and water (6.4 ml.) at S0 to 60C was added ethyl 2-(2-propancsulfonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate~
tl6.3 g.), and the mixture was refluxed for 1 hour. To the mixture was added selenium dioxide (0.6 g.3, and the mixture was further refluxed for 30 minutes and selenium dioxide (0.3 g.) was added thereto, and then the mixture was further refluxed foT 30 minutes. After the reaction, the reaction mixture was filteredl and then dioxane was distilled off. The residue was dissolved in ethyl acetate under heating and then treated with activated cilarcoal. The solvent was distilled off, and the residue was washed with a small amount of ethyl acetate and i7~
diethyl ethe~ in turn and dried to give ethyl 2-(2-propane-sulfonylamino-1,3^thiazol-4-yl)glyoxyla~e, which can be representcd as ethyl 2-(2-propanesul~onylîmino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, (12.5 g.~, mp 132 to 134C.
I.R. Spectrum (Nujol~
1690, 1725 (CO) cm 1 N.M.R. Spectrum (d6-acetone, ~3
8.3 (lH, s3 A mixture of ethyl 2~(2-propanesulfonylamin~1,3-thiazol-4-yl~glyoxylate, which can be represen~ed as ethyl 2-(2-p~opanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (12.0 g.) and lN sodium hydroxide aqueous solution (93 ml.3 was stirred for 1 hour under ice-cooling. After the reaction, to the reaction mixture was added lN hydrochloric acid ~93 ml.) and ~he ~.ixture was extrac~ed with ethyl ace~ate under satura~ion with sodium chloride. ~he extract was washed with a satu~ated aqueous solution of sodium chloride and dT;ed. The solvent was distilled off from the extract, and the residue was washed in diethyl ether, collec~ed by filt~a~ion and dried to give 2-~2-propanesulfonylamino-1,3-thiazol-4-yl~glyoxylic acid, which can be represented as 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (7.3 g~, mp. 148 to 150~.
. I.R. Spectrum (Nujol) 1685, 1720 (CO) cm 1 N M.R. Spectrum (d6-acetone, 6) .3 tl~, s) ~ 5) Preparation of 2-(2-~etrahydropyranyl?o~y-2-t2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-t2-mesylimino-2~3-dihydro-l~3--h~azQl-4-yl)acetic acid E ~ 7 ~l2~ 5~
A mixture o ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiaz~l-4-yl~acetate, ~5.6 g.) J mesyl chloride (6.g g.), pyridine tlS ml.) and methylene chloride (45 ml ) was ~efluxed for 5 hours.
A~ter the reaction, the reaction mixture was concentrated.
The residue was poured into ice-water (150 ml.) and stirred.
The precipitates were collected by fil~ration, washed with water and diethyl ether and dried to give pale brown powder of ethyl 2-~2-mesylamino-1~3-thiazol-4-yl)a.cetate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thîazol-4-yl)acetate, t6-3, 8~
I.R. Spec~rum (Nujsl) 1730 (CO) cm~l N.M.R. Spectrum (d6-dimethylsulfoxide 9 ~) 2.95 (3H, s) 3,73 (2H, s) 6.7 (lH, s) To a solu*ion prepared by stirring a mixtl2re of selenium dioxide(0.22 g.), dioxane (10 ml.) and water (0.2 ml.) or 10 minutes at 110C was added ethyl 2-(2-mesylamino-la3-thiainl-4-yl)acetate, which can be represented as ethyl 2-(2-mesylimino-2~3-dihydro-1,3-thiazol-4-yl)aceta~e, (0.53 g.~, and the mix~ure w`as refluxed for 1 hour. Afte~ the reaction, the reaction mixture was treated with activated charcoal.
The precipitated crystals in the filtrate were collected by filtra~ion and dried to gi~e white crystals of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (0.22 g.), mp. 222 to 225C. On the other hand, the remaining iltrate was concentrated and the residue was washcd S~7 with water and diethyl ether in turn and then dried to give the same objec~ ~ompound (0.12 g.) I.R. Spectrum (Nujol~
1685, 1720 (C0~ cm~l N.~I.R. Spectrum (d6-dimethylsulfoxide, ~) 3.05 (3H, s~
8.36 ~lH, s~
To a mix~ure of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl~glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate ,(3.60 g.) and ethanol (S0 ml.) was added ssdium borohydride (0.32 g.) under stirring and ice-cooling, and then the mixture was stirred fo~ 40 minutes at room ~emperature. After the reaction, the reaction ~ixture was concenkra~e~. The residue was poured into a mixture of ethyl acetate (100 ml.3 and dilute hydrochloric acid, and the aqueous solution was separated. Thus obtained aqueous solution (pH 1 to 2) was subjected to salting-out and then extracted with ethyl acetate. The extTact ~as washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The extract was ~reated with activated charcoal and then the solvent was distilled off to give a solid o ethyl 2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)aceta~e, which can be represented as ethyl 2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)aceta~e, (2.6 g.
I~R. Spectrum ~liquid) 171~ (Cn~ cm~l N.M.R. Spectrum ~d6-dimethylsul~oxide, ~) 2.9 (3H, s) 5.1 (lH, s) 6.7 tlH, s) ~Z~?~577 To a suspension o~ ethyl 2-hydroxy-2-(2-mesylamino-1~3-thiazol-4-yl)acetate, which can be represented as ethyl 2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (1.0 g.) and 3,4-dihydro-2H-pyran (0.36 g.) in ethyl acetate (S ml.) was added p-toluene sulfonic acid (10 mg.) at room temperature with stirring, and then the suspension was stirred for 8 hours at the same temperature. Af~er the reaction, the reaction mix~ure was poured into 5% sodium bicar~onate aqueous solu~ion (10 ml.~ and then ~he aqueous layer was separated. To the remaining organic layer was added diethyl ethe~ (10 ml ) and then extracted with 5% sodium bicarbonate aqueous solution t~0 ml.). Thus obtained aqueous extract was combined with the separated aqueous laycr and adjusted ts pH 4 with acetic acid and then extracted with ethyl acetate.
The ~xtract was washed with a saturated aqueous solution of sodium chloride, treated with activated charcoal and then dried over magnesium sulfa~eO The solvent was distilled of rom the extract to give dark yellow oil of ethyl 2-(2-tetrahydropyranyl~oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetate, ; which can be represen~ed as ethyl 2-(2-tetrahydropyranyl)oxy-2-t~-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)aceta~e, (1.0 g.).
N.M.R. Spectrum tCDCQ3, ~) .3.03 (3H, s3 5.2 (1/2 H, s) . 5.3 (1/2 H) s) 6.6 (lH, s) ; To e$hyl 2-(2-tetrahydropyranyl)oxy-2-(2^mesylamino-1,3-~hiazol-4-yl)aceta~e, which can be represented as e~hyl 2-(2-tetrahydropyranyl)oxy-2-(2-mesylîmino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.85 g.) was added 1l~ sodium hydroxide . .
~ 2~'~ 5 ~ ~
aqueous solution prepared by sodium hydroxide (0,28 g.) and water (7 ml.~, and then the mixture was stirred for 1 hour a~
room temperature. After the reaction, to the reaction mix~ure was added ethyl acetate. The mix~ure was adjus~ed to pH 1 to 2 with 2N hydrochloric acid, and the aqueous layer was separated. The aqueous layer was subjected to salting-out and then extrac~ed with e~hyl acetate. The extract was washed with a saturated aqueous solution o~ sodium chloride, dried over magnesium sulfate and then the sol~ent was distilled off to give a foamy substance of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl~oxy-2-(2-mesyli~lino-2,3-dihydro-1~3-thiazol-4-yl~acetic acid, (0.52 g.).
I.R. Spectrum (liquid) 1730 ~C0) cm 1 N.M.R. Spectrum (CDC~3, 3.0 (3H, s) 5.30 ~1/2 ~, s) . 5.33 (1/2 H, s) 6.7 ~lH, s) ~2~
(6) Preparation of 2-l2-~N-methyl-~-ter~-pentyloxy-ca~onylamino)-1,3-thiazol-4-yl~glyoxylic acid (a~ To a solution of ethyl 2-(2-methylamino-1,3-thiazol-4-yl)acetate, which can be rep~esented as e~hyl 2-(2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate "(8 g.) in a mixture of py~idine (80 ml.) and methylene chloride (40 ml.) was d~op~lise added ter~-pentyl chlorofoTmate o~e~ 2 hours at -25 to -20C with sSi~ring, and the mixt~e was stir~ed for 30 minutes at ~he same tempe~ature. Afte~ the Teac*ion, the reac~ion mixture was poured into wa~er (200 ml.), the mixture was extrac~ed with ethyl acetate ~300 ml.), and then the organic layer was separated.
The organic layer was washed with 2N hydrochloric acid, watcr, 5% sodium bicarbonate aqueous solution and water in turn. The oTganic layer wa5 dried over magnesium sulfate and then concen~ra~ed to giYe oil of ethyl 2-[2-(N-methyl-N-te~-pentyloxycarbonylamino)-1~3-thiazol-4-yl]acetate ~14.5 g.).
N.M.R. Spect~um (CDCQ3, ~) 0.92 ~3H, *, J=8Hz) 1.25 (3H~ t, J=8Hz) 1.52 (6H, s) l.9 (2H, q~ J~8Hz) 3 55 (3H, s) 3.7 (2H, s) 4.17 (2H, q, J=8Hz) 6.75 (lH, s~
~ b) A mixture of selenium dioxide (0.452 g.), dio~ane (9 ml.) and water (0.36 ml.) was refluxed in bath at 110C, and to the solution was added a solution of ethyl 2 [2-(N-methyl~
N-tert-pentyloxycarbonylamino)-1,3-~hiazol-4-yl]acetate (1~07 g.) _~2_ and dioxane (9 ml.), and the mixture was stirred for 4.5 hours at the same temperature. After the reaction, the reaction mixture was fil~ered, and dioxane was distilled off from the filtrate under ~educed pressure. To ~he residue wer~e added water and ethyl aceta~e with s~irring, and then ethyl acetate layer was separated. The ethyl acetate layer,was dried over magnesium sulfate and then concentrated to give oil of ethyl 2-[2-(N-methyl-N-ter~-pentyloxycarbonylamino)-1,3 thiazol-4-ylJglyoxylate (0.45 g.).
I.R. Spectrum ~Nujol) 1730, 1690 cm~l N.M~R. Spectrum (CDCQ3, ~) 0.95 (3H, t, J=8Hz) 1.4 (3H~ t, J=8Hz) 1.53 (6H~ s~
1.9 ~2H, q, J=8Hz) 3.6 ~3H, s) 4.42 (2H, q, JY8Hz~
8.17 ~lH, s) tc3 To a solution of ethyl 2-~2-(~-metllyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate (3.1 g.) in ethanol (40 ml.~ was added lN sodium hydroxide aqueous solution ~14.2 ml.~ under ice-cooling and stirring, and ~he mixture was ~urther stirred or 30 minutes at the same ~emperature.
After the reaction, e~hanol was distilled off from the reaction mixture below 20C under reduccd pressure. To the residue was added water (50 ml.), and after layering with ethyl acetate, the mixture was adjusted to pH 3 with 2N hydrochloric acid.
The ethyl acetate layer was separated from the mixture, washed with water, dried oveT magnesium su1fate and then treated with an activated charcoal. The solvent is distilled off from thc ~esulting ethyl acetate layer to give solid of 2-~2-(N-methyl-N-~ert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylic acid (2.4 g.).
I.R. Spectrum (Nujol) 1743, 1700, 1650 cm l N.M.R. Spectrum (C~CQ3, ~) 0.92 (3H, t, J=8Hz) 1 54 ~6H, s) 1.84 (2H, q~ J-8Hz) 3.6 (3H, s) 8.54 (lH, s~
(7~ Preparation of 2-(2-formylamino-S-chloro-1,3-thiazol-4-~l)glyoxylic acid which can be represented as 2-(2 formylimino-5-chlor -2,3-dihydro-1,3-thiazol.-4-yl)glyoxylic acid ta) A suspension of ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-~2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (6.9 g ) in dimethyl~ormamide (40 ml.~ was heated at 60~C to produce a solution, and to the solution was dropwise added a solution of trichloroisocyanuric acid (2.8 g.) in dimethylformamide (10 ml.) ove~ 15 minutes at the same temperature with stirTing and then the mixture was further stirred for 1 hours at the same temperature.
Rfter the reaction, the reaction mixture was poured into ice-water ~400 g.). The precipitates were collected by filtration, washed with water and then drie~ to give ethyl 2-(2-~ormylamino-5-chloro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-~2-formylimino-5-chloro-2,3-dihydro-1 9 3-thia201-~-yl)-glyoxylate, (7.1 g.), mp. 151 ~o 153~C. The remaining ~ilt~a~e was extracted with ethyl acetate9 and the extract was -washed with water and then dried over magnesium sulfate. The solvent was dis~illed of from the extract to give further the same object compound (0O75 g.~.
I.R. Spectrum (Nujol) 3150, 1740~ 1675 (broad) cm 1 N.M.R. Spectrum (d6-dime,thylsul~oxide, ~) 1.33 ~3H, t, J=13Hz) 4.40 and 4.57 t2H, ABq, J=13 Hz) 8.67 (lH, s) ~, 12.9 - 13.2 (lH, m) tb) Ethyl 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)-glyoxylate, which can be ~epresented as ethyl 2-(2-formylimino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (1.3 g.) was dissclved in lN potassium hydroxide aqueous solution tlO ml.) at room temperature with stirring and ~che solution was stirred o~ 5 minutes at the same temperature. After the reaction, the ~eaction mixture was cooled with ice and then adjusted to pH l with 10% hydrochloric acid. The precipita~es were collected by filtTation, washed with water and then dried to give 2-(2-fo~mylamino-5-chloro-133-thiazol-4-yl)glyoxylic acid ~0,91 g,), which can be represented as 2-~2-form)~limino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid,mp. 148 to 152~C
~dec,~. The remaining filtrate and washing were combined together and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sul~ate and then the solvent was distilled of to give further the same objec~
compound (0,23 g.).
I,R, Spectrum (Nujol) 3130, 2400-3000, 1735, 1670, 1640 cm 1 ~2~577 (8) Preparation of 2-(2-formylamino-1,3-thia7ol-4-1 oxvlic acid which can be re~resented as 2-(2-formylimino-Y ,.g Y
2,3-dihydro-1l3~thiazol-4-yl)~lyoxylic acid (a) To acetic anhydride (384 ml.) was drop~ise added formic acid (169.2 ml.) over 15 to 20 minutes under cooling below 3SC9 and the mixture was stirre~ for 1 hour at 55 to 60~C.
To ~he mixture was added ethyl 2-(2-amino-1,3-thiazol-4-yl)-a~etate, which can be represented as e*hyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate~ (506 g.) over 15 to 20 minutes under içe-cooling and stirring, and then the mixture l~as stirred for 1 hou~ at room temperature. After the reaction, the solvents were distilled off. To the ~esidue was added diisopropyl ether t2500 ml.), and the mixture was stirred ~or 1 hour at room tempe~ature. The precipitates were collected by filt~ation, washed with diisopropyl ether and then dried to give ethyl 2-(2-formylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (451.6 g.), mp. 125 to 126~C. The remaining ~--filtrate was concentrated, and the residue was washed with diisopropyl ethe~ (500 ml.) and then dried to give furthe~ the same object compound t7B.5 g.3.
loR~ Spectrum (Nujol3 1737, 1700 cm 1 N.M.R. Spectrum (CDCQ3, 1.25 (3H, t, J=8Hz) 3.7 (2H, s) 4.18 (2H, q7 J=8Hz3 6.9 (1~, s) 8.7 (lH, s) ~ b3~ thyl 2-(2-foTmylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2~3-dihydro-1,3-thiazol-4-yl~acetate,.~250 g.3 was treated in a similar mann~r ~o that of *he above preparatisn ~6) (~b) to give ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate~ which can be represented as ethyl 2-(2-formylimino-~2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (140.5 g.).
I.R~ Spectrum (Nujol) 1738, 1653 cm 1 .. N.M.R. Spectrum (d~-dimethylsulfoxide, ~) 1~34 ~3H, t, J-8Hz) 4.38 (~H, q, J=8Hz) 8.52 (lH, s) 8 57 (lH, s) (b)-tii) A mixture of manganous acetate tetrahydra~e ~120 g.), acetic acid (1000 ml.) and acetic anhydride (100 ml.) was stirred for 20 minutes in an oil bath heated at 130 to 135GC, and to th mixtu~e was added potassium permanganate (20 g.) over 5 m;nutes at 105 to 110C with stirring and thcn the mixture was further stirred for 30 minutes at 130 to 135C.
The mixture was cooled to room temperature~ and to ~he mixture was added ethyl 2-(2-formylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)ace~ate, (53.5 g.)~ and then the mixture was stirred for.l5 hour-s-at 38 to-40C undeT-intToduction of air at the rate o 6000 ml. per minute. Ater the reaction, the precipltates were collected by filtration. The precipitates we~e washed with acetic acid and water in turn and ~hen dried to give ethyl 2-t2-formylamino-1,3-thiazol-4-yl)glyoxylate~
which can be reprcsented as ethyl 2-(2-formylimino-2,3-dihydro-. E - 17 ~2~i7~
1,3-~hiazol-4-yl)glyoxylate, (41.5 g~), mp. 232 to 233C (dec.)~
tc) Ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be repre$ente~ as ethyl 2-(2-ormylimino-2,3-dihydro-1,3-~hiazol-4~yl)glyoxylate, (281 g.~ was treated in a simiiar manner to ~hat of the above preparation (6)(c) to give 2-t2 formylamino-1,3-thiazol-4-yl)glyoxyli~ acid, which can be rep~esented as 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylic acid, (234 g.), mp. 133 ~o 136C (dec.) N oM~ R~ Spectrum (NaDCO3, ~) . . 8.27 (1ll, s) 8.6 (lH 9 5) (9~ Preparation of_2-~2-13-~methyl)thioureido~-1,3-thiazol-4~ xoxylic acid which can be represented as 2-~2-13- (methyl)thioureido]-2,3-dihydro-1,3-thiazol-4-yl] -~lyoxylic acid (a~ To a suspension of ethyl 2- (2-formylamino-1,3-~hiazol-4-yl)glyoxylate, which can be represen~ed as e~hyl 2-t2-formylimino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate, (31.3 .) in ethanol t600 ml.) was dropwise added phosphorus oxychloride (41.9 g.) under ice-cooling and sti~ring, and the mixture was stirred for 30 minutes at 50C. After the ~eac~ion, the solvent was distilled off. The residue was washed with die~hyl ether and then dried to give ethyl 2-~2-amino-1~3-thiazol-4-yl?glyoxylate hydrochlo~ide, which can be represented as ethyl-2^(2-imino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate hydrocllloride, in quantitative ~-ield, mp. 263 to 264C (dec.)O
IlR. Spec~rum (Nujol).
1748, 1697 cm~l (b) A soiution of ethyl 2-(2-amino-1,3-thiazol-4-yl)-glyoxylate hydrochlsride, which can be ~epresented as ethyl ~Z~57'7 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (30 g.) in water (150 ml.3 was treated with an activated charcoal, and the solution was neutralized with sodium biçarbonate (10.7 g.) at room temperature with stirring. The pre~ipitates were collected by filtration, washed with water and then dried to gi~e ethyl 2-(2-amino-1,3-thiazol-4-y~)glyoxylate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1~-thiazol-4-yl~glyoxylate, (21.8 g.~, mp. 186 to 187C ~dec.).
(c) A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)-~lyoxylate, which can be represented as ethyl 2-(2-imi.no-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate, (20 g.) and methyl iso-thiocyanate (73 g.) was stirred for 5 hours a~ 90 ~o 95C.
After the ~eaction, to the reaction mixture was added diethyl e~her. The precipitates were collected by filtration, washed with diethyl ether and then dried to give ethyl 2-[2-[3-(methyl)thioureido]-193-~hiazol-4-yl]glyoxylatel which can be represented as ethyl 2-[2-[3-tmethyl)thioureido~-2p3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21.3 g.); mp. 121 to 123C.
I.R. Spectrum (Nu~ol) 173n, 16~3 cm ~
- N.M.R. Spectrum ~d~-dimethylsulfoxide, ~) 1.38 t3H9 t, J=7Hz~
3.~5 (3~i, s~
4.43 t2H~ q9 J=7Hz) .3X t~, s) ~ d) To a mixture of e~hyl 2-~2-[3-tmethyl)thioureido]-1,3-thiazol-4-yl~glyoxylate, which can be represented as-ethyl 2-[2-[3-(methyl)thioureidoJ-2,3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21 g.), ethanol (ioo ml.) and water (100 ml.) was added lN .
sodium hydroxide a~ueous solution (154 ml.) under ice-cooling ~ - 19 _49-and stirring. The mixture was further stirred for 10 minutes a~d then neutralized with lN hydrochloric acid (154 ml.). The precipi~ates were collected by filtration, ~ashed with water and then dried to give 2-[2-[3-(methyl)thioureido]~-1,3-thiazol-4-yl~-glyoxylic acid, which can be Tepresented as 2-~2- E3- (methyl)-t~ioureido3-2~3-dihydro-l~3-thiazol-4-~yl]glyoxylic acld, (17.8 gO~p mp. > 250C.
N.M.R. Spectrum (d~-dimethylsulfoxide, ~) 3,01 (3H, s) 8.25 ~lH~ s) (lO) Preparation of 2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl~acetic acid which can be_~presented as 2-hydrox~-2-~2-formyli]nino-2,3-dihydTo-1,3-thiazol-4-yl)acetic acid - To a suspension of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formyl-imino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylic acid, (20 g.) in water (400 ml.) was added sodium bicarbonate (8.4 g.~ under ice-cooling and stirring, and the mixture was stirred for 10 minutes ~t the same temperatu~e, and then diethyl ether ~10 ml.) was added theTeto~ To the mixture was added sodium borohydride (1.52 g~) over 10 minutes with stirring at the same temperature, and the miX~UT~ was stirred for 1 hour and 50 minutes at the same temperature. After the reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 4;0 with 10%
hydrochloric acid and then concentrated under reduced pressure till the volume became 100 ml. The concentTated filtrate wax adjusted to pH l with 10~ hydTochloric acid, and crystal-lization was induced by scratching. The concentra~ed ~iltrate was stirred for l hour at room temperature and then ~allowed to stand overnight in a refrigerator. The precipitates ~%~5~7 were collected by filtration, washed with ice-water ~wice and : then dried under sue~ion to give 2-hydroxy-2-~2-formylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiaz~1-4-yl)ace~ic acid, tl4.8 g.)~ mp. 188 to 189~C. (dec.).
I.R. Spectrum (Nujol) 1730, 1635 cm~l N.M.R. Spectrum (~aDCO3, ~) 5.07 (lH, s3 . 7.15 tlH, s) 8.5 ~lH9 s3 (ll~ Pre aration of 2-hvdroxY-2-(2-amino-1,3-thiazol-P ~
5-yl)acetic acid which can be re~resented as 2-hydroxy-2- (2-imino-2 3-dih dro-l 3-thiazol-S- l)acetic acid _ Y . _ Y
A mixture o~.2-amino-1,3-thiazole, which can be ~epresented as 2-imino-2,3-dihydro-1,3-thiazole, (36.3 g.), glyoxylic acid hydrate (50 g.) and lN sodium hydroxide (543 ml.3 was stirred for 1.5 hours at 90 to 93C. A~ter the reaction~
~-che reaction mixture was treated wi~h an activated charcoal and ~hen adjusted to pH 3. The mixture was allowed to stand overnight under ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-hydroxy-2-(2-amino-1,3-~hiazol-S-yl)ace~ic acid hydrate, which c~n be represented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate (48.1 g.), mp. 140 to 200C (dec.).
I.R. Spectrum (Nu~ol) 1622-1642 cm N.M.R. Spec~rum (DCQ, ~) 5.65 ~lH, d, J=1.2 Hz) 7.35 ~lH, s) ~2fL?~S7~7 (l~)Preparation of 2-(2-a~ hiazol-S-yl)-~lyoxylic acid ~hich can be_represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-~-yl)glyoxylic acid A mixture of 2-hydroxy-2-(2-amino-1~3-thiazol-S-yl)acetic acid, which can be represen~ed as 2-hydroxy-2-(2-im;no-2 J 3- dihydro -1, 3-thiazol-5-yl)acetic aGid J (O . 92 g.) and water tlO ml.) was adjusted to pH 7 to 7.5 with a 10% scdium hydroxide aqueous solution, and to ~he mixture was added manganese dioxide (1.74 g.) and then the mixture was stirred or S hours at 50 to 60C. After ~he reaction, manganese dioxide was filtered off and then washed with a small amount of water. The filtrate and washing were com~ined ~ogether, adjusted to pH 1 t~ith concentrated hydrochloric acid and then stirred for 15 minutes ~nder ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-(2-amino-1,3-thiazol-S-yl)glyoxylic acid, which can be represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)glyoxylic acidJ (0.53 g.), mp. 185 to 2S0C tdec.).
I.R. Spectrum (Nujol) 1690, 1650 cm N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 8.25 tl~, s) (l~)PrepaT~tion of 2-(2-formylamino-1,3-thia-ol-S-1 1 ox lic acid ~hich can be re resented as 2-(2-formylimino-Y, ~ g Y . Y
2,3-dihydro-1,3-thiazol-5-yl~lvoxylic acid 2-~2-Amino-1,3-thiazol-5-yl)~lyoxylic acid, which can be represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)-glyoxylic acid, (3 g.) was treated in a similar manner to that of thc above preparation (8)(a) to give 2-(2-formylamino-1,3-~thiazol-5-yl)glyoxylic acid, which can be represented as 2-(2-FA ~ 22 : ~26~57~
formylimino-2,3-dihydro-1,3-thiazol-5-yl?glyoxylic acid, ~3.15 g.~, mp. 180 to 210C.
I.R. Spec~rum tNujol) 171~, 1689, 166~ cm 1 N~M.~. Spectrum (d6-dimethylsulfoxide, ~) 8.22 (lH, s~
8.67 (1~l~ s) (14) Preparation of 2-formyloxy-2 (2-formylamino-1,3-thiazol-5- l)acetic aoid which can be re resented. as 2-fo~myl.ox -. _ _. Y_ P _ Y
2- 2-form limino-2 3-dihydro-1 3-thiazol-5- l)acetic acid ~. ( Y I , _ , _ Y
A mixture of formic acid (10 m mol) and acetic anhydride ~10 m mol~ was s*irred for 2 hours at 50 to 60C and then cooled to -7 to -5C. To the mixture was added 2-hydroxy-2-t2-amino-1,3-thiazol-5-yl)acetic acid hydratc, which can be rep~esented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate, (0.48 g.) at the same tcmperatu~, and the mixture was stirred for 3 hours at ~he same tempera~ure.
To the mixture was further added a mix~ure of ~ormic acid ,5 m mol) and acetic anhydride ~205 m.mol) at the same temper~$ure and ~hen the mixture was further stirred or 1 hour at the same tempe~ature. After the reaction, the solYent was distîlled o~. To the residue we~e added water and m0thyl isobutyl.ke~dhe and then the insoluble ma~erial was filtered sff. The flltrate was tTeated with an activated charcoal, ana the methyl isobutyl ketone layer was separated.- The remaining aqueous layer was uTther extracted with methyl isobutyl ketone~ The me~hyl isobutyl ketone layers were combined together, dried over magnesium sulfate, treated with an activated charcoal, and then the solvent was distilled o~f. The residue was pulverized in diethyl eth~r to give powdcr of 2-formyloxy-2-~2~formylamino-1~3-thiazol-5-yl)acetic acid, which can be represented as 2-foTmyloxy-2-(2-formylimino-2,3-dihydro-1,3-thlazol-5-yl)acetic acid, (0.31 g.).
I~R. Spectrum tNujol~
1723, 1685 cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) `.6.24 (lH, s) 7.54 (1~, s~
8.24 (lH~ s) . 8.45 (lH, s) ~ 15) Preparation of 2-~2-foTmylamino-1,3-thiazol-4-yl)-gl~yoxylic acid which can be re~resen~ed as 2-(2-formylimino-2~3-dihyd~o-1j3-thiazol-4-yl)~lyoxylic acid (a) Methyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be rep~esented as methyl 2-(2-imino-2,3-dihydTo-1,3-thiazol-4-yl)acetate, (100 g.) was treated in a similar manner to that of the abo~e preparation (~)~a) to give methyl 2-~2-formylamino-1,3~thiazol-4-yl)acetate, which can be represented as me~hyl 2-; ~ (2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (109.9 g.), mp. 154 to 155C.
I.R. Spect~um (Nujol) 1733, 1680 cm 1 N;M.R. Spectrum ~d6-dimethylsulfoxide, ~) 3.72 (3H, s) 3.89 (2~, s) 7.01 (lH, s}
8.45 (lH, s) (b~ Methyl 2-(2-formylamino-1,3-thiazol-4-yl)acetate, whish can be represented as methyl 2-(2-formylimino-2,3-dihydro-~1~3^~hiazol-4-yl)acetate, (60 g.~ was treated in a similar ~54-~l2~9~i77 manner to that of the above pre~aration (8)(b)-(ii) to give methyl 2-(2-formylamino-1~3-t}liazol-4-yl)glyoxylate, which can be repr~sen~ed as methyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate, (27~1 g.), mp. 223 to~ 225C ~dec.).
M.M.R. Spectrum ~d~-dimethylsuloxide, 3.95 (3H, s) 8.2 (lH, s) 8.3 tlH, s) (c) Methyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as methyl 2-(2-formylimino-2,3-dihydro-f~ lJ3-thiaæol-4-y;3glyoxylate~ was t~eated in a similar mamler to that o the above preparation (8)(c) to give 2-(2-formylamino-1,3~thiazol^4-yl~glyoxylic acid, which can be represented as 2-t2-ormylimino-2,3-dlhydro-1~3-thiazol-4-yl)glyoxylic acid, mp. 133 to 136C (dec.).
. E - 25 3L2f~b9S77 Example 1 To dimethylformamide (2.25 g.) was dropwise added phosphoTus oxychloride ~2.36 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at~ 40C. To the mixture was added e~hyl acetate (50 ~ , and ~he mixture was cooled to -20C. To the mix~ure was gradually added 2-(2-tert-pentyloxycarbonylamino-1,3-tlliazol-4-yl)glyoxylic acid, which can be represented as 2-(2-ter~-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (4.00 g.) over about 5 minutes at -20 to -10C with stirring, and the mixture was furtller stirred for 40 minutes at the same temperature.
Thus obtained mix~ure was dropwise added to the solution, which was prepared by stirring the mixture of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (5.30 g.) and bis(tTimethylsilyl)acetamide (15.4 ml.~ in ethyl acetate (100 ml.) for 30 minutes at room temperature and then by cooling to -40C. Thç ~ixture was stirred fo~ 40 minutes at the same temperature and further stirred ~or,30 minutes at -5 to O~C, ~e reaction mixture was poured into 5~ sodium bicarbonate aqueous solution, and the aqueous layer was separated.
The remaining ethyl aceta~e layer was extracted twice with 5%
sodium bicarbonate aqueous solution (40 ml.). Thus ob~ained aqueous layers were combined toge~her and washed with ethyl acetate ~50 ml.). To the aqueous solution was added ethyl acetate ~100 ml.), and pll va~ue of the aqueous portion of the mix*ure was adjusted to 2 with 10% hydrochloric acid wlder ice-cooling and stirring. Ater ~iltration of the mixture, the ethyl acetate layer was separated. The remaining aqueous layer was extracted twice with ethyl acetate (60 ml.). Thus ~btained ethyl acetate layers were combined together, washed 3~Z~57'7 with a saturated aqueous solution of sodium chloride and ~ater in turn and then dried over magnesium sulfate. Ater distillation of the solvent, the remainin~ Tesidue was pulverized in diethyl ether, collected by filtration, washed with diethyl ether and then dried to give 3-t5-me~hyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylamidoj-3-cephem-4-carboxylic acid, which can be represen~ed as 3-tS-methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihyd~o-1,3-thiazol-4-yl~glyoxylamido]-3-cephem-4-carboxylic acid, C3-79 g-~-. I.R. Spec~rum ~Nujol) 178~ (~-lactam~ cm~l NoM~R~ Spectrum (d6-dimethylsul~oxide, ~) 2~7 (3~1~ s) 3.57-3.85 (2~ broad s~
4~2 and 4.57 (2H, ABq, J=14 Hz) 5.2 (lH, d, J=5 Hz) 5 77 tlH, d, J=5 Hz) 8.4 ~lH 9 S) To dimethylformamide ~2.~4 g.) was dropwise added phosphorus oxychloride (2.36 g.) o~er 10 minutes under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40C. To the mixture was added ethyl acetate (40 ml.), and : the mixture was cooled at -20 to -15C with stirring. To the mixture was added 2-(2-tert-pentyloxycarbonylamino-1,3-thiazo1-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycaTbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-.glyoxylic acid, (4.0 gO) and the mixture was stirred or ~LZ~ 5~
30 minutes at the same temperature. Thus obtained mixture was added to the solution, which was prepared by stirring the mixture of bisttrimethylsilyl)acetamide (15 ml.~ and 3-(1, 3,4-~hiadiazol-2-yl)thiomethyl-7-amino-3-ceph~em-4-carboxylic ~cid (6 . 35 g. ~ in ethyl acetate t50 ml.) at room temperature for 10 minutes, by adding dimethylformamide (6 ml.) thereto and then cooling ~o -40C. The solution was stirred for 30 minutes at -40C and or 30 minutes at -20C; and then the reaction mixture was poured into 5% sodium bicarbonate aqucous solution. The aqueous layer was separated from the mixture 9 washed with ethyl acetate, and the precipitates were filterred.
The preci~itates were washed with a mixture of acetone and water, and the washings wcre extracted with ethyl acetate, and then the extract was washed with sodium chloride aqueous solution and water in turn. On the other hand, to the aqueous filtrate was added ethyl acetate, and the mixturc was adjusted to pH 1 to 2. The ethyl acetate layer was separa~ed from the mixture and combined with the above obtained ethyl acetate extract together~ The combined ethyl acetate layer was washed with water, dried over magnesium sulfate and then t~eated with activated charcoal. After distillation of the solvent from the ethyl acetate layer,the remaining residue was pulverized in diethyl ether, collected by filtration and then dried to give yellowish brown powder of 3-(19~,4-thiadiazol-2-yl)thiomethyl-7-[~-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-caTboxylic acid which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-(2-tert-pen~yloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, (3.2 g.).
~Z~'~5~7 NIM.R. Spectrum (d6-dimethylsulfoxide, ~) 3.57 and 3.87 ~2li, A~ lz) 3.67 and 4.27 t2H, ABq~ J=16 Hz) 5.17 (lH, d, J~5 Hz3 5,77 (lH, d, J=5 Hz) 8.33 (1~, s)
. I.R. Spectrum (Nujol) 1685, 1720 (CO) cm 1 N M.R. Spectrum (d6-acetone, 6) .3 tl~, s) ~ 5) Preparation of 2-(2-~etrahydropyranyl?o~y-2-t2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-t2-mesylimino-2~3-dihydro-l~3--h~azQl-4-yl)acetic acid E ~ 7 ~l2~ 5~
A mixture o ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiaz~l-4-yl~acetate, ~5.6 g.) J mesyl chloride (6.g g.), pyridine tlS ml.) and methylene chloride (45 ml ) was ~efluxed for 5 hours.
A~ter the reaction, the reaction mixture was concentrated.
The residue was poured into ice-water (150 ml.) and stirred.
The precipitates were collected by fil~ration, washed with water and diethyl ether and dried to give pale brown powder of ethyl 2-~2-mesylamino-1~3-thiazol-4-yl)a.cetate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thîazol-4-yl)acetate, t6-3, 8~
I.R. Spec~rum (Nujsl) 1730 (CO) cm~l N.M.R. Spectrum (d6-dimethylsulfoxide 9 ~) 2.95 (3H, s) 3,73 (2H, s) 6.7 (lH, s) To a solu*ion prepared by stirring a mixtl2re of selenium dioxide(0.22 g.), dioxane (10 ml.) and water (0.2 ml.) or 10 minutes at 110C was added ethyl 2-(2-mesylamino-la3-thiainl-4-yl)acetate, which can be represented as ethyl 2-(2-mesylimino-2~3-dihydro-1,3-thiazol-4-yl)aceta~e, (0.53 g.~, and the mix~ure w`as refluxed for 1 hour. Afte~ the reaction, the reaction mixture was treated with activated charcoal.
The precipitated crystals in the filtrate were collected by filtra~ion and dried to gi~e white crystals of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (0.22 g.), mp. 222 to 225C. On the other hand, the remaining iltrate was concentrated and the residue was washcd S~7 with water and diethyl ether in turn and then dried to give the same objec~ ~ompound (0.12 g.) I.R. Spectrum (Nujol~
1685, 1720 (C0~ cm~l N.~I.R. Spectrum (d6-dimethylsulfoxide, ~) 3.05 (3H, s~
8.36 ~lH, s~
To a mix~ure of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl~glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate ,(3.60 g.) and ethanol (S0 ml.) was added ssdium borohydride (0.32 g.) under stirring and ice-cooling, and then the mixture was stirred fo~ 40 minutes at room ~emperature. After the reaction, the reaction ~ixture was concenkra~e~. The residue was poured into a mixture of ethyl acetate (100 ml.3 and dilute hydrochloric acid, and the aqueous solution was separated. Thus obtained aqueous solution (pH 1 to 2) was subjected to salting-out and then extracted with ethyl acetate. The extTact ~as washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The extract was ~reated with activated charcoal and then the solvent was distilled off to give a solid o ethyl 2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)aceta~e, which can be represented as ethyl 2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)aceta~e, (2.6 g.
I~R. Spectrum ~liquid) 171~ (Cn~ cm~l N.M.R. Spectrum ~d6-dimethylsul~oxide, ~) 2.9 (3H, s) 5.1 (lH, s) 6.7 tlH, s) ~Z~?~577 To a suspension o~ ethyl 2-hydroxy-2-(2-mesylamino-1~3-thiazol-4-yl)acetate, which can be represented as ethyl 2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (1.0 g.) and 3,4-dihydro-2H-pyran (0.36 g.) in ethyl acetate (S ml.) was added p-toluene sulfonic acid (10 mg.) at room temperature with stirring, and then the suspension was stirred for 8 hours at the same temperature. Af~er the reaction, the reaction mix~ure was poured into 5% sodium bicar~onate aqueous solu~ion (10 ml.~ and then ~he aqueous layer was separated. To the remaining organic layer was added diethyl ethe~ (10 ml ) and then extracted with 5% sodium bicarbonate aqueous solution t~0 ml.). Thus obtained aqueous extract was combined with the separated aqueous laycr and adjusted ts pH 4 with acetic acid and then extracted with ethyl acetate.
The ~xtract was washed with a saturated aqueous solution of sodium chloride, treated with activated charcoal and then dried over magnesium sulfa~eO The solvent was distilled of rom the extract to give dark yellow oil of ethyl 2-(2-tetrahydropyranyl~oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetate, ; which can be represen~ed as ethyl 2-(2-tetrahydropyranyl)oxy-2-t~-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)aceta~e, (1.0 g.).
N.M.R. Spectrum tCDCQ3, ~) .3.03 (3H, s3 5.2 (1/2 H, s) . 5.3 (1/2 H) s) 6.6 (lH, s) ; To e$hyl 2-(2-tetrahydropyranyl)oxy-2-(2^mesylamino-1,3-~hiazol-4-yl)aceta~e, which can be represented as e~hyl 2-(2-tetrahydropyranyl)oxy-2-(2-mesylîmino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.85 g.) was added 1l~ sodium hydroxide . .
~ 2~'~ 5 ~ ~
aqueous solution prepared by sodium hydroxide (0,28 g.) and water (7 ml.~, and then the mixture was stirred for 1 hour a~
room temperature. After the reaction, to the reaction mix~ure was added ethyl acetate. The mix~ure was adjus~ed to pH 1 to 2 with 2N hydrochloric acid, and the aqueous layer was separated. The aqueous layer was subjected to salting-out and then extrac~ed with e~hyl acetate. The extract was washed with a saturated aqueous solution o~ sodium chloride, dried over magnesium sulfate and then the sol~ent was distilled off to give a foamy substance of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl~oxy-2-(2-mesyli~lino-2,3-dihydro-1~3-thiazol-4-yl~acetic acid, (0.52 g.).
I.R. Spectrum (liquid) 1730 ~C0) cm 1 N.M.R. Spectrum (CDC~3, 3.0 (3H, s) 5.30 ~1/2 ~, s) . 5.33 (1/2 H, s) 6.7 ~lH, s) ~2~
(6) Preparation of 2-l2-~N-methyl-~-ter~-pentyloxy-ca~onylamino)-1,3-thiazol-4-yl~glyoxylic acid (a~ To a solution of ethyl 2-(2-methylamino-1,3-thiazol-4-yl)acetate, which can be rep~esented as e~hyl 2-(2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate "(8 g.) in a mixture of py~idine (80 ml.) and methylene chloride (40 ml.) was d~op~lise added ter~-pentyl chlorofoTmate o~e~ 2 hours at -25 to -20C with sSi~ring, and the mixt~e was stir~ed for 30 minutes at ~he same tempe~ature. Afte~ the Teac*ion, the reac~ion mixture was poured into wa~er (200 ml.), the mixture was extrac~ed with ethyl acetate ~300 ml.), and then the organic layer was separated.
The organic layer was washed with 2N hydrochloric acid, watcr, 5% sodium bicarbonate aqueous solution and water in turn. The oTganic layer wa5 dried over magnesium sulfate and then concen~ra~ed to giYe oil of ethyl 2-[2-(N-methyl-N-te~-pentyloxycarbonylamino)-1~3-thiazol-4-yl]acetate ~14.5 g.).
N.M.R. Spect~um (CDCQ3, ~) 0.92 ~3H, *, J=8Hz) 1.25 (3H~ t, J=8Hz) 1.52 (6H, s) l.9 (2H, q~ J~8Hz) 3 55 (3H, s) 3.7 (2H, s) 4.17 (2H, q, J=8Hz) 6.75 (lH, s~
~ b) A mixture of selenium dioxide (0.452 g.), dio~ane (9 ml.) and water (0.36 ml.) was refluxed in bath at 110C, and to the solution was added a solution of ethyl 2 [2-(N-methyl~
N-tert-pentyloxycarbonylamino)-1,3-~hiazol-4-yl]acetate (1~07 g.) _~2_ and dioxane (9 ml.), and the mixture was stirred for 4.5 hours at the same temperature. After the reaction, the reaction mixture was fil~ered, and dioxane was distilled off from the filtrate under ~educed pressure. To ~he residue wer~e added water and ethyl aceta~e with s~irring, and then ethyl acetate layer was separated. The ethyl acetate layer,was dried over magnesium sulfate and then concentrated to give oil of ethyl 2-[2-(N-methyl-N-ter~-pentyloxycarbonylamino)-1,3 thiazol-4-ylJglyoxylate (0.45 g.).
I.R. Spectrum ~Nujol) 1730, 1690 cm~l N.M~R. Spectrum (CDCQ3, ~) 0.95 (3H, t, J=8Hz) 1.4 (3H~ t, J=8Hz) 1.53 (6H~ s~
1.9 ~2H, q, J=8Hz) 3.6 ~3H, s) 4.42 (2H, q, JY8Hz~
8.17 ~lH, s) tc3 To a solution of ethyl 2-~2-(~-metllyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate (3.1 g.) in ethanol (40 ml.~ was added lN sodium hydroxide aqueous solution ~14.2 ml.~ under ice-cooling and stirring, and ~he mixture was ~urther stirred or 30 minutes at the same ~emperature.
After the reaction, e~hanol was distilled off from the reaction mixture below 20C under reduccd pressure. To the residue was added water (50 ml.), and after layering with ethyl acetate, the mixture was adjusted to pH 3 with 2N hydrochloric acid.
The ethyl acetate layer was separated from the mixture, washed with water, dried oveT magnesium su1fate and then treated with an activated charcoal. The solvent is distilled off from thc ~esulting ethyl acetate layer to give solid of 2-~2-(N-methyl-N-~ert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylic acid (2.4 g.).
I.R. Spectrum (Nujol) 1743, 1700, 1650 cm l N.M.R. Spectrum (C~CQ3, ~) 0.92 (3H, t, J=8Hz) 1 54 ~6H, s) 1.84 (2H, q~ J-8Hz) 3.6 (3H, s) 8.54 (lH, s~
(7~ Preparation of 2-(2-formylamino-S-chloro-1,3-thiazol-4-~l)glyoxylic acid which can be represented as 2-(2 formylimino-5-chlor -2,3-dihydro-1,3-thiazol.-4-yl)glyoxylic acid ta) A suspension of ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-~2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (6.9 g ) in dimethyl~ormamide (40 ml.~ was heated at 60~C to produce a solution, and to the solution was dropwise added a solution of trichloroisocyanuric acid (2.8 g.) in dimethylformamide (10 ml.) ove~ 15 minutes at the same temperature with stirTing and then the mixture was further stirred for 1 hours at the same temperature.
Rfter the reaction, the reaction mixture was poured into ice-water ~400 g.). The precipitates were collected by filtration, washed with water and then drie~ to give ethyl 2-(2-~ormylamino-5-chloro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-~2-formylimino-5-chloro-2,3-dihydro-1 9 3-thia201-~-yl)-glyoxylate, (7.1 g.), mp. 151 ~o 153~C. The remaining ~ilt~a~e was extracted with ethyl acetate9 and the extract was -washed with water and then dried over magnesium sulfate. The solvent was dis~illed of from the extract to give further the same object compound (0O75 g.~.
I.R. Spectrum (Nujol) 3150, 1740~ 1675 (broad) cm 1 N.M.R. Spectrum (d6-dime,thylsul~oxide, ~) 1.33 ~3H, t, J=13Hz) 4.40 and 4.57 t2H, ABq, J=13 Hz) 8.67 (lH, s) ~, 12.9 - 13.2 (lH, m) tb) Ethyl 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)-glyoxylate, which can be ~epresented as ethyl 2-(2-formylimino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (1.3 g.) was dissclved in lN potassium hydroxide aqueous solution tlO ml.) at room temperature with stirring and ~che solution was stirred o~ 5 minutes at the same temperature. After the reaction, the ~eaction mixture was cooled with ice and then adjusted to pH l with 10% hydrochloric acid. The precipita~es were collected by filtTation, washed with water and then dried to give 2-(2-fo~mylamino-5-chloro-133-thiazol-4-yl)glyoxylic acid ~0,91 g,), which can be represented as 2-~2-form)~limino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid,mp. 148 to 152~C
~dec,~. The remaining filtrate and washing were combined together and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sul~ate and then the solvent was distilled of to give further the same objec~
compound (0,23 g.).
I,R, Spectrum (Nujol) 3130, 2400-3000, 1735, 1670, 1640 cm 1 ~2~577 (8) Preparation of 2-(2-formylamino-1,3-thia7ol-4-1 oxvlic acid which can be re~resented as 2-(2-formylimino-Y ,.g Y
2,3-dihydro-1l3~thiazol-4-yl)~lyoxylic acid (a) To acetic anhydride (384 ml.) was drop~ise added formic acid (169.2 ml.) over 15 to 20 minutes under cooling below 3SC9 and the mixture was stirre~ for 1 hour at 55 to 60~C.
To ~he mixture was added ethyl 2-(2-amino-1,3-thiazol-4-yl)-a~etate, which can be represented as e*hyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate~ (506 g.) over 15 to 20 minutes under içe-cooling and stirring, and then the mixture l~as stirred for 1 hou~ at room temperature. After the reaction, the solvents were distilled off. To the ~esidue was added diisopropyl ether t2500 ml.), and the mixture was stirred ~or 1 hour at room tempe~ature. The precipitates were collected by filt~ation, washed with diisopropyl ether and then dried to give ethyl 2-(2-formylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (451.6 g.), mp. 125 to 126~C. The remaining ~--filtrate was concentrated, and the residue was washed with diisopropyl ethe~ (500 ml.) and then dried to give furthe~ the same object compound t7B.5 g.3.
loR~ Spectrum (Nujol3 1737, 1700 cm 1 N.M.R. Spectrum (CDCQ3, 1.25 (3H, t, J=8Hz) 3.7 (2H, s) 4.18 (2H, q7 J=8Hz3 6.9 (1~, s) 8.7 (lH, s) ~ b3~ thyl 2-(2-foTmylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2~3-dihydro-1,3-thiazol-4-yl~acetate,.~250 g.3 was treated in a similar mann~r ~o that of *he above preparatisn ~6) (~b) to give ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate~ which can be represented as ethyl 2-(2-formylimino-~2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (140.5 g.).
I.R~ Spectrum (Nujol) 1738, 1653 cm 1 .. N.M.R. Spectrum (d~-dimethylsulfoxide, ~) 1~34 ~3H, t, J-8Hz) 4.38 (~H, q, J=8Hz) 8.52 (lH, s) 8 57 (lH, s) (b)-tii) A mixture of manganous acetate tetrahydra~e ~120 g.), acetic acid (1000 ml.) and acetic anhydride (100 ml.) was stirred for 20 minutes in an oil bath heated at 130 to 135GC, and to th mixtu~e was added potassium permanganate (20 g.) over 5 m;nutes at 105 to 110C with stirring and thcn the mixture was further stirred for 30 minutes at 130 to 135C.
The mixture was cooled to room temperature~ and to ~he mixture was added ethyl 2-(2-formylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)ace~ate, (53.5 g.)~ and then the mixture was stirred for.l5 hour-s-at 38 to-40C undeT-intToduction of air at the rate o 6000 ml. per minute. Ater the reaction, the precipltates were collected by filtration. The precipitates we~e washed with acetic acid and water in turn and ~hen dried to give ethyl 2-t2-formylamino-1,3-thiazol-4-yl)glyoxylate~
which can be reprcsented as ethyl 2-(2-formylimino-2,3-dihydro-. E - 17 ~2~i7~
1,3-~hiazol-4-yl)glyoxylate, (41.5 g~), mp. 232 to 233C (dec.)~
tc) Ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be repre$ente~ as ethyl 2-(2-ormylimino-2,3-dihydro-1,3-~hiazol-4~yl)glyoxylate, (281 g.~ was treated in a simiiar manner to ~hat of the above preparation (6)(c) to give 2-t2 formylamino-1,3-thiazol-4-yl)glyoxyli~ acid, which can be rep~esented as 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylic acid, (234 g.), mp. 133 ~o 136C (dec.) N oM~ R~ Spectrum (NaDCO3, ~) . . 8.27 (1ll, s) 8.6 (lH 9 5) (9~ Preparation of_2-~2-13-~methyl)thioureido~-1,3-thiazol-4~ xoxylic acid which can be represented as 2-~2-13- (methyl)thioureido]-2,3-dihydro-1,3-thiazol-4-yl] -~lyoxylic acid (a~ To a suspension of ethyl 2- (2-formylamino-1,3-~hiazol-4-yl)glyoxylate, which can be represen~ed as e~hyl 2-t2-formylimino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate, (31.3 .) in ethanol t600 ml.) was dropwise added phosphorus oxychloride (41.9 g.) under ice-cooling and sti~ring, and the mixture was stirred for 30 minutes at 50C. After the ~eac~ion, the solvent was distilled off. The residue was washed with die~hyl ether and then dried to give ethyl 2-~2-amino-1~3-thiazol-4-yl?glyoxylate hydrochlo~ide, which can be represented as ethyl-2^(2-imino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate hydrocllloride, in quantitative ~-ield, mp. 263 to 264C (dec.)O
IlR. Spec~rum (Nujol).
1748, 1697 cm~l (b) A soiution of ethyl 2-(2-amino-1,3-thiazol-4-yl)-glyoxylate hydrochlsride, which can be ~epresented as ethyl ~Z~57'7 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (30 g.) in water (150 ml.3 was treated with an activated charcoal, and the solution was neutralized with sodium biçarbonate (10.7 g.) at room temperature with stirring. The pre~ipitates were collected by filtration, washed with water and then dried to gi~e ethyl 2-(2-amino-1,3-thiazol-4-y~)glyoxylate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1~-thiazol-4-yl~glyoxylate, (21.8 g.~, mp. 186 to 187C ~dec.).
(c) A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)-~lyoxylate, which can be represented as ethyl 2-(2-imi.no-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate, (20 g.) and methyl iso-thiocyanate (73 g.) was stirred for 5 hours a~ 90 ~o 95C.
After the ~eaction, to the reaction mixture was added diethyl e~her. The precipitates were collected by filtration, washed with diethyl ether and then dried to give ethyl 2-[2-[3-(methyl)thioureido]-193-~hiazol-4-yl]glyoxylatel which can be represented as ethyl 2-[2-[3-tmethyl)thioureido~-2p3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21.3 g.); mp. 121 to 123C.
I.R. Spectrum (Nu~ol) 173n, 16~3 cm ~
- N.M.R. Spectrum ~d~-dimethylsulfoxide, ~) 1.38 t3H9 t, J=7Hz~
3.~5 (3~i, s~
4.43 t2H~ q9 J=7Hz) .3X t~, s) ~ d) To a mixture of e~hyl 2-~2-[3-tmethyl)thioureido]-1,3-thiazol-4-yl~glyoxylate, which can be represented as-ethyl 2-[2-[3-(methyl)thioureidoJ-2,3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21 g.), ethanol (ioo ml.) and water (100 ml.) was added lN .
sodium hydroxide a~ueous solution (154 ml.) under ice-cooling ~ - 19 _49-and stirring. The mixture was further stirred for 10 minutes a~d then neutralized with lN hydrochloric acid (154 ml.). The precipi~ates were collected by filtration, ~ashed with water and then dried to give 2-[2-[3-(methyl)thioureido]~-1,3-thiazol-4-yl~-glyoxylic acid, which can be Tepresented as 2-~2- E3- (methyl)-t~ioureido3-2~3-dihydro-l~3-thiazol-4-~yl]glyoxylic acld, (17.8 gO~p mp. > 250C.
N.M.R. Spectrum (d~-dimethylsulfoxide, ~) 3,01 (3H, s) 8.25 ~lH~ s) (lO) Preparation of 2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl~acetic acid which can be_~presented as 2-hydrox~-2-~2-formyli]nino-2,3-dihydTo-1,3-thiazol-4-yl)acetic acid - To a suspension of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formyl-imino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylic acid, (20 g.) in water (400 ml.) was added sodium bicarbonate (8.4 g.~ under ice-cooling and stirring, and the mixture was stirred for 10 minutes ~t the same temperatu~e, and then diethyl ether ~10 ml.) was added theTeto~ To the mixture was added sodium borohydride (1.52 g~) over 10 minutes with stirring at the same temperature, and the miX~UT~ was stirred for 1 hour and 50 minutes at the same temperature. After the reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 4;0 with 10%
hydrochloric acid and then concentrated under reduced pressure till the volume became 100 ml. The concentTated filtrate wax adjusted to pH l with 10~ hydTochloric acid, and crystal-lization was induced by scratching. The concentra~ed ~iltrate was stirred for l hour at room temperature and then ~allowed to stand overnight in a refrigerator. The precipitates ~%~5~7 were collected by filtration, washed with ice-water ~wice and : then dried under sue~ion to give 2-hydroxy-2-~2-formylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiaz~1-4-yl)ace~ic acid, tl4.8 g.)~ mp. 188 to 189~C. (dec.).
I.R. Spectrum (Nujol) 1730, 1635 cm~l N.M.R. Spectrum (~aDCO3, ~) 5.07 (lH, s3 . 7.15 tlH, s) 8.5 ~lH9 s3 (ll~ Pre aration of 2-hvdroxY-2-(2-amino-1,3-thiazol-P ~
5-yl)acetic acid which can be re~resented as 2-hydroxy-2- (2-imino-2 3-dih dro-l 3-thiazol-S- l)acetic acid _ Y . _ Y
A mixture o~.2-amino-1,3-thiazole, which can be ~epresented as 2-imino-2,3-dihydro-1,3-thiazole, (36.3 g.), glyoxylic acid hydrate (50 g.) and lN sodium hydroxide (543 ml.3 was stirred for 1.5 hours at 90 to 93C. A~ter the reaction~
~-che reaction mixture was treated wi~h an activated charcoal and ~hen adjusted to pH 3. The mixture was allowed to stand overnight under ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-hydroxy-2-(2-amino-1,3-~hiazol-S-yl)ace~ic acid hydrate, which c~n be represented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate (48.1 g.), mp. 140 to 200C (dec.).
I.R. Spectrum (Nu~ol) 1622-1642 cm N.M.R. Spec~rum (DCQ, ~) 5.65 ~lH, d, J=1.2 Hz) 7.35 ~lH, s) ~2fL?~S7~7 (l~)Preparation of 2-(2-a~ hiazol-S-yl)-~lyoxylic acid ~hich can be_represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-~-yl)glyoxylic acid A mixture of 2-hydroxy-2-(2-amino-1~3-thiazol-S-yl)acetic acid, which can be represen~ed as 2-hydroxy-2-(2-im;no-2 J 3- dihydro -1, 3-thiazol-5-yl)acetic aGid J (O . 92 g.) and water tlO ml.) was adjusted to pH 7 to 7.5 with a 10% scdium hydroxide aqueous solution, and to ~he mixture was added manganese dioxide (1.74 g.) and then the mixture was stirred or S hours at 50 to 60C. After ~he reaction, manganese dioxide was filtered off and then washed with a small amount of water. The filtrate and washing were com~ined ~ogether, adjusted to pH 1 t~ith concentrated hydrochloric acid and then stirred for 15 minutes ~nder ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-(2-amino-1,3-thiazol-S-yl)glyoxylic acid, which can be represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)glyoxylic acidJ (0.53 g.), mp. 185 to 2S0C tdec.).
I.R. Spectrum (Nujol) 1690, 1650 cm N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 8.25 tl~, s) (l~)PrepaT~tion of 2-(2-formylamino-1,3-thia-ol-S-1 1 ox lic acid ~hich can be re resented as 2-(2-formylimino-Y, ~ g Y . Y
2,3-dihydro-1,3-thiazol-5-yl~lvoxylic acid 2-~2-Amino-1,3-thiazol-5-yl)~lyoxylic acid, which can be represented as 2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)-glyoxylic acid, (3 g.) was treated in a similar manner to that of thc above preparation (8)(a) to give 2-(2-formylamino-1,3-~thiazol-5-yl)glyoxylic acid, which can be represented as 2-(2-FA ~ 22 : ~26~57~
formylimino-2,3-dihydro-1,3-thiazol-5-yl?glyoxylic acid, ~3.15 g.~, mp. 180 to 210C.
I.R. Spec~rum tNujol) 171~, 1689, 166~ cm 1 N~M.~. Spectrum (d6-dimethylsulfoxide, ~) 8.22 (lH, s~
8.67 (1~l~ s) (14) Preparation of 2-formyloxy-2 (2-formylamino-1,3-thiazol-5- l)acetic aoid which can be re resented. as 2-fo~myl.ox -. _ _. Y_ P _ Y
2- 2-form limino-2 3-dihydro-1 3-thiazol-5- l)acetic acid ~. ( Y I , _ , _ Y
A mixture of formic acid (10 m mol) and acetic anhydride ~10 m mol~ was s*irred for 2 hours at 50 to 60C and then cooled to -7 to -5C. To the mixture was added 2-hydroxy-2-t2-amino-1,3-thiazol-5-yl)acetic acid hydratc, which can be rep~esented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate, (0.48 g.) at the same tcmperatu~, and the mixture was stirred for 3 hours at ~he same tempera~ure.
To the mixture was further added a mix~ure of ~ormic acid ,5 m mol) and acetic anhydride ~205 m.mol) at the same temper~$ure and ~hen the mixture was further stirred or 1 hour at the same tempe~ature. After the reaction, the solYent was distîlled o~. To the residue we~e added water and m0thyl isobutyl.ke~dhe and then the insoluble ma~erial was filtered sff. The flltrate was tTeated with an activated charcoal, ana the methyl isobutyl ketone layer was separated.- The remaining aqueous layer was uTther extracted with methyl isobutyl ketone~ The me~hyl isobutyl ketone layers were combined together, dried over magnesium sulfate, treated with an activated charcoal, and then the solvent was distilled o~f. The residue was pulverized in diethyl eth~r to give powdcr of 2-formyloxy-2-~2~formylamino-1~3-thiazol-5-yl)acetic acid, which can be represented as 2-foTmyloxy-2-(2-formylimino-2,3-dihydro-1,3-thlazol-5-yl)acetic acid, (0.31 g.).
I~R. Spectrum tNujol~
1723, 1685 cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) `.6.24 (lH, s) 7.54 (1~, s~
8.24 (lH~ s) . 8.45 (lH, s) ~ 15) Preparation of 2-~2-foTmylamino-1,3-thiazol-4-yl)-gl~yoxylic acid which can be re~resen~ed as 2-(2-formylimino-2~3-dihyd~o-1j3-thiazol-4-yl)~lyoxylic acid (a) Methyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be rep~esented as methyl 2-(2-imino-2,3-dihydTo-1,3-thiazol-4-yl)acetate, (100 g.) was treated in a similar manner to that of the abo~e preparation (~)~a) to give methyl 2-~2-formylamino-1,3~thiazol-4-yl)acetate, which can be represented as me~hyl 2-; ~ (2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (109.9 g.), mp. 154 to 155C.
I.R. Spect~um (Nujol) 1733, 1680 cm 1 N;M.R. Spectrum ~d6-dimethylsulfoxide, ~) 3.72 (3H, s) 3.89 (2~, s) 7.01 (lH, s}
8.45 (lH, s) (b~ Methyl 2-(2-formylamino-1,3-thiazol-4-yl)acetate, whish can be represented as methyl 2-(2-formylimino-2,3-dihydro-~1~3^~hiazol-4-yl)acetate, (60 g.~ was treated in a similar ~54-~l2~9~i77 manner to that of the above pre~aration (8)(b)-(ii) to give methyl 2-(2-formylamino-1~3-t}liazol-4-yl)glyoxylate, which can be repr~sen~ed as methyl 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl~glyoxylate, (27~1 g.), mp. 223 to~ 225C ~dec.).
M.M.R. Spectrum ~d~-dimethylsuloxide, 3.95 (3H, s) 8.2 (lH, s) 8.3 tlH, s) (c) Methyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as methyl 2-(2-formylimino-2,3-dihydro-f~ lJ3-thiaæol-4-y;3glyoxylate~ was t~eated in a similar mamler to that o the above preparation (8)(c) to give 2-(2-formylamino-1,3~thiazol^4-yl~glyoxylic acid, which can be represented as 2-t2-ormylimino-2,3-dlhydro-1~3-thiazol-4-yl)glyoxylic acid, mp. 133 to 136C (dec.).
. E - 25 3L2f~b9S77 Example 1 To dimethylformamide (2.25 g.) was dropwise added phosphoTus oxychloride ~2.36 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at~ 40C. To the mixture was added e~hyl acetate (50 ~ , and ~he mixture was cooled to -20C. To the mix~ure was gradually added 2-(2-tert-pentyloxycarbonylamino-1,3-tlliazol-4-yl)glyoxylic acid, which can be represented as 2-(2-ter~-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (4.00 g.) over about 5 minutes at -20 to -10C with stirring, and the mixture was furtller stirred for 40 minutes at the same temperature.
Thus obtained mix~ure was dropwise added to the solution, which was prepared by stirring the mixture of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (5.30 g.) and bis(tTimethylsilyl)acetamide (15.4 ml.~ in ethyl acetate (100 ml.) for 30 minutes at room temperature and then by cooling to -40C. Thç ~ixture was stirred fo~ 40 minutes at the same temperature and further stirred ~or,30 minutes at -5 to O~C, ~e reaction mixture was poured into 5~ sodium bicarbonate aqueous solution, and the aqueous layer was separated.
The remaining ethyl aceta~e layer was extracted twice with 5%
sodium bicarbonate aqueous solution (40 ml.). Thus ob~ained aqueous layers were combined toge~her and washed with ethyl acetate ~50 ml.). To the aqueous solution was added ethyl acetate ~100 ml.), and pll va~ue of the aqueous portion of the mix*ure was adjusted to 2 with 10% hydrochloric acid wlder ice-cooling and stirring. Ater ~iltration of the mixture, the ethyl acetate layer was separated. The remaining aqueous layer was extracted twice with ethyl acetate (60 ml.). Thus ~btained ethyl acetate layers were combined together, washed 3~Z~57'7 with a saturated aqueous solution of sodium chloride and ~ater in turn and then dried over magnesium sulfate. Ater distillation of the solvent, the remainin~ Tesidue was pulverized in diethyl ether, collected by filtration, washed with diethyl ether and then dried to give 3-t5-me~hyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylamidoj-3-cephem-4-carboxylic acid, which can be represen~ed as 3-tS-methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihyd~o-1,3-thiazol-4-yl~glyoxylamido]-3-cephem-4-carboxylic acid, C3-79 g-~-. I.R. Spec~rum ~Nujol) 178~ (~-lactam~ cm~l NoM~R~ Spectrum (d6-dimethylsul~oxide, ~) 2~7 (3~1~ s) 3.57-3.85 (2~ broad s~
4~2 and 4.57 (2H, ABq, J=14 Hz) 5.2 (lH, d, J=5 Hz) 5 77 tlH, d, J=5 Hz) 8.4 ~lH 9 S) To dimethylformamide ~2.~4 g.) was dropwise added phosphorus oxychloride (2.36 g.) o~er 10 minutes under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40C. To the mixture was added ethyl acetate (40 ml.), and : the mixture was cooled at -20 to -15C with stirring. To the mixture was added 2-(2-tert-pentyloxycarbonylamino-1,3-thiazo1-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycaTbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-.glyoxylic acid, (4.0 gO) and the mixture was stirred or ~LZ~ 5~
30 minutes at the same temperature. Thus obtained mixture was added to the solution, which was prepared by stirring the mixture of bisttrimethylsilyl)acetamide (15 ml.~ and 3-(1, 3,4-~hiadiazol-2-yl)thiomethyl-7-amino-3-ceph~em-4-carboxylic ~cid (6 . 35 g. ~ in ethyl acetate t50 ml.) at room temperature for 10 minutes, by adding dimethylformamide (6 ml.) thereto and then cooling ~o -40C. The solution was stirred for 30 minutes at -40C and or 30 minutes at -20C; and then the reaction mixture was poured into 5% sodium bicarbonate aqucous solution. The aqueous layer was separated from the mixture 9 washed with ethyl acetate, and the precipitates were filterred.
The preci~itates were washed with a mixture of acetone and water, and the washings wcre extracted with ethyl acetate, and then the extract was washed with sodium chloride aqueous solution and water in turn. On the other hand, to the aqueous filtrate was added ethyl acetate, and the mixturc was adjusted to pH 1 to 2. The ethyl acetate layer was separa~ed from the mixture and combined with the above obtained ethyl acetate extract together~ The combined ethyl acetate layer was washed with water, dried over magnesium sulfate and then t~eated with activated charcoal. After distillation of the solvent from the ethyl acetate layer,the remaining residue was pulverized in diethyl ether, collected by filtration and then dried to give yellowish brown powder of 3-(19~,4-thiadiazol-2-yl)thiomethyl-7-[~-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-caTboxylic acid which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-(2-tert-pen~yloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, (3.2 g.).
~Z~'~5~7 NIM.R. Spectrum (d6-dimethylsulfoxide, ~) 3.57 and 3.87 ~2li, A~ lz) 3.67 and 4.27 t2H, ABq~ J=16 Hz) 5.17 (lH, d, J~5 Hz3 5,77 (lH, d, J=5 Hz) 8.33 (1~, s)
9 53 tlH, s) Example 3 .
To dimethyl~ormamide t9.0 g.~ was dropwise added ,0 . .
phosphorus oxychloride (10.3 g.) o~er 20 minutes under stirTing and ice-cooling, and the mixture was stirred for 30 minutes at 40C~ To the mixture was added ethyl acetate (140 ml.) 7 and the mixture was cooled to -20C with stirring. To the mixture was added 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycarbonyl - imino-2,3-dihydro-1,3-~hiazol-4-yl)glyoxylic ~cid, (16.0 g.), and the mixture was stirred for 30 minutes at -2Q to -15C. Thus obtained mixture was added all at o~ce to a solution, which was prepared by stirring a mixture of 7-aminocephalosporanic acid (18.2 g.) and bis(trir,lethylsilyl)-acetamide ~56 ml.) in ethyl acetate (220 ml.3 for 30 minu~es ~ room ~emperature and then by cooling it at -40C. The mixture was stirred for l hour at -50 to -40C and further for 1 hour at -25 to ~20C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution ~800 ml.). The aqueous layer was separated from the mixture, adjus~ed to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried o~er magnesium sulate and then treatcd w;th an activated ~ S 7 ~
charcoal. Ater distillation o~ e~hyl acetate from the extract, the residue was pulverized in a mixture of diethyl ether (lOO ml.) and diisopropyl ether (200 ml.), collected by filtration and d~ied to give powder of 7-[2-(2-tert-pentyloxy-carbonylamino 1,3-~hiazol-4-yl3glyoxylamido3cephalospGranic ~
acid, which can be represen~ed as 7-~2-(2 tert-pentyloxycarbonyl-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]cepllalosporanic acid, (23.1 g.~
I.R. Spectrum (Nujol3 17B3 (~-lactam) cm~l N~M~RO Spectrum (d6-dimethylsul~oxide, ~) 2~17 (3~1, S?
3.4 - 3 9 (2H, m) 4.B and S.17 (2~, ABq, J=13 Hz~
5.25 ~lH9 d, J-5 Hz) 5.9 (lH~ dJ JG5 Hz) 8.45 (lH~ s) . ~
To dim~thylormamide (1.1 g.) was dropwise added phophorus oxychloride (1.5 g.) under stirring and ice-cooling, and the mix~ure was stirred for 30 minutes at 40C. To the mixture was added ethyl acetate (10 ml.~, and the mixture was cooled to--20 to -10C with stirring. To the mixture was added a solution of 2-hydroxy-2-(2-ter~-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hyd~oxy-2-(2-tert-pentyloxyca~bonylimino-2 ,3-dihydro-193-. thiazol-4-yl)acetic acid, ~1.1 g.) in ethyl. acetate (15 ml.) below -20C under stirring~ and then the mixture was stirred for 30 minutes at thc same temperature. Thus obtained s~
mixture was added all at once to the cooled solution p~epared in the similar manller as in Example 1 from 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid tl~9 gO)~ bisttrimethylsilyl~acetamide (6 ml.~ and ethyl acetate (20 ml.). The mix~ure was stirred for 30 mi.nut~s at -40C
and urther for ln5 hours a* -20 to -10C. After the reaction, thc reaction mixtu~e was poured into 5% sodium bicarbonate aqueous solution, and the aqueous layer was separated. The remaining ethyl acetate layer was further extracted with 5~
sodium bicarbonate aqueous solution. Thus obtained aqueous layer and the solution were combined toge~her and washed wi~h di~thyl ether. To the aqueous layer was added ethyl acc~ate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and ~hen the ethyl acetate laye~ was separated. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and then dried o~er magnesium sulfate.
Ater distillation of the solven~, the residue was pulverized in diethyl ether and then collected by ~iltra~ion ~o give pale brown powder of 3~ methyl-lH-t.etrazol-5-yl)thiomethyl-7-l2-formyloxy-2-t2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3~ methyl-lH-tetrazol-5-yl)~hiomethyl-7-[2-oTmyloxy-~-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-acetamido~-3-cephem--4-carboxylic acid, tO.86 g ).
I.R. Spectrum (Nujol) 1783 (~-lactam), 1680-1740 (CO) cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide; ~) 3.7 (2H, broad s) 3.94 (3H, s3 4.3 (2}1, broad s) ~ - 31 ~2~395~7 S.0-5.15 (lH, m) 5 55-5.8 tll~, m) 6.17 ~lH, s~
7.22 (lH, s~
8.36 (1~l, s) Example 5 _ To dime~hyl~ormamide (3~74 g ~ was dropwise added phos~horus oxychloride (6.46 g.) oYer 5 minutes under stirring and ice-cooling, and the mixture was stirred ~or 30 minutes at 40C. To the mixture was added ethyl acetate tl20 ml.) with stirring, and the mixture was cooled to -20C wi~h stirring.
To ~he mixture was added all at once 2-(2-oxo-2,3-dihydro-1,3-~hiazol-4-yl)glyoxylic acid, which can be represented as 2-~2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (6.05 g.) and to th~ mixture was added dimethylformamide ~55 ml.) over 10 minutes at -20C, and then the mixture was stirred for 40 minutes at the same temperature. Thus obtained mixture was added to the solution prepared in the simiiar manner as in Example 1 from 3-(1-methyl-lH-tetrazol-5-yl)thiomethyl 7-amino-3-cephem-4-carboxylic acid (lO.S0 g.), bis(trimethylsilyl)-acetamide (35 ml.) and ethyl acetate ~150 ml.), at -50 to -40C
with stirring. The mixture was stirred for 30 minutes at -40C and further stirre~d for 30 minutes at -20C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (250 ml.), and the aqueous layer was separated. The aqueous layer was washed with ethyl ace~ate and adjusted to pH 1 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over ma~nesium sulfate and then treated .
~ Z1~577 with activated charcoal. After distillation of ethyl àce~ate from the extract, the residue was pulverized in dicthyl ether, collected by filtration and dried to give pale yellow powder of 3-(1-methyl-lH-tetrazol-5-yl~thiomethyl-7-~2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carooxylic acid,which can be represen~ed as 3-tl-methyl-lH-tetrazol-S-yl)thiomethyl-7-[2-(2-hydroxy~ thiazol-4-yl)~lyo~yl-amido~-3-cephem-4-ca~boxylic acid~ t9-2 g.).
I.R. Spectrum (Nujol~
~- 1762 ~-lactam) cm 1 N.~l.R. Spectrum ~d6-dimethylsulfoxide, ~) 3.74 (2H, broad s) 3.93 t3H, s~
402S and 4.~ ~2H, ABq, J=14 ~z) 5.18 (lH, d, J~5 Hz) 5.73 (lH, dd, J-5 and 6 Hz) 7.97 ~lH, s) i ~ Example 6 ., To dimethyl~ormamide ~1.59 ~ as dropwise added phosphorus oxychloride (4.16 g.) under s~irring and ice-cooling, and the mixture was stirred for 30 minutes at 40C. To the mixture was added ethyl acetate ~20 ml.) with stirring, and the mixture was cooled to -20 to -10C wi~h stirring. To the mixture was dropwise added- a mixture of 2-(2-propanesulfonyl-amino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-propanesul~onylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylic acid, (6.0 g.), ethyl acetate ~60 ml.) and dimethyl-formamide (4 ml.) over 10 minutes at -20 to -10C with stirring, and tllen the mixture was stirred for 40 minutes at the same .
~ - 3 -~ Z~g5~77 temperature Thus obtained mixture was dropwise added to thc solution ~epared in the similar manncr as in Example 1 from 3~ methyl~ tetrazol-5-yl~thiomethyl-7-amino-3-cephem-4-carboxylic acid (7.8 g.)~ bis(trimethylsilyl)acetamide (22.9 ml.3 and ethyl acetate (156 ml~3, at -40C over S minutes with stirring. The mixture ~.~as stirred for 30 minutes at the same temperature and fu~ther s~irred ~or 1 hour at -5 to O~C.
A~ter the reaction, the reaction mix~ure was poured into 5%
sodium bicarbonate aqueous solution (150 ml.), and ~he aqucous layer was separat~d. The remaining ethyl acetate layer was further extracted with 5% sodium bicaTbon~te aqueous solution, and the extract ~as combined with ~he separated aqueous layer.
The aqueous solution ~as washed with e~hyl acetate, and ethyl acetate was added thereto. The mixture was adjusted to pH 2 with 10% hyd~ochloric acid and fi-l~ered, and then ~he ethyl acetate layer was separated f~om the filtrate. The r~maining aqueous layer was further extracted with ethyl acetate, and the extract was combined with the se~arated ethyl acetate layer. The ethyl ~cetate layer was washed wi~h water~ dried and then the solvent was dis~illed off. The Tesidue was pulverizcd in diethyl ether~ collected by fil~ration and dried to give 3-tl-methyl~ tetrazol-5-yl)thiomethyl-7-~2-(2-propane-sulonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-ca~boxylic acid~ which can be represented as 3-tl-methyl-lH-tetrazol-5-yl)-thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid9 (11.0 g.), m.p.
150Ctdec.~.
I.~. Spect~um (Nujol) 17~0 (~-lactam) cm~l _~4-5;77 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.73 (2H J broad s) 3.95 (3~, 5) 4.2 and 4.45 (2H, ABq~ J~13 Hz) 5.15 (lH, d~ J=5 ~z~
5.7 (lH, dd, Ja4 and 5 Hz) ~.25 (1~, s~
~` . , '.
xam~c 7 (i) To dimethylformamide (0.12 g.) was dropwise added phosphorus oxychloride ~0.2g g.~ under stirri.ng and ice-cooling, and the mixture was stirred for 30 minutes at 40C and then cooled to -20C. To the mixture was added all at once a solution of 2-(2-~e~rahydropyranyljoxy-2-~2-mesylamino-~,3-thiazol-4-yl)-acetic acid, which can be represented as 2- (2-tetrahydropy~anyl) -oxy-2-t2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, ~O.S~ g.3 in ethyl acetate (7 ml.) at -20C with stirring, and then the mixture was stirred for 30 minutes at -20 to - 10C.
Thus obtained mixture ~as addcd all at. once to the solution prepared in the similar manneT as in Example 1 from 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl 7-amino-3~cephem-~-carboxylic acid ~0.51 g.), bis(trimethylsilyl)acetamide ~l.S ml.) and ethyl ac~tate tlO ml.), a~ -40C. The mixture was stirred for 30 minutes at the same temperatu~e and further stirred for 1.5 hours at -20 to -10C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (20 mlO). The mixture was washed with ethyl acetatc, and the a~ueDus layer was sepa~ated theTefrom. Thus obtained aqueous .
- ~L2~S7~
layer was post-treated in a similar manner as that of example 5 to give 3~ methyl-1~l-tetrazol-5-yl)thiomethyl-7-L2-(2-te~ra-hydropyranyl ) oxy- 2 - (~ - mesy 1 amino- 1~ 3 - th i azol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be reprcs~ented as 3- (l-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-~2-tetrahydropyranyl)oxy-2-(2-mesylimino~293-dihydro-l93-thiazol-4-yl)acekamido]-3-cephem-4 carboxylic acid, (0.41 g.) (ii) To a mixture of 2-(2-tetrahydropyranyl~oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acidD t350 mg.~, triethylamine (~6 mg.), N~N-dimethylbenzylamine (half drop) and te~rahydrofu~an (7 ml~) was dropwise added a mixture of butyl chloroforma~e tl30 mg.) and tetrahydrofu~an ~1 ml.) over 1 minute at -15C, and thcn the mixture was s~lrred fo~ 30 minutes at -15 to -10C. To the mixture was added all a~ onc0 a mixture of 3-(1-methyl-lH-tetrazol-5-yl~thiomethyl -7-amino-3-cephem-4-carboxylic acid ~2~4 mg.), triethylamine (80 mg.) and 50~ tetrahydrofuran aqueous solution tlO ml~) which was cooled at 0C~ and the mixture was stirred for 3n minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reac~ion, the reaction mixture was concentrated. The resi`due was adjus~ed to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extrac~ed with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powdcr of 3~ nlethyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahyslropyranyl)oxy-2-t2-mesylamino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, 957~
.
wh;ch call be represented as 3- (l-methyl -lH-tetrazol-5 -yl) thio-methyl-7- ~2- t2-tetrahydropyranyl)oxy-2- (2-mesylimino-2,3-dihydro-1"3-tlliazol-4-yl)acetamido~-3-cephcm-4-carboxylic acid, (270 mg.).
N.M.R. Speckrum (d6-dimethylsul~oxide, ~) 2 . 95 (3H, s) 3. 75 ~2H, broad s) 3,95 (311, s) 4. 36 t211, braod s) 4.6-4, 8 . (lH, broad s) 5.05-5.2 (lH9 m) 5.5-5.8 ~lH, m) 6 . 25-6 . 85 (lH, m) Example 8 To dimethylformamide (5 ml.) was dropwise added phosphorus oxychloride (0.794 g.) under stirring and ice~cooling, and the mixture was stirred for 30 minutes at 40C~ and then cooled ~o -20C. To the mix~u~e was gTadually added 2-hydroxy-2- t2-formylamino-1,3-thiazol-4~yl)ace~cic acid, ~ hich ` can be ~epresented as 2-hydroxy-2- (2-formylimino-2,3-dihydro~
1,3-~hiazol-4-yl)acetic acid, (0.505 g.) at -20CC, and the mixtur~ was sti~red f~r 45 minutes at -12 ~o -10C. Th~s obtained mixture was added to a solution, which was prepared by stirring a mixture of 3-(1-me*hyl-lH-tetrazol-5-yl)thiomethyl- .
~-amino-3-cephem-4-carboxylic acid (0.804 g.~ bis(trime~hyl-silyl~a~etamide (2.62 ml.) in methylene chloride (15 ml.) for an hou~ at ~oom temperature and ~or 2 hours a~ 35 to 40C and then by cooling it to -30C, at a time. The mixture was s~ir~ed for an hour at -20 to --15C? and ~hen me~hylene chloride was distilled off, The resulting res;due was purified by a conYentional manner ts give 3-~1-methyl-lH-.'~ te~razol-S-yl)thiomethyl-7-[2-hydroxy-2-(2-foTmy;amino-1,3-thiazol-4-yl)acetamidol-3-cephem-4-carboxylic acid~ which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7-12-hydroxy- 2 - ~2- ~ormylimino- 2, 3- dihydro-l, 3-thiazol-4-yl)-ace~amido~-3-cephem-4-carboxylic acld, ~OOS1 g.).
I.R. Spectrum (Nujol) 1765-(~-lactam)-cm~
Example 9 A suspension of 3-(1-methyl-lH-tetrazol-5-yl)tlliomethyl-: 7-amino-3-cephem-4-carboxylic acid (1.46 g.), triethylamine (0.~292 g.) and dimethylaniline (0.713 g.) in methylene chloride ~(30 ml.~ was stirred ~or 20 minutes at room temperature.
~2~S77 To the mixture was added a solution of trimethylsilyl chloride (1.043 g.~ in methylene chloride ~10 ml.) over 5 minutes under ice-cooling, and the mixture was stirred for 2 hours at room tempe~atur~ and then cooled to -25C. On the other hand, a suspension of 2-(2 formylamino-1,3-thiazol-4-yl~glyoxylic açid, which can be represented as 2-(2-formy~imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, ~0.96 g.), thionyl chloride (0.697 g.) and dimethylformamide (0.214 g.) in methyl~ne chloride (12 ml.) was stirred for 4 hours, and the mixture was added to ~-~he above obtained cooled mixture over 12 minutes at -25 to -20C.
: The mixture was further s~irred for 30 minutes at the same temperature and ~or 30 minutes at -20 to -10C. Af~er the reaction, the reaction mixture was added to water (100 ml.), and stirred for 30 minutes at room temperature. The white precipitates were collectcd by fil~ration and then dried to giv~ dark brown powder of 3-(1-methyl-lH-tetrazol-5-yl)thio-me~hyl-7-[2-t2-formylamino-1~3-thiazol-4-yl)glyoxylamido]-3-. cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-te~razol-5-yl)thiomethyl-7-[2-(2-formy.limino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid.
IoR~ Spectrum (Nujol~
1782 (~-lac~am) cm~
N.M.R. Spectrum (d6-dimethylsulfoxide, 3.78 (2H, broad s) : 4.0 (3H, s) 4.4 t2H 9 broad s) 5.22 (lH, d, J=5Hz) 5.8 (lH, d, JaSHz) 8.52 (lH, s) 8~62 (lH, s) E - ~9 57~
Similarly, the following compounds were obtained~
(1~ 3~ 3,4-Thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-~o~mylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be reprcsented as 3-~1,3,4-thi`adiazol-2-yl)-thiomethyl-7-~2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4- carboxylic'acid .
I.R. Spectrum(Nujol) 1778 ~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsuloxide, ~) 3.56 and 3.7 (2H, ABq, J-16Hz) 4.24 and 4.56(aH, ABq, J=14Hz) : 5.05-5.16 t2H, m) 5.62-5.78 (lH, m) 7.13 (lH, s) 8.43 ~lH, s) i 9.47 tlH, s) ~ 2) 3-(1-Methyl-lH-tet~azol-5-yl)thiomethyl~7-[2-folmyloxy-2-(~-folmylamino-1,3-thiazol-5-yl)acetamido)-3-cephem-4-carboxylic acid, which can be represented as 3~tl-methyl-lH-tetrazol-5-yl)-thiomethyl-7-~2-formyloxy-2-t2-formylimino-2,3-dihydro-1,3-; thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid.
I.R. Spec~rum (Nujol~
1780 (~-lactam) cm~l N.M.R.. Spectrum (d6-dimethylsulfoxide, ~) 3.53 and 3~77 (2H, ABq, J-19Hz) 3.92 ' (31~, s~
4.45 (2}1, broad s) 4.95-5.15 (lH, m~
5.55 5.7 (lH, m) 6.4 ~lH, s) 2~
7.6 ~ , s) ~27 (lH, ~) .8~5 . tlH, s) (3) 3~ Methyl-lH-~etTazol-5-yl)thiomethyl-7-[2-(2-; formylamino-l~3-thiazol-5-yl)glyoxylamido3-3-cephem-4-carboxylic ; acid, which can be repTesent@d as 3-(l'-methyl-lH-tetrazol-5-ylj-thiomethyl-7-[2-(2-formylimino-2,3-dihydro-l,3-thiazol-s-yl)-glyoxylamido]-3-cephem-4-carboxylic acid.
~ I.R. Spectrum (Nujol) :~ l778 (~-lac~am) cm l N.M.R. Spectrum ~d6-dime~hylsulfoxide, ~) 3.7 (2H, broad s) 3.95 (3H, s~
4~2 and 4.42 (2H, ABq, J-1811z) i . 5,15 (lH, a, J~5Hz~
5.52-5.8 (lH, m~
8.53 (lH, s) 8.65 (l1~, s) :~ ~ .(4) 7-[2-~2-Pormylamino-1,3-thiazol-4-yl)glyoxylar,lido~-cephalosporanic acid, which can be represented as 7-~2-(2-o~mylim1no-2,3-dihydro-i,3-thiazol-4-yl)glyo~ylamido3cephalos-~ poranic acid, mp. 145C.
; I.R. Spec~rum (Nujol) 1780 t~-lactam~ cm l N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 2.06 (3H, s) 3.6 ~2H, broad s) 4.7 and 5.08 ~2H, ABq, J~14Hz) 5.22 (lHJ d, J=5Hz) 5.83 (lH, d, J=5Hz~
S7~
8.47 (lH, s) 8,6 (lH, s) tS) 3-Ca~bamoyloxymethyl-7-~2-(2-formylamino-1j3-~hiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-carbamoyloxymethyl-7-~2-~2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido}-3-cephem-4-carboxylic acid.
I.R. Spec~um (Nujol) 1770 t~-lactam) cm~l N.M~R, Spectrum (d6-dimethylsulfoxide, ~) 3~57 (2H, broad s~
4.65 and 4.87 (2H, AB~, J=14 Hz) 5 ~ tlH, d, J-5Hz) 5.8 (lH~ d, Ja5H~) ~,43 ~lH, s3 : 8.58 (lH, s~
(6) 3-(1-Methyl-lH-tetrazol-5-yl)t}liomethyl-7-[2-l2-(methy.l)thiocarbamoylamino 1~3-thiazol-4-yl3glyoxylamido~-3-~ephem-4-carboxylic acid, which can be represen~ed as 3-(1-" methyl-lH-tetrazol-S yl~thiomethyl-7-[2-[2-(methyl)thio-carbamoylimino-2,3-dihydro-1,3-thia~ol-4-yl3glyoxylamido)-3-cephem-4-carboxylic acid, 148C (sinter)) 160C (expand), 200C tdec . ~ .
; I.R. 5pectrum (Nujol~
1780 (~-lactam) cnl 1 N.M.R. Spectrwn (d6-dimetllylsulfoxide, ~) 3.02 ~3H~ s) 3.75 (2H, broad s) 4-35 . t2H, broad s) 5~17 ~ J dp J=SHz) ~Z~7~
5.4-5.95 (lH, m) 8.25 (lH, s) (7) 3-(5-Methyl-1,3-4-thiadiazol-2-yl)thiomethyl-7-[2-~2-formylamino-1~3-~hiazol-4-yl~glyoxylamid~]-3-cephem-4-ca~boxylic acid, which can be represented as 3- (S-methyl-l, 3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid.
I.R. Spectrum (NUJO1) 1780 (~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsulox;de, ~) 2.7 (3H, s) 3.75 (2H, broad s~
4.25 and 4.62 (2H, ABqJ J-14Hz) 5.12 (lH~ d, J=SHz) 5.8~ (lH, d, J=SHz) 8.5 tlH, s) 8.65 .(lH, s) t8) 3-~l~394-Thiadiazol-2-yl)thiomethyl-7-[2-~2-~orm : ~ amino-1,3-~hiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can b.e represe~ted as 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-~2-(2-formylimino-293-dihyd~o-1,3-thiazol-4-yl)-glyoxylamido~-3-cephem-4-carboxylic acid, powder.
I.R. Spectrum (Nujol) 1775 t~-lactam) cm~l N.M.R.- Spectrum ~-d6-dimethylsul~oxide, ~) 3.64 and 3.8~ (2H, ABq, J=16Hz~
4O32 and 4.66 (2H, ABq7 J-14Hz) 5.22 tll~, d, J-5~z) 5.78 . (lH, d, J=5Hz) 8.45 (lH, s~
\
57~
8.57 ~lH, s) g S7 (lH, s) (g~ 3~ Methyl lH-tetrazol-5-yl)thiomethyl-7-~2-12-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl~glyoxyl-amido]-3-cephem-4-carboxylic acid, powder.
I.R. Spectrum (Nujol~ ~
1790 (~-lactam) cm 1 N.M.R. Spectrum ~CDCQ3, ~) 3.6 (3H, s) 3.73 (2H, broad s) .9 t3H~ s) 4.36 (3H, broad s) 5.13 (lH9 d; 3=5Hz) 5.83 (lH, d, J=5Hz) ~.7 (lH, s) (10~ 3-~1-Methyl-lH-tetra~ol-5-yl)thiomethyl~7-[2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-ca~boxylic acid, which can be represented as 3-(1-methyl-lH-`.~'' tetrazol-5-yl)thiomethyl-7-[2-(2-formylimino-5-~hloro-2,3-dihydro-1,3-thiazol-4-yl~glyoxylamido]-3-cephem-4-ca~boxylic acid, power, mp. 148 ~o 155C ~dec.~.
I.R. Spectrum (Nujol) 3200, 1780, 1680 (broad), 1550, 1290~ 1183, 1110 cm 1 N.M.R~ Spectrum (d6-acetone,~) : 3.85 (2H, broad s) 4.00 (3H, s) 4.45 ~2~1, broad s) S.28 . tlH, d, J-5Hz~
5.00 (lH~ d, J=5Hz~
8.71 tl~i, s) ~ - ~4 ~ S~ 7 t11~ 3-Me~hyl-7-12-t2-formylamino-1,3 thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-methyl-7-l2-(2-formylimino-2,3-dihydro-1 9 3-thiazol-4-yl)-~lyoxylamido]-3-cephem-4-carboxylic acid~ mp. 180C and carbonized at 210C.
(12) 3-(5-Pethyl-1,3,~-thiadi~zol-2~yl)thiomethyl-7-~2-hydroxy-2-(2 ami~o-l 9 3-thiazol-4-yl)acetamido~-S-cephem-4~
carbo~ylic acid, which ca~ be represe~ted ~s 3-(5 methyl-1,s,4-thiadiazol~2 yl~thiomethyl-7~[2-hydro~y-2-(2~imino-2,3-dihydro-1,3-th~azol-4~y~)acet~mido]~-cephem 4~carbo~1ic acid, pale yellow powder.
(13) 3-(1,3,4~hiadiazol-2-yl)thiomethyl~7-[2-hydro~y-2-(2-amino 1,3~thiazol-4-yl)acetamido]-3 cephem-4-carboxylic acid~ ~hich can be represent~d a~ 3-(1,3,4-thiadia~ol-2-yl~-t~iomethyl-7-[2-hydro~y-2-(2-imino-2,3-dihydro-1,3-thiazol 4-yl)-acetamido3-3-cephem-4~carbo~ylic acid, pale brown powder, mpO 151 to 180 C (dec~).
(14) 3-(5-Plethyl~ ,4-o~adiazol-2~yl)thiomethyl 7-~2-hydroxy-2-(~-amino-1,3-thiazol-4-~l)acetamido]-3-cephem-4 carbo~ylic acid, which can be repre~ented a~ 3-~5-methyl-1,3,4-oxadiazol~
2-yl)~hiomethyl-7-~ -hydro~y-2-(2-imino-2,3-dihydro-1,3-thiazol~
4-~l)acetamido]-3-cephem-4-carboxylic acid.
IJR. ~pectrum (Nujol) 1780 (~-lactam) cm~l (15) 3-(4-~ethyl-4H-1,2,4-triazol-~-yl)thiomethyl-7-[2-h~dro~y-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid~ which can be represented as so(4-m~thyl-4h-1.2,4-triazol-~yl~thiom9thyl-7-~2~hydro~y-2-(2-imino-2,~-dihydro-l,~-thiazol-4-yl)acetamido~ ~-cephem-4-carbo~ylic acid.
I.R. Spectrum (Nujol) 1760 ~-lactam~ cm~~
-75- ~-45 ~Z~357~
(16) ~-Carb~moylo~ymethyl-7-[2 hydroxy-2-(2-~mino-1,3-thiazol-4-yl)acetamidO~-3-cephem-4-carboxyliC acid, which ca~
be repre~ented ac 3-carba~oylo~ymethyl-7-~2-hydro~y-2-(2-imi~lo-2,3-dihydro-1,3-thiazol-4yl)acetamido]-3-cep~em 4-carboxylic acid, mp~ > 270C.
~ 17) 3-Methyl-7-[2-hydro~y-2-~2-amino-lJ3-thi~zol-4-yl)-acetamido]-3-cephem-4-carbo~ylic acid, which can be repr~sented aB 3-methyl-7-[~-hydroxy 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp. > 250C.
(18) 3 (1-Methgl-l~-tetrazol-5~yl)thiomethyl-7-~2-hydroxy-2-(2-amino~ thiazol-5-yl)acetamido] ~-c~phe~-4-cærboxylic acid~ which can be represented as ~ methyl-Ih-tetrazol-5-yl~thiomethyl-7 [2-hydro~y~2-t2-imi~o-2,3-dihydro-1,3-thiazol~5-yl)acetamido~ 3-cephem-4-carboxylic acid9 mp. 130 to 200C (dec.).
(19) 3~ Iethyl-lH tetrazol-5-yl)thiom~thyl-7-~2-hydroxy-2-(2-amino-5-chloro-1,3-thi&~ol-4-yl)acetamido]-3-cephem-4-carboxylic ~cid, which ca~ be represented as methyl-lH-te~razol-5 yl)thiomethyl-7-[2-h~dro~y-2-(2-imi~o-5-chloro-2,3-dihydro-1,3-thia~ol-4-yl)acetamido]-~-cephem-4-~a~boxylic acid, mp. 148 to 154C (dec.).
(2~ (1-Methyl-IHtetrazol-5-yl)thiomethyl-7-CDl,2-hydroxy-2 (2-formylamino~5-chloro-1,3-thiazol-4-yl)acetamido]-3-ceph~m-4-carbo~ylic acid 9 which can be repre~ented as 3-(1-methyl-IH-tetrazol-5~yl)thiomethyl-7-[DL,2-.hyd~.oxy-~-(2-~ormylimino-5-chloro-2,3-dihydro-1,3-thiazol 4-yl)acet~ido]-3 cephem-4~carbosylic aoid, mp. 160 to 165C (dec.).
(21) 3-(1-Methyl-lH-tetrazol-5 yl)thiomethyl~7-[2-hydroxy-2-(2-mesylaminO-li3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be repre~ented a~ 3~ methyl-lHDtetrazol-5-yl)-~ - ~6 95~7'7 thio~ethyl-7 ~2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4~yl)acetamido~-3-cephem-4-carbosylic acid, pale brown powder, mp. 120 to 146C (dec.)~
t~2) ~ ethyl-IH-tetrazol-~-yl)thiomethyl-7-[~-hydro~y-2-(2-propane~ulfonylamino-1,3-thiazol-4~yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(1m0thy~-lH-tetrazol-~-yl)thiomethyl-7-~2-hydroxy-2-(2-propane~ul~onylimino-2,3-dihydro~ -thiazol-4-yl~acetamido]-~-cephem-4-carboxylic aci~ 9 mp. 160 to 170C (dec.).
(2~) 3-(1 Methyl~ tetra~ol-5-yl)thiomethyl-7-~?-h~droxy-2-[2-(methyl)thiocarbamoylamino-1,3-thiazol-4-yl]acetamido3-3-cephem-4-carboxylic acid, which c~n be repres~ted as 3~
methyl-l~ tetrazol-5-yl~thiomethyl-7-~2-hydrox~ 2-~2-(methyl)-thiocarbamoylimino-2,3-dihydro-1,3-thiazol-4-ylJacetamido]-3-cephem-4-carboxylic acid, 155C (~inter), 160~C (dec.).
(24) ~ Methyl-I~-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-~2-methy~amino-1,3-thiazol-4-yl~ac~tamido]-3-cephem-4-carbo~ylic acid, which ca~ be repre~e~ted ~s 3-(1-methyl-lH-tetrazol-5-yl) thiomethyl-7-[2-hydroxy-2-(2-meth~limino-2,~-dihydro-1,~-thia~ol-4-yl)acetamidoJ~3-cephem-4-carboxylic acid, mp. 144 to 156C (dec.).
~ 25) ~ Methyl~ tetrazol-5-yl)thiomethyl-7-[Dr-~-hydroxy-2-[2-(N methyl~-tert-pentyloxycarbonylamino~19S-thiazol-4-~l]acetamido~-3rcephem-4-carbsxylic acid.
I.R. Spectrum (~ujol) 1770-1790 (broad) cm 1 .
_77_ E - 47 (26~ 3~ Ilet~yl-lH-tetrazol-5-yl)thiomethyl-7-[~-~ydro~y-2-(2-020~29~-dihydro 1~3-thiazol-4-yl)ac~tami~o~ cephem-4-carboxylic acid~ which oan be repre~ented ~ met~yl 1~-tetra~ol-5-yl~thiomethyl-7-[2-hydroxy-2-(2-hy~ro~y-1,~-thiazol-4-yl)acet~mido]-3-cep~em-4-carboxyliG acid, mpO 110 to 121C (Qec.)0 (27) 3-~1-Methyl-lH-~etrazol-5-yl~thiomethyl-7-[2-(2-amino-1,3-thîazol 4-yl~glyoxylamido~-3-cephem-4-carboxylic acid, which can be represented as 3~ me~hyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-imino-2,3~dihydro~1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, mp. 147 to 160C (dec.).
(28) 3-~5-Methyl-1,334-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-173-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, which can be repTesented as 3-(5-methyl-1,3,4-thiadiazol-Z-yl)-thiom~thyl-7-C2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl~glyoxyl-amido]-3-cephem-4-carboxylic acid, mp~ 156 to 160C (dec.).
(29) 3-(5-Methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7-~2-~2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1~3,4-oxadiazol-~-yl)thiomethyl-7-~2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid.
I.R. Spectrum ~Nujol) 1775 ~-lactam) cm 1 (-~0) 3-(4-Methyl-4H-1,2,4-triazol-~-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-7-~2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol) 1775 (~-lactam) cm 1 ~78- ~ - 48 ~z~s~
(31) 3-tl~3~4-Thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1~3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydro-chlorid~, which can be rep~esented as 3-(1,3,4-thiadiazol-2-yl)-~hiomethyl- 7- [2- (2-imi~o-2~3-dih~dro-1,3-thiazol-4-yl)~lyoxylamido~-~-cephem~4-carboxylic acid hydrochloride, powder.
I.R. Spec~rum ~Nujol) 1778 (~-lactam) cm ~ 32) 3-Carbamoyloxymethyl-7- [2- (2-amino-1,3-thiazol-4-yl~glyoxylamido]-3-cephem-4-carbnxylic aoid hydrochloride, which can be represented as 3-carbamoyloxymethyl-7-[2-(2-imino-2,3-dihydro-1J3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hyd~ochloride, powder.
(33) 3-Methyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, which ~an be represented as 3 - me thyl - 7 - [ 2 - ( 2 - imino - 2, 3 - dihyd~o 1 9 3 - ~ch i a zo 1- 4 - yl ) g lyoxy 1 -amido]-3~cephem-4-carboxylic acid hydrochloride, dp. > 250C.
( 34 ~ 6- [ 2- ( 2-Aml~o-1, 3-thiaæol-4-yl ) gly o~cylamido ] - 5a, 6-dihydr4 3~:I,7~[-azeto~2,1-b]~llro[3,4~d~[193]thiazine 1,7-(4~ dione hydrochloride ~ which can be repre~ented as 6-[ 2- ( 2-imirLo-2 9 3-dihydro-l, 3-thia~ol-4-yl ) glyo~ylamido3 -5a, 6 ~dihydro-3H, 7~-azeto~2,1~b~uro~3,4-d]~1,3]thiasine-1,7-(4H)-dions hydrochlorideO
I.R. Spactrum (~ujol3 1786 (~-lactam~ cm~l (35) 3~ Meth~ tetrazol-5 yl)thiomethyl 7-~2~ amino-1~3-thiazol-5-yl)glyoxylamidoJ;;~ cephem-4-carboxylic acid hydrochloride, which can be ropre~onted a~ 3~ methyl-I~-tetrazol-5-yl)thiomethyl-7~[2-(2-iml~o-2,3 dihydro-1,3-thiazol-5-yl)-glyoxylamldo]~3-cephem-40carboxylic acid hydrochloride, mp. 140 to 160C (de¢.) ~Z~. ~577 (36) 3-(1-Methyl-lH-tetrazol-S-yl)thiomethyl-7 [2-~2-methylamino-133-thiaz~1-4-yl)glyoxylamido]-3-cephem-4^carboxylic acid, which can be represented as 3-(1-me~hyl-lH-tetrazol-5-yl)-thiomethyl-7-~2-(2-methylimino-2~3-dihydTo-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acidg mp. 146 to 155C (dec.).
~ - 50 ~ Z~t~ ~ ~ 7 Example lO
To a solution of 3-~5-methyl^1,3,4-thiadiazol-2^yl~-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, wh~ch can be represented as 3-~5-methyl-1,3,4-thiadiazol-2-yl~thiomethyl-7-L2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid~ (3.36 g.) in methanol (35 ml.) was added lN sodium hydroxide aqueous solution (5.5 ml.) under ice cooling, and to the m;xture was d~opwise added an aqueous solution of sodium borohydride (~1 mg~) in water t2.5 ml.) over 2 minutes f at 10 to 15C. The mixture was stirred for 10 minutes at the same ~emperature, and then methanol was distilled off from the mixture helow 40C under reduced pressure. The remaining aqueous solution was washed with a small amount of ethyl acetate, adjusted to pH 5 to 6, with 10~ hydrochloric acid, further washed with a small amount of ethyl acetate. The solution was adjusted to pH 2 with 10~ hydrochloric acid, and then extracted with e~hyl acetate. The extract was washed with water and a sa~urated aqueous solu~ion of sodium chloride in turn, dried over magnesium sulfate and ~hen treated with an activated charcoal. The sol~ent was distilled off from the extract till the volume of the extract became a small amount. l~e p~ecipitates were collected by filtration, washed with a small amount of ethyl acetate, and then dried t~ give 3-~5-methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-hydroxy-2-(2-tert-pentyloxy-carbonylamino-1,3-thiazol-4-yl)acetamïdo]-3-cephem-4-carboxylic acid, which can be ~epresented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)acetamidoJ-3-cephem-4-carboxylic acid, (1.69 g.). On the o~her hand, the mother liqu~r and _81-~ 2 ~
the ethyl aceta~e washing were combined togethcr and concentrated under reduced pressure, and then the prccipitates were similarly treated as aforemcntioned to give the same object compound (0.~0 g-)~
I.R. Spectrum ~Nujol) 1785 (~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 2.S7 ' (3H, s3 3.55-3.83 (21~, broad s~
4.25 and 4.53 (2H, ABq 9 J=14 Hz) 5.1 (lH, s) 5.13 (lH, d3 5.7 tl~, d) 7.05 ~lH, s) Example 11 To a solution of 3~ 3,4-thiadiazol-2-yl)thiomethyl-7-[2-~2-tert-pentylQxycarbonylamino-1,3-thiazol 4-yl)glyoxyl-~mido]-3-cephem-4-carboxylic acid, which can be represented as 3~(1,3,4-thiadiazol-2^yl)thiomethyl-7-~2-(2-teTt-pentyloxy-carbonylimino-2~3-dihydro-1,3-thiazol-4-yl)glyoxylamid~]-3-cephem-4-carboxylic acid, t3.1 g.) in methanol ~30 ml.) was added lN
sodium hydroxide aqueous solution ~S. 2 ml . ~ under ice-~ooling and stirring. To the mixture was drop-ise added a solution of sodium borohydride ~0.074 g.) in water (2 mlO) over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature.
After the reaction, the reaction mixture was concentratcd under reduced pressure. To the residue were added water and e~hyl ace~ate, and the aqueous layer was separated. The a~ueous layer was adjusted ~o pH 5 to 6 with 10~ hydrochloric acid and then washed with ethyl acetate. To the aqueous layer was added ethyl acetateS and the mixture was adjusted to pH 1 to 2 wi~h 10%
hydrochloric acid. The ethyl ace~ate layer was separated, washed with wa~er, dried oYer magnesium sulfate and then trea~ed with ~cti~ated charcoal. After distillation of the sol~ent ~rom the ethyl acetate laye~, ~he remaining residue was pulverized in diethyl ether, collected by fil~ration and then dried to gi~e pale yellow powder o 3~ 3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-~hiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid~ which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2^tert-pentyloxycaTbonylimino-2,3-dihydro-1~3-thiazol-4-yl)ace~amido~-3-cephem-~-carboxylic acid, ~2.2 g ).
N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.53 and 308 (2H9 AB~, J=17 Hz) 4~33 and 4.7 ~2ll, ABq, J=13 Hz) 5.0 (lH, s) 5.15 (1}~ d, J=4 Hz) 5.6 ~lH, d, J-4 Hz) 7.0 ~lH, s) 9.43 tlH~ s) Example 12 To a solution of 7-~2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]cephalosporanic acid, which can be represented as 7-~2-(2-~ert-pen~yloxycarbonylimino-2,3-dihydro-193-thiazol-4-yl)glyoxylamido~cephalosporanic acid, t5.4 g,) in methanol (54 ml.) was added lN sodium hydroxide aqueous solution (10 ml.) under cooling at 10 ~o 15C. To the mixture was dropwise added a solution o sodium borohydride (142.~ mg.) ~L2~ S~t~
in water ~3.~ ml.) over 30 minutes at the same temperature, and ~hen the mixture was stirred for 15 minutes at the same tempera-ture. After the reaction~ the reaction mixture was concen~rated at 30 to 35C under ~educed pressure. -The~residue was post-treated in a similar malmer as that of examplell to give powdeT
of 7-[2 hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid, which can be reprcsented as 7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]cephalosporanic acid, (4.2 g.~.
I.R~ Spectrum (Nujol~
1783 ~-lactam) cm 1 N~Mo R. Spectrum ~d6-dimethylsulfoxide, ~) 2.07 (3H, s) 4.7 and 5.07 ~2H, ABq~ J=14 Hz~
5~08 ~lH, s) 5~13 ~lH, d, J~5 Hz~
5.53-5.95 tl~ m) 7.03 (lH, s) Ex mple 1~
To a mixture of 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7-12-(2-propanesulfonylamino-1,3-thiaæol-4~1)glyoxyla~ido~
cephem-4-carboxylic acidg which can be represented as 3-(1-methyl-lH-te~razol-5-yl)thiom0thyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, t$rO g.), methanol (160 ml.) and lN sodium hydroxide aqueous solution (13.6 ml.) was dropwise added a mixture of sodium borohydride ~0.26 g.) and ethanol (15 ml.) over 20 minutes under sti~ring and ice-cooling. The mixture was furthcr stirred for 1 hour, and then methanol was distilled off. ~Ic residue -84- E - 54`
-5~7 was dissol~ea in water, and the solution was washed ~ith ethyl acetate. To ~he aqueous solution was added ethyi acetate, and the mixture was adjusted to pH 2 with 10~ hydrochloric acid, and ~hen the ethyl acetate layer was separat~d from the mixture.
The remaining aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate extract was combined with the separated ethyl ace~a~e layer, washed with a saturated aqueous solution of sodium chloride and then dried, The solvent was distilled off, and ~he residue was washed with die~hyl ether and then dried to give 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7- [2-hydroxy-2- t2-propanesulfonylamino-lp3~thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3- ~1-methyl-lH-te~razol-5-yl) thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (5.5 gO), mp. 160 to 170C (dec.).
NoM~R~ Spectrllm (d6-dimethylsulfoxide, ~5) 3.73 (2H, broad s~
J 3.97 ~3H, s3 4.35 (2H, broad s) 5.03 (lH, broad s) 5.13 (lH, d, J=5 Hz) 5.5-SO~ 1, m) 6.67 (lH, s) .
Example 14 To a mixture o 3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-7-[2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephe~-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetTazol-5-yl)chiomethyl-7-[2-(2-hydroxy-1~3-thiazol-F. - 55 --8~---4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (5.2 g.3, methanol (200 ml.) and lN sodium hydroxide aqueous solution (10.8 ml.) was dropwise added a mixture of sodium borohydride t0.205 g.) and ethanol ~8 ml.) over 10 minutes at 5 ~o 10C with stirring.
The mixture was further stirred for 20 minutes at the same temperature, and then a mixture o~ sodium borohydride (0.01 ~.) and ethanol ~0.5 ml.) was further added thereto at the same temperature. The mixture was further stirred for 30 minutes at the same temperature 9 and then ~he r~action mixture was concentrated under reduced pressure~ To the residue was added water (200 ml.), and the solution was washed with ethyl acetate.
The aqueous solu~ion was adjus~ed ~o pH 5 with 10% hydrochloric ~cid and washed with ethyl acetate. The solution was adju~ted to pH 1 with 10% hydrochloric asid and extracted with ethyl ace~ate. The remaining aqueous layer was subjected to salting-out and then u~ther extracted with ethyl acetate. The ethyl acetate extracts were combined together, washed wit~ a saturated aqueous soluti~n o sodium chloride 3 dried over magnesium sulfat~ and ~hen treated with activated charcoal.
The solven~ was distilled off, and the residue ~as pulverized in diethyl ether, collected by filtration and then dried to give pale yellow powde~ o~ 3-tl methyl-lH-tetrazol-5-yl)thiomethyl-7-l2-hydroxy-2-(2-oxo-~,3-dihydro-1~3-thiazol 4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-7-~2-hydroxy-2-~2-hydroxy-1, 3-thiazol-4-yl)ace~amido~-3-cephem-4-carboxylic acid, (3.6 g.), mp. 110 to 121QC (dec.).
I.R. Spectrum tNujol) 1780 (~-lactam) cm 1 N.M.R. Spectrum (NaDCO3, ~) 3,45 and 3.83 (~H, ABq, J=18 Hz) 4.08 (3H, s) 4.04 and 4.42 ~2H, ABq~ J=14 Hz3 4.85 (lH, s) 5.15 tlH, d, J=4 Hz) 5.6 t~H, d, J=4 ~z~
: 6.5 tlH, s) BxamPl-e 15 To a solution of 3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-7-~2-[2-(N-methyl-N-~ert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylamido]-3-cephem-4-carboxylic acid (2.2 g.
ln methanol ~22 ml.) was added a lN sodium hydroxide aqueous solution (3.6 ml.~ under cooling a~ 10C, and to the mixture was dTopwise added an aqueous solution of sodium borohydride ~41 mg.) in water (1 ml.~ over 20 minutes under cooling at 10 to 15~C. The mixture was sti~red for 30 minutes at the same t temperature, and then methanol was distilled of~ from the mixture underreducedpressure. To the residue were added water ~20 ml.) and ethyl acetate (40 ml.), and the aqueous layer was separated.
T~ tlle aqueous layer was added ethyl ace~ate~ and the mixture was adjus~ed to pH 1 to 2 with hydrochloric acid, and then the ethyl acetate layer was separated. The e~hyl aceta~e layer was washea with a saturated aqueous solution o sodium chloride, -dried over ma~nesium sul~ate and then treated with an activated cha~coal. The solvent was dis~illed off from ~he ethyl ace~ate laye~, and ~he remaining oily subs~ance was pulverized in diethyl e~her. The powder was collec~ed by fil~ration and then dried to give 3~ metnyl-lH-tetrazol-5-yl)thiometnyl--~7- ~ - 57 7-[DL-2-hydroxy-2-[2-(N-me~hyl-N-ter~-pelltyloxycarbonylamino)-1)3-thiazol-4-yl]acetamidoj-3-cephem-4-carboxylic acid (1.7 g.).
Spectrum (Nujol~
1770-1790 (bro~d) cm 1 N.M.R. Spectrum ~CDCQ39 ~) 3.5 (3H, s) 3.65 (2H, broad s) 3.9 (3~, s~
4.35 - (2H, broad s) 5.05 ~lH "d~ J-5Hz) . 5025 (lH, s) 5.8 ~lH, d, J=5Hz~
` 6.95 (lH, s) Similarly the ollowing compounds were obtained.
tl) 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2- t2-amino-1 ,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid9 which can be represented as 3-~5-methyl-1,3,4-thiadiazol-2-yi)tlliomethyl-7-[2-hydroxy-2-(2-imino-2,3-di}lydro-1,3-thiazol-4 yl)acetamido]-3-cephem-4-carboxylic acid, pale : yellow powder.
(2) 3-(1,3,4-Thiadiazol-2-yl~thiomethyl-7-~2-hydroxy-2-t2-amino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic ~acidJ which can be represented as 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-L2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)-~cetamido]-3-cephem-4-carboxylic acid, pale brown powder, mp. 151 to 180C (d~c.), -8~-~2~57~
~ ) 3~ Methyl ~ - te~razol- ~-yl~ thiomethyl - 7 - ~2-hydroxy-2-(2- mesylamino-1,3-thiazol-~-yl)acetamido~-3-cephem-4-carboxylic ~cid7 which can be represented as 3-(1-methyl-lH-te~razol-5-yl3-thiomethyl-7- [2-hydToxy-2--(2-mesylimino-2,3-dihydro-1,3-thiazol-4~yl)acetamido]-3-cephem-4-carboxylic acid, pale brolYn powder, mp~ 120 to 146C tdec. ) .
(~) 3-(1-Methyl-lH-tetrazol-S-yl~thiomethyl-7-~2-hydroxy-2 (2-tert-pentyloxycarbonylamino-l,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3- (l-methyl-lH- tetrazol- 5-yl) ~hiomethyl ~ 7- ~2 -hydrox~- 2 - (2 -tert-pentyloxy-carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, pale brown powder.
~ 5) 3- t5-Methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7- [2-hydroxy-2-(2 amino-1,3-thiazol-4~yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3v4-oxadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl~ace~amido~-3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol) 1780 (~-lac~am) cm~l t6) 3-~4-Methyl-4H- 192, 4-triazol-~-yl) thiomethyl - 7- ~2-hydroxy-2-(2-amino-1~3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acidg which can be represented as 3-(4-methyl-4~l-1,2, 4-triazol~3-yl)thiomethyl-7-[2-hydroxy-2- ~2-imino 2 ~3-dihyd~o-l ,3-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol~
1760 (~-lactam) cm 1 ~ ~z~s~ ~
(7) 3-(l Methyl lH tetrazol-5-yl)thiomethyl-7-~2-hydroxy-2-(2-ormylamino-1,3-thia~ol-4-yl~acetamido]-3-cephem-4-carboxylic acid, whi.ch can be represented as 3-(1-methyl-lH-t~trazol-5-yl)-thiomethyl-7-~2-hydroxy-2-(2-~ormylimino-2,3-dihydro-1,3-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, bro~rnish white powder.
N.M.R. Spec~rum (d6-dimethylsulfoxide, ~) 3.67 (2H, broad s) 3.9 t3H. s) 4~25 t2H, broad s) ; 5.05 tlH, d9 J-5Hz~
` ~.1 (lH, s?
5.53-5,8 ~lH, m) 7.07 (lH, s?
8.45 (lH, s) (~) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-~DL-2-hydroxy-2-t2-formylamino-5-chloro-1,3-thiazol-4-yl)acetamido3-3-cephem-4-carboxylic acid, ~hich can be represcnted as 3-tl-methyl-lH-te~razol-S-yl)thiomethyl-7-EDL-2-hydroxy-2-~2-, fol~mylim;no-S-chloro-2,3-dihydTo-1,3-thiazol-4-yl)acctamidoJ-3-cephem-4-carboxylic acid, mp. 160 ~o 165C (dec.).
~90~ ~ - 60 ~L2~9S~rdJ
: I.R. Spectrum ~Nujol) 3100-3600, 1780~ 1680 (broad), 1530, 1280, 1175, 1100, 1055 cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, 3.83 (2~, broad s~
4.03 ~3H~s) 4.43 (2H9 broad s) 5.23 tlH, d, J=5Hz) ; 5.42 ~lH, s3 5.87 (1HJ d9 J-SHz) , 8~78 tlH, S) t9) 3-(l-Methy~ -tetrazol-s-yl~*hiomethyl-7-l2-hydr 2-[2-(methyl3thiocarbamoylamino-153-thia~ol-4-yllacetamido]-3-cephem-4-ca~boxylic acid, which can be TepTesen~ed as 3-(1-methyl-lH-tetrazol-S-yl)tlliomethyl-7-~2-hydroxy-2-~2-(methyl)-thiocar~amoylimino-2,3-dihydro-1,3-~hiazol-4-yl~-acetamido]-3-cephem-4-carboxylic acid, 155C (sinter~, 160~C (dec.).
I.R. Spectrum (Nujol) 17$0 (~-lactam) cm l ; N~M.R. SpectTum (d6-dimethylsulfoxide, ~) 3.06 (3H, s) 3.75 (2H, broad 5) 4.33 t2H, broad s) 5.15 ~2H, m~
.5.64 and 5.78 (lH, m) 7,05 ' ~lH, s) (lO) 3-tl~3~4-Thiadiazol-2-yl~thiomethyl-7-[2-hydroxy-2-(2-fo~mylamino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic scid, which can be represented as 3-(1,3,4-~hiadiazol-2-yl)-~hiomethyl-7-~2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-2~ ~ ~7 ~
~hiazol-4-yl)acetam~do]-3-cephem-4-carboxylic acid, pale yellow powder, mp. 105 to 130C (dec.).
I.R. Spectrum (Nujol) 1760-1780 (~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, 3 . 37 (2H "broad s) 4.2S and 4.62 (21i, ABq, J~14Hz) 5.1 (lH, d, J~5Hz) 5.15 (lH, s) 5~3-5.9 ~lH, m~
.~ 7.15 . (~HD S) 8,45 (lH, s) 9~62 (lH, s) ~1) 3-Carbamoyloxymethyl- 7 - I 2 -hydroxy-2-~2-amino-1,3-thiazol-4-yl)acetamido~-3 cephem-4-carboxylic acid, which can be represented as 3-carbamoyloxymethyl-7-[2-hydroxy-2-~2-imino-2,3-dihydro-1,3-~hiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, mp. ~ ~70~C.
. ~ I.R. Spect~um ~Nujol~
1780 ~-lac~am) cm~l N.M~n. Spectrum (d6-dimethylsulfoxide~ ~) 3.43 and 3.65 (2H, ABq, J=14Hz~
4.6 and 4.85 (2H, AB~ J=15Hz~
: 4.86 ~1~, s) 5,1 (lH, d, J~5Hz) 2.6-2.75 (lH, m) 6.43 ~lH, s) ~ 2) 3-Methyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)-acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-methyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-E - ~2 _92-yl)acetamidoJ-3-cephem-4-carboxylic acid9 mp. ~ 250C.
I .R. Speotrum (Nuj ol) 1760-1780 (~-lac1:am) cm~l N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 2.07 t3H, s) : 3.33 and 3.68 (2H "ABq~ J=18~z) 4,93 (lH; s) 5.1 (lH, d) 5~57-5.7 (lH, m) $.5 ~lH, s) f tl3~ Meth~ tetrazol-5-yl)~hiome~hyl-7-[2-hydroxy-2-(2-amino~ thiazol~5-yl~acetamido]-3-cephem-4 carbo~ylic acid7 which ca~ be represe~ted as 3~ methyl-I~
tetrazol-5-yl)thicmethyl-7-t2-hydrox~-2-~2-imino-2,~-dihydro-1~3-thiazol-5~ acetamidoJ-3 cephem-4~carbo~ylic acid, mp. 130 to 200C (decO).
(14) 3-(1-M~thyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2(2-amino-5-chloro 1,~ thiazol-4-yl)acetamido~
c~phem-4~carbo~ylic acid, which ca~ be represented as 3~ met~yl-lH-tetrazol-5-yl~thiomethyl-7-~2-hydroxy-2-(2-iml~o-5-chloro-2,~-dihydro-~,3 thiazol-4-yl)acetami~o~-3-o~hem-4-~arbo~ylic acid, mp~ 148 to 154C (dec.).
tl5) 3-(1-Methyl~ tetrazol-5-yl~thiomethyl-7-[2-hydroxy-, 2-(2-methylamino-19~-thiazol-4yl)acetamido~-3-c0phem-4-carb3xylic acid, which c~ be repre~ented as 3-~1-methyl-~-tetrazol-5-yl~-th~omethyl;~7-[2-hydro~y-2-(2-methyl~mino-2,3-dihydrG;l,~j-thiazol~
. ~-yl)acet~do]-~-cephem-4-~arboxylio. acid~ mp. 144 to 156C (dec.).
Example 16 A solution of 3-(S-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-hydroxy-2-(2-ter~-pen~yloxycarbonylamino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-caTboxylic acid, which can be represented as 3-(5-methyl-193,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid ~2.30 gO) in g8~ formic acid (25 ml.) was stirred for 2.5 hours at room temperature. A~ter the reaction~ formic acid was distilled off under reduced pressure. The residue was pulverized in acetonitrile ~25 ml.), collected by filtration, washed wi~h a small amount of acetonitrile and then dissolved in 5~ sodium bicar~onate aqueous solution (14 ml.). The solu~ion was adjusted to p~ 6 with acetic acid and subjected to alumina column chromatography by using pE~ 5 ~ O acetate buffer as an eluent. The eluate containing the object com~ound (300 ml.) was adjusted to pH 3 with 10% hyd~ochloric acid and then washed twice with ethyl acetate (50 ml.). The a~ue~us layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm ~ Haas Co.) J and ~he column was washed with water and then eluted with 20% methanol aqueous solution ~100 ml.), 50 methanol aqueous solution (lO0 ml.) and 70% methanol aqueous solution (400 ml.) in turn. The eluates containing the obj~ct compound (500 ml.) were collected and then methanol was distilled off at 30 to 35C under reduced pressure. The T~maining aqueous solution was lyophi~ized to give pale yellow powder of 3-tS-methyl-1,374-~hiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1 9 3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2 7 3-dihydro-~%~77 1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.60 g.), IoRo Spectrum (Nujol) i770 (~-lactam) cm l N.M.R. Spec~rum (NaDCO3, ~) 2. 7S ~3}IJ S~
3.4 and 3.75 ~2H, ABq~ J=14 Hz) 4.0 and 4.52 (2H, ABq~ J-14 Hz) 5~15 (lH, d9 J=S Hz) 5.2 . (lH, s) 5-7 tlH, m~-6,76 ~1/2H, s~
6~9 (1/2H, s) Ex~mple 17 A mixtu~e of 3-tl,3J4-thiadiazol-2-yl)thiomethyl-7 ~2-hydroxy-2-(2-t~rt-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid9 which can be represented as 3-tl,3,4-thiadiazol-2-yl)thiomet}lyl-7-[2-hydroxy-2-~2-tert-pentyloxycarbonylimino-2~3-dihydro-193-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, ~2.1 g..) and 98 to 100% formic acid (40 ml.) was stirred for 2.5 hours at room temperature. After the react;on, ~he reaction mixture was concentrated under reduced pressure. The residue was pulverized in acetonitrile, collected by filtration and then washed wi~h e~her to produce brown po~lder (1.3 g.j. The powder was dissolved in 5% sodium bicarbonate aqueous solution (20 ml.~ and then adjusted to pH 6 with acetic a~id. The mixture was subjected to neutral almina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluates containing object compound (230 ml.) were collected, adjusted to pH 2.8 to 3.0 with 10% hydrochloric . _95_ E - 65 57~
acid, washed with ethyl acetate~ and then remaining cthyl ace~ate was distilled off from the eluates under reduced pTcssure.
The resulting aqueous layer was subjected ~o column chromato-graphy (Amb~rlite XAD-4 prepared by Rohm ~ I-laas Co.), and the column was washed with water and then eluted with 20% methanol (80 ml.~ 9 50% methanol (80 ml.) and 70~ methanol (300 ml.) in turn. The elua~es containing the object compound were collected and then methanol was distilled o~f under ~educed pressure. The remaining aqueous solution was lyophillized to Kive pale brown powder of 3-(1,3,4-thiadiazol-2-yl)thio-methyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be repr~sented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3 thiazol-4-yl)ace~amido~-3-cephem-4-carboxylic acid, (0.40 g.), mp. 151 to 180C (dec.).
I.R. Spectrum (Nujol) 1770, 1680, 16209 1520 cm~l N.M.R. Spectrum (d6-dimethylsulfoxide9 ~3 . 3.6B f2H, m) 4.43 (2H~ dd, J=12.8 and 22.6 Hz~
40 87 ~lH, broad s) 5.11 (11!~ d~ J=5.0 Hz) 5.2-6.1 (3H, m) 6.43 (lH, s) 9~ 57 (lH, s~
Example 1~
A mixture of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxyl--amidol-3-cephem-4-carboxylic acîd3 which can be represented as 3-tl-methyl-lH-~et~azol-5-yl)thiomethyl-7~2-~2-tert-pentyloxy-: ca~bonylimino-2~3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, (lo8 ~.~ and 98 to lO0~ formic acid (40 ml.) was allowed ~c s~and fo~ 5 hours. After the rcactiona the reaction mixture was post-treated in the similar manners as in Examples 16 *o 17 to give 3-(1-me~hyl-lH-tetrazol-5-yl)thiomethyl 7-~2-(~ amino-1,3-thiazol-4-yl)~lyo~ylamido]-~-( cephem^4-carboxylic acid, which can be represented as 3-(1-methyl~ etrazol-5-yl)thiomethyl-7-l2-(2-imino-2,3-dihydro-1, 3-~hiazol-4-yl)glyoxylamido]-~-cep}lem-4-carboxylic acid3 (0.32 g.), mp. 147 to 160~C (dec.).
I.R. Spect~um (Nujol~
1770 (~-lactam) cm 1 N.M.R. Spectrum td6 dimethylsulfoxide, ~) 3.73 (2H, broad sj 3.95 (3H~ s) 4 2 and 4.5(2H, ABq~ J=15 Hz) 5.15 (lH, d, J=5 Hz) 5.75 (lH9 d, J-5Hz) 7.8 (1~ s) E - ~7 Example i~
A solution of 3-(5-methyl-1,3j4-thiadiazol-2-yl)-thiomethyl-7-E2-(2-tert-~entyloxycarbonylamino-l~3-thiazol-q yl)glyoxylamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomcthyl-7-12 (2-tert-pentyloxycarbonylimino-2,3-dillydro 1,3-thiazol-4-yl)-glyoxylamido~-3-cephem-4-carboxylic acid, (8.56 ~.) in formic acid (180 ml.~ was stirred for 5.5 hours at room temperature.
Afte~ the reaction~ the reaction mixture was post-treated in the similar manners as in Examplesl6 to 17 to gi~e 3-(5-methyl-1~3,4-thiadiazol-2-yl)thiomethyl-7- E2-~2-amino-l~3-thiazol-4 yl)glyoxylamido~-3-cephem-4 caTboxylic acid, which ean be represented as 3-~5-methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-t2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, (2.6 g.)~ mp. 156 to 16~C (dec.).
.
~ o a mixture of 3-(1-methyl-lH-tetrazol-S-yl)thiome~hyl-7-t2-formyloxy-2-(2-ormylamino-1,3-thiazol-5-yl)acet~mido]-3-cephem-4-carboxylic acid, which can be represented as 3-tl-methyl-lH-tetrazol-5-yl~thiomethyl-7-~2-formyloxy-2-~2-formylimino-2,3-dihydro-1~3~thiazol-5-yl)acetamido]-3-cephem-4-carboxy~ic acid, tl.5 g.) in methanol (30 ml.) was added phosphorus oxychloride (1.06 g.~ under ice-cooling and stirring, and the mixture was stirred for 1 hour at the same tempera~ure and then ~urther stir~ed for 4 hours at room temperature. To the reaction ~ixture was added diethyl ether (150 ml.)~ and the prccipita~es were collected by filtration and then dried. Thus obtained pale yellow powder (1.30 g.) was added to water (30 ml.), and _98- ~ - 68 ~Z~35~'7 the mixtu~e was adjusted to pH 1 to 2 with 10% hydrochlo~ic acid.
The resulting solution was treated wi~h an acti~ated charcoal, washed with ethyl ace~ate and then adjusted to pH 7 with a 5%
sodium bicarbonate aqueous solution. The solution l~as ~ashcd with ethyl aceta~e, adjusted to pH 3 with 10~ hydrochloric acid and then filtered. The aqueous solution was adsorbed on a HP-20 (neutral resin) colu~n, which was washc~ with water and then eluted ~ith an aqueous methanol solution. The eluates containing th~ object compound wer~ collected and then methanol as distill~d off under reduced pressure. The remaining aqueous solution was lyophilized to give 3~ me~hyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-~2-amino-1,3-~hiazol-5-yl)acetamido~-3 cephem-4-carboxylic acid, which can ~e represente~ as 3-tl-methyl-lH-tetrazol-S-yl)thiomethyl-7-~2-hydroxy-2-t2-imino-2,3-dihyd~o-1,3-thiazol-5-yl~acetamido]-3-cephem-4-caTboxylic acid, ~0.63 g.), mp. 130 to 200C ~dec.).
I.R. Spectrum (Nujol) 1768 (~-lactam~ cm~
N.M.R. Spectrum (d6-dimethylsulfoxide 9 3.72 ~2H, broad s) 3.92 t3H~ s) 4.3 ~2H, broad s) 5.05-5.25 ~2H, m~
5.66 (lH, d, J=5Hz) 7.0 (lH, s) ( .
~x~mple 21 To a mixture of 7-[2-(2-formylamino-1,3-~hia~ol-4-yl)-glyoxylamido]cephalosporanic acid, which can be represen~ed as 7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-cephalosporanic acid, (30 g.~ in methanol ~500 ml.) was dropwise added phosphorus oxychloride ~22e2 g~ over 30 minutes under ic~-cooling and stirring, and the mixture was stirred for 2.25 ~`hours at the same temperature. The mix~ure was poured into diethyl ethe~ (2500 ml.)) and the mix~ure was s~irred for 1 hour at room temperature. The precipitates were collected by ~iltration and then dried to give 6- [2- ~2-amino-1 ,3-thiazol-4-yl~glyoxylamido]-5~,6-dihydro-3H,7H-azeto~2, 1-b~fu~o [3,4-d~ [1,3~ -thiazine-1~97- C4H~-dione llJrdroehloride9 which can be ~epresen~ced as ~-[2-(2-imino-2,3-dihydro-1,3-thiazol'-4-yl)glyoxylamido]-Sa,6-dihydro-3H,7H-azeto[2,1-b]furo[~,4-d~ .3]-thiazine-1,7-t4H)-dione hydrochloride, (24.2 g.~.
I . R. Spectrum (Nuj ol~
1786 (~-lactam) cm 1 ~ ~ 70 ~100-~2~95i~7 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.84 (2H, broad s) 5 07 (2H, s) 5.2S (lH, d, 3=5Hz3 So83 tlH~ d, J-SHz) :~ 8.32 (l~ "s) Exam~le 22 To a mixture of 3-(l-methyl-lH-tetrazol-5-yl)-thiomethyl-7-e2-t2-~ormylamino-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, which can be represented as 3- ~1-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-~2-ormylimino-2,3-'dihydro-1,3-tllia~ol-~-yl)glyoxylamido~-3-cephem-4-carboxylic acid, (24;8 g.) in methanol (500 ml.) was dro~wise added phosphorus oxychloride (1~4 g.) over lS minutes under cooling.
at 5 to 10C wi~h stirring, and ~he mixture was stir~ed or 2.5 hours at the same temperature. The 3/4 amount of methanol was distilled o~f from ~he reaction mixt~re under reduced pressure, and the r~sidue was pulveTi~ed in diethyl ethe~. The powder was collected by filtration and th~n dried to give 3-(1-methyl-lH-tetra~ol S-yl)thiomethyl-7-[2-~2-amino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, wh;ch can be represented as 3-~1-me~hyl-lH-tetrazol-5-yl)thiomet]lyl-7-t2-(2 imino-2~3-dihydro 1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride9 I.R. Spectrum (Nujol) 1778 (~-lactam~ cm~
N~M.R. Spectrum (d6-dimethylsulfoxide, ; 3.7 ~2H, broad s) 4.0 (31~, s) 4.37 (2H, broad s) 5.23 (1~ d, Ja5Hz) 5 75 tlH~ d, J-SHz) .8.27 (lH, s) 8.35 (lH~ s) Similarly, ~he following compounds were obtainedO
tl~ 3~ (5-Methyl-1~3 ,4-oxadiazol-2-yl) thiomethyl-7- ~2-hydroxy-2 (~-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-ca~boxylic acid, which can be represented as 3-(5-me*hyl-1,3~4-oxadiazol- 2-yl) thiomethyl - 7-~2-hydroxy-2-(2 - imino- 2, 3-dihydro-1~3-thiazol-4-yl)acetamido]-3-cepllem-4-carboxylic acid.
I.R. Spectrum (Nujol~
1780 (~-lac~am) cm~l t~ 3-(S-Methyl-1,3,4-oxadiazol-2-yl) thiomethyl-7 - ~2 - (2 -~mino-1,3-thiazol-4-yl~glyoxylamido~-3-cephem~4-carboxylic acid9 which can be represented as 3-~5-methyl-1,3,4-oxadiazol-2-yl)~hiomethyl-7-[2-t2-imino-253-di.hydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic ~ci~
I~R. Spectrum (Nujol) 1775 (~-lactam) cm~l ' (3) 3-~4^~Se~hyl ~H-1j294-~riazol-3-yl)thiu]nethyl-7-~2-hydroxy-2-~2-amino-153-thiazol-4-yl)aGetamido]-3-cephem-4-carboxylic acid9 which can be represented as 3-t4 metllyl~ H-1,2,4-triazol-3-yl~thiomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro- 1, 3 - thia zol - 4 -yl~ ace tamido 3 - 3 - cephem- 4 - carboxyl i c aci d ,, I~Ro Spec~rum (Nujol) 1760 (~-lactam~ cm~l (4~ 3-(4-Methyl-4H-1,2,4-triazol-3-yl)thiomethyl-7-~2-(2-amino-1,3-thi~zol-4-yl)glyoxylamido]-3-cephem-4-carboxylic . -102- ~ - 72 ~ S ~ 7 acid, which can be represented as 3-(4-methyl-4}~ 2g4-tria .~-yl~thiomethyl-7-t2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl) glyoxylamido~-3-cephem-4-carboxylic acid.
I, R. Spect~um (Nujol~
1775 (~-lactam) cm~l (S) 3-Carbamoyloxymethyl-7-~2-hydroxy-2-(2-amino-l,3-thiazol-4-yl)acetamido]-3-~ephem-4-carboxylic acid, which can ; be represented as 3-carbamoyloxymethyl-7-[2-hydroxy-2-(2-imîno-2 ~3-dihydro-1 ,3-thiazol-4-yl)asetamido]-3-cephem-4-carboxylic acid, mp. ~ 27ûC.
I . R . Spectrum ~Nuj ol) l780 (~-lactam) cm l N.M.R. Spec*rum (d6-dimethylsulfoxide, ~) 3.43 an~ 3.65 (2H9 AB~, J=l4Hz) 4.6 and 4.85 ~2H, ABq, J=15Hz) 4.86 (l~, s) 5.1 (lH, d, J~SHz) 2.6-2.75 tlH, m) 6.43 (lH, s) (6~ 3-~l-Methyl-lH-tetrazol-5-y1)~hiomethyl-7-~2-hydroxy-2^(2-methylamino-1,3-thiazol-4-yl)acetamido~-3-cepllem-4-carbo~cylic acid, which can be represented as 3- tl-methyl-lH-tetrazol-5-yl) -thiometllyl-7-.~2-hydroxy-2-(2-metllylimino-2,3-dihyd~o-1,3-thiazol-4~yl)acetamido]-3-cephem-4-caTboxylic acid, mpO 144 to l56C
(dec.).
I.R, Spectrum ~Nu~ol~
l764-l780 (broad9 e-lactam) cm N.M.R. Spectrum ~d6-dimethylsuloxidc,~) 2.8 (3}~, s) 3.S7 and 3.78 (2H, ~Bq, J=1711z) -103~ E - 73 ~ Z ~ ~ S 7 7 309 (3H, s) 4.21 and 4.42 (2H, ABq, J=15H~) 4.95 (1~, s) 5~12 (lH, d, J=5Hz) 5.65-~.75 (lH, m) 6.57 tlH~ ~) (7) 3-tl-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-5-chloro-1,3-thiazol-4-yl)acetamido~-3-cephe~-4-carboxylic acid, which can be represented as 3-(1-methyl-1l-l-_ tetrazol-S-yl)thiome~hyl-7-[2-hydroxy-2-(2-imino-5-ch~oro-2,3-dihydro-1,3-thiazol-4-yl)ace~amido~-3-cephem-4-carboxylic acid, mp. 148 to 154C tdec.~
I.R. Spectrum (Nujol) ; 3300 (broad), 1780, 1680, 1620 cm 1 N.M.R. Spectrum ~d~-acetone, ~
3.~87 (2H, broad s) 4.07 (3H, s) 4.37 t2H, broad s) .. 5.17 (lH, d, J-4Hz) 5.20 (lH, s3 5.88 ~lH, d, J=4Hz) (8~ ethyl-7o[2-(2-amino-l~3-thiazol-4-yl)glyoxylamid 3-cephem-4-carboxylic acid hydrochlvride, which can be represented as 3-methyl-7-l2-tZ-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxyl-amido3-3-cephem-4-carboxylic acid hydrochloride, dp. > 250C.
I . R. Spectrum (Nujol) ; 1780 (~-lactam) cm : N M.R. Spectrum (d6-dimethylsulfoxide, ~) 2 12 (3H, s) 3.S2 (2H, broad s) 5.17 ~lH, d, J-5Hz3 5.68 (lH, d3 J=5}1z) 8.3 ~lH, s) ~ (9) 3-Carbamoyloxymethyl-7-[2-(2-amino-193-~hiazol 4-:~ yl)glyoxylamido~-3-cephcm-4-carboxyli.c acid hydrochloride, which : can be Tepresented as 3- arbamoyloxymethyl-7-[2-(2-imino-2,3-dihydro-l~3-thia~ol-4-yl)glyoxylamidol-3-cephem-4-carboxylic ~cid hydrochloride, powder.
(1O)3-(5-Methyl-1,394-thiadiazol-2-yl)thiome~hyl-7-[2-,~t2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cepllem-4-carboxylic ~cid hydrochloride, which can be represented as 3-(5^methyl-1,3,4-thiadiazol-2-yl~*hiomethyl-7-[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamldo]-3-cephem-4-carboxylic acid hydrochloridea powde~.
- I.R. Spectrum ~Nujol) cm 1 1760-1780 tbroad, ~-lactam) cm 1 ; N.~.R. SpectTum (d6-dimethylsulfoxide, ~) 2.72 (3~ s) 3~75 (2H, broad s) 4.25 and 4~62 (2H, AB~, J=14Hz) : S.23 tl~, d, J=5Hz) 5.75 (lH9 d9 J=5H2) 8.33 ~lH, s) (`ll) 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cep~em-4-carboxylic acid hydro-chloride, which can be represented as 3-(1,3,4-*hiadia~ol-2-yl)-thiomethyl-7-~2-(2-imino-2,~-dihydro-1,3-thiazol 4-yl)glyoxylamido~-3-cephem 4-carboxylic acid hydrochloride, powder.
I.R. Spect~um (Nujol) 1778 (~-lactam) cm 1 -105- ~ ~ 75 5~
.
N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.7 (2H, broad s) 4.22 and 4.62 (2H, ABq~ J=16Hz) 5.17 (lH, d, J=5Hz) 5.7 ~lH, d, J=5Hz~
B.3 (l~l"s) 9067 (1~, s~
(12) 3~ Methyl~ tetrazol-S-yl)thiomethYl-7-[2-(2-a~i~o-1,3-th;azol-S-yl)glyoxylamido~-3-cephem-4-carboxylic acid hydrochloride 9 which can be represented as 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-~2-imino-2 7 3-dihydro-1,3-thiazol-5-yl)-glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, mp~ 140 , to 160C ~d~c.~.
; I.R. Spectrum (Nlljol) 1778 (R lactam) cm 1 N.M.R. Spect~um (d6-dime~hylsulfoxide, ` 3.7 . ~2H, broad s~
3.95 t3H, s) - ~- 4.3 (2H, b~oad s) 5.12 tl~l, d3 J~6Hz) 5.65 (lH, d" J~6Hz) 803 (lH7 s) 3-~1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-methylamino-1,3-~hiazQl-4-yl)glyoxylamido]-3-cep]lem-4-carboxylic zcid, which can be ~epresented as 3~ methyl-lH-tetrazol-5-yl)-thiomethyl-7-~2-(2-methylimino-2~3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, mp. 146 to 155C (dec.).
I.R. Sp~ctrum (Nujol) 1798 (~-lactam) cm 1 -106- ~ 7 ~ 3 ~
N.M.R. Spec~rum ~d~-dimethylsulfoxide, ~) 2085 (3H, s) 3.58 and 3.79 (2H9 ABq~ J-17Hz~
3.92 (3~, s) 4~2~ and 4.4 ~2H! AB~, J=14Hz) : 5.12 (lH,~d, J-.SHz) 5.75 (lH, d, J~S}-lz) 7,95 (~H, ~) (14) 3-i~eth~7-~2-hydro~y-2-(2~amino-1,3-t~.azol-4-yl) acetamido3-3-cephem-4-carbo~ylic acldt which ca~ be represented as 3 methyl-7-~2-hydroxy-2-(2-imino 2~3-dihgdro-1,3-thiazol-4-yl)acetamido~-3~cephem-4-carbosy'ic ac~d, mpO ~ 2503C~
:~2~?~Si7'7 ~ ' A mixture of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7- ~20 (2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which~can be represented as 3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-7-[2-(2-tetrahydro-pyranyl)oxy-2-(2-mesyli.mino-2,3-dihydro-1,3-thiazol-4-yl)ace~amido]-3-cephem-4-carboxylic acid, (0.85 g.), ethanol tl5 ml.), water (5 ml.) and 2N hydrochloric acid (5 ml.) was stirred for 2O5 hours at room temperature. After the reaction; the ~eaction mixtur~ was diluted with water ~20 ml~, adjusted ~o p~ B with 5~ sodium bicarbona~e aqueous solution and then washed wi~h diethyl ether. Thus obtained aqueous layer was adjusted to pH 4 to S with 10~ hydrochloric acid a~d washed with ethyl acetate. The aqueolls layer wasadiusted to pH l to 2 with
To dimethyl~ormamide t9.0 g.~ was dropwise added ,0 . .
phosphorus oxychloride (10.3 g.) o~er 20 minutes under stirTing and ice-cooling, and the mixture was stirred for 30 minutes at 40C~ To the mixture was added ethyl acetate (140 ml.) 7 and the mixture was cooled to -20C with stirring. To the mixture was added 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycarbonyl - imino-2,3-dihydro-1,3-~hiazol-4-yl)glyoxylic ~cid, (16.0 g.), and the mixture was stirred for 30 minutes at -2Q to -15C. Thus obtained mixture was added all at o~ce to a solution, which was prepared by stirring a mixture of 7-aminocephalosporanic acid (18.2 g.) and bis(trir,lethylsilyl)-acetamide ~56 ml.) in ethyl acetate (220 ml.3 for 30 minu~es ~ room ~emperature and then by cooling it at -40C. The mixture was stirred for l hour at -50 to -40C and further for 1 hour at -25 to ~20C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution ~800 ml.). The aqueous layer was separated from the mixture, adjus~ed to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried o~er magnesium sulate and then treatcd w;th an activated ~ S 7 ~
charcoal. Ater distillation o~ e~hyl acetate from the extract, the residue was pulverized in a mixture of diethyl ether (lOO ml.) and diisopropyl ether (200 ml.), collected by filtration and d~ied to give powder of 7-[2-(2-tert-pentyloxy-carbonylamino 1,3-~hiazol-4-yl3glyoxylamido3cephalospGranic ~
acid, which can be represen~ed as 7-~2-(2 tert-pentyloxycarbonyl-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]cepllalosporanic acid, (23.1 g.~
I.R. Spectrum (Nujol3 17B3 (~-lactam) cm~l N~M~RO Spectrum (d6-dimethylsul~oxide, ~) 2~17 (3~1, S?
3.4 - 3 9 (2H, m) 4.B and S.17 (2~, ABq, J=13 Hz~
5.25 ~lH9 d, J-5 Hz) 5.9 (lH~ dJ JG5 Hz) 8.45 (lH~ s) . ~
To dim~thylormamide (1.1 g.) was dropwise added phophorus oxychloride (1.5 g.) under stirring and ice-cooling, and the mix~ure was stirred for 30 minutes at 40C. To the mixture was added ethyl acetate (10 ml.~, and the mixture was cooled to--20 to -10C with stirring. To the mixture was added a solution of 2-hydroxy-2-(2-ter~-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hyd~oxy-2-(2-tert-pentyloxyca~bonylimino-2 ,3-dihydro-193-. thiazol-4-yl)acetic acid, ~1.1 g.) in ethyl. acetate (15 ml.) below -20C under stirring~ and then the mixture was stirred for 30 minutes at thc same temperature. Thus obtained s~
mixture was added all at once to the cooled solution p~epared in the similar manller as in Example 1 from 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid tl~9 gO)~ bisttrimethylsilyl~acetamide (6 ml.~ and ethyl acetate (20 ml.). The mix~ure was stirred for 30 mi.nut~s at -40C
and urther for ln5 hours a* -20 to -10C. After the reaction, thc reaction mixtu~e was poured into 5% sodium bicarbonate aqueous solution, and the aqueous layer was separated. The remaining ethyl acetate layer was further extracted with 5~
sodium bicarbonate aqueous solution. Thus obtained aqueous layer and the solution were combined toge~her and washed wi~h di~thyl ether. To the aqueous layer was added ethyl acc~ate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and ~hen the ethyl acetate laye~ was separated. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and then dried o~er magnesium sulfate.
Ater distillation of the solven~, the residue was pulverized in diethyl ether and then collected by ~iltra~ion ~o give pale brown powder of 3~ methyl-lH-t.etrazol-5-yl)thiomethyl-7-l2-formyloxy-2-t2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3~ methyl-lH-tetrazol-5-yl)~hiomethyl-7-[2-oTmyloxy-~-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-acetamido~-3-cephem--4-carboxylic acid, tO.86 g ).
I.R. Spectrum (Nujol) 1783 (~-lactam), 1680-1740 (CO) cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide; ~) 3.7 (2H, broad s) 3.94 (3H, s3 4.3 (2}1, broad s) ~ - 31 ~2~395~7 S.0-5.15 (lH, m) 5 55-5.8 tll~, m) 6.17 ~lH, s~
7.22 (lH, s~
8.36 (1~l, s) Example 5 _ To dime~hyl~ormamide (3~74 g ~ was dropwise added phos~horus oxychloride (6.46 g.) oYer 5 minutes under stirring and ice-cooling, and the mixture was stirred ~or 30 minutes at 40C. To the mixture was added ethyl acetate tl20 ml.) with stirring, and the mixture was cooled to -20C wi~h stirring.
To ~he mixture was added all at once 2-(2-oxo-2,3-dihydro-1,3-~hiazol-4-yl)glyoxylic acid, which can be represented as 2-~2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (6.05 g.) and to th~ mixture was added dimethylformamide ~55 ml.) over 10 minutes at -20C, and then the mixture was stirred for 40 minutes at the same temperature. Thus obtained mixture was added to the solution prepared in the simiiar manner as in Example 1 from 3-(1-methyl-lH-tetrazol-5-yl)thiomethyl 7-amino-3-cephem-4-carboxylic acid (lO.S0 g.), bis(trimethylsilyl)-acetamide (35 ml.) and ethyl acetate ~150 ml.), at -50 to -40C
with stirring. The mixture was stirred for 30 minutes at -40C and further stirre~d for 30 minutes at -20C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (250 ml.), and the aqueous layer was separated. The aqueous layer was washed with ethyl ace~ate and adjusted to pH 1 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over ma~nesium sulfate and then treated .
~ Z1~577 with activated charcoal. After distillation of ethyl àce~ate from the extract, the residue was pulverized in dicthyl ether, collected by filtration and dried to give pale yellow powder of 3-(1-methyl-lH-tetrazol-5-yl~thiomethyl-7-~2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carooxylic acid,which can be represen~ed as 3-tl-methyl-lH-tetrazol-S-yl)thiomethyl-7-[2-(2-hydroxy~ thiazol-4-yl)~lyo~yl-amido~-3-cephem-4-ca~boxylic acid~ t9-2 g.).
I.R. Spectrum (Nujol~
~- 1762 ~-lactam) cm 1 N.~l.R. Spectrum ~d6-dimethylsulfoxide, ~) 3.74 (2H, broad s) 3.93 t3H, s~
402S and 4.~ ~2H, ABq, J=14 ~z) 5.18 (lH, d, J~5 Hz) 5.73 (lH, dd, J-5 and 6 Hz) 7.97 ~lH, s) i ~ Example 6 ., To dimethyl~ormamide ~1.59 ~ as dropwise added phosphorus oxychloride (4.16 g.) under s~irring and ice-cooling, and the mixture was stirred for 30 minutes at 40C. To the mixture was added ethyl acetate ~20 ml.) with stirring, and the mixture was cooled to -20 to -10C wi~h stirring. To the mixture was dropwise added- a mixture of 2-(2-propanesulfonyl-amino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-propanesul~onylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylic acid, (6.0 g.), ethyl acetate ~60 ml.) and dimethyl-formamide (4 ml.) over 10 minutes at -20 to -10C with stirring, and tllen the mixture was stirred for 40 minutes at the same .
~ - 3 -~ Z~g5~77 temperature Thus obtained mixture was dropwise added to thc solution ~epared in the similar manncr as in Example 1 from 3~ methyl~ tetrazol-5-yl~thiomethyl-7-amino-3-cephem-4-carboxylic acid (7.8 g.)~ bis(trimethylsilyl)acetamide (22.9 ml.3 and ethyl acetate (156 ml~3, at -40C over S minutes with stirring. The mixture ~.~as stirred for 30 minutes at the same temperature and fu~ther s~irred ~or 1 hour at -5 to O~C.
A~ter the reaction, the reaction mix~ure was poured into 5%
sodium bicarbonate aqueous solution (150 ml.), and ~he aqucous layer was separat~d. The remaining ethyl acetate layer was further extracted with 5% sodium bicaTbon~te aqueous solution, and the extract ~as combined with ~he separated aqueous layer.
The aqueous solution ~as washed with e~hyl acetate, and ethyl acetate was added thereto. The mixture was adjusted to pH 2 with 10% hyd~ochloric acid and fi-l~ered, and then ~he ethyl acetate layer was separated f~om the filtrate. The r~maining aqueous layer was further extracted with ethyl acetate, and the extract was combined with the se~arated ethyl acetate layer. The ethyl ~cetate layer was washed wi~h water~ dried and then the solvent was dis~illed off. The Tesidue was pulverizcd in diethyl ether~ collected by fil~ration and dried to give 3-tl-methyl~ tetrazol-5-yl)thiomethyl-7-~2-(2-propane-sulonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-ca~boxylic acid~ which can be represented as 3-tl-methyl-lH-tetrazol-5-yl)-thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid9 (11.0 g.), m.p.
150Ctdec.~.
I.~. Spect~um (Nujol) 17~0 (~-lactam) cm~l _~4-5;77 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.73 (2H J broad s) 3.95 (3~, 5) 4.2 and 4.45 (2H, ABq~ J~13 Hz) 5.15 (lH, d~ J=5 ~z~
5.7 (lH, dd, Ja4 and 5 Hz) ~.25 (1~, s~
~` . , '.
xam~c 7 (i) To dimethylformamide (0.12 g.) was dropwise added phosphorus oxychloride ~0.2g g.~ under stirri.ng and ice-cooling, and the mixture was stirred for 30 minutes at 40C and then cooled to -20C. To the mixture was added all at once a solution of 2-(2-~e~rahydropyranyljoxy-2-~2-mesylamino-~,3-thiazol-4-yl)-acetic acid, which can be represented as 2- (2-tetrahydropy~anyl) -oxy-2-t2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, ~O.S~ g.3 in ethyl acetate (7 ml.) at -20C with stirring, and then the mixture was stirred for 30 minutes at -20 to - 10C.
Thus obtained mixture ~as addcd all at. once to the solution prepared in the similar manneT as in Example 1 from 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl 7-amino-3~cephem-~-carboxylic acid ~0.51 g.), bis(trimethylsilyl)acetamide ~l.S ml.) and ethyl ac~tate tlO ml.), a~ -40C. The mixture was stirred for 30 minutes at the same temperatu~e and further stirred for 1.5 hours at -20 to -10C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (20 mlO). The mixture was washed with ethyl acetatc, and the a~ueDus layer was sepa~ated theTefrom. Thus obtained aqueous .
- ~L2~S7~
layer was post-treated in a similar manner as that of example 5 to give 3~ methyl-1~l-tetrazol-5-yl)thiomethyl-7-L2-(2-te~ra-hydropyranyl ) oxy- 2 - (~ - mesy 1 amino- 1~ 3 - th i azol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be reprcs~ented as 3- (l-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-~2-tetrahydropyranyl)oxy-2-(2-mesylimino~293-dihydro-l93-thiazol-4-yl)acekamido]-3-cephem-4 carboxylic acid, (0.41 g.) (ii) To a mixture of 2-(2-tetrahydropyranyl~oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acidD t350 mg.~, triethylamine (~6 mg.), N~N-dimethylbenzylamine (half drop) and te~rahydrofu~an (7 ml~) was dropwise added a mixture of butyl chloroforma~e tl30 mg.) and tetrahydrofu~an ~1 ml.) over 1 minute at -15C, and thcn the mixture was s~lrred fo~ 30 minutes at -15 to -10C. To the mixture was added all a~ onc0 a mixture of 3-(1-methyl-lH-tetrazol-5-yl~thiomethyl -7-amino-3-cephem-4-carboxylic acid ~2~4 mg.), triethylamine (80 mg.) and 50~ tetrahydrofuran aqueous solution tlO ml~) which was cooled at 0C~ and the mixture was stirred for 3n minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reac~ion, the reaction mixture was concentrated. The resi`due was adjus~ed to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extrac~ed with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powdcr of 3~ nlethyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahyslropyranyl)oxy-2-t2-mesylamino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, 957~
.
wh;ch call be represented as 3- (l-methyl -lH-tetrazol-5 -yl) thio-methyl-7- ~2- t2-tetrahydropyranyl)oxy-2- (2-mesylimino-2,3-dihydro-1"3-tlliazol-4-yl)acetamido~-3-cephcm-4-carboxylic acid, (270 mg.).
N.M.R. Speckrum (d6-dimethylsul~oxide, ~) 2 . 95 (3H, s) 3. 75 ~2H, broad s) 3,95 (311, s) 4. 36 t211, braod s) 4.6-4, 8 . (lH, broad s) 5.05-5.2 (lH9 m) 5.5-5.8 ~lH, m) 6 . 25-6 . 85 (lH, m) Example 8 To dimethylformamide (5 ml.) was dropwise added phosphorus oxychloride (0.794 g.) under stirring and ice~cooling, and the mixture was stirred for 30 minutes at 40C~ and then cooled ~o -20C. To the mix~u~e was gTadually added 2-hydroxy-2- t2-formylamino-1,3-thiazol-4~yl)ace~cic acid, ~ hich ` can be ~epresented as 2-hydroxy-2- (2-formylimino-2,3-dihydro~
1,3-~hiazol-4-yl)acetic acid, (0.505 g.) at -20CC, and the mixtur~ was sti~red f~r 45 minutes at -12 ~o -10C. Th~s obtained mixture was added to a solution, which was prepared by stirring a mixture of 3-(1-me*hyl-lH-tetrazol-5-yl)thiomethyl- .
~-amino-3-cephem-4-carboxylic acid (0.804 g.~ bis(trime~hyl-silyl~a~etamide (2.62 ml.) in methylene chloride (15 ml.) for an hou~ at ~oom temperature and ~or 2 hours a~ 35 to 40C and then by cooling it to -30C, at a time. The mixture was s~ir~ed for an hour at -20 to --15C? and ~hen me~hylene chloride was distilled off, The resulting res;due was purified by a conYentional manner ts give 3-~1-methyl-lH-.'~ te~razol-S-yl)thiomethyl-7-[2-hydroxy-2-(2-foTmy;amino-1,3-thiazol-4-yl)acetamidol-3-cephem-4-carboxylic acid~ which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7-12-hydroxy- 2 - ~2- ~ormylimino- 2, 3- dihydro-l, 3-thiazol-4-yl)-ace~amido~-3-cephem-4-carboxylic acld, ~OOS1 g.).
I.R. Spectrum (Nujol) 1765-(~-lactam)-cm~
Example 9 A suspension of 3-(1-methyl-lH-tetrazol-5-yl)tlliomethyl-: 7-amino-3-cephem-4-carboxylic acid (1.46 g.), triethylamine (0.~292 g.) and dimethylaniline (0.713 g.) in methylene chloride ~(30 ml.~ was stirred ~or 20 minutes at room temperature.
~2~S77 To the mixture was added a solution of trimethylsilyl chloride (1.043 g.~ in methylene chloride ~10 ml.) over 5 minutes under ice-cooling, and the mixture was stirred for 2 hours at room tempe~atur~ and then cooled to -25C. On the other hand, a suspension of 2-(2 formylamino-1,3-thiazol-4-yl~glyoxylic açid, which can be represented as 2-(2-formy~imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, ~0.96 g.), thionyl chloride (0.697 g.) and dimethylformamide (0.214 g.) in methyl~ne chloride (12 ml.) was stirred for 4 hours, and the mixture was added to ~-~he above obtained cooled mixture over 12 minutes at -25 to -20C.
: The mixture was further s~irred for 30 minutes at the same temperature and ~or 30 minutes at -20 to -10C. Af~er the reaction, the reaction mixture was added to water (100 ml.), and stirred for 30 minutes at room temperature. The white precipitates were collectcd by fil~ration and then dried to giv~ dark brown powder of 3-(1-methyl-lH-tetrazol-5-yl)thio-me~hyl-7-[2-t2-formylamino-1~3-thiazol-4-yl)glyoxylamido]-3-. cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-te~razol-5-yl)thiomethyl-7-[2-(2-formy.limino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid.
IoR~ Spectrum (Nujol~
1782 (~-lac~am) cm~
N.M.R. Spectrum (d6-dimethylsulfoxide, 3.78 (2H, broad s) : 4.0 (3H, s) 4.4 t2H 9 broad s) 5.22 (lH, d, J=5Hz) 5.8 (lH, d, JaSHz) 8.52 (lH, s) 8~62 (lH, s) E - ~9 57~
Similarly, the following compounds were obtained~
(1~ 3~ 3,4-Thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-~o~mylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be reprcsented as 3-~1,3,4-thi`adiazol-2-yl)-thiomethyl-7-~2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4- carboxylic'acid .
I.R. Spectrum(Nujol) 1778 ~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsuloxide, ~) 3.56 and 3.7 (2H, ABq, J-16Hz) 4.24 and 4.56(aH, ABq, J=14Hz) : 5.05-5.16 t2H, m) 5.62-5.78 (lH, m) 7.13 (lH, s) 8.43 ~lH, s) i 9.47 tlH, s) ~ 2) 3-(1-Methyl-lH-tet~azol-5-yl)thiomethyl~7-[2-folmyloxy-2-(~-folmylamino-1,3-thiazol-5-yl)acetamido)-3-cephem-4-carboxylic acid, which can be represented as 3~tl-methyl-lH-tetrazol-5-yl)-thiomethyl-7-~2-formyloxy-2-t2-formylimino-2,3-dihydro-1,3-; thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid.
I.R. Spec~rum (Nujol~
1780 (~-lactam) cm~l N.M.R.. Spectrum (d6-dimethylsulfoxide, ~) 3.53 and 3~77 (2H, ABq, J-19Hz) 3.92 ' (31~, s~
4.45 (2}1, broad s) 4.95-5.15 (lH, m~
5.55 5.7 (lH, m) 6.4 ~lH, s) 2~
7.6 ~ , s) ~27 (lH, ~) .8~5 . tlH, s) (3) 3~ Methyl-lH-~etTazol-5-yl)thiomethyl-7-[2-(2-; formylamino-l~3-thiazol-5-yl)glyoxylamido3-3-cephem-4-carboxylic ; acid, which can be repTesent@d as 3-(l'-methyl-lH-tetrazol-5-ylj-thiomethyl-7-[2-(2-formylimino-2,3-dihydro-l,3-thiazol-s-yl)-glyoxylamido]-3-cephem-4-carboxylic acid.
~ I.R. Spectrum (Nujol) :~ l778 (~-lac~am) cm l N.M.R. Spectrum ~d6-dime~hylsulfoxide, ~) 3.7 (2H, broad s) 3.95 (3H, s~
4~2 and 4.42 (2H, ABq, J-1811z) i . 5,15 (lH, a, J~5Hz~
5.52-5.8 (lH, m~
8.53 (lH, s) 8.65 (l1~, s) :~ ~ .(4) 7-[2-~2-Pormylamino-1,3-thiazol-4-yl)glyoxylar,lido~-cephalosporanic acid, which can be represented as 7-~2-(2-o~mylim1no-2,3-dihydro-i,3-thiazol-4-yl)glyo~ylamido3cephalos-~ poranic acid, mp. 145C.
; I.R. Spec~rum (Nujol) 1780 t~-lactam~ cm l N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 2.06 (3H, s) 3.6 ~2H, broad s) 4.7 and 5.08 ~2H, ABq, J~14Hz) 5.22 (lHJ d, J=5Hz) 5.83 (lH, d, J=5Hz~
S7~
8.47 (lH, s) 8,6 (lH, s) tS) 3-Ca~bamoyloxymethyl-7-~2-(2-formylamino-1j3-~hiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-carbamoyloxymethyl-7-~2-~2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido}-3-cephem-4-carboxylic acid.
I.R. Spec~um (Nujol) 1770 t~-lactam) cm~l N.M~R, Spectrum (d6-dimethylsulfoxide, ~) 3~57 (2H, broad s~
4.65 and 4.87 (2H, AB~, J=14 Hz) 5 ~ tlH, d, J-5Hz) 5.8 (lH~ d, Ja5H~) ~,43 ~lH, s3 : 8.58 (lH, s~
(6) 3-(1-Methyl-lH-tetrazol-5-yl)t}liomethyl-7-[2-l2-(methy.l)thiocarbamoylamino 1~3-thiazol-4-yl3glyoxylamido~-3-~ephem-4-carboxylic acid, which can be represen~ed as 3-(1-" methyl-lH-tetrazol-S yl~thiomethyl-7-[2-[2-(methyl)thio-carbamoylimino-2,3-dihydro-1,3-thia~ol-4-yl3glyoxylamido)-3-cephem-4-carboxylic acid, 148C (sinter)) 160C (expand), 200C tdec . ~ .
; I.R. 5pectrum (Nujol~
1780 (~-lactam) cnl 1 N.M.R. Spectrwn (d6-dimetllylsulfoxide, ~) 3.02 ~3H~ s) 3.75 (2H, broad s) 4-35 . t2H, broad s) 5~17 ~ J dp J=SHz) ~Z~7~
5.4-5.95 (lH, m) 8.25 (lH, s) (7) 3-(5-Methyl-1,3-4-thiadiazol-2-yl)thiomethyl-7-[2-~2-formylamino-1~3-~hiazol-4-yl~glyoxylamid~]-3-cephem-4-ca~boxylic acid, which can be represented as 3- (S-methyl-l, 3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid.
I.R. Spectrum (NUJO1) 1780 (~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsulox;de, ~) 2.7 (3H, s) 3.75 (2H, broad s~
4.25 and 4.62 (2H, ABqJ J-14Hz) 5.12 (lH~ d, J=SHz) 5.8~ (lH, d, J=SHz) 8.5 tlH, s) 8.65 .(lH, s) t8) 3-~l~394-Thiadiazol-2-yl)thiomethyl-7-[2-~2-~orm : ~ amino-1,3-~hiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can b.e represe~ted as 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-~2-(2-formylimino-293-dihyd~o-1,3-thiazol-4-yl)-glyoxylamido~-3-cephem-4-carboxylic acid, powder.
I.R. Spectrum (Nujol) 1775 t~-lactam) cm~l N.M.R.- Spectrum ~-d6-dimethylsul~oxide, ~) 3.64 and 3.8~ (2H, ABq, J=16Hz~
4O32 and 4.66 (2H, ABq7 J-14Hz) 5.22 tll~, d, J-5~z) 5.78 . (lH, d, J=5Hz) 8.45 (lH, s~
\
57~
8.57 ~lH, s) g S7 (lH, s) (g~ 3~ Methyl lH-tetrazol-5-yl)thiomethyl-7-~2-12-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl~glyoxyl-amido]-3-cephem-4-carboxylic acid, powder.
I.R. Spectrum (Nujol~ ~
1790 (~-lactam) cm 1 N.M.R. Spectrum ~CDCQ3, ~) 3.6 (3H, s) 3.73 (2H, broad s) .9 t3H~ s) 4.36 (3H, broad s) 5.13 (lH9 d; 3=5Hz) 5.83 (lH, d, J=5Hz) ~.7 (lH, s) (10~ 3-~1-Methyl-lH-tetra~ol-5-yl)thiomethyl~7-[2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-ca~boxylic acid, which can be represented as 3-(1-methyl-lH-`.~'' tetrazol-5-yl)thiomethyl-7-[2-(2-formylimino-5-~hloro-2,3-dihydro-1,3-thiazol-4-yl~glyoxylamido]-3-cephem-4-ca~boxylic acid, power, mp. 148 ~o 155C ~dec.~.
I.R. Spectrum (Nujol) 3200, 1780, 1680 (broad), 1550, 1290~ 1183, 1110 cm 1 N.M.R~ Spectrum (d6-acetone,~) : 3.85 (2H, broad s) 4.00 (3H, s) 4.45 ~2~1, broad s) S.28 . tlH, d, J-5Hz~
5.00 (lH~ d, J=5Hz~
8.71 tl~i, s) ~ - ~4 ~ S~ 7 t11~ 3-Me~hyl-7-12-t2-formylamino-1,3 thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-methyl-7-l2-(2-formylimino-2,3-dihydro-1 9 3-thiazol-4-yl)-~lyoxylamido]-3-cephem-4-carboxylic acid~ mp. 180C and carbonized at 210C.
(12) 3-(5-Pethyl-1,3,~-thiadi~zol-2~yl)thiomethyl-7-~2-hydroxy-2-(2 ami~o-l 9 3-thiazol-4-yl)acetamido~-S-cephem-4~
carbo~ylic acid, which ca~ be represe~ted ~s 3-(5 methyl-1,s,4-thiadiazol~2 yl~thiomethyl-7~[2-hydro~y-2-(2~imino-2,3-dihydro-1,3-th~azol-4~y~)acet~mido]~-cephem 4~carbo~1ic acid, pale yellow powder.
(13) 3-(1,3,4~hiadiazol-2-yl)thiomethyl~7-[2-hydro~y-2-(2-amino 1,3~thiazol-4-yl)acetamido]-3 cephem-4-carboxylic acid~ ~hich can be represent~d a~ 3-(1,3,4-thiadia~ol-2-yl~-t~iomethyl-7-[2-hydro~y-2-(2-imino-2,3-dihydro-1,3-thiazol 4-yl)-acetamido3-3-cephem-4~carbo~ylic acid, pale brown powder, mpO 151 to 180 C (dec~).
(14) 3-(5-Plethyl~ ,4-o~adiazol-2~yl)thiomethyl 7-~2-hydroxy-2-(~-amino-1,3-thiazol-4-~l)acetamido]-3-cephem-4 carbo~ylic acid, which can be repre~ented a~ 3-~5-methyl-1,3,4-oxadiazol~
2-yl)~hiomethyl-7-~ -hydro~y-2-(2-imino-2,3-dihydro-1,3-thiazol~
4-~l)acetamido]-3-cephem-4-carboxylic acid.
IJR. ~pectrum (Nujol) 1780 (~-lactam) cm~l (15) 3-(4-~ethyl-4H-1,2,4-triazol-~-yl)thiomethyl-7-[2-h~dro~y-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid~ which can be represented as so(4-m~thyl-4h-1.2,4-triazol-~yl~thiom9thyl-7-~2~hydro~y-2-(2-imino-2,~-dihydro-l,~-thiazol-4-yl)acetamido~ ~-cephem-4-carbo~ylic acid.
I.R. Spectrum (Nujol) 1760 ~-lactam~ cm~~
-75- ~-45 ~Z~357~
(16) ~-Carb~moylo~ymethyl-7-[2 hydroxy-2-(2-~mino-1,3-thiazol-4-yl)acetamidO~-3-cephem-4-carboxyliC acid, which ca~
be repre~ented ac 3-carba~oylo~ymethyl-7-~2-hydro~y-2-(2-imi~lo-2,3-dihydro-1,3-thiazol-4yl)acetamido]-3-cep~em 4-carboxylic acid, mp~ > 270C.
~ 17) 3-Methyl-7-[2-hydro~y-2-~2-amino-lJ3-thi~zol-4-yl)-acetamido]-3-cephem-4-carbo~ylic acid, which can be repr~sented aB 3-methyl-7-[~-hydroxy 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp. > 250C.
(18) 3 (1-Methgl-l~-tetrazol-5~yl)thiomethyl-7-~2-hydroxy-2-(2-amino~ thiazol-5-yl)acetamido] ~-c~phe~-4-cærboxylic acid~ which can be represented as ~ methyl-Ih-tetrazol-5-yl~thiomethyl-7 [2-hydro~y~2-t2-imi~o-2,3-dihydro-1,3-thiazol~5-yl)acetamido~ 3-cephem-4-carboxylic acid9 mp. 130 to 200C (dec.).
(19) 3~ Iethyl-lH tetrazol-5-yl)thiom~thyl-7-~2-hydroxy-2-(2-amino-5-chloro-1,3-thi&~ol-4-yl)acetamido]-3-cephem-4-carboxylic ~cid, which ca~ be represented as methyl-lH-te~razol-5 yl)thiomethyl-7-[2-h~dro~y-2-(2-imi~o-5-chloro-2,3-dihydro-1,3-thia~ol-4-yl)acetamido]-~-cephem-4-~a~boxylic acid, mp. 148 to 154C (dec.).
(2~ (1-Methyl-IHtetrazol-5-yl)thiomethyl-7-CDl,2-hydroxy-2 (2-formylamino~5-chloro-1,3-thiazol-4-yl)acetamido]-3-ceph~m-4-carbo~ylic acid 9 which can be repre~ented as 3-(1-methyl-IH-tetrazol-5~yl)thiomethyl-7-[DL,2-.hyd~.oxy-~-(2-~ormylimino-5-chloro-2,3-dihydro-1,3-thiazol 4-yl)acet~ido]-3 cephem-4~carbosylic aoid, mp. 160 to 165C (dec.).
(21) 3-(1-Methyl-lH-tetrazol-5 yl)thiomethyl~7-[2-hydroxy-2-(2-mesylaminO-li3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be repre~ented a~ 3~ methyl-lHDtetrazol-5-yl)-~ - ~6 95~7'7 thio~ethyl-7 ~2-hydroxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4~yl)acetamido~-3-cephem-4-carbosylic acid, pale brown powder, mp. 120 to 146C (dec.)~
t~2) ~ ethyl-IH-tetrazol-~-yl)thiomethyl-7-[~-hydro~y-2-(2-propane~ulfonylamino-1,3-thiazol-4~yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(1m0thy~-lH-tetrazol-~-yl)thiomethyl-7-~2-hydroxy-2-(2-propane~ul~onylimino-2,3-dihydro~ -thiazol-4-yl~acetamido]-~-cephem-4-carboxylic aci~ 9 mp. 160 to 170C (dec.).
(2~) 3-(1 Methyl~ tetra~ol-5-yl)thiomethyl-7-~?-h~droxy-2-[2-(methyl)thiocarbamoylamino-1,3-thiazol-4-yl]acetamido3-3-cephem-4-carboxylic acid, which c~n be repres~ted as 3~
methyl-l~ tetrazol-5-yl~thiomethyl-7-~2-hydrox~ 2-~2-(methyl)-thiocarbamoylimino-2,3-dihydro-1,3-thiazol-4-ylJacetamido]-3-cephem-4-carboxylic acid, 155C (~inter), 160~C (dec.).
(24) ~ Methyl-I~-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-~2-methy~amino-1,3-thiazol-4-yl~ac~tamido]-3-cephem-4-carbo~ylic acid, which ca~ be repre~e~ted ~s 3-(1-methyl-lH-tetrazol-5-yl) thiomethyl-7-[2-hydroxy-2-(2-meth~limino-2,~-dihydro-1,~-thia~ol-4-yl)acetamidoJ~3-cephem-4-carboxylic acid, mp. 144 to 156C (dec.).
~ 25) ~ Methyl~ tetrazol-5-yl)thiomethyl-7-[Dr-~-hydroxy-2-[2-(N methyl~-tert-pentyloxycarbonylamino~19S-thiazol-4-~l]acetamido~-3rcephem-4-carbsxylic acid.
I.R. Spectrum (~ujol) 1770-1790 (broad) cm 1 .
_77_ E - 47 (26~ 3~ Ilet~yl-lH-tetrazol-5-yl)thiomethyl-7-[~-~ydro~y-2-(2-020~29~-dihydro 1~3-thiazol-4-yl)ac~tami~o~ cephem-4-carboxylic acid~ which oan be repre~ented ~ met~yl 1~-tetra~ol-5-yl~thiomethyl-7-[2-hydroxy-2-(2-hy~ro~y-1,~-thiazol-4-yl)acet~mido]-3-cep~em-4-carboxyliG acid, mpO 110 to 121C (Qec.)0 (27) 3-~1-Methyl-lH-~etrazol-5-yl~thiomethyl-7-[2-(2-amino-1,3-thîazol 4-yl~glyoxylamido~-3-cephem-4-carboxylic acid, which can be represented as 3~ me~hyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-imino-2,3~dihydro~1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, mp. 147 to 160C (dec.).
(28) 3-~5-Methyl-1,334-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-173-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, which can be repTesented as 3-(5-methyl-1,3,4-thiadiazol-Z-yl)-thiom~thyl-7-C2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl~glyoxyl-amido]-3-cephem-4-carboxylic acid, mp~ 156 to 160C (dec.).
(29) 3-(5-Methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7-~2-~2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1~3,4-oxadiazol-~-yl)thiomethyl-7-~2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid.
I.R. Spectrum ~Nujol) 1775 ~-lactam) cm 1 (-~0) 3-(4-Methyl-4H-1,2,4-triazol-~-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-7-~2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol) 1775 (~-lactam) cm 1 ~78- ~ - 48 ~z~s~
(31) 3-tl~3~4-Thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1~3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydro-chlorid~, which can be rep~esented as 3-(1,3,4-thiadiazol-2-yl)-~hiomethyl- 7- [2- (2-imi~o-2~3-dih~dro-1,3-thiazol-4-yl)~lyoxylamido~-~-cephem~4-carboxylic acid hydrochloride, powder.
I.R. Spec~rum ~Nujol) 1778 (~-lactam) cm ~ 32) 3-Carbamoyloxymethyl-7- [2- (2-amino-1,3-thiazol-4-yl~glyoxylamido]-3-cephem-4-carbnxylic aoid hydrochloride, which can be represented as 3-carbamoyloxymethyl-7-[2-(2-imino-2,3-dihydro-1J3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hyd~ochloride, powder.
(33) 3-Methyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, which ~an be represented as 3 - me thyl - 7 - [ 2 - ( 2 - imino - 2, 3 - dihyd~o 1 9 3 - ~ch i a zo 1- 4 - yl ) g lyoxy 1 -amido]-3~cephem-4-carboxylic acid hydrochloride, dp. > 250C.
( 34 ~ 6- [ 2- ( 2-Aml~o-1, 3-thiaæol-4-yl ) gly o~cylamido ] - 5a, 6-dihydr4 3~:I,7~[-azeto~2,1-b]~llro[3,4~d~[193]thiazine 1,7-(4~ dione hydrochloride ~ which can be repre~ented as 6-[ 2- ( 2-imirLo-2 9 3-dihydro-l, 3-thia~ol-4-yl ) glyo~ylamido3 -5a, 6 ~dihydro-3H, 7~-azeto~2,1~b~uro~3,4-d]~1,3]thiasine-1,7-(4H)-dions hydrochlorideO
I.R. Spactrum (~ujol3 1786 (~-lactam~ cm~l (35) 3~ Meth~ tetrazol-5 yl)thiomethyl 7-~2~ amino-1~3-thiazol-5-yl)glyoxylamidoJ;;~ cephem-4-carboxylic acid hydrochloride, which can be ropre~onted a~ 3~ methyl-I~-tetrazol-5-yl)thiomethyl-7~[2-(2-iml~o-2,3 dihydro-1,3-thiazol-5-yl)-glyoxylamldo]~3-cephem-40carboxylic acid hydrochloride, mp. 140 to 160C (de¢.) ~Z~. ~577 (36) 3-(1-Methyl-lH-tetrazol-S-yl)thiomethyl-7 [2-~2-methylamino-133-thiaz~1-4-yl)glyoxylamido]-3-cephem-4^carboxylic acid, which can be represented as 3-(1-me~hyl-lH-tetrazol-5-yl)-thiomethyl-7-~2-(2-methylimino-2~3-dihydTo-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acidg mp. 146 to 155C (dec.).
~ - 50 ~ Z~t~ ~ ~ 7 Example lO
To a solution of 3-~5-methyl^1,3,4-thiadiazol-2^yl~-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, wh~ch can be represented as 3-~5-methyl-1,3,4-thiadiazol-2-yl~thiomethyl-7-L2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid~ (3.36 g.) in methanol (35 ml.) was added lN sodium hydroxide aqueous solution (5.5 ml.) under ice cooling, and to the m;xture was d~opwise added an aqueous solution of sodium borohydride (~1 mg~) in water t2.5 ml.) over 2 minutes f at 10 to 15C. The mixture was stirred for 10 minutes at the same ~emperature, and then methanol was distilled off from the mixture helow 40C under reduced pressure. The remaining aqueous solution was washed with a small amount of ethyl acetate, adjusted to pH 5 to 6, with 10~ hydrochloric acid, further washed with a small amount of ethyl acetate. The solution was adjusted to pH 2 with 10~ hydrochloric acid, and then extracted with e~hyl acetate. The extract was washed with water and a sa~urated aqueous solu~ion of sodium chloride in turn, dried over magnesium sulfate and ~hen treated with an activated charcoal. The sol~ent was distilled off from the extract till the volume of the extract became a small amount. l~e p~ecipitates were collected by filtration, washed with a small amount of ethyl acetate, and then dried t~ give 3-~5-methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-hydroxy-2-(2-tert-pentyloxy-carbonylamino-1,3-thiazol-4-yl)acetamïdo]-3-cephem-4-carboxylic acid, which can be ~epresented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)acetamidoJ-3-cephem-4-carboxylic acid, (1.69 g.). On the o~her hand, the mother liqu~r and _81-~ 2 ~
the ethyl aceta~e washing were combined togethcr and concentrated under reduced pressure, and then the prccipitates were similarly treated as aforemcntioned to give the same object compound (0.~0 g-)~
I.R. Spectrum ~Nujol) 1785 (~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 2.S7 ' (3H, s3 3.55-3.83 (21~, broad s~
4.25 and 4.53 (2H, ABq 9 J=14 Hz) 5.1 (lH, s) 5.13 (lH, d3 5.7 tl~, d) 7.05 ~lH, s) Example 11 To a solution of 3~ 3,4-thiadiazol-2-yl)thiomethyl-7-[2-~2-tert-pentylQxycarbonylamino-1,3-thiazol 4-yl)glyoxyl-~mido]-3-cephem-4-carboxylic acid, which can be represented as 3~(1,3,4-thiadiazol-2^yl)thiomethyl-7-~2-(2-teTt-pentyloxy-carbonylimino-2~3-dihydro-1,3-thiazol-4-yl)glyoxylamid~]-3-cephem-4-carboxylic acid, t3.1 g.) in methanol ~30 ml.) was added lN
sodium hydroxide aqueous solution ~S. 2 ml . ~ under ice-~ooling and stirring. To the mixture was drop-ise added a solution of sodium borohydride ~0.074 g.) in water (2 mlO) over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature.
After the reaction, the reaction mixture was concentratcd under reduced pressure. To the residue were added water and e~hyl ace~ate, and the aqueous layer was separated. The a~ueous layer was adjusted ~o pH 5 to 6 with 10~ hydrochloric acid and then washed with ethyl acetate. To the aqueous layer was added ethyl acetateS and the mixture was adjusted to pH 1 to 2 wi~h 10%
hydrochloric acid. The ethyl ace~ate layer was separated, washed with wa~er, dried oYer magnesium sulfate and then trea~ed with ~cti~ated charcoal. After distillation of the sol~ent ~rom the ethyl acetate laye~, ~he remaining residue was pulverized in diethyl ether, collected by fil~ration and then dried to gi~e pale yellow powder o 3~ 3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-~hiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid~ which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2^tert-pentyloxycaTbonylimino-2,3-dihydro-1~3-thiazol-4-yl)ace~amido~-3-cephem-~-carboxylic acid, ~2.2 g ).
N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.53 and 308 (2H9 AB~, J=17 Hz) 4~33 and 4.7 ~2ll, ABq, J=13 Hz) 5.0 (lH, s) 5.15 (1}~ d, J=4 Hz) 5.6 ~lH, d, J-4 Hz) 7.0 ~lH, s) 9.43 tlH~ s) Example 12 To a solution of 7-~2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]cephalosporanic acid, which can be represented as 7-~2-(2-~ert-pen~yloxycarbonylimino-2,3-dihydro-193-thiazol-4-yl)glyoxylamido~cephalosporanic acid, t5.4 g,) in methanol (54 ml.) was added lN sodium hydroxide aqueous solution (10 ml.) under cooling at 10 ~o 15C. To the mixture was dropwise added a solution o sodium borohydride (142.~ mg.) ~L2~ S~t~
in water ~3.~ ml.) over 30 minutes at the same temperature, and ~hen the mixture was stirred for 15 minutes at the same tempera-ture. After the reaction~ the reaction mixture was concen~rated at 30 to 35C under ~educed pressure. -The~residue was post-treated in a similar malmer as that of examplell to give powdeT
of 7-[2 hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid, which can be reprcsented as 7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]cephalosporanic acid, (4.2 g.~.
I.R~ Spectrum (Nujol~
1783 ~-lactam) cm 1 N~Mo R. Spectrum ~d6-dimethylsulfoxide, ~) 2.07 (3H, s) 4.7 and 5.07 ~2H, ABq~ J=14 Hz~
5~08 ~lH, s) 5~13 ~lH, d, J~5 Hz~
5.53-5.95 tl~ m) 7.03 (lH, s) Ex mple 1~
To a mixture of 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7-12-(2-propanesulfonylamino-1,3-thiaæol-4~1)glyoxyla~ido~
cephem-4-carboxylic acidg which can be represented as 3-(1-methyl-lH-te~razol-5-yl)thiom0thyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, t$rO g.), methanol (160 ml.) and lN sodium hydroxide aqueous solution (13.6 ml.) was dropwise added a mixture of sodium borohydride ~0.26 g.) and ethanol (15 ml.) over 20 minutes under sti~ring and ice-cooling. The mixture was furthcr stirred for 1 hour, and then methanol was distilled off. ~Ic residue -84- E - 54`
-5~7 was dissol~ea in water, and the solution was washed ~ith ethyl acetate. To ~he aqueous solution was added ethyi acetate, and the mixture was adjusted to pH 2 with 10~ hydrochloric acid, and ~hen the ethyl acetate layer was separat~d from the mixture.
The remaining aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate extract was combined with the separated ethyl ace~a~e layer, washed with a saturated aqueous solution of sodium chloride and then dried, The solvent was distilled off, and ~he residue was washed with die~hyl ether and then dried to give 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7- [2-hydroxy-2- t2-propanesulfonylamino-lp3~thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3- ~1-methyl-lH-te~razol-5-yl) thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (5.5 gO), mp. 160 to 170C (dec.).
NoM~R~ Spectrllm (d6-dimethylsulfoxide, ~5) 3.73 (2H, broad s~
J 3.97 ~3H, s3 4.35 (2H, broad s) 5.03 (lH, broad s) 5.13 (lH, d, J=5 Hz) 5.5-SO~ 1, m) 6.67 (lH, s) .
Example 14 To a mixture o 3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-7-[2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephe~-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetTazol-5-yl)chiomethyl-7-[2-(2-hydroxy-1~3-thiazol-F. - 55 --8~---4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (5.2 g.3, methanol (200 ml.) and lN sodium hydroxide aqueous solution (10.8 ml.) was dropwise added a mixture of sodium borohydride t0.205 g.) and ethanol ~8 ml.) over 10 minutes at 5 ~o 10C with stirring.
The mixture was further stirred for 20 minutes at the same temperature, and then a mixture o~ sodium borohydride (0.01 ~.) and ethanol ~0.5 ml.) was further added thereto at the same temperature. The mixture was further stirred for 30 minutes at the same temperature 9 and then ~he r~action mixture was concentrated under reduced pressure~ To the residue was added water (200 ml.), and the solution was washed with ethyl acetate.
The aqueous solu~ion was adjus~ed ~o pH 5 with 10% hydrochloric ~cid and washed with ethyl acetate. The solution was adju~ted to pH 1 with 10% hydrochloric asid and extracted with ethyl ace~ate. The remaining aqueous layer was subjected to salting-out and then u~ther extracted with ethyl acetate. The ethyl acetate extracts were combined together, washed wit~ a saturated aqueous soluti~n o sodium chloride 3 dried over magnesium sulfat~ and ~hen treated with activated charcoal.
The solven~ was distilled off, and the residue ~as pulverized in diethyl ether, collected by filtration and then dried to give pale yellow powde~ o~ 3-tl methyl-lH-tetrazol-5-yl)thiomethyl-7-l2-hydroxy-2-(2-oxo-~,3-dihydro-1~3-thiazol 4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-7-~2-hydroxy-2-~2-hydroxy-1, 3-thiazol-4-yl)ace~amido~-3-cephem-4-carboxylic acid, (3.6 g.), mp. 110 to 121QC (dec.).
I.R. Spectrum tNujol) 1780 (~-lactam) cm 1 N.M.R. Spectrum (NaDCO3, ~) 3,45 and 3.83 (~H, ABq, J=18 Hz) 4.08 (3H, s) 4.04 and 4.42 ~2H, ABq~ J=14 Hz3 4.85 (lH, s) 5.15 tlH, d, J=4 Hz) 5.6 t~H, d, J=4 ~z~
: 6.5 tlH, s) BxamPl-e 15 To a solution of 3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-7-~2-[2-(N-methyl-N-~ert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylamido]-3-cephem-4-carboxylic acid (2.2 g.
ln methanol ~22 ml.) was added a lN sodium hydroxide aqueous solution (3.6 ml.~ under cooling a~ 10C, and to the mixture was dTopwise added an aqueous solution of sodium borohydride ~41 mg.) in water (1 ml.~ over 20 minutes under cooling at 10 to 15~C. The mixture was sti~red for 30 minutes at the same t temperature, and then methanol was distilled of~ from the mixture underreducedpressure. To the residue were added water ~20 ml.) and ethyl acetate (40 ml.), and the aqueous layer was separated.
T~ tlle aqueous layer was added ethyl ace~ate~ and the mixture was adjus~ed to pH 1 to 2 with hydrochloric acid, and then the ethyl acetate layer was separated. The e~hyl aceta~e layer was washea with a saturated aqueous solution o sodium chloride, -dried over ma~nesium sul~ate and then treated with an activated cha~coal. The solvent was dis~illed off from ~he ethyl ace~ate laye~, and ~he remaining oily subs~ance was pulverized in diethyl e~her. The powder was collec~ed by fil~ration and then dried to give 3~ metnyl-lH-tetrazol-5-yl)thiometnyl--~7- ~ - 57 7-[DL-2-hydroxy-2-[2-(N-me~hyl-N-ter~-pelltyloxycarbonylamino)-1)3-thiazol-4-yl]acetamidoj-3-cephem-4-carboxylic acid (1.7 g.).
Spectrum (Nujol~
1770-1790 (bro~d) cm 1 N.M.R. Spectrum ~CDCQ39 ~) 3.5 (3H, s) 3.65 (2H, broad s) 3.9 (3~, s~
4.35 - (2H, broad s) 5.05 ~lH "d~ J-5Hz) . 5025 (lH, s) 5.8 ~lH, d, J=5Hz~
` 6.95 (lH, s) Similarly the ollowing compounds were obtained.
tl) 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2- t2-amino-1 ,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid9 which can be represented as 3-~5-methyl-1,3,4-thiadiazol-2-yi)tlliomethyl-7-[2-hydroxy-2-(2-imino-2,3-di}lydro-1,3-thiazol-4 yl)acetamido]-3-cephem-4-carboxylic acid, pale : yellow powder.
(2) 3-(1,3,4-Thiadiazol-2-yl~thiomethyl-7-~2-hydroxy-2-t2-amino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic ~acidJ which can be represented as 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-L2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)-~cetamido]-3-cephem-4-carboxylic acid, pale brown powder, mp. 151 to 180C (d~c.), -8~-~2~57~
~ ) 3~ Methyl ~ - te~razol- ~-yl~ thiomethyl - 7 - ~2-hydroxy-2-(2- mesylamino-1,3-thiazol-~-yl)acetamido~-3-cephem-4-carboxylic ~cid7 which can be represented as 3-(1-methyl-lH-te~razol-5-yl3-thiomethyl-7- [2-hydToxy-2--(2-mesylimino-2,3-dihydro-1,3-thiazol-4~yl)acetamido]-3-cephem-4-carboxylic acid, pale brolYn powder, mp~ 120 to 146C tdec. ) .
(~) 3-(1-Methyl-lH-tetrazol-S-yl~thiomethyl-7-~2-hydroxy-2 (2-tert-pentyloxycarbonylamino-l,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3- (l-methyl-lH- tetrazol- 5-yl) ~hiomethyl ~ 7- ~2 -hydrox~- 2 - (2 -tert-pentyloxy-carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, pale brown powder.
~ 5) 3- t5-Methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7- [2-hydroxy-2-(2 amino-1,3-thiazol-4~yl)acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3v4-oxadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl~ace~amido~-3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol) 1780 (~-lac~am) cm~l t6) 3-~4-Methyl-4H- 192, 4-triazol-~-yl) thiomethyl - 7- ~2-hydroxy-2-(2-amino-1~3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acidg which can be represented as 3-(4-methyl-4~l-1,2, 4-triazol~3-yl)thiomethyl-7-[2-hydroxy-2- ~2-imino 2 ~3-dihyd~o-l ,3-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol~
1760 (~-lactam) cm 1 ~ ~z~s~ ~
(7) 3-(l Methyl lH tetrazol-5-yl)thiomethyl-7-~2-hydroxy-2-(2-ormylamino-1,3-thia~ol-4-yl~acetamido]-3-cephem-4-carboxylic acid, whi.ch can be represented as 3-(1-methyl-lH-t~trazol-5-yl)-thiomethyl-7-~2-hydroxy-2-(2-~ormylimino-2,3-dihydro-1,3-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, bro~rnish white powder.
N.M.R. Spec~rum (d6-dimethylsulfoxide, ~) 3.67 (2H, broad s) 3.9 t3H. s) 4~25 t2H, broad s) ; 5.05 tlH, d9 J-5Hz~
` ~.1 (lH, s?
5.53-5,8 ~lH, m) 7.07 (lH, s?
8.45 (lH, s) (~) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-~DL-2-hydroxy-2-t2-formylamino-5-chloro-1,3-thiazol-4-yl)acetamido3-3-cephem-4-carboxylic acid, ~hich can be represcnted as 3-tl-methyl-lH-te~razol-S-yl)thiomethyl-7-EDL-2-hydroxy-2-~2-, fol~mylim;no-S-chloro-2,3-dihydTo-1,3-thiazol-4-yl)acctamidoJ-3-cephem-4-carboxylic acid, mp. 160 ~o 165C (dec.).
~90~ ~ - 60 ~L2~9S~rdJ
: I.R. Spectrum ~Nujol) 3100-3600, 1780~ 1680 (broad), 1530, 1280, 1175, 1100, 1055 cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, 3.83 (2~, broad s~
4.03 ~3H~s) 4.43 (2H9 broad s) 5.23 tlH, d, J=5Hz) ; 5.42 ~lH, s3 5.87 (1HJ d9 J-SHz) , 8~78 tlH, S) t9) 3-(l-Methy~ -tetrazol-s-yl~*hiomethyl-7-l2-hydr 2-[2-(methyl3thiocarbamoylamino-153-thia~ol-4-yllacetamido]-3-cephem-4-ca~boxylic acid, which can be TepTesen~ed as 3-(1-methyl-lH-tetrazol-S-yl)tlliomethyl-7-~2-hydroxy-2-~2-(methyl)-thiocar~amoylimino-2,3-dihydro-1,3-~hiazol-4-yl~-acetamido]-3-cephem-4-carboxylic acid, 155C (sinter~, 160~C (dec.).
I.R. Spectrum (Nujol) 17$0 (~-lactam) cm l ; N~M.R. SpectTum (d6-dimethylsulfoxide, ~) 3.06 (3H, s) 3.75 (2H, broad 5) 4.33 t2H, broad s) 5.15 ~2H, m~
.5.64 and 5.78 (lH, m) 7,05 ' ~lH, s) (lO) 3-tl~3~4-Thiadiazol-2-yl~thiomethyl-7-[2-hydroxy-2-(2-fo~mylamino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic scid, which can be represented as 3-(1,3,4-~hiadiazol-2-yl)-~hiomethyl-7-~2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-2~ ~ ~7 ~
~hiazol-4-yl)acetam~do]-3-cephem-4-carboxylic acid, pale yellow powder, mp. 105 to 130C (dec.).
I.R. Spectrum (Nujol) 1760-1780 (~-lactam) cm 1 N.M.R. Spectrum (d6-dimethylsulfoxide, 3 . 37 (2H "broad s) 4.2S and 4.62 (21i, ABq, J~14Hz) 5.1 (lH, d, J~5Hz) 5.15 (lH, s) 5~3-5.9 ~lH, m~
.~ 7.15 . (~HD S) 8,45 (lH, s) 9~62 (lH, s) ~1) 3-Carbamoyloxymethyl- 7 - I 2 -hydroxy-2-~2-amino-1,3-thiazol-4-yl)acetamido~-3 cephem-4-carboxylic acid, which can be represented as 3-carbamoyloxymethyl-7-[2-hydroxy-2-~2-imino-2,3-dihydro-1,3-~hiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, mp. ~ ~70~C.
. ~ I.R. Spect~um ~Nujol~
1780 ~-lac~am) cm~l N.M~n. Spectrum (d6-dimethylsulfoxide~ ~) 3.43 and 3.65 (2H, ABq, J=14Hz~
4.6 and 4.85 (2H, AB~ J=15Hz~
: 4.86 ~1~, s) 5,1 (lH, d, J~5Hz) 2.6-2.75 (lH, m) 6.43 ~lH, s) ~ 2) 3-Methyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)-acetamido~-3-cephem-4-carboxylic acid, which can be represented as 3-methyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-E - ~2 _92-yl)acetamidoJ-3-cephem-4-carboxylic acid9 mp. ~ 250C.
I .R. Speotrum (Nuj ol) 1760-1780 (~-lac1:am) cm~l N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 2.07 t3H, s) : 3.33 and 3.68 (2H "ABq~ J=18~z) 4,93 (lH; s) 5.1 (lH, d) 5~57-5.7 (lH, m) $.5 ~lH, s) f tl3~ Meth~ tetrazol-5-yl)~hiome~hyl-7-[2-hydroxy-2-(2-amino~ thiazol~5-yl~acetamido]-3-cephem-4 carbo~ylic acid7 which ca~ be represe~ted as 3~ methyl-I~
tetrazol-5-yl)thicmethyl-7-t2-hydrox~-2-~2-imino-2,~-dihydro-1~3-thiazol-5~ acetamidoJ-3 cephem-4~carbo~ylic acid, mp. 130 to 200C (decO).
(14) 3-(1-M~thyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2(2-amino-5-chloro 1,~ thiazol-4-yl)acetamido~
c~phem-4~carbo~ylic acid, which ca~ be represented as 3~ met~yl-lH-tetrazol-5-yl~thiomethyl-7-~2-hydroxy-2-(2-iml~o-5-chloro-2,~-dihydro-~,3 thiazol-4-yl)acetami~o~-3-o~hem-4-~arbo~ylic acid, mp~ 148 to 154C (dec.).
tl5) 3-(1-Methyl~ tetrazol-5-yl~thiomethyl-7-[2-hydroxy-, 2-(2-methylamino-19~-thiazol-4yl)acetamido~-3-c0phem-4-carb3xylic acid, which c~ be repre~ented as 3-~1-methyl-~-tetrazol-5-yl~-th~omethyl;~7-[2-hydro~y-2-(2-methyl~mino-2,3-dihydrG;l,~j-thiazol~
. ~-yl)acet~do]-~-cephem-4-~arboxylio. acid~ mp. 144 to 156C (dec.).
Example 16 A solution of 3-(S-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-hydroxy-2-(2-ter~-pen~yloxycarbonylamino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-caTboxylic acid, which can be represented as 3-(5-methyl-193,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid ~2.30 gO) in g8~ formic acid (25 ml.) was stirred for 2.5 hours at room temperature. A~ter the reaction~ formic acid was distilled off under reduced pressure. The residue was pulverized in acetonitrile ~25 ml.), collected by filtration, washed wi~h a small amount of acetonitrile and then dissolved in 5~ sodium bicar~onate aqueous solution (14 ml.). The solu~ion was adjusted to p~ 6 with acetic acid and subjected to alumina column chromatography by using pE~ 5 ~ O acetate buffer as an eluent. The eluate containing the object com~ound (300 ml.) was adjusted to pH 3 with 10% hyd~ochloric acid and then washed twice with ethyl acetate (50 ml.). The a~ue~us layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm ~ Haas Co.) J and ~he column was washed with water and then eluted with 20% methanol aqueous solution ~100 ml.), 50 methanol aqueous solution (lO0 ml.) and 70% methanol aqueous solution (400 ml.) in turn. The eluates containing the obj~ct compound (500 ml.) were collected and then methanol was distilled off at 30 to 35C under reduced pressure. The T~maining aqueous solution was lyophi~ized to give pale yellow powder of 3-tS-methyl-1,374-~hiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1 9 3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(S-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2 7 3-dihydro-~%~77 1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.60 g.), IoRo Spectrum (Nujol) i770 (~-lactam) cm l N.M.R. Spec~rum (NaDCO3, ~) 2. 7S ~3}IJ S~
3.4 and 3.75 ~2H, ABq~ J=14 Hz) 4.0 and 4.52 (2H, ABq~ J-14 Hz) 5~15 (lH, d9 J=S Hz) 5.2 . (lH, s) 5-7 tlH, m~-6,76 ~1/2H, s~
6~9 (1/2H, s) Ex~mple 17 A mixtu~e of 3-tl,3J4-thiadiazol-2-yl)thiomethyl-7 ~2-hydroxy-2-(2-t~rt-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid9 which can be represented as 3-tl,3,4-thiadiazol-2-yl)thiomet}lyl-7-[2-hydroxy-2-~2-tert-pentyloxycarbonylimino-2~3-dihydro-193-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, ~2.1 g..) and 98 to 100% formic acid (40 ml.) was stirred for 2.5 hours at room temperature. After the react;on, ~he reaction mixture was concentrated under reduced pressure. The residue was pulverized in acetonitrile, collected by filtration and then washed wi~h e~her to produce brown po~lder (1.3 g.j. The powder was dissolved in 5% sodium bicarbonate aqueous solution (20 ml.~ and then adjusted to pH 6 with acetic a~id. The mixture was subjected to neutral almina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluates containing object compound (230 ml.) were collected, adjusted to pH 2.8 to 3.0 with 10% hydrochloric . _95_ E - 65 57~
acid, washed with ethyl acetate~ and then remaining cthyl ace~ate was distilled off from the eluates under reduced pTcssure.
The resulting aqueous layer was subjected ~o column chromato-graphy (Amb~rlite XAD-4 prepared by Rohm ~ I-laas Co.), and the column was washed with water and then eluted with 20% methanol (80 ml.~ 9 50% methanol (80 ml.) and 70~ methanol (300 ml.) in turn. The elua~es containing the object compound were collected and then methanol was distilled o~f under ~educed pressure. The remaining aqueous solution was lyophillized to Kive pale brown powder of 3-(1,3,4-thiadiazol-2-yl)thio-methyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be repr~sented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3 thiazol-4-yl)ace~amido~-3-cephem-4-carboxylic acid, (0.40 g.), mp. 151 to 180C (dec.).
I.R. Spectrum (Nujol) 1770, 1680, 16209 1520 cm~l N.M.R. Spectrum (d6-dimethylsulfoxide9 ~3 . 3.6B f2H, m) 4.43 (2H~ dd, J=12.8 and 22.6 Hz~
40 87 ~lH, broad s) 5.11 (11!~ d~ J=5.0 Hz) 5.2-6.1 (3H, m) 6.43 (lH, s) 9~ 57 (lH, s~
Example 1~
A mixture of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxyl--amidol-3-cephem-4-carboxylic acîd3 which can be represented as 3-tl-methyl-lH-~et~azol-5-yl)thiomethyl-7~2-~2-tert-pentyloxy-: ca~bonylimino-2~3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, (lo8 ~.~ and 98 to lO0~ formic acid (40 ml.) was allowed ~c s~and fo~ 5 hours. After the rcactiona the reaction mixture was post-treated in the similar manners as in Examples 16 *o 17 to give 3-(1-me~hyl-lH-tetrazol-5-yl)thiomethyl 7-~2-(~ amino-1,3-thiazol-4-yl)~lyo~ylamido]-~-( cephem^4-carboxylic acid, which can be represented as 3-(1-methyl~ etrazol-5-yl)thiomethyl-7-l2-(2-imino-2,3-dihydro-1, 3-~hiazol-4-yl)glyoxylamido]-~-cep}lem-4-carboxylic acid3 (0.32 g.), mp. 147 to 160~C (dec.).
I.R. Spect~um (Nujol~
1770 (~-lactam) cm 1 N.M.R. Spectrum td6 dimethylsulfoxide, ~) 3.73 (2H, broad sj 3.95 (3H~ s) 4 2 and 4.5(2H, ABq~ J=15 Hz) 5.15 (lH, d, J=5 Hz) 5.75 (lH9 d, J-5Hz) 7.8 (1~ s) E - ~7 Example i~
A solution of 3-(5-methyl-1,3j4-thiadiazol-2-yl)-thiomethyl-7-E2-(2-tert-~entyloxycarbonylamino-l~3-thiazol-q yl)glyoxylamido~-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomcthyl-7-12 (2-tert-pentyloxycarbonylimino-2,3-dillydro 1,3-thiazol-4-yl)-glyoxylamido~-3-cephem-4-carboxylic acid, (8.56 ~.) in formic acid (180 ml.~ was stirred for 5.5 hours at room temperature.
Afte~ the reaction~ the reaction mixture was post-treated in the similar manners as in Examplesl6 to 17 to gi~e 3-(5-methyl-1~3,4-thiadiazol-2-yl)thiomethyl-7- E2-~2-amino-l~3-thiazol-4 yl)glyoxylamido~-3-cephem-4 caTboxylic acid, which ean be represented as 3-~5-methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-[2-t2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, (2.6 g.)~ mp. 156 to 16~C (dec.).
.
~ o a mixture of 3-(1-methyl-lH-tetrazol-S-yl)thiome~hyl-7-t2-formyloxy-2-(2-ormylamino-1,3-thiazol-5-yl)acet~mido]-3-cephem-4-carboxylic acid, which can be represented as 3-tl-methyl-lH-tetrazol-5-yl~thiomethyl-7-~2-formyloxy-2-~2-formylimino-2,3-dihydro-1~3~thiazol-5-yl)acetamido]-3-cephem-4-carboxy~ic acid, tl.5 g.) in methanol (30 ml.) was added phosphorus oxychloride (1.06 g.~ under ice-cooling and stirring, and the mixture was stirred for 1 hour at the same tempera~ure and then ~urther stir~ed for 4 hours at room temperature. To the reaction ~ixture was added diethyl ether (150 ml.)~ and the prccipita~es were collected by filtration and then dried. Thus obtained pale yellow powder (1.30 g.) was added to water (30 ml.), and _98- ~ - 68 ~Z~35~'7 the mixtu~e was adjusted to pH 1 to 2 with 10% hydrochlo~ic acid.
The resulting solution was treated wi~h an acti~ated charcoal, washed with ethyl ace~ate and then adjusted to pH 7 with a 5%
sodium bicarbonate aqueous solution. The solution l~as ~ashcd with ethyl aceta~e, adjusted to pH 3 with 10~ hydrochloric acid and then filtered. The aqueous solution was adsorbed on a HP-20 (neutral resin) colu~n, which was washc~ with water and then eluted ~ith an aqueous methanol solution. The eluates containing th~ object compound wer~ collected and then methanol as distill~d off under reduced pressure. The remaining aqueous solution was lyophilized to give 3~ me~hyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-~2-amino-1,3-~hiazol-5-yl)acetamido~-3 cephem-4-carboxylic acid, which can ~e represente~ as 3-tl-methyl-lH-tetrazol-S-yl)thiomethyl-7-~2-hydroxy-2-t2-imino-2,3-dihyd~o-1,3-thiazol-5-yl~acetamido]-3-cephem-4-caTboxylic acid, ~0.63 g.), mp. 130 to 200C ~dec.).
I.R. Spectrum (Nujol) 1768 (~-lactam~ cm~
N.M.R. Spectrum (d6-dimethylsulfoxide 9 3.72 ~2H, broad s) 3.92 t3H~ s) 4.3 ~2H, broad s) 5.05-5.25 ~2H, m~
5.66 (lH, d, J=5Hz) 7.0 (lH, s) ( .
~x~mple 21 To a mixture of 7-[2-(2-formylamino-1,3-~hia~ol-4-yl)-glyoxylamido]cephalosporanic acid, which can be represen~ed as 7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-cephalosporanic acid, (30 g.~ in methanol ~500 ml.) was dropwise added phosphorus oxychloride ~22e2 g~ over 30 minutes under ic~-cooling and stirring, and the mixture was stirred for 2.25 ~`hours at the same temperature. The mix~ure was poured into diethyl ethe~ (2500 ml.)) and the mix~ure was s~irred for 1 hour at room temperature. The precipitates were collected by ~iltration and then dried to give 6- [2- ~2-amino-1 ,3-thiazol-4-yl~glyoxylamido]-5~,6-dihydro-3H,7H-azeto~2, 1-b~fu~o [3,4-d~ [1,3~ -thiazine-1~97- C4H~-dione llJrdroehloride9 which can be ~epresen~ced as ~-[2-(2-imino-2,3-dihydro-1,3-thiazol'-4-yl)glyoxylamido]-Sa,6-dihydro-3H,7H-azeto[2,1-b]furo[~,4-d~ .3]-thiazine-1,7-t4H)-dione hydrochloride, (24.2 g.~.
I . R. Spectrum (Nuj ol~
1786 (~-lactam) cm 1 ~ ~ 70 ~100-~2~95i~7 N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.84 (2H, broad s) 5 07 (2H, s) 5.2S (lH, d, 3=5Hz3 So83 tlH~ d, J-SHz) :~ 8.32 (l~ "s) Exam~le 22 To a mixture of 3-(l-methyl-lH-tetrazol-5-yl)-thiomethyl-7-e2-t2-~ormylamino-1,3-thiazol-4-yl)glyoxylamido~-3-cephem-4-carboxylic acid, which can be represented as 3- ~1-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-~2-ormylimino-2,3-'dihydro-1,3-tllia~ol-~-yl)glyoxylamido~-3-cephem-4-carboxylic acid, (24;8 g.) in methanol (500 ml.) was dro~wise added phosphorus oxychloride (1~4 g.) over lS minutes under cooling.
at 5 to 10C wi~h stirring, and ~he mixture was stir~ed or 2.5 hours at the same temperature. The 3/4 amount of methanol was distilled o~f from ~he reaction mixt~re under reduced pressure, and the r~sidue was pulveTi~ed in diethyl ethe~. The powder was collected by filtration and th~n dried to give 3-(1-methyl-lH-tetra~ol S-yl)thiomethyl-7-[2-~2-amino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, wh;ch can be represented as 3-~1-me~hyl-lH-tetrazol-5-yl)thiomet]lyl-7-t2-(2 imino-2~3-dihydro 1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride9 I.R. Spectrum (Nujol) 1778 (~-lactam~ cm~
N~M.R. Spectrum (d6-dimethylsulfoxide, ; 3.7 ~2H, broad s) 4.0 (31~, s) 4.37 (2H, broad s) 5.23 (1~ d, Ja5Hz) 5 75 tlH~ d, J-SHz) .8.27 (lH, s) 8.35 (lH~ s) Similarly, ~he following compounds were obtainedO
tl~ 3~ (5-Methyl-1~3 ,4-oxadiazol-2-yl) thiomethyl-7- ~2-hydroxy-2 (~-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-ca~boxylic acid, which can be represented as 3-(5-me*hyl-1,3~4-oxadiazol- 2-yl) thiomethyl - 7-~2-hydroxy-2-(2 - imino- 2, 3-dihydro-1~3-thiazol-4-yl)acetamido]-3-cepllem-4-carboxylic acid.
I.R. Spectrum (Nujol~
1780 (~-lac~am) cm~l t~ 3-(S-Methyl-1,3,4-oxadiazol-2-yl) thiomethyl-7 - ~2 - (2 -~mino-1,3-thiazol-4-yl~glyoxylamido~-3-cephem~4-carboxylic acid9 which can be represented as 3-~5-methyl-1,3,4-oxadiazol-2-yl)~hiomethyl-7-[2-t2-imino-253-di.hydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic ~ci~
I~R. Spectrum (Nujol) 1775 (~-lactam) cm~l ' (3) 3-~4^~Se~hyl ~H-1j294-~riazol-3-yl)thiu]nethyl-7-~2-hydroxy-2-~2-amino-153-thiazol-4-yl)aGetamido]-3-cephem-4-carboxylic acid9 which can be represented as 3-t4 metllyl~ H-1,2,4-triazol-3-yl~thiomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro- 1, 3 - thia zol - 4 -yl~ ace tamido 3 - 3 - cephem- 4 - carboxyl i c aci d ,, I~Ro Spec~rum (Nujol) 1760 (~-lactam~ cm~l (4~ 3-(4-Methyl-4H-1,2,4-triazol-3-yl)thiomethyl-7-~2-(2-amino-1,3-thi~zol-4-yl)glyoxylamido]-3-cephem-4-carboxylic . -102- ~ - 72 ~ S ~ 7 acid, which can be represented as 3-(4-methyl-4}~ 2g4-tria .~-yl~thiomethyl-7-t2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl) glyoxylamido~-3-cephem-4-carboxylic acid.
I, R. Spect~um (Nujol~
1775 (~-lactam) cm~l (S) 3-Carbamoyloxymethyl-7-~2-hydroxy-2-(2-amino-l,3-thiazol-4-yl)acetamido]-3-~ephem-4-carboxylic acid, which can ; be represented as 3-carbamoyloxymethyl-7-[2-hydroxy-2-(2-imîno-2 ~3-dihydro-1 ,3-thiazol-4-yl)asetamido]-3-cephem-4-carboxylic acid, mp. ~ 27ûC.
I . R . Spectrum ~Nuj ol) l780 (~-lactam) cm l N.M.R. Spec*rum (d6-dimethylsulfoxide, ~) 3.43 an~ 3.65 (2H9 AB~, J=l4Hz) 4.6 and 4.85 ~2H, ABq, J=15Hz) 4.86 (l~, s) 5.1 (lH, d, J~SHz) 2.6-2.75 tlH, m) 6.43 (lH, s) (6~ 3-~l-Methyl-lH-tetrazol-5-y1)~hiomethyl-7-~2-hydroxy-2^(2-methylamino-1,3-thiazol-4-yl)acetamido~-3-cepllem-4-carbo~cylic acid, which can be represented as 3- tl-methyl-lH-tetrazol-5-yl) -thiometllyl-7-.~2-hydroxy-2-(2-metllylimino-2,3-dihyd~o-1,3-thiazol-4~yl)acetamido]-3-cephem-4-caTboxylic acid, mpO 144 to l56C
(dec.).
I.R, Spectrum ~Nu~ol~
l764-l780 (broad9 e-lactam) cm N.M.R. Spectrum ~d6-dimethylsuloxidc,~) 2.8 (3}~, s) 3.S7 and 3.78 (2H, ~Bq, J=1711z) -103~ E - 73 ~ Z ~ ~ S 7 7 309 (3H, s) 4.21 and 4.42 (2H, ABq, J=15H~) 4.95 (1~, s) 5~12 (lH, d, J=5Hz) 5.65-~.75 (lH, m) 6.57 tlH~ ~) (7) 3-tl-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-5-chloro-1,3-thiazol-4-yl)acetamido~-3-cephe~-4-carboxylic acid, which can be represented as 3-(1-methyl-1l-l-_ tetrazol-S-yl)thiome~hyl-7-[2-hydroxy-2-(2-imino-5-ch~oro-2,3-dihydro-1,3-thiazol-4-yl)ace~amido~-3-cephem-4-carboxylic acid, mp. 148 to 154C tdec.~
I.R. Spectrum (Nujol) ; 3300 (broad), 1780, 1680, 1620 cm 1 N.M.R. Spectrum ~d~-acetone, ~
3.~87 (2H, broad s) 4.07 (3H, s) 4.37 t2H, broad s) .. 5.17 (lH, d, J-4Hz) 5.20 (lH, s3 5.88 ~lH, d, J=4Hz) (8~ ethyl-7o[2-(2-amino-l~3-thiazol-4-yl)glyoxylamid 3-cephem-4-carboxylic acid hydrochlvride, which can be represented as 3-methyl-7-l2-tZ-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxyl-amido3-3-cephem-4-carboxylic acid hydrochloride, dp. > 250C.
I . R. Spectrum (Nujol) ; 1780 (~-lactam) cm : N M.R. Spectrum (d6-dimethylsulfoxide, ~) 2 12 (3H, s) 3.S2 (2H, broad s) 5.17 ~lH, d, J-5Hz3 5.68 (lH, d3 J=5}1z) 8.3 ~lH, s) ~ (9) 3-Carbamoyloxymethyl-7-[2-(2-amino-193-~hiazol 4-:~ yl)glyoxylamido~-3-cephcm-4-carboxyli.c acid hydrochloride, which : can be Tepresented as 3- arbamoyloxymethyl-7-[2-(2-imino-2,3-dihydro-l~3-thia~ol-4-yl)glyoxylamidol-3-cephem-4-carboxylic ~cid hydrochloride, powder.
(1O)3-(5-Methyl-1,394-thiadiazol-2-yl)thiome~hyl-7-[2-,~t2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cepllem-4-carboxylic ~cid hydrochloride, which can be represented as 3-(5^methyl-1,3,4-thiadiazol-2-yl~*hiomethyl-7-[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamldo]-3-cephem-4-carboxylic acid hydrochloridea powde~.
- I.R. Spectrum ~Nujol) cm 1 1760-1780 tbroad, ~-lactam) cm 1 ; N.~.R. SpectTum (d6-dimethylsulfoxide, ~) 2.72 (3~ s) 3~75 (2H, broad s) 4.25 and 4~62 (2H, AB~, J=14Hz) : S.23 tl~, d, J=5Hz) 5.75 (lH9 d9 J=5H2) 8.33 ~lH, s) (`ll) 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cep~em-4-carboxylic acid hydro-chloride, which can be represented as 3-(1,3,4-*hiadia~ol-2-yl)-thiomethyl-7-~2-(2-imino-2,~-dihydro-1,3-thiazol 4-yl)glyoxylamido~-3-cephem 4-carboxylic acid hydrochloride, powder.
I.R. Spect~um (Nujol) 1778 (~-lactam) cm 1 -105- ~ ~ 75 5~
.
N.M.R. Spectrum (d6-dimethylsulfoxide, ~) 3.7 (2H, broad s) 4.22 and 4.62 (2H, ABq~ J=16Hz) 5.17 (lH, d, J=5Hz) 5.7 ~lH, d, J=5Hz~
B.3 (l~l"s) 9067 (1~, s~
(12) 3~ Methyl~ tetrazol-S-yl)thiomethYl-7-[2-(2-a~i~o-1,3-th;azol-S-yl)glyoxylamido~-3-cephem-4-carboxylic acid hydrochloride 9 which can be represented as 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-~2-imino-2 7 3-dihydro-1,3-thiazol-5-yl)-glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, mp~ 140 , to 160C ~d~c.~.
; I.R. Spectrum (Nlljol) 1778 (R lactam) cm 1 N.M.R. Spect~um (d6-dime~hylsulfoxide, ` 3.7 . ~2H, broad s~
3.95 t3H, s) - ~- 4.3 (2H, b~oad s) 5.12 tl~l, d3 J~6Hz) 5.65 (lH, d" J~6Hz) 803 (lH7 s) 3-~1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-methylamino-1,3-~hiazQl-4-yl)glyoxylamido]-3-cep]lem-4-carboxylic zcid, which can be ~epresented as 3~ methyl-lH-tetrazol-5-yl)-thiomethyl-7-~2-(2-methylimino-2~3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, mp. 146 to 155C (dec.).
I.R. Sp~ctrum (Nujol) 1798 (~-lactam) cm 1 -106- ~ 7 ~ 3 ~
N.M.R. Spec~rum ~d~-dimethylsulfoxide, ~) 2085 (3H, s) 3.58 and 3.79 (2H9 ABq~ J-17Hz~
3.92 (3~, s) 4~2~ and 4.4 ~2H! AB~, J=14Hz) : 5.12 (lH,~d, J-.SHz) 5.75 (lH, d, J~S}-lz) 7,95 (~H, ~) (14) 3-i~eth~7-~2-hydro~y-2-(2~amino-1,3-t~.azol-4-yl) acetamido3-3-cephem-4-carbo~ylic acldt which ca~ be represented as 3 methyl-7-~2-hydroxy-2-(2-imino 2~3-dihgdro-1,3-thiazol-4-yl)acetamido~-3~cephem-4-carbosy'ic ac~d, mpO ~ 2503C~
:~2~?~Si7'7 ~ ' A mixture of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7- ~20 (2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which~can be represented as 3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-7-[2-(2-tetrahydro-pyranyl)oxy-2-(2-mesyli.mino-2,3-dihydro-1,3-thiazol-4-yl)ace~amido]-3-cephem-4-carboxylic acid, (0.85 g.), ethanol tl5 ml.), water (5 ml.) and 2N hydrochloric acid (5 ml.) was stirred for 2O5 hours at room temperature. After the reaction; the ~eaction mixtur~ was diluted with water ~20 ml~, adjusted ~o p~ B with 5~ sodium bicarbona~e aqueous solution and then washed wi~h diethyl ether. Thus obtained aqueous layer was adjusted to pH 4 to S with 10~ hydrochloric acid a~d washed with ethyl acetate. The aqueolls layer wasadiusted to pH l to 2 with
10% hydrochloric acid and then extracted with ethyl acetate.
The extraGt was washed with à saturated aqueous solution of sodium chloride and drled over magnesium sulfate. The solvcnt was distilled off from the extract~ and the residue was washed in diethyl ether9 collected by filtration and then dried to give pale brown powder of 3~ methyl-lH-~etrazol-5-yl)-~hiomethyl-7-[2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)acet-amido]-3-cephem-4-carboxylic acid, which can be represen~ed as 3~1 methyl-lH-te~razol-5-yl~thiomethyl-7-~2-hydroxy-2-(2-mesylimino-293-dihydro-1,3-thiazol-4-yl)acetamido]-3-cepllem-4-carboxylic acid~ (0~2 g.), mp. 120 to 146C (dec.).
I . R. Spec~rum ~Nuj ol) 1780 (~-lactam) cm~
N.~l.R. Spectrum (d6-dimethylsulfoxide, 2.9 (3~l, 5) 3.57 and 3. 8(2~1, ABq, J=18 }~z) -` ~Z~S77 3.9 t3~l, 5) 4,2 and 4.4 (2H9 ABq, J=13 Hz) 4.~-S.15 (2H~ m) 5.5-5~75 tlH~ m) ~.65 (1~ s) Example ~4 A mixture of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl~lH-tetrazol-5-yl)thiomethyl-7-[2-~ormyloxy-2-(2-tert-pentylox~carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-acetamido] -3-cephem-4-carboxylic aoid9 (1.49 g.) and 5% sodium bicarbonate aqueous solution (100 ml.) was allowed ~o stand for 6 hours. After the reaction, the reaction mixture was washed with ethyl acetate. To ~he reaction mixtur0 was added ethyl acetate, and the mixture was adjusted to pH 7 with dilute hydrochloric acid and ~hen ~he aqueous layer was separatedO
To the aqueous layer was added ethyl acetate, and the mixture w~s adjusted to pH 1 to 2 with dilute hydrochloric acid~ and the ethyl acetate layer was separated. The ~emaining aqueous layer was subjected to salting-out and then extraoted with ethyl acetate. The ethyl acetate layer and the ethyl ace~ate extract were com~ined together, washed with water; dried over magnesium sulfate, and then the solvent was distilled off~ To the ~esidue ~2.0 g.) was added diethyl ether, and the mixture was stirred for overnight, collected by filtration and then dried to give pale brown powder of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7-[~-hydroxy-2-(2-teTt-pentyloxycarbonylamino-1~3-thiazol-4-yl)-acetaDido~-3-cephem-4-ca~boxylic acid, which can be represented as 3~ me~hyl-lH-te~razol-5-yl)thiomethyl-7-l2-hydroxy-2-~2--lO9- E - 79 ` ~ 2~ ~ 5 7~
tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl~-acetamido]-3-cephem-4-carboxylic acid, tO.90 g.~.
I.R, Spectrum (Nujol) 1785 (~-lactam), 1680-1730 (CO) cm^
N.M.R. Spectrum ~d6-dimethylsulfoxide, ~) 3.58 and 3.82 ~2H, ABq~ J~18 Hz~
3.93 (3H, s~
4.22 and 4.33 t2H, ABq, J=12 Hz) 5.0 5.12 (2Ha m) 5 55-5.8 (lH, m) 7.03 (lH~ s) Similarly, the following compou~ds were obtained.
(1) 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-l2-hydroxy-2-t2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which can be represen~ed as 3-~5-me~hyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-l2--hydroxy-2~2-tert-pentyloxycarbonylimino-293-dihydro-1,3-tlliazol-4-yl)-acetamido~-3-cephem-4-carboxylic acid.
I . R. Spect~um ~Nujol) 1785 ~-lactam) cm 1 ~ ) 3-~1,3,4-Thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2-tert-pentyloxycarbonylamino-193-thiazol-4-yl~acetamido3-3-cephem-4-carboxylic acid, which can be Tepresented as 3-~1,3,4 thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-~2-ter~--pentyloxy-carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acidJ pale yellow powder.
t33 7-[2-Hydroxy-2-(2-~er~-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid, which can be ~epresented as 7-~2-hydroxy-2-t2-tert-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl~acetamido]cephalosporanic acid.
-llO- E - 80 57'7 I . R. Spectrum (Nujol) 1783 (~-lactam) cm^l (4) 3-(1-Methyl-lH-.tetrazol-S-yl)thiomethyl-7-[2-hydroxy-2-t2-propanesulfonylamino-1,3-thiazol-4-yl)ace~amido]-3-cephem-4-carboxylic acid, which can be represented as 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7- [2-hydroxy-2- (2-propanesulfonyl-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3~cephem-4-carboxylic acid, mp. 160 to 170C (dec.~.
(5) 3- ~1-Methyl-lH-tetrazol-5-yl) thiomethyl-7-~2-hydroxy-2 - ~2 - oxo - 2 ~ 3 - dihy dro -1 9 3 - th i a ~ol - 4 -y 1 ) ace tami do ] - 3 - cephem- 4 -carboxylic acid, which can be rep~esented as 3- (l-methyl-lH-tetrazol-5-yl3thiomethyl-7-L2-hydroxy-2-(2-hydroxy-173-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp~ 110 to 121C
(dec.) t6) 3-t5-Methyl-1,394-thiadiazol-2-yl)thiomethyl-7-~2-~ydroxy-2-(2-amino-lp3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be rep~esented as 3-tS-me~hyl-1~3j4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, pale yellow powder.
t7) 3-tl,3,4-Thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be ~epresented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-t2-imino-2,3-dihydro-1,3-thiazol 4-yl~acetamido3-3-cephem-4-carboxylic acid, mp. 151 to 180C dec.).
~ E - 81 ~ 3L2~ii7'~
( ) 3-(5-Methyl-1,3,4-oxadiazol-2-yl)thiomethyl~ 2-hydroxy-2 (2-amino-1~3-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,374-oxadiazol-2-yl)tlliomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro-1, 3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol~
17~0 t~-lactam~ cm 1 ( 9~ 3-(~-Methyl-4H-1,2,~-triazol-~-yl)thiomethyl-7-C2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)ace~amido]-3-cep)lem-4-ca~boxyllc acid, which can be rep~esen~ed as 3-(4.-methyl-4H-- 1,2,4-triazol-3-yl)thiomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid.
I R. Spectrum ~Nujol) ; 1760 t~-lactam) cm 1 ~10) ~ Carbamoyloxymethyl-7-~2 hydro~y-2-(2-a~i~o-1,3-. ~ thiazol-4-yl~acetamido]-3 cephem 4-carboxylic acid, which ca~
be represe~ted ~s ~-carbamoylo~ymethyl-7-~2 hydro~y-2 (2-imino-~,7 dihydro-1,3-thia~ol-4-yl~acetamido]-3-cephem-4-carbo~ylic ac~d, mp. > ~70C.
(1}) 3 Meth~l-7 [2-hydro~y-2-~2-amino-1,3-thiazol-4-yl)-aoetamido~-3-cephem-4-carbo~ylic acia, which can be represented a8 3~methyl-7-[2-hydroxy-2(2-Imino-2,3 dihydro-1,3-thiazol-4-~l)acetamido~-3-cephem-4-carbo~ylic ac~d~ mp. > 250C.
(12) ~ Methyl-lE-tetrazol-5-yl~thiomethyl-7-[2-~hydro~y 2 (2-amino-1,~-thiazol~5~yl)acetamido]-j-cephem-~-carboxylic acid, which can be represen~ed as ~ methyl-lH-t~t~zol-5-yl)thionsthyl-7-[2hydro~y-2-(2-imino~2~-di.hydro-E ~ 82 1,3-thiazol~5-yl)acetamido]-3-cephem-4~carboxylic acid, mp. 130 to 200~ ~dec~
~ 3~ let~yl-lX-tetrazol-5-yl)thiomethyl-7-[~-hydroxy-2-(2-amino-5-chloro-1,3-thia7,ol-4~yl)acetamido]-3-cephem-4-oarboxylic acid, which can be represented as 3 (1-methyl~ tetrazol-5~yl)thiomethyl-7-~2-hydro~y-2-(2-lmi~o-5-chloro-2,~ dihydro-1,3-thiazol-4-yl)acet~.mido]-3-cephem-4-carboxylic acid, m~, 148 to 154C (dec.).
(14) 3~(1-Methyl-l~-tetrazol-5-yl)thiomethyl-7~[2-hydro~y-2-(2~ormylamino~ thiazol-4-yl)acetamido3~-cephem-4-carboxylic aeid, which can be repre~ented as 3~ ~ethyl-1~ tetrazol-5-yl)-thiomethyl~7-[2 hydro~y-2-(2-formyli~ino-2,~-dihydro-1,3-thiazol-4-yl)acetamid~-3-cephem-4-c~.rbo~ylic acidt brownish white powder.
(15) 3-(19~,4-Thiadiazol-2-yl)thiomethyl-7 [2-hydro~y-2-~2-formylami~o-1,3-thiazol-4-yl)acetamldo]=~3~cephem-4carbo~ylic acid~ which can be repre~ented as 3-(193~4-thiadiazol-2-yl)-thiomethyl-7-[2-hydro~y-2-(2-formyli~i~o-2~-dihydro-1,3-thiazol-4~yl)acetamido]-3 cephem-4-carbo~ylic acid~ mp, 105 to 130~C (dec.).
(16) ~-(1-Me~hyl-lH~tetrazol-5-yl)~hiomet~yl--7-[DL~2-hydro~y-2 (2 formylamino-5 chloro-1,3-thiazol-4-yl)ac0tamido]-3-cephem-4carbo~ylic acid, which ca~ be represented as 3-(1-methyl-lH-tet~azol-5-yl~thiomethyl-7-~D3-2-hydroxy~2-(2-~ormylimino-5-ch~oro-2~3-dihydro-1,3~thiazol-4-gl)aceta~ido~-3-c~phe~-4-car~c~ylic acid9 mp. 160 to 1~5~. (dec.).
(17) 3~ ethyl-lH-tetrazol-5-yl)thiomethyl-7-~2-hydroxy-2-~2-(methyl)thio~arbamuylamino-1,3-thiazol-4-yl]acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl~ tetrazol-~-yl~thiomethyl-7-~2~hydroxy-2~[2~(methyl)-thio6arbamoylimino~2.3~dihydro-1,3-thia~ol-4-yl~aceta~ido]-3 icephe~-4-carbo~ylic acid. 155C ~ ter) J 160C (dec.~.
- -113- ~ - 83 9~
(la) 3-~ ethyl-IH-tetra~ol-5-gl)thiomethyl-7-~2-hydro~y-2~(2-methylamir,o-1,3-thiazol-4-yl)acetamido~-3-cephem-4-c~rbo~ylic acid, whic~ can be repre~ted as 3-(1-methyl-IH-~etra~ol-5-yl~-th~omethyl-7-[~-hydro~y-2-~2-methylimino-2j~dihydro-1.,3-thiazol~
; 4-~l)ace~amido3-~-cephem-4-carbo~ylic acid, ~p. 14~ to 156C (dec.).
~9 ) ~ ethyl-lH-tetrazol-5-yl)thiomethyl-7-~L-~
hydro~y-2-~2-(N-~ethyl-N-tert-pentyloxyc~rbonylamino3 thiazol-4-yl~acetamido]-~- ephem-4 carboxylic acid.
IoXo~ ~pec~rum (Nujol) ~- 1770-1790 (broad) cm 1 .
(20~ 3~ 'lethyl-lH tetr~zol-5yl)thio~et~yl-7-~2-hydroxy-2-(2-o~o-2,3-di~ydro-l,~-thiazol-4-yl)acet2~ido~ cephem-4-carbo~ylic acid, which can be represented as ~ (l-me~hyl-l~-tetrazol~5-yl)thiomethyl-7-~2-hydroxy-2-(2-hydro~y-l~j-thiazol-4-yl)acetamido~-cephem-4-carboxylic acid, mp. 110 to 121C (~ec.3.
~ ' , .
~ 7 Example 25 A solution of 7-~2-hydroxy-2 (2-tert-pentyloxycarbonyl-~mino-1,3-thiazol~4-yl)acetamido~cephalosporanic acid, which can be represented as 7-[2-hydroxy-2~(2-tert-pentyloxycarbonyli~ino-2~3-dihydro-1,3-thiazol-4-yl)acetamido~cephalosporanic acid, ~3B9 mg.), 5-methyl-193,4-oxadiazol~-t~iol(116.13 m~.), sodium bicarbonate (119.4 mg.) in p~ 5.2 phosphate ~uffer (15 ml.) was adjusted to pH 5.2 with 10~ hyd~ochloric acid and was stirred for 7 hours at 60 at 63C. Af~er ~he reaction, to the ~eaction mixture was added e~hyl ace~ate, and the mixture was a~usted to pH 2 with 2N hydrochloric acid. The precipitates WeTe collected by iltration and dried to give 3-~5-methyl 1~3, 4-oxadiazol-2-yl)thiomethyl-7-[2-hydroxy-Z~(2-amino-1,3-~hiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, which can be`
represented as 3-~5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-t2-imino-2,3-dihydro-193-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, (60 mg.). On the other hand, from the remaining filtrate was separa~ed the aqueous layer.
The aqueous layer was washed with ethyl acetate, and the remaining ethyl acetate in the aqueous layer was distilled off under ~educed pressure. The aqueous layer was sub3ected to column chromatography tnon-ionic adsorption resin9 Diaion HP 20 prepared by Mitsubishi Chemical Industries)~ washed with water and then eluted with 10% isopropyl alcohol. The eluates containing the object compound were collected and then isopropyl alcohol was distilled off under reduce-d pressure. The remaining aqueous solu~ion was lyophilized to give the same object compound (75 mg.) I.R. Spectrum (Nujol) 1780 (e-lactam) cm^l i~9s~ i~
N.M.R. Spectrum (d6-dimethylsulfoxide, C) 3.65 (2H, broad s) 4~ and 4. 45 t2H, ABq ~ J=15 }Iz) 4.95 (lH,, s) 5.1 (lH, d, J=S Hz) 5.55-5. 8 ~lH, m) 6.7 (lH, s) i Bxample 26 f A solution of 7~2-~-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]cephalosporanic acid, which can be r~presented as 7- [2-t2-tert-pen~yloxycarbonylimino-~,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~cephalosporanic acid, (389 mg.), S-methyl-1,3,4-oxadiazole-2-thi.ol (I16.3 mg.), sodium bica~bona~e (ll9.fl mg.3 in p}~ 5.2 phosphate buffer (lS ml.~ was adjusted to pH 5.2 with 10~ hydrochloric acid and was stirred for 7 hours a~ 60 to 63C. After the reaction, to the reac~ion mixture was added ethyl ace*ate, and th~ mixture was ad justed ~o pH 4 . 5 with 2N hydrochloric ~cid, and then the aqueous layer was separated. To the aqueous . layer was added ethyl acetate~ and the mixture was adjusted to pH 1~5 with 2N hydrochloric acid9 and then the aqueous laye~ was separated. The aqueous layer was adjus~ed to pH 3 with lN sodium hydroxide aqueous solution and ~hen allowed ~o stand for overnight at cooling plac~. The precipita~es we~e collected by filtration and then dried to gi~e 3-~5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7-[2-~2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-metl;yl-1,3,4-oxadiazol-2-.yl)thiomethyl-7-[2 ~2~imino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid9 ~30 mg.~. On the .other hand, the filt~ate was sub~ccted to column rhromato~raphy ~z~gs~
in similar manner as that of example ~5 to give further the : ~ame object compound t65 mg.~
I.R. Spectrum (Nujol) 1775 (~-lactam) cm^l ~
N~Mo R. Spectrum (d6-dimethyls~loxide, ~) 3.7 (2H, broad s) . 4.2 and 4.45 (2H~ ABqJ J-14 Hz~
5.2 (lH, d, J=5Hz) ; S.75 tlH, d~ J=5 Hz) . . 8.1 (lH, s3 i, .
Example ~7 A mixture of 7-~2-hydroxy-2-(2-te~t-pentyloxycarbonyl-amilio-1,3-thiazol-4-yl)acetamido~cephalosporanic acid5 which can be ~epresented as 7-~2-hydroxy-2-(2-tert-pentyloxycarbonyl-imino-2,3-dihydro-1~3 thiazol-4-yl)acetamidoJcephalosporanic acid, . (389 mg.), 4-methyl-4H-1,2,4-t~iazole-~-thiol (115.2 mg.) 3 ' sodium bicarbonate (119.4 mg~) and pH 5.2 phosphate buf~er was J stirred for 3 hours at 60 to 65C. After the reaction, ~o the reaction mix~ure was added ethyl acetate, and the aqueous l~yer was separated. To the aqueous layer was added ethyl acetate, and the mixtu~e was adjusted to pH 1 with 2N hydrochlori.c acid. The aqueous laye~ was separa~ed, and the remaining ethyl acetate in the aqueous layer was ~emoved under reduced pressure. The remaining aqueous solution was subjected to column chromatography ~berlite XAD-4 prepa~ed by Rohm ~ Haas Co.), and the column was washed with water and then eluted with 20 to 50% methanol aqueous solution. The eluates containing the object compounds were collected and the methanol l~as distilled off therefrom. The remaining aqueous solution was lyophilized ~''3S7'~
to gi~e 3-(4-methyl-4H-l~2J4-triazo~ yl)thiomethyl-7 ~2-hydroxy-2-(2-amino-1,3-thiazol-4 -r l)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(4-methyl-4.H-~ 2~4-triazol-~-yl)thiomethyl-7-~2-hydroxy-2-~(2-imino-2,3-dihyd~o-193-khiazol-4-yl)acetamido]-3-cephem-4-carboxyli~ scid, : (149 mg.).
IoR~ Spectrum (Nujol) 1760 ~-lactam) cm~l NrN~R~ Spectrum ~d6-dimethylsul~oxide,~) 3.57 ~3H, s) 3O69 t2H, broad s) 4.0-4.3 (2H, m) 4.9 (lH, s~
; - 5.1 (lH~ d, J=S Hz) So6~5~ (lH, m) 6.6 (lH, s) F.xample ~
(. A mixture of ?-[2-t2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido~cephalosporanic acid, which can be r~pr~sented as 7-[2-~2-~ert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl3glyoxylamido]cephalosporanic acid, (378 mg.), 4-methyl-4H-1,294-triazole-3-thiol ~115.2 mg.~, sodium bicarbonate ~119.4 mg.) and pH 5.2 phospha~e buffer (15 ml. was stirred for 6 hours at 60 to 63~C. AfteT the reaction, the reaction mixture was post-treated by ~on~entional manners to ~ive 3-~4-methyl4 H-172l4-t~iazol-3-yl)thiomethyl-7-[2-(2-amino-1~3-thia~ol-4-yl)glyoxylamido~-3-cephem-4-carboxyl;c acid, which can be ~epresented as 3-(4-methyl-4H-1,2,4-triazol-~-yl)~hio-methyl-7-[2-~ ino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-9~
3-cephem-4~carboxylic acid, (160 mg.).
I.R. Spectrum (Nujol) 1775 (~ -lactam) cm 1 Similarly, the following compounds were obtained.
(1) 3-~-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-oxo-2, 3-dihydro-1,3-thiazol 4--yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-7--[2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, pale yellow powder.
(2) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-propane-sulfonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, mp. 150C (dec.).
(3) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesul~onylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3~(1-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp. 160 to 170C ~dec.).
(4) 3-(1-Methyl-lH-tetrazol-5~-yl)thiomethyl-7-~2-hydroxy-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5yl)thiomethyl-7-[2-hydroxy-2-(2-hydroxy-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp. 110 to 121C
(dec.).
(5) 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3-4-thiadiazol-2yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-5~
1;3-thi~zol^4-yl)acetamido]-3-ce~hem-4-carboxylic acid, pale yellow powder.
t6~ 3-(1,3,4-~hiadiazol-2-yl)thiome~hyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl~acetamido~-3-cephem-4-carboxylic acid, which can be ~epresented as 3-(1,3,4~thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)ace~amido3-3-cephem-4-carboxylic acid, mp. 151 tb 180C (dec.).
(7~ 3-(1-Methyl-l~l-tetrazo~-5-yl)thiomethyl-7-[2-~-amino-1,3-thiazol-4-yl3glyoxylamido]-3-cephem-4-carboxylic acid~ which can be represented as 3-~1-methyl-1l~-tetrazol-5-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro-1,3'-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, mp. 147 to 160C (dec.).
(8 ~ 3-(S-Methyl-1,394-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl~glyoxylamido3-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-~2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxyl-amido~-3-cephem-4-carboxylic acid, mp. 156 to 160C (dec.).
(9 ) 3-(1-Methyl-l~l-tetrazol-5-yl)thiomethyl-7-~2-hydroxy--~2-mesylamillo-1,3-thiazol-4-yl)acetamido3-3-cephem-4-carboxylic acid, which can be Tepresented as 3-(l-methyl-lH-tetra701-5-yl)-thiom~thyl-7-~2-hydroxy-2-(2-mesylimino-2~3-dihydro-1,3-thiazol-4-yl~acetamido]-3-cephem~4-ca~boxylic acid, mp. 120 to 146C ~dcc ~.
~lO) 3~ Mc~hyl~ tetrazol-5~yl)thiomethyl-7-[2-hydro~y-2-(20amino-1,3-thiazol-5-yl)acetamido3-~-cephem-4-carboxylic acidt which can be represented as 3-(l-methyl-IH-tetrazol-5 yl)thiomethyl-7~[2-hydro~Y-2-(2-imino-2~3-dihydro-l~3-thiazol-5-yl)acetamido]-3-cephem-4-CarbO~ylic acid, mp. 130 to 200C (dec.).
-129- ~ - 90 s~
(11~ 3~ Methyl-lH-tetrazol-5-yl)thiomethyl-7-~2-hydroxy-2-(2-amino-5~chloro-1,~-thiazol-4-yl)ace~amido]-3 cephem-4-carbo~ylic acid, which can be represented as 3-(l methyl~
tetrazol-5-yl)thiom~thyl-7-[2-hydro~y-2-(2-imino-5-cnloro-2 9 3-d~hydro~ 3-thiazol-4-yl)acetamido~ 3-cephem-4-c~rboxylic acid7 mp. 148 to 154C (dec.).
~ 12) ~ Methyl-IH-tetrazol-5-yl)thiomethyl-7-[2-hydro~y-2-~2-(methyl)thiocarbamoylami~o-19 3~thiazol-4-yl]ace'~,ido~-3-cephem 4-carboxylic acid, which can be represented as ~
methyl-I~tetrazol-~5-yl)thiomethyl-7-~2-h~droxy-?-~2-(methyl3-thiocarbamoylimi~o~2,3-dinydro-i,3~thiazol-4-yl3aceta~idoJ-3-cephem-4~c2rboxJlic acid, 155G (5in~ar)~ 160C ~dec.)O
(13~ 3~ Methyl-l~-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-methylamino 1,3~thiazol-4-yl)acetamido]-3~cephem-4-carb~xylic acid, which can be repre~ented a~ 3-(1-methyl-IH-tetr~zol-5-yl)-thiomethyl-7-~2-hydro~y-2-(2-methyli~ino-2,3-dihydro-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, mp. 144 to 156~C (dec.).
(14~ 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-(~-amino-~-~ 1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-caTboxylic acid hydro-chloride, which can be represented as 3-(1,37~-thiadiazol-2-yl)-thîomethyl-7-[2-(2-imino-2,3-dihydro-1,3~thiazol-4-~l)glyoxylamido~-3-cephem~4-carbo~yl~o acid hydrochloride, powder.
I.R. Spect~um (Nujol) 1778 (~-lactam) cm 1 M~thyl-lE-tetrazo~-5~yl3thiomethyl~7~2-(2-ahlino-1,3~thiazol~5-yl)glyo~ylamido]-3-cephem-4-carboxylic acid hydrochloride~ which can be repre~e~ted as 3^~ methyl-~H-te~razol-5-yl)thiomethyl-7-[2-(2-imi~o 2,3-dihydro-1,3-thiazol-5-yl)O
glyo~ylamido~ 3-cephem-4-carboxylic ~cid hydrochlolide, mp. 140 to 160C ~dec.~
-121- ~ - 91 ;i7~
~16) 3~ ethyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-methylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-y)-thiomethyl-7-~2-(2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxyli.c acid, mp. 146 to 155C
(dec.).
(17) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-[2-(methyl)thiocarbamoylamino-1,3-thiazol-4-yl]glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-[2-(methyl)thio-carbamoylimino-2,3-dihydro-1,3-thiazol-4-yl]glyoxylamido]-3-cephem-4-carboxylic acid, 148C (sinter), 160C (expand), 200C (decO).
In this specification the expression "such as" means "for example" and is not intended to be construed as limiting the values which it qualifies.
The extraGt was washed with à saturated aqueous solution of sodium chloride and drled over magnesium sulfate. The solvcnt was distilled off from the extract~ and the residue was washed in diethyl ether9 collected by filtration and then dried to give pale brown powder of 3~ methyl-lH-~etrazol-5-yl)-~hiomethyl-7-[2-hydroxy-2-(2-mesylamino-1,3-thiazol-4-yl)acet-amido]-3-cephem-4-carboxylic acid, which can be represen~ed as 3~1 methyl-lH-te~razol-5-yl~thiomethyl-7-~2-hydroxy-2-(2-mesylimino-293-dihydro-1,3-thiazol-4-yl)acetamido]-3-cepllem-4-carboxylic acid~ (0~2 g.), mp. 120 to 146C (dec.).
I . R. Spec~rum ~Nuj ol) 1780 (~-lactam) cm~
N.~l.R. Spectrum (d6-dimethylsulfoxide, 2.9 (3~l, 5) 3.57 and 3. 8(2~1, ABq, J=18 }~z) -` ~Z~S77 3.9 t3~l, 5) 4,2 and 4.4 (2H9 ABq, J=13 Hz) 4.~-S.15 (2H~ m) 5.5-5~75 tlH~ m) ~.65 (1~ s) Example ~4 A mixture of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl~lH-tetrazol-5-yl)thiomethyl-7-[2-~ormyloxy-2-(2-tert-pentylox~carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-acetamido] -3-cephem-4-carboxylic aoid9 (1.49 g.) and 5% sodium bicarbonate aqueous solution (100 ml.) was allowed ~o stand for 6 hours. After the reaction, the reaction mixture was washed with ethyl acetate. To ~he reaction mixtur0 was added ethyl acetate, and the mixture was adjusted to pH 7 with dilute hydrochloric acid and ~hen ~he aqueous layer was separatedO
To the aqueous layer was added ethyl acetate, and the mixture w~s adjusted to pH 1 to 2 with dilute hydrochloric acid~ and the ethyl acetate layer was separated. The ~emaining aqueous layer was subjected to salting-out and then extraoted with ethyl acetate. The ethyl acetate layer and the ethyl ace~ate extract were com~ined together, washed with water; dried over magnesium sulfate, and then the solvent was distilled off~ To the ~esidue ~2.0 g.) was added diethyl ether, and the mixture was stirred for overnight, collected by filtration and then dried to give pale brown powder of 3~ methyl-lH-tetrazol-5-yl)thiomethyl-7-[~-hydroxy-2-(2-teTt-pentyloxycarbonylamino-1~3-thiazol-4-yl)-acetaDido~-3-cephem-4-ca~boxylic acid, which can be represented as 3~ me~hyl-lH-te~razol-5-yl)thiomethyl-7-l2-hydroxy-2-~2--lO9- E - 79 ` ~ 2~ ~ 5 7~
tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl~-acetamido]-3-cephem-4-carboxylic acid, tO.90 g.~.
I.R, Spectrum (Nujol) 1785 (~-lactam), 1680-1730 (CO) cm^
N.M.R. Spectrum ~d6-dimethylsulfoxide, ~) 3.58 and 3.82 ~2H, ABq~ J~18 Hz~
3.93 (3H, s~
4.22 and 4.33 t2H, ABq, J=12 Hz) 5.0 5.12 (2Ha m) 5 55-5.8 (lH, m) 7.03 (lH~ s) Similarly, the following compou~ds were obtained.
(1) 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiome~hyl-7-l2-hydroxy-2-t2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which can be represen~ed as 3-~5-me~hyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-l2--hydroxy-2~2-tert-pentyloxycarbonylimino-293-dihydro-1,3-tlliazol-4-yl)-acetamido~-3-cephem-4-carboxylic acid.
I . R. Spect~um ~Nujol) 1785 ~-lactam) cm 1 ~ ) 3-~1,3,4-Thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2-tert-pentyloxycarbonylamino-193-thiazol-4-yl~acetamido3-3-cephem-4-carboxylic acid, which can be Tepresented as 3-~1,3,4 thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-~2-ter~--pentyloxy-carbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acidJ pale yellow powder.
t33 7-[2-Hydroxy-2-(2-~er~-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid, which can be ~epresented as 7-~2-hydroxy-2-t2-tert-pentyloxycarbonylimino-2~3-dihydro-1,3-thiazol-4-yl~acetamido]cephalosporanic acid.
-llO- E - 80 57'7 I . R. Spectrum (Nujol) 1783 (~-lactam) cm^l (4) 3-(1-Methyl-lH-.tetrazol-S-yl)thiomethyl-7-[2-hydroxy-2-t2-propanesulfonylamino-1,3-thiazol-4-yl)ace~amido]-3-cephem-4-carboxylic acid, which can be represented as 3-tl-methyl-lH-tetrazol-5-yl)thiomethyl-7- [2-hydroxy-2- (2-propanesulfonyl-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3~cephem-4-carboxylic acid, mp. 160 to 170C (dec.~.
(5) 3- ~1-Methyl-lH-tetrazol-5-yl) thiomethyl-7-~2-hydroxy-2 - ~2 - oxo - 2 ~ 3 - dihy dro -1 9 3 - th i a ~ol - 4 -y 1 ) ace tami do ] - 3 - cephem- 4 -carboxylic acid, which can be rep~esented as 3- (l-methyl-lH-tetrazol-5-yl3thiomethyl-7-L2-hydroxy-2-(2-hydroxy-173-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp~ 110 to 121C
(dec.) t6) 3-t5-Methyl-1,394-thiadiazol-2-yl)thiomethyl-7-~2-~ydroxy-2-(2-amino-lp3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be rep~esented as 3-tS-me~hyl-1~3j4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, pale yellow powder.
t7) 3-tl,3,4-Thiadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, which can be ~epresented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-t2-imino-2,3-dihydro-1,3-thiazol 4-yl~acetamido3-3-cephem-4-carboxylic acid, mp. 151 to 180C dec.).
~ E - 81 ~ 3L2~ii7'~
( ) 3-(5-Methyl-1,3,4-oxadiazol-2-yl)thiomethyl~ 2-hydroxy-2 (2-amino-1~3-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,374-oxadiazol-2-yl)tlliomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro-1, 3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid.
I.R. Spectrum (Nujol~
17~0 t~-lactam~ cm 1 ( 9~ 3-(~-Methyl-4H-1,2,~-triazol-~-yl)thiomethyl-7-C2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)ace~amido]-3-cep)lem-4-ca~boxyllc acid, which can be rep~esen~ed as 3-(4.-methyl-4H-- 1,2,4-triazol-3-yl)thiomethyl-7-~2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid.
I R. Spectrum ~Nujol) ; 1760 t~-lactam) cm 1 ~10) ~ Carbamoyloxymethyl-7-~2 hydro~y-2-(2-a~i~o-1,3-. ~ thiazol-4-yl~acetamido]-3 cephem 4-carboxylic acid, which ca~
be represe~ted ~s ~-carbamoylo~ymethyl-7-~2 hydro~y-2 (2-imino-~,7 dihydro-1,3-thia~ol-4-yl~acetamido]-3-cephem-4-carbo~ylic ac~d, mp. > ~70C.
(1}) 3 Meth~l-7 [2-hydro~y-2-~2-amino-1,3-thiazol-4-yl)-aoetamido~-3-cephem-4-carbo~ylic acia, which can be represented a8 3~methyl-7-[2-hydroxy-2(2-Imino-2,3 dihydro-1,3-thiazol-4-~l)acetamido~-3-cephem-4-carbo~ylic ac~d~ mp. > 250C.
(12) ~ Methyl-lE-tetrazol-5-yl~thiomethyl-7-[2-~hydro~y 2 (2-amino-1,~-thiazol~5~yl)acetamido]-j-cephem-~-carboxylic acid, which can be represen~ed as ~ methyl-lH-t~t~zol-5-yl)thionsthyl-7-[2hydro~y-2-(2-imino~2~-di.hydro-E ~ 82 1,3-thiazol~5-yl)acetamido]-3-cephem-4~carboxylic acid, mp. 130 to 200~ ~dec~
~ 3~ let~yl-lX-tetrazol-5-yl)thiomethyl-7-[~-hydroxy-2-(2-amino-5-chloro-1,3-thia7,ol-4~yl)acetamido]-3-cephem-4-oarboxylic acid, which can be represented as 3 (1-methyl~ tetrazol-5~yl)thiomethyl-7-~2-hydro~y-2-(2-lmi~o-5-chloro-2,~ dihydro-1,3-thiazol-4-yl)acet~.mido]-3-cephem-4-carboxylic acid, m~, 148 to 154C (dec.).
(14) 3~(1-Methyl-l~-tetrazol-5-yl)thiomethyl-7~[2-hydro~y-2-(2~ormylamino~ thiazol-4-yl)acetamido3~-cephem-4-carboxylic aeid, which can be repre~ented as 3~ ~ethyl-1~ tetrazol-5-yl)-thiomethyl~7-[2 hydro~y-2-(2-formyli~ino-2,~-dihydro-1,3-thiazol-4-yl)acetamid~-3-cephem-4-c~.rbo~ylic acidt brownish white powder.
(15) 3-(19~,4-Thiadiazol-2-yl)thiomethyl-7 [2-hydro~y-2-~2-formylami~o-1,3-thiazol-4-yl)acetamldo]=~3~cephem-4carbo~ylic acid~ which can be repre~ented as 3-(193~4-thiadiazol-2-yl)-thiomethyl-7-[2-hydro~y-2-(2-formyli~i~o-2~-dihydro-1,3-thiazol-4~yl)acetamido]-3 cephem-4-carbo~ylic acid~ mp, 105 to 130~C (dec.).
(16) ~-(1-Me~hyl-lH~tetrazol-5-yl)~hiomet~yl--7-[DL~2-hydro~y-2 (2 formylamino-5 chloro-1,3-thiazol-4-yl)ac0tamido]-3-cephem-4carbo~ylic acid, which ca~ be represented as 3-(1-methyl-lH-tet~azol-5-yl~thiomethyl-7-~D3-2-hydroxy~2-(2-~ormylimino-5-ch~oro-2~3-dihydro-1,3~thiazol-4-gl)aceta~ido~-3-c~phe~-4-car~c~ylic acid9 mp. 160 to 1~5~. (dec.).
(17) 3~ ethyl-lH-tetrazol-5-yl)thiomethyl-7-~2-hydroxy-2-~2-(methyl)thio~arbamuylamino-1,3-thiazol-4-yl]acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl~ tetrazol-~-yl~thiomethyl-7-~2~hydroxy-2~[2~(methyl)-thio6arbamoylimino~2.3~dihydro-1,3-thia~ol-4-yl~aceta~ido]-3 icephe~-4-carbo~ylic acid. 155C ~ ter) J 160C (dec.~.
- -113- ~ - 83 9~
(la) 3-~ ethyl-IH-tetra~ol-5-gl)thiomethyl-7-~2-hydro~y-2~(2-methylamir,o-1,3-thiazol-4-yl)acetamido~-3-cephem-4-c~rbo~ylic acid, whic~ can be repre~ted as 3-(1-methyl-IH-~etra~ol-5-yl~-th~omethyl-7-[~-hydro~y-2-~2-methylimino-2j~dihydro-1.,3-thiazol~
; 4-~l)ace~amido3-~-cephem-4-carbo~ylic acid, ~p. 14~ to 156C (dec.).
~9 ) ~ ethyl-lH-tetrazol-5-yl)thiomethyl-7-~L-~
hydro~y-2-~2-(N-~ethyl-N-tert-pentyloxyc~rbonylamino3 thiazol-4-yl~acetamido]-~- ephem-4 carboxylic acid.
IoXo~ ~pec~rum (Nujol) ~- 1770-1790 (broad) cm 1 .
(20~ 3~ 'lethyl-lH tetr~zol-5yl)thio~et~yl-7-~2-hydroxy-2-(2-o~o-2,3-di~ydro-l,~-thiazol-4-yl)acet2~ido~ cephem-4-carbo~ylic acid, which can be represented as ~ (l-me~hyl-l~-tetrazol~5-yl)thiomethyl-7-~2-hydroxy-2-(2-hydro~y-l~j-thiazol-4-yl)acetamido~-cephem-4-carboxylic acid, mp. 110 to 121C (~ec.3.
~ ' , .
~ 7 Example 25 A solution of 7-~2-hydroxy-2 (2-tert-pentyloxycarbonyl-~mino-1,3-thiazol~4-yl)acetamido~cephalosporanic acid, which can be represented as 7-[2-hydroxy-2~(2-tert-pentyloxycarbonyli~ino-2~3-dihydro-1,3-thiazol-4-yl)acetamido~cephalosporanic acid, ~3B9 mg.), 5-methyl-193,4-oxadiazol~-t~iol(116.13 m~.), sodium bicarbonate (119.4 mg.) in p~ 5.2 phosphate ~uffer (15 ml.) was adjusted to pH 5.2 with 10~ hyd~ochloric acid and was stirred for 7 hours at 60 at 63C. Af~er ~he reaction, to the ~eaction mixture was added e~hyl ace~ate, and the mixture was a~usted to pH 2 with 2N hydrochloric acid. The precipitates WeTe collected by iltration and dried to give 3-~5-methyl 1~3, 4-oxadiazol-2-yl)thiomethyl-7-[2-hydroxy-Z~(2-amino-1,3-~hiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, which can be`
represented as 3-~5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7-~2-hydroxy-2-t2-imino-2,3-dihydro-193-thiazol-4-yl~acetamido]-3-cephem-4-carboxylic acid, (60 mg.). On the other hand, from the remaining filtrate was separa~ed the aqueous layer.
The aqueous layer was washed with ethyl acetate, and the remaining ethyl acetate in the aqueous layer was distilled off under ~educed pressure. The aqueous layer was sub3ected to column chromatography tnon-ionic adsorption resin9 Diaion HP 20 prepared by Mitsubishi Chemical Industries)~ washed with water and then eluted with 10% isopropyl alcohol. The eluates containing the object compound were collected and then isopropyl alcohol was distilled off under reduce-d pressure. The remaining aqueous solu~ion was lyophilized to give the same object compound (75 mg.) I.R. Spectrum (Nujol) 1780 (e-lactam) cm^l i~9s~ i~
N.M.R. Spectrum (d6-dimethylsulfoxide, C) 3.65 (2H, broad s) 4~ and 4. 45 t2H, ABq ~ J=15 }Iz) 4.95 (lH,, s) 5.1 (lH, d, J=S Hz) 5.55-5. 8 ~lH, m) 6.7 (lH, s) i Bxample 26 f A solution of 7~2-~-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]cephalosporanic acid, which can be r~presented as 7- [2-t2-tert-pen~yloxycarbonylimino-~,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~cephalosporanic acid, (389 mg.), S-methyl-1,3,4-oxadiazole-2-thi.ol (I16.3 mg.), sodium bica~bona~e (ll9.fl mg.3 in p}~ 5.2 phosphate buffer (lS ml.~ was adjusted to pH 5.2 with 10~ hydrochloric acid and was stirred for 7 hours a~ 60 to 63C. After the reaction, to the reac~ion mixture was added ethyl ace*ate, and th~ mixture was ad justed ~o pH 4 . 5 with 2N hydrochloric ~cid, and then the aqueous layer was separated. To the aqueous . layer was added ethyl acetate~ and the mixture was adjusted to pH 1~5 with 2N hydrochloric acid9 and then the aqueous laye~ was separated. The aqueous layer was adjus~ed to pH 3 with lN sodium hydroxide aqueous solution and ~hen allowed ~o stand for overnight at cooling plac~. The precipita~es we~e collected by filtration and then dried to gi~e 3-~5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-7-[2-~2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-metl;yl-1,3,4-oxadiazol-2-.yl)thiomethyl-7-[2 ~2~imino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid9 ~30 mg.~. On the .other hand, the filt~ate was sub~ccted to column rhromato~raphy ~z~gs~
in similar manner as that of example ~5 to give further the : ~ame object compound t65 mg.~
I.R. Spectrum (Nujol) 1775 (~-lactam) cm^l ~
N~Mo R. Spectrum (d6-dimethyls~loxide, ~) 3.7 (2H, broad s) . 4.2 and 4.45 (2H~ ABqJ J-14 Hz~
5.2 (lH, d, J=5Hz) ; S.75 tlH, d~ J=5 Hz) . . 8.1 (lH, s3 i, .
Example ~7 A mixture of 7-~2-hydroxy-2-(2-te~t-pentyloxycarbonyl-amilio-1,3-thiazol-4-yl)acetamido~cephalosporanic acid5 which can be ~epresented as 7-~2-hydroxy-2-(2-tert-pentyloxycarbonyl-imino-2,3-dihydro-1~3 thiazol-4-yl)acetamidoJcephalosporanic acid, . (389 mg.), 4-methyl-4H-1,2,4-t~iazole-~-thiol (115.2 mg.) 3 ' sodium bicarbonate (119.4 mg~) and pH 5.2 phosphate buf~er was J stirred for 3 hours at 60 to 65C. After the reaction, ~o the reaction mix~ure was added ethyl acetate, and the aqueous l~yer was separated. To the aqueous layer was added ethyl acetate, and the mixtu~e was adjusted to pH 1 with 2N hydrochlori.c acid. The aqueous laye~ was separa~ed, and the remaining ethyl acetate in the aqueous layer was ~emoved under reduced pressure. The remaining aqueous solution was subjected to column chromatography ~berlite XAD-4 prepa~ed by Rohm ~ Haas Co.), and the column was washed with water and then eluted with 20 to 50% methanol aqueous solution. The eluates containing the object compounds were collected and the methanol l~as distilled off therefrom. The remaining aqueous solution was lyophilized ~''3S7'~
to gi~e 3-(4-methyl-4H-l~2J4-triazo~ yl)thiomethyl-7 ~2-hydroxy-2-(2-amino-1,3-thiazol-4 -r l)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(4-methyl-4.H-~ 2~4-triazol-~-yl)thiomethyl-7-~2-hydroxy-2-~(2-imino-2,3-dihyd~o-193-khiazol-4-yl)acetamido]-3-cephem-4-carboxyli~ scid, : (149 mg.).
IoR~ Spectrum (Nujol) 1760 ~-lactam) cm~l NrN~R~ Spectrum ~d6-dimethylsul~oxide,~) 3.57 ~3H, s) 3O69 t2H, broad s) 4.0-4.3 (2H, m) 4.9 (lH, s~
; - 5.1 (lH~ d, J=S Hz) So6~5~ (lH, m) 6.6 (lH, s) F.xample ~
(. A mixture of ?-[2-t2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido~cephalosporanic acid, which can be r~pr~sented as 7-[2-~2-~ert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl3glyoxylamido]cephalosporanic acid, (378 mg.), 4-methyl-4H-1,294-triazole-3-thiol ~115.2 mg.~, sodium bicarbonate ~119.4 mg.) and pH 5.2 phospha~e buffer (15 ml. was stirred for 6 hours at 60 to 63~C. AfteT the reaction, the reaction mixture was post-treated by ~on~entional manners to ~ive 3-~4-methyl4 H-172l4-t~iazol-3-yl)thiomethyl-7-[2-(2-amino-1~3-thia~ol-4-yl)glyoxylamido~-3-cephem-4-carboxyl;c acid, which can be ~epresented as 3-(4-methyl-4H-1,2,4-triazol-~-yl)~hio-methyl-7-[2-~ ino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido~-9~
3-cephem-4~carboxylic acid, (160 mg.).
I.R. Spectrum (Nujol) 1775 (~ -lactam) cm 1 Similarly, the following compounds were obtained.
(1) 3-~-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-oxo-2, 3-dihydro-1,3-thiazol 4--yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-7--[2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, pale yellow powder.
(2) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-propane-sulfonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, mp. 150C (dec.).
(3) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesul~onylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3~(1-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp. 160 to 170C ~dec.).
(4) 3-(1-Methyl-lH-tetrazol-5~-yl)thiomethyl-7-~2-hydroxy-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5yl)thiomethyl-7-[2-hydroxy-2-(2-hydroxy-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, mp. 110 to 121C
(dec.).
(5) 3-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3-4-thiadiazol-2yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-5~
1;3-thi~zol^4-yl)acetamido]-3-ce~hem-4-carboxylic acid, pale yellow powder.
t6~ 3-(1,3,4-~hiadiazol-2-yl)thiome~hyl-7-~2-hydroxy-2-(2-amino-1,3-thiazol-4-yl~acetamido~-3-cephem-4-carboxylic acid, which can be ~epresented as 3-(1,3,4~thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)ace~amido3-3-cephem-4-carboxylic acid, mp. 151 tb 180C (dec.).
(7~ 3-(1-Methyl-l~l-tetrazo~-5-yl)thiomethyl-7-[2-~-amino-1,3-thiazol-4-yl3glyoxylamido]-3-cephem-4-carboxylic acid~ which can be represented as 3-~1-methyl-1l~-tetrazol-5-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro-1,3'-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, mp. 147 to 160C (dec.).
(8 ~ 3-(S-Methyl-1,394-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl~glyoxylamido3-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-~2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxyl-amido~-3-cephem-4-carboxylic acid, mp. 156 to 160C (dec.).
(9 ) 3-(1-Methyl-l~l-tetrazol-5-yl)thiomethyl-7-~2-hydroxy--~2-mesylamillo-1,3-thiazol-4-yl)acetamido3-3-cephem-4-carboxylic acid, which can be Tepresented as 3-(l-methyl-lH-tetra701-5-yl)-thiom~thyl-7-~2-hydroxy-2-(2-mesylimino-2~3-dihydro-1,3-thiazol-4-yl~acetamido]-3-cephem~4-ca~boxylic acid, mp. 120 to 146C ~dcc ~.
~lO) 3~ Mc~hyl~ tetrazol-5~yl)thiomethyl-7-[2-hydro~y-2-(20amino-1,3-thiazol-5-yl)acetamido3-~-cephem-4-carboxylic acidt which can be represented as 3-(l-methyl-IH-tetrazol-5 yl)thiomethyl-7~[2-hydro~Y-2-(2-imino-2~3-dihydro-l~3-thiazol-5-yl)acetamido]-3-cephem-4-CarbO~ylic acid, mp. 130 to 200C (dec.).
-129- ~ - 90 s~
(11~ 3~ Methyl-lH-tetrazol-5-yl)thiomethyl-7-~2-hydroxy-2-(2-amino-5~chloro-1,~-thiazol-4-yl)ace~amido]-3 cephem-4-carbo~ylic acid, which can be represented as 3-(l methyl~
tetrazol-5-yl)thiom~thyl-7-[2-hydro~y-2-(2-imino-5-cnloro-2 9 3-d~hydro~ 3-thiazol-4-yl)acetamido~ 3-cephem-4-c~rboxylic acid7 mp. 148 to 154C (dec.).
~ 12) ~ Methyl-IH-tetrazol-5-yl)thiomethyl-7-[2-hydro~y-2-~2-(methyl)thiocarbamoylami~o-19 3~thiazol-4-yl]ace'~,ido~-3-cephem 4-carboxylic acid, which can be represented as ~
methyl-I~tetrazol-~5-yl)thiomethyl-7-~2-h~droxy-?-~2-(methyl3-thiocarbamoylimi~o~2,3-dinydro-i,3~thiazol-4-yl3aceta~idoJ-3-cephem-4~c2rboxJlic acid, 155G (5in~ar)~ 160C ~dec.)O
(13~ 3~ Methyl-l~-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-methylamino 1,3~thiazol-4-yl)acetamido]-3~cephem-4-carb~xylic acid, which can be repre~ented a~ 3-(1-methyl-IH-tetr~zol-5-yl)-thiomethyl-7-~2-hydro~y-2-(2-methyli~ino-2,3-dihydro-1,3-thiazol-4-yl)acetamido~-3-cephem-4-carboxylic acid, mp. 144 to 156~C (dec.).
(14~ 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-(~-amino-~-~ 1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-caTboxylic acid hydro-chloride, which can be represented as 3-(1,37~-thiadiazol-2-yl)-thîomethyl-7-[2-(2-imino-2,3-dihydro-1,3~thiazol-4-~l)glyoxylamido~-3-cephem~4-carbo~yl~o acid hydrochloride, powder.
I.R. Spect~um (Nujol) 1778 (~-lactam) cm 1 M~thyl-lE-tetrazo~-5~yl3thiomethyl~7~2-(2-ahlino-1,3~thiazol~5-yl)glyo~ylamido]-3-cephem-4-carboxylic acid hydrochloride~ which can be repre~e~ted as 3^~ methyl-~H-te~razol-5-yl)thiomethyl-7-[2-(2-imi~o 2,3-dihydro-1,3-thiazol-5-yl)O
glyo~ylamido~ 3-cephem-4-carboxylic ~cid hydrochlolide, mp. 140 to 160C ~dec.~
-121- ~ - 91 ;i7~
~16) 3~ ethyl-lH-tetrazol-5-yl)thiomethyl-7-[2-(2-methylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-y)-thiomethyl-7-~2-(2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxyli.c acid, mp. 146 to 155C
(dec.).
(17) 3-(1-Methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-[2-(methyl)thiocarbamoylamino-1,3-thiazol-4-yl]glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7-[2-[2-(methyl)thio-carbamoylimino-2,3-dihydro-1,3-thiazol-4-yl]glyoxylamido]-3-cephem-4-carboxylic acid, 148C (sinter), 160C (expand), 200C (decO).
In this specification the expression "such as" means "for example" and is not intended to be construed as limiting the values which it qualifies.
Claims (118)
1. A process for the preparation of a compound of the formula (III) :
(III) wherein R1 is amino, lower alkylamino, a protected amino or a protected lower alkylamino, R4 is hydrogen ox halogen, and R5 is carboxy or a protected carboxy, or a salt thereof, which comprises (a) reacting a compound of the formula :
(IIIi) wherein R1 is amino or lower alkylamino, and Z is a protected carboxy, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, to give a compound of the formula :
(IIIa) wherein R1' is a protected amino or a protected lower alkylamino, and Z is as defined above, or (b) reacting a compound of the formula :
(III?) wherein R1" is as defined above, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, to give a compound of the Formula :
(IIIb) wherein R1' is as defined above, or (c) oxidizing a compound of the formula :
(VII) wherein R1' and Z are each as defined above, to give a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, or (d) subjecting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, to elimination reaction of the protective group of the carboxy, to give a compound of the formula :
(IIIb) wherein R1' is as defined above, or (e) subjecting a compound of the formula :
(IIIj) wherein R1' and Z are each as defined above, and R4 is halogen, to elimination reaction of the protective group of the carboxy, to give a compound of the formula (IIIk) wherein R1' and R4 are each as defined above, or (f) subjecting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, to elimination reaction of the protective group of the amino, to give a compound of the formula :
(IIIi) wherein R1' and Z are each as defined above, or a salt thereof, or (g) reacting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, with a halogenating agent to give a compound of the formula :
(IIIj) wherein R1', R4' and Z are each as defined above, or (h) oxidizing a compound of the formula :
(IIIm) wherein R1" is as defined above, or a salt thereof, to give a compound of the formula :
(III?) wherein R1" is as defined above, or a salt thereof, and when desired converting the compound obtained to a corresponding salt.
(III) wherein R1 is amino, lower alkylamino, a protected amino or a protected lower alkylamino, R4 is hydrogen ox halogen, and R5 is carboxy or a protected carboxy, or a salt thereof, which comprises (a) reacting a compound of the formula :
(IIIi) wherein R1 is amino or lower alkylamino, and Z is a protected carboxy, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, to give a compound of the formula :
(IIIa) wherein R1' is a protected amino or a protected lower alkylamino, and Z is as defined above, or (b) reacting a compound of the formula :
(III?) wherein R1" is as defined above, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent, to give a compound of the Formula :
(IIIb) wherein R1' is as defined above, or (c) oxidizing a compound of the formula :
(VII) wherein R1' and Z are each as defined above, to give a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, or (d) subjecting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, to elimination reaction of the protective group of the carboxy, to give a compound of the formula :
(IIIb) wherein R1' is as defined above, or (e) subjecting a compound of the formula :
(IIIj) wherein R1' and Z are each as defined above, and R4 is halogen, to elimination reaction of the protective group of the carboxy, to give a compound of the formula (IIIk) wherein R1' and R4 are each as defined above, or (f) subjecting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, to elimination reaction of the protective group of the amino, to give a compound of the formula :
(IIIi) wherein R1' and Z are each as defined above, or a salt thereof, or (g) reacting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, with a halogenating agent to give a compound of the formula :
(IIIj) wherein R1', R4' and Z are each as defined above, or (h) oxidizing a compound of the formula :
(IIIm) wherein R1" is as defined above, or a salt thereof, to give a compound of the formula :
(III?) wherein R1" is as defined above, or a salt thereof, and when desired converting the compound obtained to a corresponding salt.
2. A process for the preparation of a compound of the formula (IIIa) :
(IIIa) wherein R1' is a protected amino or a protected lower alkylamino, and Z is a protected carboxy, which comprises reacting a compound of the formula (IIIi) wherein R1" is amino or lower alkylamino, and Z is as defined above, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent.
(IIIa) wherein R1' is a protected amino or a protected lower alkylamino, and Z is a protected carboxy, which comprises reacting a compound of the formula (IIIi) wherein R1" is amino or lower alkylamino, and Z is as defined above, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent.
3. A process according to claim 2 for the preparation of a compound of the formula (IIIa') :
(IIIa') wherein R1' and Z are each as defined in claim 2, which comprises reacting a compound of the formula :
(IIIi') wherein R1" and Z are each as defined in claim 2, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent.
(IIIa') wherein R1' and Z are each as defined in claim 2, which comprises reacting a compound of the formula :
(IIIi') wherein R1" and Z are each as defined in claim 2, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent.
127 1. A process of claim 3, wherein R1' is acylamino, R1" is amino, Z is an esterified carboxy, and amino-protecting agent is acylating agent.
5. A process of claim 4, wherein R1' is lower alkyl(thiocarbamoyl)amino, and amino-protecting agent is lower alkyl isothiocyanate.
6. A process of claim 5, wherein Z is lower alkoxycarbonyl.
7. A process of claim 6, wherein R1' is 3-(methyl)thioureido, R1" is amino, Z is ethoxycarbonyl, and amino-protecting agent is methyl isothiocyanate.
8. A process for the preparation of a compound of the formula (IIIb) :
(IIIb) wherein R is a protected amino or a protected lower alkylamino, which comprises reacting a compound of the formula :
(III?) wherein R1" is amino or lower alkylamino, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent.
(IIIb) wherein R is a protected amino or a protected lower alkylamino, which comprises reacting a compound of the formula :
(III?) wherein R1" is amino or lower alkylamino, or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent.
9. A process of claim 8, wherein R1' is acylamino, R1" is amino, and amino-protecting agent is acylating agent.
10. A process of claim 9, wherein R1' is lower alkanoylamino, and amino-protecting agent is lower alkanoic acid ox its reactive derivative.
11. A process according to claim 10 for the preparation of a compound of the formula (IIIb') :
(IIIb') wherein R1' is as defined in claim 10, which comprises reacting a compound of the formula :
(III?') wherein R1" is as defined in claim 10, or its reactive derivative at the amino group or a salt thereof with lower alkanoic acid or its reactive derivative.
(IIIb') wherein R1' is as defined in claim 10, which comprises reacting a compound of the formula :
(III?') wherein R1" is as defined in claim 10, or its reactive derivative at the amino group or a salt thereof with lower alkanoic acid or its reactive derivative.
12. A process of claim 11, wherein R1' is formylamino, R1" is amino, and lower alkanoic acid is formic acid.
13. A process for the preparation of a compound of the formula (IIIa) :
(IIIa) wherein R1' is a protected amino or a protected lower alkylamino, and Z is a protected carboxy, which comprises oxidizing a compound of the formula :
(VII) wherein R1' and Z are each as defined above,
(IIIa) wherein R1' is a protected amino or a protected lower alkylamino, and Z is a protected carboxy, which comprises oxidizing a compound of the formula :
(VII) wherein R1' and Z are each as defined above,
14. A process according to claim 13 for the preparation of a compound of the formula (IIIa') :
(IIIa') wherein R1' and Z are each as defined in claim 13, which comprises oxidizing a compound of the formula :
(VII') wherein R1' and Z are each as defined in claim 13.
(IIIa') wherein R1' and Z are each as defined in claim 13, which comprises oxidizing a compound of the formula :
(VII') wherein R1' and Z are each as defined in claim 13.
15. A process of claim 14, wherein R1' is acylamino or N-acyl-N-lower alkylamino, and Z is an esterified carboxy.
16. A process of claim 15, wherein R1' is lower alkanoylamino, lower alkoxy-carbonylamino, lower alkanesulfonylamino or N-lower alkoxycarbonyl-N-lower alkylamino, and Z is lower alkoxy-carbonyl.
17. A process of claim 16, wherein R1' is lower alkoxycarbonylamino.
18. A process of claim 17, wherein R1' is tert-pentyloxycarbonylamino, and Z is ethoxycarbonyl.
19. A process of claim 16, wherein R1' is lower alkanesulfonylamino.
A process of claim 19, wherein R1' is propanesulfonylamino, and Z is ethoxycarbonyl.
21. A process of claim 19, wherein R1' is mesylamino, and Z is ethoxycarbonyl.
22. A process of claim 16, wherein R1' is N-lower alkoxycarbonyl-N-lower alkylamino.
23. A process-of claim 22, wherein R1' is N-methyl-N-tert-pentyloxycarbonylamino, and Z is ethoxycarbonyl.
24. A process of claim 16, wherein R1' is lower alkanoylamino.
25. A process of claim 24, wherein R1' is formylamino, and Z is ethoxycarbonyl.
26. A process of claim 24, wherein R1' is formylamino, and Z is methoxycarbonyl.
27. A process for the preparation of a compound of the formula (IIIb) :
(IIIb) wherein R1' is a protected amino or a protected lower alkylamino, which comprises subjecting a compound of the formula :
(IIIa) wherein R1' is as defined above, and Z is a protected carboxy, to elimination reaction of the protective group of the carboxy.
(IIIb) wherein R1' is a protected amino or a protected lower alkylamino, which comprises subjecting a compound of the formula :
(IIIa) wherein R1' is as defined above, and Z is a protected carboxy, to elimination reaction of the protective group of the carboxy.
28. A process according to claim 27 for the preparation of a compound of the formula (IIIb') :
(IIIb') wherein R1' is as defined in claim 27, which comprises subjecting a compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 27 to elimination reaction of the protective group of the carboxy.
(IIIb') wherein R1' is as defined in claim 27, which comprises subjecting a compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 27 to elimination reaction of the protective group of the carboxy.
29. A process of claim 28, wherein R1' is acylamino or N-acyl-N-lower alkylamino, and Z is an esterified carboxy.
30. A process of claim 29, wherein R1' is lower alkanoylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, lower alkyl(thiocarbamoyl)amino or N-lower alkoxycarbonyl-N-lower alkylamino, and Z is lower alkoxycarbonyl.
31. A process of claim 30, wherein R1' is lower alkoxycarbonylamino.
32. A process of claim 31, wherein R1' is tert-pentyloxycarbonylamino, and Z is ethoxycarbonyl.
33. A process of claim 30, wherein R1' is lower alkanesulfonylamino.
34. A process of claim 33, wherein R1' is propanesulfonylamino, and Z is ethoxycarbonyl.
35. A process of claim 30, wherein R1' is N-lower alkoxycarbonyl-N-lower alkylamino.
36. A process of claim 35, wherein R1' is N-methyl-N-tert-pentyloxycarbonylamino, and Z is ethoxycarbonyl.
37. A process of claim 30, wherein R1' is lower alkanoylamino.
38. A process of claim 37, wherein R1' is formylamino, and Z is ethoxycarbonyl.
39. A process of claim 37, wherein R1' is formylamino, and Z is methoxycarbonyl.
40. A process of claim 30, wherein R1' is lower alkyl(thiocarbamoyl)amino.
41. A process of claim 40, wherein R1' is 3-(methyl)thioureido, and Z is ethoxycarbonyl.
42. A process for the preparation of a compound of the formula (IIIk) :
(IIIk) wherein R1' is a protected amino or a protected lower alkylamino, and R4' is halogen, which comprises subjecting a compound of the formula :
(IIIj) wherein R1' and R4' are each as defined above, and Z is a protected carboxy, to elimination reaction of the protective group of the carboxy.
(IIIk) wherein R1' is a protected amino or a protected lower alkylamino, and R4' is halogen, which comprises subjecting a compound of the formula :
(IIIj) wherein R1' and R4' are each as defined above, and Z is a protected carboxy, to elimination reaction of the protective group of the carboxy.
43. A process according to claim 42 for the preparation of a compound of the formula (IIIk') :
(IIIk') wherein R1' and R4' are each as defined in claim 42, which comprises subjecting a compound of the formula :
(IIIj') wherein R1', R4' and Z are each as defined in claim 42, to elimination reaction of the protective group of the carboxy.
(IIIk') wherein R1' and R4' are each as defined in claim 42, which comprises subjecting a compound of the formula :
(IIIj') wherein R1', R4' and Z are each as defined in claim 42, to elimination reaction of the protective group of the carboxy.
44. A process of claim 43, wherein R1' is acylamino, and Z is an esterified carboxy.
45. A process of claim 44, wherein R1' is lower alkanoylamino, and Z is lower alkoxycarbonyl.
46. A process of claim 45, wherein R1' is formylamino, R4' is chloro, and Z is ethoxycarbonyl.
47. A process for the preparation of a compound of the formula (IIIi) :
(IIIi) wherein R1" is amino or lower alkylamino, Z is a protected carboxy, or a salt thereof, which comprises subjecting a compound of the formula :
(IIIa) wherein Z is as defined above, and R1' is a protected amino or a protected lower alkylamino, to elimination reaction of the protective group of the amino, and when desired converting the compound obtained to a corresponding salt.
(IIIi) wherein R1" is amino or lower alkylamino, Z is a protected carboxy, or a salt thereof, which comprises subjecting a compound of the formula :
(IIIa) wherein Z is as defined above, and R1' is a protected amino or a protected lower alkylamino, to elimination reaction of the protective group of the amino, and when desired converting the compound obtained to a corresponding salt.
48. A process according to claim 47 for the preparation of a compound of the formula (IIIi') :
(IIIi') wherein R1" and Z are each as defined in claim 47, or a salt thereof, which comprises subjecting a compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 47 to elimination reaction of the protective group of the amino, and when desired converting the compound obtained to a corresponding salt.
(IIIi') wherein R1" and Z are each as defined in claim 47, or a salt thereof, which comprises subjecting a compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 47 to elimination reaction of the protective group of the amino, and when desired converting the compound obtained to a corresponding salt.
49. A process of claim 48, wherein R1' is acylamino, R1" is amino, and Z is an esterified carboxy.
50. A process of claim 49, wherein R1' is lower alkanoylamino, and Z is lower-alkoxycarbonyl.
51. A process of claim 50, wherein R1' is formylamino, and Z is ethoxycarbonyl.
52. A process for the preparation of a compound of the formula (IIIj) :
(IIIj) wherein R1' is a protected amino or a protected lower alkylamino;
R4' is halogen, and Z is a protected carboxy, which comprises reacting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, with a halogenating agent.
(IIIj) wherein R1' is a protected amino or a protected lower alkylamino;
R4' is halogen, and Z is a protected carboxy, which comprises reacting a compound of the formula :
(IIIa) wherein R1' and Z are each as defined above, with a halogenating agent.
53. A process according to claim 52 for the preparation of a compound of the formula (IIIj') :
(IIIj') wherein R1', R4' and Z are each as defined in claim 52, which comprises reacting a compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 52, with a halogenating agent.
(IIIj') wherein R1', R4' and Z are each as defined in claim 52, which comprises reacting a compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 52, with a halogenating agent.
54. A process of claim 53, wherein R1' is acylamino, and Z is an esterified carboxy.
55. A process of claim 54, wherein R1' is lower alkanoylamino, and Z is lower alkoxycarbonyl.
56. A process of claim 55, wherein R1' is formylamino, R4' is chloro, Z is ethoxycarbonyl, and halogenating agent is trichloroisocyanuric acid.
57. A process for the preparation of a compound of the formula (III?) :
(III?) wherein R1" is amino or lower alkylamino, or a salt thereof, which comprises oxidizing a compound of the formula :
(IIIm) wherein R1" is as defined above, or a salt thereof, and when desired converting a compound obtained to a corresponding salt.
(III?) wherein R1" is amino or lower alkylamino, or a salt thereof, which comprises oxidizing a compound of the formula :
(IIIm) wherein R1" is as defined above, or a salt thereof, and when desired converting a compound obtained to a corresponding salt.
58. A process according to claim 57 for the preparation of a compound of the formula (III?') :
(III?') wherein R1" is as defined in claim 57, or a salt thereof, which comprises oxidizing a compound of the formula :
(IIIm') wherein R1" is as defined in claim 57, or a salt thereof, and when desired converting the compound obtained to a corresponding salt.
(III?') wherein R1" is as defined in claim 57, or a salt thereof, which comprises oxidizing a compound of the formula :
(IIIm') wherein R1" is as defined in claim 57, or a salt thereof, and when desired converting the compound obtained to a corresponding salt.
59. A process of claim 58, wherein R1" is amino.
60. A compound of the formula :
(III) wherein R1, R4 and R5 are each as defined in claim 1, or a salt thereof whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.
(III) wherein R1, R4 and R5 are each as defined in claim 1, or a salt thereof whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.
61. A compound of the formula :
(IIIa) wherein R1' and Z are each as defined in claim 2, whenever prepared by the process of claim 2, or by an obvious chemical equivalent thereof.
(IIIa) wherein R1' and Z are each as defined in claim 2, whenever prepared by the process of claim 2, or by an obvious chemical equivalent thereof.
62. A compound of the formula :
(IIIa') wherein R1' and Z are each as defined in claim 3, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.
(IIIa') wherein R1' and Z are each as defined in claim 3, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.
63. A compound of the formula (IIIa'), as defined in claim 62, wherein R1' and Z are each as defined in claim 4, whenever prepared by the process of claim 4, or by an obvious chemical equivalent thereof.
64. A compound of the formula (IIIa'), as defined in claim 62, wherein R1' and Z are each as defined in claim 5, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.
65. A compound of the formula (IIIa'), as defined in claim 62, wherein R1' and Z are each as defined in claim 6, whenever prepared by the process of claim 6, or by an obvious chemical equivalent thereof.
66. Ethyl 2-[2-[3-(methyl)thioureido]-1,3-thiazol-4 yl]glyoxylate, whenever prepared by the process of claim 7, or by an obvious chemical equivalent thereof.
67. A compound of the formula :
(IIIb) wherein 1' is as defined in claim 8, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.
(IIIb) wherein 1' is as defined in claim 8, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.
68. A compound of the formula (IIIb), as defined in claim 67, wherein R1' is as defined in claim 9, whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.
69. A compound of the formula (IIIb), as defined in claim 67, wherein R1 is as defined in claim 10, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.
70. A compound of the formula :
(IIIb') wherein R1' is as defined in claim 11, whenever prepared by the process of claim 11, or by an obvious chemical equivalent thereof.
(IIIb') wherein R1' is as defined in claim 11, whenever prepared by the process of claim 11, or by an obvious chemical equivalent thereof.
71. 2-(2-Formylamino-1,3-thiazol-5-yl)glyoxylic acid, whenever prepared by the process of claim 12, or by an obvious chemical equivalent thereof.
72. A compound of the formula :
(IIIa) wherein R1' and Z are each as defined in claim 13, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.
(IIIa) wherein R1' and Z are each as defined in claim 13, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.
73. A compound of the formula:
(IIIa') wherein R1' and Z are each as defined in claim 14 whenever prepared by the process of claim 14, or by an obvious chemical equivalent thereof.
(IIIa') wherein R1' and Z are each as defined in claim 14 whenever prepared by the process of claim 14, or by an obvious chemical equivalent thereof.
74 . A compound of the formula (IIIa'), as defined in claim 73, wherein R1' and Z are each as defined in claim 15, whenever prepared by the process of claim 15, or by an obvious chemical equivalent thereof.
75. A compound of the formula (IIIa'), as defined in claim 73, wherein R1' and Z are each as defined in claim 16, whenever prepared by the process of claim 16, or by an obvious chemical equivalent thereof.
76. A compound of the formula (IIIa'), as defined in claim 73, wherein R1' and Z are each as defined in claim 17, whenever prepared by the process of claim 17, or by an obvious chemical equivalent thereof.
77. Ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate, whenever prepared by the process of claim 18, or by an obvious chemical equivalent thereof.
78. A compound of the formula (IIIa'), as defined in claim 73, wherein R1' and Z are each as defined in claim 19, whenever prepared by the process of claim 19, or by an obvious chemical equivalent thereof.
79. Ethyl 2-(2-propanesulfonylamino-1,3-thiazol-4-yl)-glyoxylate, whenever prepared by the process of claim 20, or by an obvious chemical equivalent thereof.
80. Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate, whenever prepared by the process of claim 21, or by an obvious chemical equivalent thereof.
81. A compound of the formula (IIIa'), as defined in claim 73, wherein R1' and Z are each as defined in claim 22, whenever prepared by the process of claim 22, ox by an obvious chemical equivalent thereof.
82. Ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate, whenever prepared by the process of claim 23, or by an obvious chemical equivalent thereof.
83. A compound of the formula (IIIa'), as defined in claim 73, wherein R1' and Z are each as defined in claim 24, whenever prepared by the process of claim 24, or by an obvious chemical equivalent thereof.
84. Ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.
85. Methyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, whenever prepared by the process of claim 26, or by an obvious chemical equivalent thereof.
86. A compound of the formula :
(IIIb) wherein R1' is as defined in claim 27, whenever prepared by the process of claim 27, or by an obvious chemical equivalent thereof.
(IIIb) wherein R1' is as defined in claim 27, whenever prepared by the process of claim 27, or by an obvious chemical equivalent thereof.
87. A compound of the formula :
(IIIb') wherein R1' is as defined in claim 28, whenever prepared by the process of claim 28, or by an obvious chemical equivalent thereof.
(IIIb') wherein R1' is as defined in claim 28, whenever prepared by the process of claim 28, or by an obvious chemical equivalent thereof.
88. A compound of the formula (IIIb'), as defined in claim 87, wherein R1' is as defined in claim 29, whenever prepared by the process of claim 29, or by an obvious chemical equivalent thereof.
89. A compound of the formula (IIIb'), as defined in claim 37, wherein R1' is as defined in claim 30, whenever prepared by the process of claim 30, or by an obvious chemical equivalent thereof.
90. A compound of the formula (IIIb'), as defined in claim 87, wherein R1' is as defined in claim 31, whenever prepared by the process of claim 31, or by an obvious chemical equivalent thereof.
91. 2-(2-tert-Pentyloxycarbonylamino-1,3-thiazol-4-yl)-glyoxylic acid, whenever prepared by the process of claim 32, or by an obvious chemical equivalent thereof.
92. A compound of the formula (IIIb'), as defined in claim 87, wherein R1' is as defined in claim 33, whenever prepared by the process of claim 33, or by an obvious chemical equivalent thereof.
93. 2-(2-Propanesulfonylamino-1,3-thiazol-4-yl)-glyoxylic acid, whenever prepared by the process of claim 34, or by an obvious chemical equivalent thereof.
94, A compound of the formula (IIIb'), as defined in claim 87, wherein R1' is as defined in claim 35, whenever prepared by the process of claim 35, or by an obvious chemical equivalent thereof.
95. 2-[2-(N-Methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylic acid, whenever prepared by the process of claim 36, or by an obvious chemical equivalent thereof.
96. A compound of the formula (IIIb'), as defined in claim 87, wherein R1' is as defined in claim 37, whenever prepared by the process of claim 37, or by an obvious chemical equivalent thereof.
97. 2-(2-Formylamino-1,3-thiazol-4-yl)glyoxylic acid, whenever prepared by the process of claim 38, or by an obvious chemical equivalent thereof.
98. 2-(2-Formylamino-1,3-thiazol-4-yl)glyoxylic acid, whenever prepared by the process of claim 39, or by an obvious chemical equivalent thereof.
99. A compound of the formula (IIIb'), as defined in claim 87, wherein R1' is as defined in claim 40, whenever prepared by the process of claim 40, or by an obvious chemical equivalent thereof.
100. 2-[2-[3-(Methyl)thioureido]-1,3-thiazol-4-yl]-glyoxylic acid, whenever prepared by the process of claim 41, or by an obvious chemical equivalent thereof.
101. A compound of the formula :
(IIIk) wherein R1' and R4 are each as defined in claim 42, whenever prepared by the process of claim 42, or by an obvious chemical equivalent thereof.
(IIIk) wherein R1' and R4 are each as defined in claim 42, whenever prepared by the process of claim 42, or by an obvious chemical equivalent thereof.
102. A compound of the formula :
(IIIk') wherein R1' and R4' are each as defined in claim 43, whenever prepared by the process of claim 43, or by an obvious chemical equivalent thereof.
(IIIk') wherein R1' and R4' are each as defined in claim 43, whenever prepared by the process of claim 43, or by an obvious chemical equivalent thereof.
103. A compound of the formula (IIIk'), as defined in claim 102, wherein R1' and R4' are each as defined in claim 44, whenever prepared by the process of claim 44, or by an obvious chemical equivalent thereof.
104. A compound of the formula (IIIk'), as defined in claim 102, wherein R1' and R4' are each as defined in claim 45, whenever prepared by the process of claim 45, or by an obvious chemical equivalent thereof.
105. 2-(2-Formylamino-5-chloro-1,3-thiazol-4-yl) glyoxylic acid, whenever prepared by the process of claim 46, or by an obvious chemical equivalent thereof.
106. A compound of the formula :
(IIIi) wherein R1' and Z are each as defined in claim 47, or a salt thereof whenever prepared by the process of claim 47, or by an obvious chemical equivalent thereof.
(IIIi) wherein R1' and Z are each as defined in claim 47, or a salt thereof whenever prepared by the process of claim 47, or by an obvious chemical equivalent thereof.
107, A compound of the formula :
( IIIi') wherein R1' and Z are each as defined in claim 48, or a salt thereof whenever prepared by the process of claim 48, or by an obvious chemical equivalent thereof,
( IIIi') wherein R1' and Z are each as defined in claim 48, or a salt thereof whenever prepared by the process of claim 48, or by an obvious chemical equivalent thereof,
108. A compound of the formula (IIIi'), as defined in claim 107, wherein R1' and Z are each as defined in claim 49, or a salt thereof whenever prepared by the process of claim 49, or by an obvious chemical equivalent thereof.
109. A compound of the formula (IIIi'), as defined in claim 107, wherein R1' and Z are each as defined in claim 50, or a salt thereof whenever prepared by the process of claim 50, or by an obvious chemical equivalent thereof.
110. Ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate, or a salt thereof whenever prepared by the process of claim 51, or by an obvious chemical equivalent thereof.
111. A compound of the formula :
(IIIj) wherein R1', R4' and Z are each as-defined in claim 52, whenever prepared by the process of claim 52, or by an obvious chemical equivalent thereof.
(IIIj) wherein R1', R4' and Z are each as-defined in claim 52, whenever prepared by the process of claim 52, or by an obvious chemical equivalent thereof.
112. A compound of the formula :
(IIIj') wherein R1', R4' and Z are each as defined in claim 53, whenever prepared by the process of claim 53, or by an obvious chemical equivalent thereof.
(IIIj') wherein R1', R4' and Z are each as defined in claim 53, whenever prepared by the process of claim 53, or by an obvious chemical equivalent thereof.
113. A compound of the formula (IIIj'), as defined in claim 112, wherein R1', R4' and Z are each as defined in claim 54, whenever prepared by the process of claim 54, or by an obvious chemical equivalent thereof.
114. A compound of the formula (IIIj'), as defined in claim 112, wherein R1', R4' and Z are each as defined in claim 55, whenever prepared by the process of claim 55, or by an obvious chemical equivalent thereof.
115. Ethyl 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl) glyoxylate, whenever prepared by the process of claim 56, or by an obvious chemical equivalent thereof.
116. A compound of the formula :
(III?) wherein R1" is as defined in claim 57, or a salt thereof whenever prepared by the process of claim 57, or by an obvious chemical equivalent thereof.
(III?) wherein R1" is as defined in claim 57, or a salt thereof whenever prepared by the process of claim 57, or by an obvious chemical equivalent thereof.
117. A compound of the formula :
(III?') wherein R1" is as defined in claim 58, or a salt thereof whenever prepared by the process of claim 58, or by an obvious chemical equivalent thereof.
(III?') wherein R1" is as defined in claim 58, or a salt thereof whenever prepared by the process of claim 58, or by an obvious chemical equivalent thereof.
118. 2-(2-Amino-1,3-thiazol-5-yl)glyoxylic acid, or a salt thereof whenever prepared by the process of claim 59, or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000477197A CA1209577A (en) | 1976-03-09 | 1985-03-21 | 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9425/76A GB1575803A (en) | 1976-03-09 | 1976-03-09 | 3,7 disubstituted 3 cephem 4 carboxylic acid compounds andprocesses for the preparation thereof |
| GB9425/76 | 1976-03-09 | ||
| GB41145/76 | 1976-10-04 | ||
| GB4114576 | 1976-10-04 | ||
| CA000273202A CA1218054A (en) | 1976-03-09 | 1977-03-04 | 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof |
| CA000477197A CA1209577A (en) | 1976-03-09 | 1985-03-21 | 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000273202A Division CA1218054A (en) | 1976-03-09 | 1977-03-04 | 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1209577A true CA1209577A (en) | 1986-08-12 |
Family
ID=27164946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000477197A Expired CA1209577A (en) | 1976-03-09 | 1985-03-21 | 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1209577A (en) |
-
1985
- 1985-03-21 CA CA000477197A patent/CA1209577A/en not_active Expired
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