IE46437B1 - Cephalosporin synthesis - Google Patents
Cephalosporin synthesisInfo
- Publication number
- IE46437B1 IE46437B1 IE453/78A IE45378A IE46437B1 IE 46437 B1 IE46437 B1 IE 46437B1 IE 453/78 A IE453/78 A IE 453/78A IE 45378 A IE45378 A IE 45378A IE 46437 B1 IE46437 B1 IE 46437B1
- Authority
- IE
- Ireland
- Prior art keywords
- methyl
- acetamido
- compound
- formula
- reacted
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
3-(Thiomethyl)cephalosporins of the formula in which the substituents are defined in Claim 1 are prepared by a novel process. These compounds are obtained by replacing, in a corresponding cephalosporanic acid which has an acyloxy group in the 3-position, this group by the group -SR<13> by reaction with a sulphur nucleophile in an organic solvent under virtually anhydrous conditions. The compounds obtained can be used for the control of infections in warm-blooded animals (mammals) or as an intermediate for the preparation of other cephalosporins.
Description
The present invention provides a process for the displacement of the acetoxy group of a cephalosporanic acid by a sulfur nucleophil%, in an organic solvent and under essentially anhydrous conditions.
The displacement of the acetoxy group of a cephalosporin by a:sulfur nucleophile is a known reaction (U.S. •Patent 3,278,531). :This patent and other publications (J.
D. Cocker, J. Chem. Soc., 1965, 5015) teach that the reaction occurs only in an aqueous medium. Practical dis10 placements have utilized a salt of the cephalosporanic acid in water along with the sulfur nucleophile or its salt at pH 5-8. The combination of aqueous medium, elevated temperature (35-70eC.),.and near neutral to basic pH are generally destructive of much of the cephalosporin nucleus, and products prepared in this manner often require extensive purification. Attempts to conduct the displacement on cephalosporanic acids in water at lower pH (pH 2-3) lead to substantial lactone formation, a side-reaction that dramatically lowers the yield of desired product.
It has now been discovered that the displacement of the acetoxy group (as well as other 3-acyloxy groups) of cephalosporanic acids by sulfur nucleophiles can be achieved in organic solvents under essentially anhydrous conditions. Reactions under these conditions are not complicated by lactone formation; yields are generally higher; and products are more easily isolated. Some of the products spontaneously precipitate from the reaction mixture. The present process is believed to be general in nature, and applicable to essentially any sulfur nucleophile and any cephalosporanic .
acid.
The object of this invention is to provide an improved process for preparing 3-(thiomethyl)cephalosporins.
The present invention is a novel process for preparing a cephalosporin compound of the rj-rmula
;ooh
Ί -Λ wherein Rx is
-C -C alkyl, 14
or z; or
is hydrogen or methoxy;
κ is phthalimido, succinimido, a radical of the formula /
\=ZT
L-ρς yjwherein L is hydrogen or nitroso e
CH Z XCH 3 S
or a radical of the formula 0 3 . R is 3 R -C-NH-; 5 « (1) hydrogen, (2) C1~C6 alkyl, (3) -CH2—(Ci-C3 chloroalkyl), (4) i -CH2—(C-^-C^ fluoroalkyl), ( (5) *1-C4 cyanoaTkylr | 10 (6)C1_C4 hydrcxyaikyi> (7) p-nitrobenzyloxy, (8) tert-butoxy, (9) 2,2,2-trichloroethoxy, (10) a protected 4-amino-4-carboxybutyl 15 radical of the formula 0 r12o-c-ch-(ch2)2-ch2A1 wherein A^ is a protected amino group 12 and R is hydrogen or C1~C4 alkyl; (11) 4-oxo-4-carboxybutyl; 20 (12) 3-carboxypropyl; (13) a radical of the formula /-ν,ζ, -c„. ,,/.=/ n s
(14) (a) (b) (c) (a) (b) (c) (d) (e) if) in which each of a and a*· is independently hydrogen, C^-C^ alkyl, C^-C^ alkoxy, halogen, hydroxy, or A^CHg- wherein A^ is, as above, protected amino: /, is ' or S; and a is 0 or 1;
a radical of the formula
P-CHf
Q wherein P is
2- thienyl,
3- thienyl, or formula a phenyl group of the y-v in which a and a^ are and wherein Q is hydroxy, formyloxy, acetoxy, as defined above;
-C-O-A wherein
A is diphenylmethyl, p-nitrobenzyl, benzyl, 2,2,2-trichloroethyl, tert-butyl, or p-methoxybenzyl;
alkali metal oxysulfonyl, a protected amino group, carboxy of the formula (g) an acylated amino group of the formula
II
-NH-C-T wherein T represents amino,
NH R7 0
II · I II p
-NH-C-NHg , -N—C-R ,
wherein R is hydrogen or G^-Cg alkyl; o
R is phenyl, halophenyl, furyl, monob methylamino, dimethylamino, monoethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, diisopropyl. . 9 amino, phenylamino, or diphenylamino; R is hydrogen, C^-C^ alkyl, or phenyl; R^ is hydrogen, C^-Cg alkyl, or methylsulfonyl; and rH is ethylene, trimethylene, or vinylene;
6 4 37 (15) a radical of the formula
N—OH 0
Ρ'-C-C-,—OCH, or —O$CH, wherein P’ is P as defined above, protected 2-amino-4-thiazolyl, or 2-furyl;
(16) a radical of the formula V-S(O) -CHgwherein V represents -CFg or -CHg-X wherein X represents hydrogen, methyl, CF,, CN, or Ng, and n represents 0, 1, or 2; or (17) a radical of the formula Υ-CHg- in which Y is
2- thienyl,
3- thienyl,
2-furyl,
2-oxazolyl,
2-thiazolyl,
1-tetrazolyl,
1- benzotriazolyl,
2- oxazolylthi.o,
2-thiazolylthio,
1.2.3- triazol-5-ylthio,
1.3.4- triazol-2-ylthio,
1.3.4- thiadiazol-2-ylthio, protected 5-amino-l,3,4-thiadiazol-2-ylthio,
-methyl-l,3,4-thiadiazol-2ylthio,
1.2.4- thiadiazol-5-ylthio,
3- methyl-l,2,4-thiadiazol-5ylthio,
1,2,5-thiadiazol-3-ylthio,
1,3,4-oxadiazol-2-ylthio,
-methyl-l,3,4-oxadiszcl-2. ylthio, 1 l-methyl-5-tetrazolylthio, pyridylthio,
4- cyano-l,2,3-triazol-l-yl, 3-cyano-l,2,4-triazol-l-yl, or protected 2-amino-4-thiazolyl;
each R is independently hydrogen,
Ci-C4 alkyl,
C2~C3 alkenyl, cyclohexyl, or phenyl;
each R is independently C^-C^ alkyl, C^-C^ alkoxy, halo, hydroxy, nitro, cyano, methanesulfonamido, or trifluoromethyl; and
R is a unit which with the -C , comprises an unsubstituted or substituted, five or six-membered, heteroaromatic ring having a total of from 1 to 4 hetero atoms selected from the following combinations:
nitrogen and 0 or 1 oxygen or sulfur, nitrogens and 0 or 1 oxygen or sulfur, nitrogens, and 0 or 1 oxygen, or nitrogens, all other ring atoms being carbon; or
a unit which with the comprises 2-benzimidazolyl, 2-benzothiazolyl, 2-benzoxazolyl, or a radical of the formula
N=N \__/ \=N which process comprises reacting a compound of the formula
CH OCOR II s
OOH
2 wherein R and R are as defined above, and
R is
C^-Cg alkyl,
C^-Cg cycloalkyl, amino, mono- or di(C^-C3 alkyl)amino,
-C =
I
OCH
CH— •—OH
CH—/·~0Η y-X
OH , °r
-C = CH—ι I
OCH
S—OSO ll? /
I
6 4 3?
III with a sulfur nucleophile of the formula
R13-S-R14
14 wherein R is as defined above, and R is hydrogen, or when and only When S'*·3 is a methyleneami!iium group, ?.~4 combines with R33and the 'S atom to form a thiourea; in an organic solvent under essentially anhydrous con' i ditions.
Ihe term Cg—Cg alkyl, representing R, may far example be methyl. The products of the present process exhibit antibacterial?
activity; in addition, many of than: serve as intermediates to yet other cephalosporin products vhich also athibit antibacterial aotivity, see, i I
e.g. U.S. 3,932,393. |
In the foregoing definitions, the various alkyl terms refer to both straight and.·branched chain alkyl groups. In the definitions cf R as Cg—Cg alkyl, alkyl refers to groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, arcyl·, isoamyl, hexyl and 2,3-dimethylbutyl.
r
The terms —CHg—(Cg—Cg ehlaroalkyl) and
-CHg-(Cg-Cg fluoroalkyl) refer to such groups as chloroethyl, fluoroethyl, 2-chloroethyl, 2-chloropropyl, 3-fluoropropyl and 4-chlorobutyl. The term Cg-C^ oyanoalkyl refers to such groups as cyanomethyl, 2-cyanoethyl, 3eyanopropyl and 2-cyanopropyl. The term Cg-C^ hydroxyalkyl refers to such groups as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-hydroxypropyl.
In both the 3-(acyloxymethyl)cephalosporin of
Formula II and the sulfur nucleophile, amino groups are desirably protected. The practice of protecting amino groups is well known. See protective Groups In Organic
Chemistry, edited J. T. W. McOmie (Plenum Press, London and
New York, 1973). Xn general, protection of an amino group implies removability of the protection group; but that is not necessary as, for example, in a 7-acylamido radical of the formula
0 R120-C-CH-(CH2)2-CH2-C-NHA1 which is subsequently to be cleaved from the cephalosporin. Suitable protecting groups for this radical include C2~C4 alkanoyl, C^-C^ chloro- or fluoroalkanoyl, benzoyl, and substituted benzoyl. The term C2~C4 alkanoyl refers to acetyl, propionyl and'butyryl. The term C3“C4 chloro- or fluoroalkanoyl refers e.g. to 3-chloropropionyl and 3-fluoropropionyl The term substituted benzoyl includes halo-substituted benzoyl groups such as 4chlorobenzoyl, 4-bromobenzoyl, and 2,4-dichlorobenzoyl.
Such groups can also be employed for the protection of amino groups at other locations in the 3-(acyloxymethyl)cephalosporin, and in the sulfur nucleophile. However, when it is desired to regain a free amino group, the protecting group should be one which is readily removable. See McOmie, supra. Suitable protecting groups which are readily removable are benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, pmethoxybenzyloxycarbonyl, and diphenylmethoxycarbonyl. The amino group of the formula
0 r12O-C-CH-(CH2)2-CH2-C-NHA1 can also be protected as described in Belgian patent 771,694.
SI
46437.
As used herein, the term halogen and the term halo refer to fluoro, chloro, bromo, or iodo. The term C^-C^ alkoxy refers e.g to methoxy, ethoxy, isopropoxy and n-butoxy. The term alkali metal preferably designates sodium, potassium, and lithium.
The following are illustrative of the group ” 3
R -C-NH- wherein R is any of moieties (1) to (12):
formamido, acetamido, propionamido, butyramido, a-methylpropionamido, valeramido, a-methylbutyramido, trimethylacetamido, hexanamido, heptanamido, 3-chloropropionamido,
3- chlorobutyramido, 4-fluorobutyramido, 5-chlorovaleramido, cyanoacetamido, 2-cyanopropiOnamido, 3-cyanopropionamido,
4- cyanobutyramido, hydroxyacetamido, 2-hydroxypropionamido, 3-hydroxybutyramido, p-nitrobenzyloxycarbonylainino, tertbutoxycarbonylamino, (2,2,2-trichloroethoxy)carbonylamino,
- (2,5-dichlorobenzamido)-5-carboxyvaleramido, 5-acetamido5-carboxyvaleramido, 5-carbomethoxy-5-(2,4-dichlorobenzamido)valeramido, 5-carbo-n-butoxy-5-(2,4-dichlorobenzamido)valeramido, 5-carboxy-5-(2,4-dichlorobenzamido, valeramido, 5-(p-chlorobenzamido)-5-carboxyvaleramido, 5-propionamido-5-carboxyvaleramido, 5-(3-chloropropionamido) -5-carboxyvaleramido, 5-benzamido-5-carboxyvaleramido, 5-oxo-5-carboxyvaleramido and 4-carboxybutyramido.
The following are illustrative of the groups
3
R -C-NH- in the above definition in which R is y-\
/.=/ (z) -CH m 2
4643 and in which m is 0: phenylacetamido, 2-(p-methylphenyl)acetamido, 2-(m-ethylphenyl)acetamido, 2-(p-isopropylphenyl)acetamido, 2-(o-methylphenyl)acetamido, 2-(p-chlorophenyl)acetamido, 2-(p-bromophenyl)acetamido, 2-(2,45 dichlorophenyl)acetamido, 2-(m-bromophenyl)acetamido,
2-(p-fluorophenyl)acetamido, 2-(o-fluorophenyl)acetamido, 2-(3,4-dihydroxyphenyl)acetamido, 2-(p-hydroxyphenyl)acetamido, 2-(m-hydroxyphenyl)acetamido, 2-(2,6-dimethoxyphenyl)acetamido, 2-(m-methoxyphenyl)acetamido, 2-(p-isopropoxy10 phenyl)acetamido, 2-(m-ethoxyphenyl)acetamido, 2-(p-methoxyphenyl) acetamido, 2-(3,4-dimethoxyphenyl)acetamido, 2-(ptert-butoxyphenyl)acetamido, 2-(p-(acetamidomethyl)phenyl)acetamido, 2-(p-(tert-butoxycarbonylaminomethyl)phenyl)acetamido, 2-(o-(tert-butoxycarbonylaminomethyl)phenyl)acetamido, 2-(m-butoxyphenyl)acetamido and 2-(3-chloro-4methylphenyl)acetamido. When, ir. the above formula, m = 1 and Z represents -0-, illustrative groups include the following : phenoxyacetamido, 2-(p-methylphenoxy)acetamido,
2-(m-ethylphenoxy)acetamido, 2-(p-isopropylphenoxy)acet20 amido, 2-(o-methylphenoxy)acetamido, 2-(p-chlorophenoxy)acetamido, 2-(p-bromophenoxy)acetamido, 2-(2,4-dichlorophenoxy)acetamido, 2-(m-bromophenoxy)acetamido, 2-(pfluorophenoxy)acetamido, 2-(o-fluorophenoxy)acetamido,
2-(2,6-dimethoxyphenoxy)acetamido, 2-(m-ethoxyphenoxy)acet25 amido, 2-(p-methoxyphenoxy)acetamido, 2-(3,4-dimethoxyphenoxy) acetamido, 2-(p-tert-butoxyphenoxy)acetamido, 2-(o-butoxyphenoxy) acetamido, 2-(3-chloro-4-methylphenoxy) acetamido,
2-(3-hydroxy-4-methylphenoxy)acetamido, 2-(o-chlorophenoxy)acetamido, 2-(3-hydroxy-4-methylphenoxy)acetamido, 2-(o53 chlorophenoxy)acetamido, 2-(p-isopropoxyphenoxy)acetamido, 2-(o-acetamidomethyl)phenoxy)acetamido and 2-(p-(tertbutoxycarbonylaminomethyl)phenoxy)acetamido. When in the foregoing formula, m = 1 and Z represents -S-, illustrative groups include the following: 2-(phenylthio)acetamido,
2-(p-methylphenylthio)acetamido, 2-(m-ethylphenylthio)acetamido, 2-(p-isopropylphenylthio)acetamido, 2-(o-methylphenylthio)acetamido, 2-(p-chlorophenylthio)acetamido,
2-(p-bromophenylthio)acetamido, 2-(2,4-dichlorophenylthio)acetamido, 2-(m-bromophenylthio)acetamido, 2-{p-fluorophenylthio)acetamido, 2-(o-fluorophenylthio)acetamido,
2-(3,4-dihydroxyphenylthio)acetamido, 2-(p-hydroxyphenylthio)acetamido, 2-(m-hydroxyphenylthio)acetamido, 2-(2,6dimethoxyphenylthio)acetamido, 2-(m-ethoxyphenylthio)acetamido , 2-(p-methoxyphenylthio) acetamido, 2-(3,4-dimethylphenylthio)acetamido, 2-(p-tert-butoxyphenylthio)acetamido, 2-(m-butoxyphenylthio)acetamido, 2-(3-chloro-4-methylphenylthio)acetamido, 2-(3,4-dimethylphenylthio)acetamido, 2-(3,4-dichlorophenylthio)acetamido, 2-(2,5-dichlorophenylthio)acetamido, 2-(3— fluoro-4-chlorophenylthio)acetamido,
2-(3-chloro-4-fluorophenylthio)acetamido, 2-(2,6-difluorophenyl thio) acetamido, 2-(m-fluorophenylthio)acetamido,
2-(o-(acetamidomethyl)phenylthio)acetamido and 2-(p-(tertbutoxycarbonylaminomethyl)phenylthio)acetamido.
When R represents a group of the formula P-CHI
Q
O . 3 illustrative groups having the overall formula R -C-NHinclude the mandelamido group, and the O-formyl and O-acetyl derivatives thereof; the 2-carboxy-2-phenylacetamido group; the alkali metal salt of the 2 - sulfo - 2 - phenylacetamido group; ttic protcctect 2 - amino - 2 - phenylacetamido group; in which the protected amino group is. for st ample, a carbonylamino group such as tert - hitcxycarbonylamino, triehloroathoxycarUnylamino, cr p nitrobenzyloxy - carbonylamino; and the 2 - (acylated amino)-2 phenylacetamido group. Also included are those 2- substituted 2 thienylacetamido and 3-thienylacetamido groups in which the phenyl group is replaced by a 2-thienyl or a 3-thienyl ring.
Illustrative of the foregoing acetamido groups are mandelamido, p-methylmandelamido, p-hydroxymandelamido, m-hydroxymandelamido, jo-methoxymandelamido, nv-bromomandelamido, £-chloromandelamido, 3-methy1-4-fluoromandelamido, o-fluoromandelamido, jo-fluoromandelamido, p-isopropylmandelamido, 3,4-dimethyl-O-formylmandelaniido, _£-chloro-0formylmandelamido, m-isopropoxy-O-formylmandelamido, mbromo-O-formylmandelamido, O-formylmandelamido, 3,4dimethoxy-O-formylmandelamido, O-acetylmandelamido, phydroxy-O-acetylmandelamido, p-(acetamidomethyl)mandelamido, p-hydroxy-O-formylmandelamido, 2-hydroxy-2-(2-thienyl)acetamido, 2-hydroxy-2-(3-thienyl)acetamido, 2-formyloxy2-(2-thienyl)acetamido, 2-acetoxy-2-(2-thienyl)acetamido, 2formyloxy-2-(3-thienyl)acetamido, 2-acetoxy-2-(3-thienyl)acetamido, 2-(tert-butoxycarbonyl)-2-phenylacetamido, 225 (2,2,2-trichloroethoxycarbonyl)-2-(p-methylphenyl)acetamido,
2-(benzyloxycarbonyl)-2-(p-hydroxyphenyl)acetamido, 2(tert-butoxycarbonyl)-2-(p-hydroxyphenyl)acetamido, 2-(£nitrobenzyloxycarbonyl)-2-(m-hydroxypheny1)acetamido, i5
2-(p-methoxybenzyloxycarbonyl)-2-(p-methoxyphenyl)acetamido,
2-(diphenylmethoxycarbonyl)-2-(m-bromophenyl)acetamido,
2-(tert-butoxycarbonyl)-2-(p-chlorophenyl)acetamido, 2(2,2,2-trichloroethoxycarbonyl)-2-(3-methyl-4-fluorophenyl)acetamido, 2-(benzyloxycarbonyl)-2-(o-fluorophenyl)acetamido, 2-(p-nitrobenzyloxycarbonyl)-2-(p-fluorophenyl)acetamido,
2-(p-methoxybenzyloxycarbonyl)-2-(p-isopropylphenyl)acetamido, 2-(tert-butoxycarbonyl)-2-(3,4-dimethylphenyl)acetamido,
2-(tert-butoxycarbonyl)-2-(m-isopropoxyphenyl)acetamido,
2-(diphenylmethoxycarbonyl)-2-(3,4-dimethoxyphenyl)acetamido, 2-(tert-butoxycarbonyl)-2-(p-(2,5-dichlorobenzamidomethyl)phenyl) acetamido, 2-(tert-butoxycarbonyl)-2-(2-thienyl) acetamido, 2-(tert-butoxycarbonyl)-2-(3-thienyl)acetamido,
2-(sodiooxysulfonyl)-2-phenylacetamido, 2-(sodiooxysulfonyl)2-(p-methylphenyl)acetamido, 2-(potassiooxysulfonyl)-2-(phydroxyphenyl)acetamido, 2-(lithiooxysulfonyl)-2-(m-hydroxyphenyl) acetamido, 2-(sodiooxysulfonyl)-2-(p-methoxyphenyl)acetamido, 2-(sodiooxysulfonyl)-2-(m-bromophenyl)acetamido,
2-(sodiooxysulfonyl)-2-(p-chlorophenyl)acetamido, 2-(sodiooxysulfonyl) -2-(3-methyl-4-fluorophenyl)acetamido, 2-(sodiooxysulfonyl) -2-(o-fluorophenyl)acetamido, 2-(sodiooxysulfonyl)2-(p-fluorophenyl)acetamido, 2-(sodiooxysulfonyl)-2-(pacetamidomethylphenyl)acetamido, 2-(sodiooxysulfonyl)-2(p-isopropylphenyl)acetamido, 2-(sodiooxysulfonyl)-2-(3,4dimethylphenyl)acetamido, 2-(sodiooxysulfonyl)-2-(m-isopropoxyphenyl)acetamido, 2-(sodiooxysulfonyl)-2-(3,4dimethoxyphenyl)acetamido, 2-(sodiooxysulfonyl)-2-(2thienyl)acetamido, 2-(potassiooxysulfonyl)-2-(3-thienyl)acetamido, 2-(p-nitrobenzyloxycarbonylamino)-2-phenylacet6
6437 amido, 2-(tert-butoxycarbonylamino)-2-(2-thienyl)acetamido,
2-(benzyloxycarbonylamino)-2-(m-hydroxyphenyl)acetamido,
2-(tert-butoxycarbonylamino)-2-(p-hydroxyphenyl)acetamido, 2-ureJ.do-2-nhenyJacetamido, 2-ureido-2-(2-thienyl'acetamido, 2-(3-guanyl-l-ureido)-2-phenylacetamido, 2-(3methylaminocarbonyl-l-ureido)-2-phenylacetamido, 2-(3dimethylaminocarbonyl-3-methyl-l-ureido)-2-phenylacetamido,
2-[N-(imidazolidine-2-one-l-ylcarbonyl)amino]-2-phenylacetamido, 2-(N-(3-methylimidazolidine-2-one-l-ylcarbonyl)amino]-2-phenylacetamido; 2-[N-(hexahydropyrimidine-2one-l-ylcarbonyl)amino]-2-phenylacetamido; 2-[N-(3-methylhexahydropyrimidine-2-one-l-ylcarbonyl)amino]-2-phenylacetamido; 2-[N-(3-methanesulfonylhexahydropyrimidine-2-one1- ylcarbonyl)amino]-2-phenylacetamido; 2-(3-di-n-propylaminocarbonyl-l-ureido)-2-phenylacetamido, 2-((4-ethyl-2,3dioxo-l-piperazinyl)carbonylamino)-2-phenylacetamido, 2(3-(methylsulfonyl)-2-oxo-l-imidazolidinyl)carbonylamino)2- phenylacetamido, 2-(2-oxo-4-imidazolin-l-yl)carbonylamino) -2-phenylacetamido, 2-((4-oxo-4H-thiopyran-3-yl)carbonylamino)-2-phenylacetamido, 2-(3-methyl-3-(methylcarbamoyl) ureido) -2-phenylacetamido, 2-(3-methyl-3-(cinnamoylureido))-2-phenylacetamido, 2-(3-methyl-3-(acryloylureido)) 2-phenylacetamido, 2-((4-ethyl-2,3-dioxo-l-piperazinyl)carbonylamino)-2-thienylacetamido, 2-((4-ethyl-2,3-dioxo1- piperazinyl) carbonylamino)-2-(p-hydroxyphenyl)acetamido,
2- ((4-ethy1-2,3-dioxo-l-piperazinyl)carbonylamino)-2-phenylacetamido, 2-((2-oxoimidazolidin-l-yl)carbonylamino)-3thienylacetamido and 2-((2-oxo-3-(methylsulfonyl)-4-imidazolin1-yl)carbonylamino)-2-(p-hydroxyphenyl)acetamido.
\7
The following are illustrative of the group
3
R -C-NH- wherein R is moiety (15): 2-(hydroxyimino) 2-phenylacetamido, 2-(methoxyimino)-2-phenylacetamido,
- (ace‘coxy intino) -2-phenylacetamido, 2-(hydroxyimino) --£·· (2-thienyl)acetamido, 2-(hydroxyimino)-2-(2-furyl)acetamido, 2-(methoxyimino)-2-(3-thienyl)acetamido, 2-(methoxyimino)2-(2-furyl)acetamido, 2-(methoxyimino)-2-(p-hydroxyphenyl)acetamido, 2-(hydroxyimino)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-4-thiazolyl)acetamido/ (tautomeric with 2-(hydroxyimino)-2-(2-(2,2,2-trichloroethoxycarbonylimino)4-thiazolin-4-yl)acetamido), 2-(methoxyimino)-2-(2-(pnitrobenzyloxycarbonylamino)-4-thiazolyl)acetamido (tautomeric with 2-(methoxyimino)-2-(2-(p-nitrobenzyloxycarbonylimino)-4-thiazolin-4-yl)acetamido) and 2-(methoxyimino)-2(4-chlorophenyl)acetamido.
The following are illustrative of the group
3
R -C-NH- whereih R is moiety (16): 2-(trifluoromethylthio)acetamido, 2-(methylsulfonyl)acetamido, 2-(cyanomethylthio)acetamido, 2-(azidomethylthio)acetamido, 2-(ethylsulfonyl)acetamido, 2-(2,2,2-trifluoroethylthio)acetamido,
2-(methylsulfinyl)acetamido and 2-(cyanomethylsulfinyl)acetamido.
Illustrative of the group R3-C-NH- in the above definition in which R3 is Y “CHg- are the following: 2-(2thienyl)acetamido, 2-(3-thienyl)acetamido, 2-(2-furyl)acetamido, 2-(2-oxazolyl)acetamido, 2-(2-thiazolyl)acetamido,
2-(1-tetrazolyl)acetamido, 2-(1-benzotriazolyl) acetamido,
2-(2-oxazolylthio)acetamido, 2-(2-thiazolylthio)acetamido,
6 4 3 7
2- (1,2,3-triazol-5-ylthio)acetamido, 2-(1,3,4-triazol-2yl-thio)acetamido, (1,3,4-thiadiazol-2-ylthio)acetamido, 2-(5-(protected amino)-1,3,4-thiadiazol-2-ylthio)acetamido, 2-(5-methyl-1,3,4-thjadiazol-2-ylthio)acetamido, 2-(1,2,4thiadiazol-5-ylthio)acetamido, 2-(3-methy1-1,2,4-thiadiazol5-ylthio)acetamido), 2-(1,2,5-thiadiazol-3-ylthio)acetamido, 2-(1,3,4-oxadiazol-2-ylthio)acetamido, 2-(5-methy1-1,3,4. I oxadiazol-2-ylthio)acetamido, 2-(l-methyl-5-tetrazolyl-‘ thio)acetamido, 2-(pyridylthio)acetamido, 2-(4-cyano-i,2,3triazol-l-yi)acetamido, 2-(3-cyano-l,2,4-triazol-l-yl)acetamido, and 2-(2-(protected amino)-4-thiazolyl)acetamido (tautomeric with 2-(2- protected imino - 4 - thiazolin - 4 yi)acetamido). - J
Many of the cephalosporanic acids to bd, employed as starting material in the present process are known compounds, and all are prepared by methods known to those skilled in the art. Attention is directed to Cephalosporins And Penicillins, Chemistry and Biology, edited by Edwin H. Flynn (Academic Press, New York, 1972). See especially Chapters 3, 4, and 15, and the references there cited. See also U.S. Patent 3,914,157 and South African Patent 71/3229.
The preferred sulfur nucleophiles of Formula III are those wherein R13 is of the formula
R .
Suitable five-membered heteroaromatic rings of said formula include the following:
pyrrole oxazole isoxazole thiazole isothiazole pyrazole imidazole
1.2.3- oxadiazole
1.2.4- oxadiazole
1.2.5- oxadiazole
1,3,4-oxadiazole
1.2.3- thiadiazole
1.2.4- thiadiazole
1.2.5- thiadiazole
1.3.4- thiadiazole •1,2,’3-triazole
1.2.4- triazole oxatriazole tetrazole
Suitable six-membered rings include the following:
pyridine pyridazine pyrimidine pyrazine
1.2.3- triazine
1.2.4- triazine
1.3.5- triazine •1,2,3,4-tetrazine
1.2.4.5- tetrazine
Certain of the heteroarylthiols, as well as certain of the alkylthiols and phenylthiols of Formula III, actually exist as, thiones or as tautomeric mixtures of thiol and thione. As an example, the compound 2-methyl-l,3,4thiadiazole-5-thiol exists as a tautomer:
However, the present reaction proceeds with the designated classes of sulfur nucleophiles regardless of whether the reactant is in the thiol or in the thione form. Accordingly, it is within the scope of the present invention to conduct the reaction employing a thione or thiol-thione tautomer of a designated reactant.
The heteroarylthiol can be unsubstituted or can be substituted by one or more substituents. In general, the identity of substituents is not critical. For best results, any primary or secondary amino group should be protected.
Where a heteroarylthiol contains more than one thiol group, the one which is desired not to undergo reaction should be protected. Methods for protection of thiols are well known; see McOmie, supra. Assuming the protection of such groups, the reaction goes forward regardless of the identity of substituent.
It is preferred to avoid excessively bulky substitution; generally, substitution not exceeding a molecular weight of about 500 is preferred. Most common substituted heteroaromatic rings contain substitution of a total molecular weight less than about 250.
Suitable substituents include C^-C4 alkyl, Cg-C^ alkenyl, Cg-C^ alkynyl, C^-Cg cycloalkyl, benzyl, phenethyl, aryl including phenyl and substituted phenyl as defined hereinabove, halo -CFg, —OH, protected amino or 2 alkylamino, -COOH, -COOA , -CONHg, protected aminomethyl or C^-C^ alkylaminomethyl, -CHgSOg-alkali metal, -CHgCOOH, -CHgCOOA2, or - (CHg)gN(CHg)2.
Representative sulfur nucleophiles of Formula III include the following:
Thioureas allylthiourea N,N'-di-n-butylthiourea Ν,N1-di-tert-butyIthiourea Ν,N'-dicyclohexylthiourea
JO
Ν,Ν'-diisopropylthiourea ί
Ν,Ν'-dimethylthiourea N-methylthiourea Ν,Ν,Ν',Ν'-tetraethylthiourea N,Ν,Ν',Ν'-tetramethylthiourea thiourea
N-phenylthiourea Ν,Ν'-diphenylthiourea N,N-dimethylthiourea
' Thiobenzoic acid
Alkylthiols mephanethiol ethanethiol
1- or 2-propanethiol
1- or 2-butanethiol
2- methy1-1-propanethiol Benzenethiols benzenethiol
4-bromo-3-methylbenzenethiol p-bromobenzenethiol p-chlorobenzenethiol
2,5-dichlorobenzenethiol
3,4-diohlorobenzenethiol
4-fluorobenzenethio1 m-methoxybenzenethiol p-methoxybenzenethiol p-nitrobenzenethiol p-methylbenzenethiol
Heteroarylthiols
2- pyrrolethiol
3- pyraz0lethiol 2-methyl-3-pyrazr lethiol
2-methyl-4-imidazolethiol
2- imidazolethiol
4- oxazolethiol
3- isoxazolethiol
2-thiazolethiol
. 3-isothiazolethiol
1-methyl-l,2,3-triazole-5-thiol
1- benzyl-l,2,3-triazole-4-thiol
2- methyl-l,2,3-triazole-4-thiol
3,5-dimethyl-l, 2,3-triazole-4-thi‘ol 15 l,2,4-triazole-3-thiol
4- methyl-l,2,4-triazole-5-thiol
3- methyl-l,2,4-triazole-5-thiol
3,4-dimethyl-l,2,4-triazole-5-thiol
2- methyl-l,2,4-triazole-5-thiol 20 2-benzyl-l,2,4-triazole-5-thiol
2,3-dimethyl-l,2,4-triazole-5-thiol
4- methyl-3-(trifluoromethyl)-1,2,4-triazole5- thiol
3- carbamoyl-4-methyl-l,2,4-triaZole-5-thiol
3-(carboxymethyl)-4-methy1-1,2,4-triazole5-thiol
3-{carboethoxymethyl)-4-methyl-l,2,4-triazole-5-thiol protected 3-amino-4-methyl-l,2,4-triazole30 5-thiol
3-hydroxy-4-methyl-l,2,4-triazole-5-thiol
-methyl-l,2,3-oxadiazole-4-thiol
1.2.4- oxadiazole-3-thiol 3-methyl-l,2,4-oxadiazole-5-thiol 3-methyl-l,2,5-oxadiazole-4-thiol
2-methyl-l,3,4-oxadiazole-5-thiol
3-methyl-l,2,4-thiadiazole-5-thiol
1.3.4- thiadiazole-5-thiol 2-methyl-l,3,4-thiadiazole-5-thiol
2-(N-methylacetamido)-1,3,4-thiadiazole-510 thiol
-tetrazolethiol
1-methyltetrazole-5-thiol
1-benzyltetrazole-5-thiol
1- (carboxymethyl) tetrazole-5-thiol 15 1-((sodiooxysulfonyl)methyl)tetrazole-5thiol
1- (2-dimethylaminoethyl)tetrazole-5-thiol
1.2.3.4- oxatriazole-5-thiol
2- pyridinethiol 20 2-pyridinethiol, 1-oxide .3-pyridazinethiol 2-pyrimidinethiol 2-pyrazinethiol
1,2,3-triazine-4-thiol 2$ l,2,4-triazine-3-thiol
4.5- dihydro-6-hydroxy-4-methyl-5-oxo-l,2,4triazine-3-thiol
1.3.5- triazine-2-thiol .1,2,4,5-tetrazine-3-thiol
2-benzimidazolethiol
2-benzothiazolethiol
2-benzoxazolethiol tetrazolo(1,5-b)pyridazine-6-thiol.
Most of the sulfur nucleophiles to be employed in the present process are known compounds, and all can be prepared in accordance with prior art procedures. In the case of the heteroarylthiols, attention is directed to the numerous volumes of Heterocyclic Compounds, edited by Robert C. Elderfield (John Wiley and Sons, Inc., N.Y.), as well as the various volumes on the particular heterocyclic systems in the series The Chemistry of Heterocyclic Compounds, edited by Weissberger et al. (John Wiley and Sons, N.Y.).
It is critical to the present invention that the reaction be carried out in an organic solvent. ’However, the identity of the solvent is not critical, since a great variety of organic solvents has proven satisfactory. In general, members of the following classes of solvents have been found satisfactory: hydrocarbons, both aliphatic and aromatic, alcohols, amides, ethers, ketones, carboxylic acids, carboxylic acid esters, haiogenated hydrocarbons, nitro compounds, nitriles, and thioethers. Since certain of the nucleophiles are liquids, an excess of such reactant can also be employed as solvent.
-- The solvent should be inert, in the sense that it 25 does not undergo a competing reaction with either reactant.
Particular solvents which are suitable in carrying out the present practice include pentane, cyclopentane, hexane, heptane, octane, benzene, toluene, ο-, m-, or pxylene, cumene, mesitylene, p-cymene, 1-pentene, isopropanol diethyl r
2d ether, butyl ethyl ether, diamyl ether, benzyl ethyl ether, acetone, methyl ethyl ketone, 2-butanone, 3-pentanone, methyl isobutyl ketone, cyclohexanone, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl propionate, butyl acetate, isobutyl acetate, sec-butyl acetate, amyl acetate, isoamyl acetate, ethyl isovalerate, methyl benzoate, benzyl acetate, methyl butyrate, diethyl carbonate, dimethyl maleate, diethyl oxalate, ethylene glycol diacetate, diethyl malonate, fluorobenzene, chlorobenzene, bromobenzene, ο-, m- or pfluorotoluene, ο-, m-, or p-chlorotoluene, ο-, m-, or pbromotoluene, 2-chloroethane, 1- or 2-chloropropane, 1- or 2-chlorobutane, l-chloro-2-methylpropane, 1, 2, or 3-chloro pentane, 1-chloronaphthalene, methylene chloride, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, ο-, m-, or p-dichlorobenzene, nitromethane, nitroethane, 1- or 2-nitropropane, nitrobenzene, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, benzonitrile, phenylacetonitrile, and thiophene.
Preferred solvents are;
Hydrocarbons;
benzene toluene ο—, m-, or p-xylene .cumene mesitylene
Halogenated Hydrocarbons:
chloroethane
1- or 2-ch.ioropropane
1- or 2-chlorobutar.e . isobutyl chloride
1,2, or 3-chloropentane methylene chloride chloroform
1.2- dichloroethane carbon tetrachloride
1,1,1-trichloroethane 1,ϊ,2-trichloroethane
1.1.2.2- tetrachloroethane fluorobenzene chlorobenzene bromobenzene
ο-, m-, in-, m-, or p-fluorotoluene or p-chlorotoluene 0-, ο-. or p-bromotoluene 20 O-, nt-, or p-dichlorobenzene
Acids:
acetic acid propionic acid butyric acid isobutyric acid valeric acid methyl acetate ethylene glycol diacetate ethyl acetate propyl acetate isopropyl acetate butyl acetate isobutyl acetate sec-butyl acetate pentyl acetate ethyl propionate methyl butyrate n-butyl formate propylene carbonate ethylene carbonate
Nitro Compounds:
nitrobenzene nitromethane nitroethane nitropropane
Nitriles:
acetonitrile propionitrile butyronitrile isobutyronitrile valeronitrile benzonitrile phenylacetonitrile
Ketones:
•methyl isobutyl ketone methyl ethyl ketone
Especially preferred solvents -’’-e .--efiifi)'?,
1,2-dichloroethane, methylene chloride, propionitrile, nitromethane, nitroethane, acetic acid, isopropyl acetate, butyl acetate, and'methyl isobutyl ketone.
The 3-(acyloxymethyl)cephalosporin of Formula II has been defined as the acid. It is believed to be the acid which undergoes reaction, since cephalosporin salts are generally not soluble in organic solvents. The exception is the solubility of cephalosporin salts in carboxylic acid solvents, such as acetic acid. Therefore, the present reaction can be accomplished by dissolving a 3-(acyloxy15 methyl)cephalosporin salt, such as a metal salt, in a carboxylic acid solvent.
Regardless of the identity of the solvent, it is necessary that the present process be conducted under essentially anhydrous conditions. In general, the reaction mixture should contain less than 5 percent of water, and preferably less than 1 percent of water. It is even more preferred that the amount of water be less than 0.5 percent. Where commercial sources of reactants and solvents are not dry enough, removal of water can be carried out in accor'5 dance with known procedures, including azeotroping and the use of drying agents such as alumina, silica gel and anhydrous calcium sulfate a
The present reaction goes forward under a wide range of temperatures. In general, reaction temperatures of 50-140°C. can be used; but better results are usuallyachieved at temperatures of 70-120°C. The reaction can be conducted at elevated pressures, but no advantages have been observed. Hence atmospheric pressure is generally preferred because of its simplicity.
The amounts of the reactants are not critical. In general, an excess of the sulfur nucleophile is preferred, such as 1.0 to 5.0 molar equivalents of sulfur nucleophile per molar equivalent of the 3-(acyloxymethyl)cephalosporin reactant.
The present process is particularly useful for the introduction into cephalosporins of the following 315 heteroarylthio groups:
-methyl-l,3,4-thiadiazol-2-ylthiol-methyl-lH-tetrazol-5-ylthiol-carboxymethyl-lH-tetrazol-5-ylthio4-methyl-6-hydroxy-5-oxo-l,2,4-triazin20 3-ylthio1- methyl-l,3,4-triazol-2-ylthio2- methyl-1,3,4-triazol-5-ylthio1,2-(limethyl-l,3,4-triazol-5-ylthio3- methyl-l, 3,4-triazol-5-ylthio25 2,3-dimethyl-l,3,4-triazol-5-ylthiol-methyl-2-trifluoromethyl-l,3,4-triazol5-ylthiol-itethyl-2-carbanqyl-l ,3,4-triazol-5-ylthio30 l-methyl-2-carboxymethyl-l,3,4-triazol-5-ylthiol-methyl-2-carboalkoxy-l,3,4-triazol-5-ylthio1-methyl-2-(protected aminomethyl)-1,3,4-triazol1 1-methyl-2-(protected amino)-1,3,4-triazol-5ylthiol-meth’yl-2-hydroxy-l,3,4-triazol-5-ylthiolH-tetrazol-5-ylthio1-(2-dimethylaminoethyl)-lH-tetrazol-5-ylthio10 1-(sulfomethyl)-lH-tetrazol-5-ylthio-, alkali metal salt
-methyl-l,3,4-oxadiazol-2-ylthio1,3,4-thiadiazol-2-ylthio3-methyl-l,2,4-thiadiazol-5-ylthio- and
2-(protected aminomethyl)-1,3,4-thiadiazol5-ylthio-.
Among the important known cephalosporin compounds of Formula I which can be prepared by synthetic routes incorporating the present process are the following:
cefamandole:
'V
COOH
CH cefamandole β_ θ ς
OCHO ft
OOH \/ ' ΪΗ cefazolin:
A f-CH -C-NH· * * ' ,Η_Π J |f>—N. Λ-CH -S-< „·-!
f
CO(
COOH ceftezole:
II
CH -C-NHz
A π ί >—β
1—Fl zi-CH -S-·. ,· ,
COOH cefazaflur:
II
CF SCH CNH—f— s a _ A i—1 i-CHj-SCOC
COOH
CH
SCE-963: Τ Γ \y »
I
NH ° A
-CVCNH-r» | |fi-CHA-., COOH
CH -CH -N(CH ) a 2 3 s
BLS-786: / \_CH CNH\___/ a
-.,. XA “0H in COOH „ OCH . “3
CS-1170: NCCH SCH CNHJ A Av A, j,
OOH
SQ-57,590: NCCH SCH CNH2 2
XAa
COGH bi-I
SKF-75073: ζ·~% / %-CH-CNHI
OH
V' •CH -S2
6h so h £>. Z
BBS-226:
.•-CH -CNH-»—1 /2
A.
SQ-14,359:
CH NH 2 2
v
COOH .N-•ch -s-·; .· 8 W =ljl —Ν , and
NH /
C=O I
NH
V
COOH ~CH_-S-· ji ί
The products of the present invention, their deblocked derivatives, and the pharmaceutically acceptable salts of the same are useful in combating infections in
6 43 7 warm-blooded mammals when administered parenterally in non-toxic doses between about 10 and 500 mg./kg. of body weight. The compounds are formulated in conventional procedures.
The following examples illustrate the present invention and will enable those skilled in the art to practice the same.
EXAMPLE 1: PREPARATION OP 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN ACETONITRILE.
-7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.2 grams; 5.5 mmole) and l-methyl-lH-tetrazole-5-thiol (1.0 gram; 8.6 mmole) were added to 25 ml. of acetonitrile in a flask equipped with a condenser with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite. The reaction mixture was refluxed, with stirring, and the progress of the reaction was monitored by thinlayer chromatography (TLC). After 90 minutes at reflux, TLC showed about two-thirds cephalosporanic acid starting material and one-third of the desired product. After 3 hours of reflux, TLC showed about one-third cephalosporanic acid starting material and two-thirds product. After 6 hours, at which time TLC showed the reaction essentially complete, the reaction mixture was cooled to room temperature and allowed to stand overnight. Solvent was removed on a rotary evaporator, leaving as a residue a foam which was dissolved in 10 ml. of ethanol. Dropwise addition of 1 ml. of dicyclohexylamine in 10 ml. of ethanol resulted in the precipitation of product as the dicyclohexylamine salt which, after 15 minutes of stirring, was separated by filtration. The isolated product was washed with 15 ml. of ethanol, and the product was vacuum dried at 40°C. for 2 hours· ’’.SO grams (76.1 percent yield), v· ·?., ’82--4eC.
(dec). The product was subjected to NMR, IR, and TLC, and all of these analyses were identical with analyses of an authentic sample of the product prepared by the prior art aqueous displacement. NMR(DMSO-dg) δ 3.52 (m, 2, 2-CH2>, 3.76 (s, 2, -CHgCONH-), 3.92 (s, 3, -CH3 of tetrazole), 4.35 (s, 2, 3-CH2S), 5.00 (d, 1, Cg-H, J=5 Hz), 5.55 (q, 1,
C7-H, J=5 Hz, J=9 Hz), 6.95 (d, 2, thiophene 3 and 4-H, J=3 Hz), 7.35 (t, 1, thiophene 5-H, J=3 Hz), and 8.75 (d,
1, -CHjCONH-, J=9 H?).
EXAMPLE 2: PREPARATION OP 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN ACETONITRILE
7-(2-(2-Thienyl) acetamido)cephalosporanic acid (4.0 grams; 10 mmole) and l-methyl-in-tetrazole-5-thiol (5.8 grams; 50 mmole) were refluxed in 50 ml. of dry acetonitrile (treated over a anhydrous sulfonic acid resin sold under the trademark Amberlite 15), under a dry atmosphere, for 8 3/4 hours. The reaction was followed by TLC and was nearly complete at the end of 8 3/4 hours.
Solvent was removed by evaporation and the residue added to 125 ml. of ethanol. Dicyclohexylamine (6 ml.) in 75 ml. of ethanol was added and the product precipitated as the dicyclohexylamine salt. It was separated by filtration, washed, and dried, 4.50 grams (71.0 percent yield). IR,
NMR, and TLC were identical to an authentic sample prepared by aqueous displacement. The NMR was also identical with the NMR on the product of Example 1.
EXAMPLE 3: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-45 CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1-methyl-lH-tetrazole-5-thiol (1.2 grams; 10 mmole) in 25 ml. of 1,2-dichloroethane were refluxed under a dry atmosphere for a total of 5.5 hours.
Solvent was then removed on a rotary evaporator, and 25 ml. of ethanol was added to the filtrate followed by dropwise addition of a solution of 2 ml. of dicyclohexylamine in 25 ml. of ethanol. The product crystallized as the dicyclo hexylamine salt and was stirred for 20 minutes at room temperature, then filtered, washed with 25 ml. of ethanol, and dried at 40“C. under vacuum, 2.34 grams of off-white solid (73.8 percent yield). IR and NMR were identical with an authentic sample prepared by aqueous displacement. The NMR was also identical with the NMR on the product of
Example 1.
EXAMPLE 4: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL) THIO) METHYL)-7 - FCRMRMIDO - 3 - CEPHEM - 4 - CARBOXYLIC ACID IN 1,2-DIQJLCRETHANE
7-Formamidocephalosporanic acid (3.0 grams; 10 mmole) and l-methyl-lH-tetrazole-5-thiol (2.4 grams; 20 mmole) in 50 ml. of 1,2-dichloroethane were stirred and refluxed for 7 hours. The reaction mixture was then cooled to room temperature and allowed to stand overnight at room temperature. A red gummy solid precipitated. The product was identified by removing the 7-formyl group as follows.
Solvent was removed on a rotary evaporator and the residue was dissolved in 25 ml. of methanol and 2.8 ml. of concentrated HCl and permitted to stand overnight at room temperature. The solution was then diluted to 50 ml. with water, and the pH, initially 0.9, was raised to 3.6 by dropwise addition of triethylamine. Light brown crystals were filtered, washed with water, and dried, 2.10 grams (64 percent yield). The NMR was identical with the same product made by aqueous displacement. NMRJDgO, NaHCOg) ί 3.65 (q,
2, 2-CH,,, 0,=16.5 Hz), 4.08 (s, 3, -CH. on tetrazole), 4.16 —•z -Ab —J (q, 2, 3-CH2S-, Jab=12.5 Hz), 5.05 (d, 1, Cg-H, J=5 Hz), and 5.45 (d, 1, C?-H, J=5 Hz).
EXAMPLE 5: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-415 CARBOXYLIC ACID IN ISOPROPYL ACETATE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and l-methyl-lH-tetrazole-5-thiol (1.2 grams: 10 mmole) in 25 ml. of isopropyl acetate were refluxed (90°C.) with stirring for 23 hours.
The reaction mixture was then cooled to room temperature. TLC showed some of the cephalosporanic acid starting material remaining. The light cream colored solid was separated by filtration, washed with isopropyl acetate and dried, 1.60 grams (70.8 percent yield). NMR confirmed the identity of the product and showed less than 1 percent of the cephalosporanic acid starting material present. NMR (DMSO-dg) δ 3.72 (s, 2, 2-CH2), 3.80 (s, 2, -CH2CONH-),
3.95 (s, 3, -CHg of tetrazole), 4.30 (s, 2, 3-CH2S~), 5.10 (d, 1, Cg-H, J=5 Hz), 5.70 (q, 1, C?-H, J=5 Hz, J=8 Hz),
6.92 (d, 2, thiophene 3- and 4-H, J=3 Hz), 7.35 (t, 1, thiophene 5-H, J=3 Hz), and 8.78 (d, 1, -CH2CONH-, J=8 Hz). EXAMPLE 6: PREPARATION OF 3-(((l-METHYL-lH-TETRAZOL-5THIO)METHYL)-7-(2-(2-THISNYL)ACETAMIDO)-3-CEFHEM-4CARBOXYLIC ACID IN PROPIONITRILE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and l-methyl-lH-tetrazole-5-thiol (1.2 grams; 10 mmole) were refluxed in 25 ml. of dry propionitrile (97°C.) until TLC showed the complete disappearance of cephalosporanic acid starting material (4.5 hours). The reaction mixture was then cooled to room temperature, and solvent was removed on a rotary evaporator, during which process some of the solution was lost due to bumping. The residue was dissolved in 35 ml. of warm ethanol and a solution of 2 ml. of dicyclohexylamine in 10 ml. of ethanol was added. The'product precipitated as the dicyclohexylamine salt and was stirred 10 minutes at room temperature, then filtered, washed with ethanol and dried, 1.24 grams (39.0 percent yield, not including product lost on the rotary evaporator). The NMR of the product was identical with the NMR on the Example 1 product.
EXAMPLE 7: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN ACETONITRILE, 3,5-DICHLOROPHENYL DIHYDROGEN
PHOSPHATE ADDED
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole), l-methyl-lH-tetrazole-5-thiol (0.87 gram; 7.5 mmole), and 3,5-dichlorophenyl dihydrogen phosphate (0.122 grams; 0.5 mmole) were heated overnight in 25 ml. of ϋ
dry acetonitrile at 70°C. Solvent was then removed on a rotary evaporator to 8-10 ml. The product began to crystallize. After stirring for 1/2 hour, isopropyl acetate (25 ml.) was added dropwise durinq 1/2 hour to ef*:?t further crystallization. After an additional 1/2 hour of stirring, the product was separated by filtration, washed with isopropyl acetate and dried, 0.98 gram (43.4 percent yield).
The NMR of the product was identical with the NMR on the Example 5 product.
EXAMPLE 8 : EREPARATICN OF 3 - (((1 - METHYL - 3K - TETRAZOL - 5 - YL)THIO METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC
ACID IN ACETIC ACID
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and l-methyl-lH-tetrazole-5-thiol (0.87 grams; 7.5 mmole) were added to glacial acetic acid (25 ml.). The reaction mixture was heated to 60°C. and held at this temperature for an hour. Only a trace of product was evident on TLC. The reaction mixture was heated to 80°C. and held at this temperature for 5 hours. The reaction mixture was then allowed to stand overnight, and the product was separated by filtration, washed with acetic acid, and dried, 0.71 gram (31 percent yield). The NMR of the product was identical with the NMR on the Example 5 product.
EXAMPLE 9: PREPARATION OF 3-(((4,5-DIHYDRO-6-HYDROXY-4METHYL-5-OXO-1,2,4-TRIAZIN-3-YL)THIO)METHYL)-7-(2-(2THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 4,5-dihydro-6-hydroxy-4-methyl5-oxo-l,2,4-triazine-3-thiol (1.2 grams; 7.5 mmole) were added to 25.ml. of dry acetonitrile in a reaction flask immersed in an oil bath at 84-85°C. The flask was equipped with a condenser with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite. The reaction mixture was maintained for 16 hours in this condition, with slow magnetic agitation.
The product crystallized from the hot solution.
The reaction mixture was cooled to room temperature, filtered, washed with acetonitrile, washed with acetone, and vacuum dried, 1.81 grams (72.6 percent yield). The product was off-white crystals, m.p. 161°C. (dec).
On standing, the filtrate deposited a second crop of crystals. This crop was separated by filtration, washed with acetonitrile, and dried, 0.26 gram (10.5 percent yield). This second crop also melted at 161°C. (dec).
Total' yield was therefore 83.1 percent.
EXAMPLE 10: PREPARATION OF 3-(((5-METHYL-l,3,4-OXADIAZOL2-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 5-methyl-l,3,4-oxadizaole-2-thiol (0.87 gram; 7.5 mmole) in 25 ml. of 1,2-dichloroethane were placed in a flask equipped with magnetic stirring bar and condenser with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite. The flask was immersed in an oil bath at 84-85°C. and held for 8 hours, then refrigerated for two days.
A portion of product had crystallized; it was separated by filtration, washed with 1,2-dichloroethane, and dried, 1.10 grams (48.7 percent yield). It was dissolved in
4643?
ml. of acetone and filtered to remove an insoluble product. Then 75 ml. of deionized water was added dropwise and the product was separated by filtration and dried, 0.61 gram, m.p. >114°C. (dec.).
Evaporation of solvent from the filtrate yielded
0.23 gram of a mixture of product and both starting materials. EXAMPLE 11: PREPARATION OP 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN NITROMETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1-methyl-lH-tetrazole-5-thiol (0.87 gram; 7.5 mmole) were added to 25 ml. of dry nitromethane in a flask; the flask was immersed in an oil bath at 100-101oC. for 4.5 hours, then cooled to room temperature. TLC showed that the reaction was complete.
Solvent was removed on a rotary evaporator, and the residue was dissolved in 75 ml. of warm ethyl acetate.
The solution was filtered to remove a small amount of insolubles, then extracted with two 25-ml. portions of 5 percent aqueous sodium bicarbonate. The combined extracts were layered with 50 ml. of ethyl acetate and acidified to pH about 1.0 with 70 percent aqueous methanesulfonic acid.
The ethyl acetate layer was separated and the water layer was extracted with 25 ml. of ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated to 25 ml. on a rotary evaporator. Dropwise addition of 50 ml. of diethyl ether resulted in crystallization of the product. It was separated by fil tration, washed with diethyl ether, and dried, 1.27 gram (56.2 percent yield), off-white crystals, m.p. 156-159°C. (dec.). The identity of the product was confirmed by NMR. EXAMPLE 12: PREPARATION OP 3-(({l-METHYL~lK-TETRASQL-55 YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN METHYLENE CHLORIDE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (11.9 grams: 30 mmole) and 1-methyl-lH-tetrazole-5-thiol (7.0 grams; 60 mmole) in 300 ml. of methylene chloride (cyclohexane stabilized) were placed in a one-liter stainless steel autoclave equipped with heater. The reaction mixture was stirred and heated to 83-86°C., developing a pressure of 42 p.s.i., for 16 hours. The reaction mixture was then cooled to room temperature. TLC showed conversion to product, with only a trace of the starting cephalosporanic acid remaining. The reaction mixture was permitted to stand at room temperature, which resulted in crystallization of the product, and then concentrated to 200 ml. The crystals were filtered off and washed with methylene chloride, 7.37 grams (54.3 percent yield), white crystals, m.p. 163.5-164°C. (dec.).
A second crop of light tan crystals was obtained by diluting the filtrate with 100 ml. of diethyl ether, filtering, washing with diethyl ether, and drying, 1.40 25 grams (10.3 percent yield).
A third crop was obtained by diluting the filtrate with isopropyl acetate, 1.18 grams (8.7 percent yield).
Total yield was therefore 73.3 percent.
EXAMPLE 13; PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN FLUOROBENZENE
7- (2- (2-Thienyl) acetamido) cephTlosrrrar.’c acid (2.0 grams; 5.04 mmole) and l-methyl-lH-tetrazole-5-thiol (1.2 grams; 10 mmole) in 75 ml. of fluorobenzene (b.p. 85.1’C.) were mixed in a flask equipped with a condenser with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite. The mixture was heated to reflux and progress of the reaction was followed by TLC in 7/1 ethyl acetate/acetic acid. The reaction, which remained heterogeneous throughout, was essentially complete in 72 hours.
The reaction mixture was then cooled to room temperature and filtered to separate the precipitated product. The product was washed with fluorobenzene and vacuum dried at 40°C. for five hours, 2.13 grams (93.4 percent yield), off-white crystals, 161-162°C. (dec). Identity of the product was confirmed by NMR.
EXAMPLE 14; PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN THIOPHENE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and l-methyl-lH-tetrazole-5-thiol (0.87 gram: 7.5 mmole) in 25 ml. of thiophene were refluxed for 7 hours, during which time the product crystallized. The reaction mixture was cooled to room temperature, stirred for 30 minutes to complete crystallization, and filtered. The separated product was washed with 0.5 ml. of thiophene, then vacuum dried for 2 hours, 1.82 grams (80.2 percent yield), white crystals, m.p. 162-163°C. (dec). TLC showed that the filtrate contained additional product.
EXAMPLE 15: PREPARATION OP 3-(((5-METHYL-l,3,4-THIADIAZOL5 2-YL)THIO)METHYL,-7-(2-(1H-TETRAZOL-1(-YL)ACETAMIDO)-3CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE
7-(2-(lH-Tetrazol-l-yl)acetamido)cephalosporanic acid (0.76 gram; 2 mmole) and 5-methyl-l,3,4-thiadiazole2-thiol (0.33 gram; 2.5 mmole) in 10 ml. Of reagent grade acetonitrile were refluxed for two hours and forty minutes. The product crystallized. The reaction mixture was cooled in an ice bath and filtered to separate the product, which was washed with three ml. of acetonitrile and dried at 40° under vacuum, 0.61 gram (67 percent yield). The identity of the product was confirmed by NMR, δ 2.68 (s, 3, -CH3 of tetrazole), 3.72 (s, 2, 2-CH2), 4.40 (q, 2, 3-CH2S-, JAB=13 Hz), 5.12 (d, 1, Cg-H, J=5 Hz), 5.38 (s, 2, -CU^CONII-) ,
.72 (q, 1, C^-H, J=5 llz, J=9 Ilz), 9.00 (s, 1, tetrazole 5-H), and 9.17 (d, 1, -CH2CONH-).
EXAMPLE 16: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-FORMYLOXY-2-PHENYLACETAMIDO)-3-CEPHEM4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid (2.17 grams; 5 mmole) and l-methvl-lH-tetrazole-525 thiol (0.87 grams; 7.5 mmole) were added to 25 ml. of 1,2dichloroethane, and the resulting reaction mixture refluxed for six hours. Samples were taken for TLC at 3 and 6 hours. The reaction mixture was heated for an additional hour, then allowed to cool overnight.
Solvent was removed by evaporation. Diethyl ether was added to the residue, which turned gummy and then solid. The product was separated by filtration, washed with diethyl ether, and dried, 1.90 grams (77.0 percent yield) NMR(DMSO-dg) δ 3.52 (s, 2, 2-¾) , 3.88 (s, 3, -¾ of tetrazole), 4.10 (s, 2, 3-CHgS-) , 4.92 (d, 1, Cg-H,, 5.62 (q, 1, C7-H, J=5 Hz, J=9 Ha), 6.06 (s, 1, -CHCONH-), 7.26 O (s, 5, pheny1-H), and 8.28 (s, 1, -OCH).
EXAMPLE 17: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO,METHYL)-7-(5-CARBOXY-5-(2,4-DICHLOROBENZAMIDO)VALERAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN (A) ACETONITRILE AND (B) 1,2-DICHLOROETHANE (A) 7-(5-Carboxy-5-(2,4-dichlorobenzamido)valeramido)cephalosporanic acid (2.9 grams; 5 mmole), 1-methy1lH-tetrazole-5-thiol (1.2 grams; 10 mmole), and 50 ml. of acetonitrile were refluxed overnight (18 hours). TLC showed reaction had taken place, estimated to be about 90 percent complete. The reaction mixture was evaporated and the residue slurried in ethyl acetate and filtered, 1.51 grams (48.3 percent yield).
(B) 7-(5-Carboxy~5-(2,4-dichloroben2amido)valeramido)cephalosporanic acid (2.9 grams; 5 mmole), 1-methyllH-tetrazole-5-thiol (1.2 grams; 10 mmole) and 50 ml. of 1,2-dichloroethane were refluxed for five and one-half hours. TLC showed that reaction was 90 percent complete.
Solvent was decanted from the reaction mixture, leaving a plastic-like solid which was triturated under refluxing ether. The product was separated by filtration, . f.
Λ J
2.83 grams (89.3 percent yield), tan crystals. NMR corroborated the identity of the product but showed ether. NMR (DMSO-dg) δ 1.78 and 2.26 (each m, adipoyl side chain), 3.66 (m, 2, 2-CHg), 3.95 (s, 3, -CHg of tetrazole), 4.30 (m, 2,
3-CHgS-) , 5.08 (d, 1, Cg-H, J=5 Hz), 5'.68 (q, 1, C?-H, J=5 Hz), 7.50 and 7.62 (each s, 2,4-dichlorophenyl), and 9.00 (m, 2, two -CONH).
EXAMPLE 18: PREPARATION OF 3-{((l-METHYL-lH-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (0.99 gram; 2.5 mmole) and l-methyl-lH-tetrazole-5-thiol (0.58 gram; 5 mmole) were added to 12.5 ml. of 1,2-dichloroethane and the reaction mixture was refluxed. The reflux was conducted to permit removal of the acetic acid by-product; this was accomplished by returning the 1,2-dichloroethane reflux through calcium oxide.
After 5 3/4 hours of reflux, the reaction mixture was cooled to room temperature and filtered. The fluffy needles were washed in 10 ml. of 1,2-dichloroethane and dried, 0.77 grams (68.1 percent yield).
Evaporation of the filtrate gave another 0.04 gram of product (3.5 percent yield).
The identity of the product was confirmed by TLC and, in the case of the main product, by NMR. The NMR was identical with the NMR on the Example 5 product.
EXAMPLE 19: PREPARATION OF 3-(((5-METHYL-l,3,4-THIADIAZOL2-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN ACETONITRILE ”?~'2 '(2-Thienyl)acetamido)ceph--’1osn''(-£nJc acid (2.0 grams; 5 mmole) and 5-methyl-l,3,4-thiadiazole-2thiol (2.64 grams; 20 mmole) in 25 ml. of acetonitrile were refluxed overnight at 79°C. TLC showed only a trace of cephalosporanic acid starting material. The reaction mixture was filtered, to remove an oily residue, and solvent was removed on a rotary evaporator. The residue was crystallized from 1:1 acetonitrile:isopropyl acetate, separated by filtration, washed and vacuum dried, 1.59 gram (33.9 percent yield) m.p. 166°C. The identity of the product was confirmed by IR, OV, NMR, MS, and elemental analyses. NMR (DMSO-dg)
2.68 (s, 3, -C«3 of tetrazole), 3.68 (s, 2, 2-CH.2) , 3.76 (s, 2, -CH2CONH-), 4.38 (q, 2, 3-CH2S-, J=13 Hz), 5.10 (d,
1, Cg-H, J=5 Hz), 5.70 (q, 1, C-,-Η, J=5 Hz, J=9 Hz), 6.92 (d, 2, thiophene 3- and 4-H), 7.37 (t, 1, thiophene 5-H), and 9.10 (d, 1, -CH2CONH, J=9 Hz).
EXAMPLE 20: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,1,2-TRICHLOROETHANE
7-(2-(2-Thienyl) acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and l-methyl-lH-tetrazole-5-thiol (1.2 grams; 10 mmole) were added to 25 ml. of 1,1,2-trichloroethane and heated to 100-l°C. The reaction was followed by TLC; after 4 hours at 100-l°C., with stirring, TLC showed no cephalosporanic acid starting material remaining. The reaction mixture was cooled to room temperature, with stirring.
Λ seed was introduced and the reaction mixture was allowed to stir overnight. The product crystallized. Solvent was removed by evaporation and 25 ml. of 1,2-dichloroethane added. Solvent was again removed by filtration, and the product was washed and vacuum dried.
- There was obtained 0.98 gram of 3-(((1-methyllH-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)3-cephem-4-carboxylic acid, m.p. 158°C (dec) (43.4 percent yield).
EXAMPLE 21: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN (A) METHYL ETHYL KETONE AND (B) 1,1,2-TRICHLOROETHANE (A) 7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and l-methyl-lH-tetrazole-5thiol (1.2 grams; 10 mmole) were added to 25 ml. of methyl ethyl ketone and refluxed 48 hours. TLC showed that only a trace of cephalosporanic acid starting material remained.
The reaction mixture was washed with a mixture of 2.5 grams of sodium bicarbonate in 50 ml. of water. The water layer was treated with 1 gram of carbon and 50 ml. of ethyl acetate was added. The pH was then lowered to pH 1.6 with 4 ml. of methanesulfonic acid in 30 ml. of water. The ethyl acetate layer was dried over sodium sulfate and evaporated to an oil on a rotary evaporator.
The product was crystallized by dropwise addition of 50 ml. of ether. The product was separated by filtration, washed, and vacuum dried, 0.94 gram (41.6 percent yield).
The NMR was identical with the NMR of the product of Example
.
(B) The reaction was repeated with the same starting materials and amounts as in part (A), except that 50 ml. of 1,1,2-trichloroethane was used as solvent. The reaction mi.xture was refluxed for 16 hours, et which tim;
TLC showed that no cephalosporanic acid starting material was present. The product was separated as described in part (A), 0.47 gram (20.8 percent yield). The NMR was identical with the NMR of the product of Example 5.
EXAMPLE 22: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-PHENYLACETAMIDO)-7-METHOXY-3-CEPHEM4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-Phenylacetamido)-7-methoxycephalosporanic acid (210 mg.; 0.5 mmole), l-methyl-lH-tetrazole-5-thiol (87 mg.; 0.75 mmole) and 15 ml. of 1,2-dichloroethane were mixed and refluxed for 6 hours under nitrogen, at which time TLC showed only a trace of cephalosporanic acid starting material. Additional l-methyl-lH-tetrazole-5-thiol (29 mg.; 0.25 mmole) was added and the reaction mixture refluxed for an additional three hours. TLC showed no appreciable change.
The reaction mixture was washed four times with saturated sodium bicarbonate, and the bicarbonate layer was washed three times with ethyl acetate, an amount of fresh ethyl acetate added, cooled to 0°C. and adjusted to pH 2.2 with 20 percent HCl. The layers were separated, and the aqueous layer washed with ethyl acetate. The acetate layers were combined, washed with saturated NaCl, dried over magnesium sulfate, filtered, and evaporated, leaving a pale green foam as a residue, 199 mg. (83.6 percent yield). The identity of the product was confirmed by TLC and NMR.
NMR(CDCl + Id acetone-d,) δ 3.45 (s, 3, -OCH-,) , 3.55 (s, 2,
J o —J
2-CH,), 3.75 (s, 2, 0CH CO-), 3.9 (s, 3, CH, on tetrazole), J
4.4 (s, 2, 3-CH2S-), 5.15 (s, 1, Cg-H), 7.35 (s, 5, 0) , 8.0 (s, 1, -CH2CONH-), and * 11.2 (s, 1, -COOH).
EXAMPLE 23: PREPARATION OP 3-(((2-BENZOTHIAZOLYL)THIO) METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (1.0 gram; 2.5 mmole) and 2-mercaptobenzothiazole (0.625 gram; 3.75 mmole) were placed in a flask, the air displaced with a head pf nitrogen, 25 ml. of 1,2-dichloroethane added, and the reaction mixture heated to reflux and refluxed for about 24 hours, with stirring. The reaction mixture was then cooled and filtered, yielding the product as an offwhite material, 1.1 grams (88 percent yield), m.p. 190.5-191°C. (dec). It was dried overnight at 40°C., under vacuum, and submitted for analyses. The identity of the product was confirmed by NMR, UV, mass spectroscopy, IR, and elemental analysis. NMR(DMSO-dg) 6 3.74 (s, 2, 2-CH.2), 3.80 (s, 2, -CH2CONH-), 4.58 (q, 2, 3-CH2S-, J=13 Hz), 5.14 (d, 1, C6-H, J=5 Hz), 5.73 (q, 1, C?-H, J=5 Hz, J=8 Hz), 6.96,
7.43, and 7.96 (each m, phenyl and thienyl rings), 9.10 (d,
1, -CH2CONH-, J=8 Hz) .
EXAMPLE 24: PREPARATION OP 3-(((5-(N-METHYLACETAMIDO)
1,3,4-THIADIAZOL-2-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO) -3-CEPHEM-4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienylacetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 5-(N-methylacetamido)-1,3,4-thiadiazole2-thiol (1.42 grams; 7.5 mmole) were added to 50 ml. of 1,2j dichloroethane and the reaction mixture refluxed for 10 hours. The reaction mixture was cooled, filtered, washed with 1,2-dichloroethane, and vacuum dried, 2.06 grams (78.3 percent), m.p. 178-9°C. The identity of the product was confirmed by IR, UV, NMR, mass spectroscopy, and elemental analysis. NMR(DMSO-dg) δ 2.42 (s, 3, -COCHg), 3.74 (m, 7, 2-CHg, -CHg of tetrazole, and -CHgCONH-), 4.35 (q, 2, 3-CHg, J=13 Hz), 5.10 (d, 1, Cg-H, J=5 Hz), 5.70 (q, 1, Cg-H,
J=5 Hz, J=9 Hz), 6.96 and 7.36 (each m, 3, thiophene Η), and
9.10 (d, 1, -CHgCONH-, J=9 Hz).
EXAMPLE 25: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(N-tert-BUTbXYCARBONYL)-2-PHENYLGLYCYLAMINO)-3-CEPHEM-4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
1,2-Dichloroethane (45 ml.) was refluxed to remove 15 water-solvent azeotropes, then distilled down to 30 ml., which was permitted to cool. 7-(N-tert-Butoxycarbonyl2-phenylglycylamino)cephalosporanic acid (253 mg.; 0.5 mmole) was added and the solution distilled further, down to 15 ml. and again cooled. l-Methyl-lH-tetrazole-5-thiol (87 mg.; 0.75 mmole) was added and the reaction mixture refluxed under nitrogen and monitored by TLC. At 16 hours, TLC showed only a trace of starting material.
The reaction mixture was washed four times with saturated sodium bicarbonate and the bicarbonate layers combined and washed twice with ethyl acetate. To the washed bicarbonate layers, fresh ethyl acetate was added, and the solution was cooled to 0°C. and adjusted to pH 2.4 with 20 percent HCl. The layers were separated. The aqueous layer was washed with ethyl acetate.
-5146437
The ethyl acetate layers were combined, washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated, yielding a white foam, 224 mg. (80 percent yield). The identity of the product was confirmed by TLC and NMR. NMR showed a small amount (£.10 percent) of the cephalosporanic acid starting material.
The product was suspended in 10 ml. of diethyl ether and triturated for 1 hour. The ether was decanted, and 10 ml. of fresh diethyl ether added and triturated for 1 hour. The ether was decanted and evaporated to dryness, yielding the product as a white powder. The identity of the product was confirmed by TLC and NMR. NMR (CDC13) δ 1.45 (s, 9, -COO tert C4Hg) , 3.6 (s, 2, 2-CH2) , 3.95 (s, 3, CH,3 on tetrazole), 4.3 (s, 2, 3-CH2S-), 4.9 (d, 1, J=6 Hz, 15 c6~^' 5,4 (d' i=8 Hz' 0CH-) , 5.75 (q, 1, J=4 Hz, C?-H) ,
6.2 (d, 1, J=8 Hz, 0CH-), 7.4 (s, 5, 0) , 7.65 (d, 1, J=8 NH
Hz, -CONH), and τ, 9.3 (s, 1, COOH).
EXAMPLE 26: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-52Q YL)THIO)METHYL)-7-(N-(tert-BUTOXYCARBONYL)-2-(p-HYDROXYPHENYL)GLYCYLAMINO )-3-CEPHEM-4-CARBOXYLIC ACID IN 1,2DICHLOROETHANE
1,2-Dichloroethane (45 ml.) was refluxed with a trap and 15 ml. solvent removed. The remaining 30 ml. was cooled. 7-(N-(tert-Butoxycarbohyl)-2-(p-hydroxyphenyl)glycylamino) cephalosporanic acid (260.5 mg.; 0.5 mmole) was added and the solution distilled further, down to 15 ml. and cooled again. 1-Methyl-lH-tetrazole-5-thiol (87 mg.; 0.75 mmole) was added and the reaction mixture heated to 65-70°C.
-5246437 and followed by TLC. TLC showed almost no starting material after 3 hours, and the reaction mixture was worked up at the end of 4 hours.
The workup and purification was essentially the same α ·1·ϋ..· .xbed· in the preceding example The y'eld was
189 mg. of crude product (65.5 percent) and 46 mg. of purified product (about 16 percent). NMRfCDCl^ + 2d acetone dg) δ 1.45 (s, 9, -C00tertC4Hg) , 3.35 (s, 2, 2-¾) , 3.85 (s, 3, CH-j on tetrazole), 4.3 (s, 2, 3-CH2S-) , 4.9 (d, 1,
J=6 Hz, C,-H), 5.3 (q, 1, J=3 Hz, C--H), 5.4 (s, 1, HO-0CH-), — b — — I —
.75 (d, 1, J=6 Hz, HO0CH-), 6.4 (s, 1, COOH), 6.8 (d, 2,
NH
J=8 Hz, HO—/ S-CH-), and 7.9 (d, 1, -CONH).
Η-·=·
EXAMPLE 27: PREPARATION OF 3-(((l-METHYL-lH-TETRAZOL-5~
YL) THIO)METHYI)-7- (2-PHENOXYACETAMIDO)-3-CEPHEM-4-CARBOXYLIC
ACID IN 1,2-DICHLOROETHANE
1,2-Dichloroethane (60 ml.) was refluxed with a trap and 15 ml. of solvent removed, leaving 45 ml., which was cooled. 7-(2-Phenoxyacetamido)cephalosporanic acid (406 mg.; 1 mmole) was added and the solution distilled further, down to 30 ml. and cooled again. l-Methyl-lH-tetrazole-5thiol (174 mg.; 1.5 mmole) was added and the reaction mixture was refluxed under nitrogen for 12 hours, at which time TLC in 10:3 diethyl ether/(3:1 acetic acid/water) showed product, excess thiol reactant, a little cephalosporanic acid reactant, and an unknown.
The reaction mixture was then worked up in essentially the same procedures reported in the preceding two examples.
-5346437
TLC of the final product showed it to be identical with an authentic sample of product prepared by prior art methods.
NMR (CDCl3) δ 3.65 (s, 2, 2-CH2), 3.9 (s, 3, CHj of tetrazole) 4.35 (s, 2, 3-CH2S-) , 4.65 (s, 2, 0OCH.,-) , 5.1 (d, 1, J=4 Hz, Cg-H), 5.9 (q, 1, J=4 Hz, Cy-H), 7.1 (m, 5, 0-), 7.b (d„
1, J=10 Hz, -CONH-), and -v 9 (s, 1, -COOH).
EXAMPLE 28-31: PREPARATION OP 3—(((1-METHYL-1H-TETRAZOL5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN FLUOROBENZENE
3-(((l-Methyl-lH-tetrazol-5-yl)thio)methyl)-7(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid was prepared in four different reactions, each utilizing a different cephalosporanic acid starting material, as follows:
28: 3-(propionyloxymethyl)-7-(2-(2-thienyl)acetamido)15 3-cephem-4-carboxylic acid (41 mg.; 0.1 mmole)
29: 3-(2-methylpropionyloxymethyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid (42 mg.;
0.1 mmole)
: 3-(n-butyryloxymethyi)-7-(2-(2-thienyl)acetamido)20 3-cephem-4-carboxylic acid (42 mg.; 0.1 mmole)
31: 3-(cyclobutylcarbonyloxymethyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid (43 mg.;
0.1 mmole)
In each instance the compound was suspended iii 25 10 ml. of fluorobenzene (which had been dried over an aluminosilicate desiccant sold under the term 4-A Linde molecular sieve). l-Methyl-lH-tetrazole-5-thiol (in each reaction 18 mg.; 0.15 mmole) was added and the reaction mixture was refluxed for about 24 hours. In each reaction the product precipitated and was separated by filtration and dried. TLC of the product in ethyl acetate/acetic acid showed that each displacement had been quantitative. The
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NMR of each product was consistent with that of an authentic sample of the product prepared by aqueous displacement.
EXAMPLE 32: PREPARATION OP 3-(((3-METHYL-l,2,4-OXADIAZOL5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,1,2-TRICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (396 mg.; 1 mmole) was suspended in 40 ml. of 1,1,2trichloroethane and 3-methyl-l,2,4-oxadiazole-5-thiol (116 mg.; 1 mmole) added. The reaction mixture was heated to 113°C. in an oil bath for about 3 hours, then allowed to cool overnight and evaporated to an oil. Ethyl acetate and saturated sodium bicarbonate were added. The ethyl acetate portion was rinsed again with saturated sodium bicarbonate, and the aqueous portions were combined and extracted again with ethyl acetate. The aqueous portion was layered with fresh ethyl acetate, cooled in an ice bath, and the pH adjusted to 2.5 with 20 percent HCl. The layers were separated and the aqueous layer extracted again. The ethyl acetate layer was washed, combined with saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated. 1,1,2-Trichloroethane was added to the residue, whereupon the product formed a solid, 220 mg. (48 percent yield). Identity of the product was confirmed by NMR, IR,
UV, and bioautogram. NMR (DMSO-dg) δ 2.35 (s, 3, CHg on oxadiazole), 3.7 (q, 2, J=18 Hz, 2-CHg) , 3.8 (s, 2, -CHgCONH-) , 4.4 (q, 2, J=14 Hz, 3-CKgS-), 5.1 (d, 1, J=5 Hz, Cg-H),
.6 (q, 1, J=4 Hz, C?-H), 6.9, 7.3 (t, d, 3, thiophene Η), and 9.1 (d, 1, J=8 Hz, -CHgCONH-).
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EXAMPLE 33: PREPARATION OF 3-(((lH-l,3,4-TRIAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN 1,1,2-TRICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid ' (396 mg.; 1 mmole) was suspended in 30 · ol ±,1,2trichloroethane and lH-l,3,4-triazole-5-thiol (100 mg.; 1 mmole) added. The reaction mixture was heated to 105°c. Within 30 minutes, product was precipitating. Heating to 100°C. was continued for about 6 hours, at which time the reaction mixture was cooled to room temperature. Product was collected by filtration and rinsed with 1,1,2-trichloroethane 380 mg. (87 percent yield). The identity of the product was confirmed by IR, NMR, UV, and bioautogram. Bioautogram also showed the presence of the cephalosporanic acid starting material, which high pressure liquid chromatography showed to be present in the amount of 6.8 percent. NMR (DMSO-dg) δ 3.7 (s, 2, 2-0½), 3.8 (s, 2, -CHjCONH-),
4.2 (q, 2, J=5 Hz, 3-CH.2S-) , 5.1 (d, 1, J=5 Hz, Cg-H), 5.7 (q, 1, J=4 Hz, Cy-H), 7.0, 7.4 (t, d, 3, thiophene H), 8.45 (s, 3, triazole ^NH) , and 9.13 (d, 1, J=8 Hz, -CH2CONH-).
EXAMPLE 34: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-PHENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN CHLOROFORM
7-(2-Phenylacetamido)cephalosporanic acid (195 mg.; 0.5 mmole) was suspended in 75 ml. of chloroform and 1methyl-lH-tetrazole-5-thiol (75 mg.; 0.65 mmole) added. The reaction mixture was heated in an oil bath at 80-85°C. for
-5646437 hours and 60 ml. distilled off. TLC showed very little product, whereupon 20 ml. of 1,2-dichloroethane was added and heating continued overnight. TLC of the reaction mixture the following morning showed little cephalosporanic acid starting material. After a total reaction time of 26 hours, the reaction mixture was cooled to room temperature. The product was worked up in essentially the same procedures as reported in Example 32, yielding 80 mg. of purified material (35 percent yield). Identity of the product was confirmed by NMR, IR, UV, and bioautogram. NMR (DMSO-dg) 5 3.6 (s, 2, 2-CH/, 3.7 (s, 2, -CHGCONH-) , 4.0 (s, 3, CHg on tetrazole), 4.3 (s, 2, 3-CH2S-), 5.1 (d, 1, J=5 Hz, Cg-H), 5.7 (q, 1, J=4 Hz, Cg-H), 7.3 (s, 5, 0) , and 9.13 (s, 1, J=8 Hz, -CH2CONH-).
EXAMPLE 35: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-ACETAM1DO-3-CEPHEM-4-CARBOXYLIC ACID IN
1,2-DICHLOROETHANE
7-Acetamidocephalosporanic acid (314 mg.; 1 mmole) and l-methyl-lH-tetrazole-5-thiol (98 mg.; 0.65 mmole) were mixed in 70 ml. of 1,2-dichloroethane; 50 ml.
were distilled off and the reaction mixture than refluxed for about 24 hours.
The reaction mixture was worked up in essentially the procedures reported in Example 32 yielding 120 mg. of product (yield, 32 percent). Identity of the product was confirmed by NMR, IR, UV, and bioautogram. NMR (DMSO-dg) δ 1.97 (s, 3, CHgCONH-), 3.7 (s, 2, 2-CH2), 4.0 (s, 3, CHg on tetrazole), 4.35 (s, 2, 3-CH2S-), 5.1 (d, 1, J=5 Hz, CgH), 5.7 (q, 1, J=4 Hz, Cg-H), and 8.8 id, 1, J=8 Hz, -CI^CONH).
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EXAMPLE 36: PREPARATION OF 3-(((3-METHYL-l,2,4-THIADIAZOL5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (200 mg.; 0.5 mmole) and 3-methyl-l,2,4“thiadiazole-5thiol (85 mg.; 0.65 mmole) were mixed in 50 ml. of 1,2dichloroethane and heated to 95°C. on an oil bath. The bath temperature was maintained at 90°C, for 19 hours. The reaction mixture was then removed from the bath and allowed ύ
to cool and refrigerated for a day. Three volumes of ethyl acetate were then added and washed with two 50 ml. portions of saturated sodium bicarbonate. The combined aqueous portions were extracted with ethyl acetate, layered with fresh ethyl acetate, and cooled in an ice bath. The pH was adjusted to 2.0. The layers were separated and the aqueous layer extracted again with ethyl acetate. The combined ethyl acetate portions were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated, yielding 252 mg. of a foam. It crystallized from acetone/diethyl ether, 153 mg. (65 percent yield).
Identity of the product was confirmed by NMR, UV, IR, and bioautogram. NMR (DMSO-dg) δ 3.7 (s, 2, 2-CHg) , 3.8 (s,
2, -CHgCONH), 4.5 (q, 2, J=15 Hz, 3-CHgS-), 5.1 (d, 1, J=5 Hz, Cg-H), 5.7 (q, 1, J=4 Hz, Cg-H), 6.96, 7.38 (t, d, 3, thiophene Η), and 9.13 (d, 1, J=8 Hz, -CHgCONH).
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EXAMPLE 37: PREPARATION OF 3-(((2-PYRIMIDINYL)THIO)METHYL)~
7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN
ACETONITRILE
7-(2-ί 2-Thienyl)acetamido)cepha)osporard c acid (2.0 grams; 5 mmole) and 2-mercaptopyrimidine (0.62 grams;
.5 mmole) were mixed in 25 ml. of dry acetonitrile and the mixture refluxed overnight (16 hours) with stirring. TLC showed complete conversion to product. The reaction mixture was cooled to room temperature and the product separated by filtration. It was then washed with 50 ml. of acetonitrile and vacuum dried at 50°C. for 4 hours, 1.86 grams of offwhite crystals (83.0 percent yield), m.p. 217°C. (dec). NMR in DMSO-dg showed neither starting material. The identity of the product was confirmed by IR, UV, and NMR. NMR 15 (DMSOg-dg) 0 3.55 (q, 2, 2-CHg, J=18 H2,, 3.74 (s, 2,
-CHgCONH), 4.28 (q, 2, 3-CHgS-, J=13 Hz), 5.00 (d, 1, Cg-H, J=5 Hz), 5.64 (q, 1, C7~H, J=5 Hz, J=9 Hz), 7.08 (m) and 8.52 (d) (6, thiophene and pyrimidine Η), and 9.00 (d,
1, -CHgCONH-, J=9. Hz).
EXAMPLE 38: PREPARATION OF 3-(((2-PYRIMIDINYL)THIO)METHYL)7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN
ACETIC ACID
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole), 2-mercaptopyrimidine (0.6 gram; 5.4 mmole), and sodium acetate (0.41 gram; 5 mmole) in 25 ml. of glacial acetic acid were heated to 85°C. for 4 hours.
Product crystallized during the course of reaction. The reaction mixture was then cooled to room temperature and the product separated by filtration, washed in acetic acid, and
-59dried, 1.58 grains (70.5 percent yield) of white crystals, m.p. 218°C. (dec.). Identity of the product was confirmed by IR, UV, NMR, and elemental analysis. The NMR was identical with the NMR of the product of Example 37.
EXAMPLE 39: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)CEPHALOSPORANIC
ACID IN ACETIC ACID
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole), l-methyl-lH-tetrazole-5-thiol (0.81 gram; 7 mmole), and sodium acetate (0.41 gram; 5 mmole) in 25 ml. of glacial acetic acid were heated to 75-77°C. and held there over 8 hours. TLC was run every hour and at eight hours, TLC showed that the reaction was complete. The reaction mixture was cooled to 40-45°C. and the acetic acid removed under vacuum. To the residue was then added 50 ml.
of ethyl acetate and 50 ml. of water. The aqueous layer was acidified to pH 1.5 with IN HgSO^. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and the ethyl acetate removed on a rotary evaporator. The residue, a light weight oil, was redissolved in 50 ml. of ethanol and a solution of 2 ml. of dicyclohexylamine (10.2 mmole) in 10 ml. of ethanol was added. The product precipitated almost immediately as the dicyclohexylamine salt but was stirred an additional 15 minutes; it was then separated by filtration, washed with ethanol and dried, 1.2 grams (37.8 percent yield), m.p. 185-6°C. IR, NMR, and UV were identical with previously prepared samples of the same product.
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EXAMPLE 40: PREPARATION OF 3-(((1-BENZYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl) acetamido)cephalosporanic acid 5 (2.0 grams? 5 mmole) and l-benzyl-lH-tetrazole-5-c.iiol (1.44 grains; 7.5 mmole) were added to 25 ml. of 1,2-dichloroethane and the reaction mixture heated to 85°C. in an oil bath and maintained at that temperature overnight, with stirring.
TLC showed no cephalosporanic acid starting material.
Solvent was removed on a rotary evaporator, leaving a foam.
To the foam, 25 ml. of methanol was added and the mixture warmed on a steam bath until the sample dissolved. Solvent was evaporated on a rotary evaporator and the product crystallized. It was stirred for 15 minutes, then separated by
-5 filtration, washed with methanol, and vacuum dried, 1.6 grams (60.6 percent yield), m.p. 171-171.5°C.
EXAMPLE 41: PREPARATION OF 3-AMIDINOTHIOMETHYL-7-(2-(2THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (3.12 grams? 8 mmole) and thiourea (912 mg.? 12 mmole) in ml. of acetonitrile (which had been dried over an aluminosilicate desiccant sold under the term 4-A Linde molecular sieve) were heated at 87°C. with stirring for 24 hours.
Within one hour, precipitate began forming in the reaction mixture.
At the end of 24 hours, the product was separated by filtration of the hot reaction mixture, and dried, 2.5 grams (76 percent yield). Elemental analysis showed
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Theory: C, 43.68; H, 3.91; N, 13.58.
Found: C, 43.50; H, 4.03; N, 13.29.
NMR confirmed the identity of the product.
EXAMPLE 42: PREPARATION OF 3-BENZOYLTHIOMETHYL-7-(2-(25 THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN ISOPROPYL
ACETATE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (1.0 gram; 2.5 mmole) and thiolobenzoic acid (510 mg.; 3.7 mmole) were suspended in 20 ml. of anhydrous isopropyl acetate and the suspension heated under reflux for 31 hours, by which time all reactants were in solution. Solvent was evaporated under vacuum, leaving a residue which TLC indicated was a 60-40 mixture of product and unreacted starting material.
Preparative thick-layer chromatography over silica plates using acetone: acetic acid (16:1) as eluent afforded a purified sample of product. NMR (DMSO-dg/D2O) δ 3.50 (ABq, 2H, 2-CH2, J=6 Hz, J=19 Hz), 3.82 (s, 2H, -CH2CONH-), 4.20 (d, 2H, 3-CH2S-, J=5 Hz), 5.03 (d, IH, Cg-H, J=5 Hz),
.69 (d, IH, Cy-H, J=5 Hz), 6.89-8.0 (m, 8H, aromatic H).
EXAMPLE 43: PREPARATION OF 3-((PHENYLTHIO)METHYL)-7-(2(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN 1,2DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid 25 (2.0 grams; 5 mmole) and benzenethiol (0.75 ml.; 7.5 mmole) were added to 25 ml. of 1,2-dichloroethane. The reaction mixture was refluxed overnight; TLC showed no cephalosporanic acid starting material remaining.
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Solvent was evaporated on a rotary evaporator and 25 ml. of ethanol added to the residue and heated to get the residue into partial solution. To get the remainder into solution, 25 ml. of methanol was added and heated. The resulting solution was filtered through cotton, treated with 2.0 grams of carbon, stirred 5 minutes, and filtered through filter aid. Solvent was removed on a rotary evaporator.
NMR of the residue showed some thiol starting material present.
The residue was slurried in 25 ml. of isopropyl acetate, filtered, .and refrigerated overnight. The filtrate was then diluted with 25 ml. of ethyl acetate and washed with 25 ml. of dilute sodium bicarbonate to remove thiol.
The ethyl acetate layer was added to 25 ml. of water and the pH at 8.5 was adjusted to pH 1.4 with H9SO.. The ethyl acetate layer was then dried over magnesium sulfate, filtered, and evaporated to a foam on a rotary evaporator, 0.92 gram (19.4 percent yield). NMR (DMSO-dg) δ 3.58 (m, 2, 2-¾) , 3.75 (s, 2, -CH2CONH-\, 4.12 (q, 2, 3-CH2S-, J=13
Hz), 5.08 (d, 1, Cg-H, J=5 Hz), 5.66 (q, 1, Cy-H, J=5 Hz,
J=9 Hz), 7.15 (m, 8, thiophene H and phenyl H), and 9.10 (d, 1, -CH2CONH-, J=9 Hz).
EXAMPLE 44: PREPARATION OF 3-(((5-METHYL-l,3,4-THIADIAZOL2-YL)THIO)METHYL)-7-(2-PHENYLACETAMIDO)-3-CEPHEM-4-CAR25 BOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-Phenylacetamido)cephalosporanic acid (1.95 grams; 5 mmole) and 5-methyl-l,3,4-thiadiazole~2-thiol (0.99 gram; 7.5 mmole) in 25 ml. of 1,2-dichloroethane were refluxed for 16 hours. TLC showed a trace of cephalosporanic acid starting material. Product crystallized during the reaction.
The reaction mixture was cooled to 0-5°C. and filtered, and the product washed with cold 1,2-dichloro5 ethane and vacuum dried, 1.82 grams (78.8 percent yield),
m.p. 171-2’C. NMR (DMSO-dg) δ 2.70 (s, 3, -CH3 of thiadiazolyl), 3.58 (s, 2, -CH^CONH-), 3.70 (broad s, 2, 2-CH2), 4.40 (g, 2, 3-CH2S-, J=13 Hz), 5.12 (d, 1, Cg-H, J=5 Hz),
.72 (g, 1, C-j-H, J=5 Hz, J=9 Hz), 7.28 (s, 5, phenyl H) , and 9.08 (d, 1, -CH2CONH-, J=9 Hz).
EXAMPLE 45: PREPARATION OP 3-((METHYLTHIO)METHYL)-7-(2(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN METHYLENE
CHLORIDE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (24 IS grams; 60 mmole), 7.0 ml. of methanethiol, and 600 ml. of methylene chloride were stirred and heated in a bomb for 18 hours at 84-86°C. The reaction mixture was then cooled to room temperature. A small amount of insoluble material was filtered off and the filtrate was evaporated. The residue was taken up in ethyl acetate and filtered. The filtrate was layered with about 150 ml. of water and stirred; IN NaOH was added dropwise to a pH 5.5. The aqueous phase was separated and concentrated to a volume of about 75 ml., then diluted to 700 ml. with water, and glacial acetic acid added to pH 3.8. An amorphous solid precipitated and was stirred for 3 hours on an ice bath, then refrigerated overnight.
The solid was then filtered. The filtrate was layered with 100 ml. of ethyl acetate and the pH adjusted to 2.0 with concentrated HCl. The organic phase was separated
-6446437 and extracted with one-100 ml. portion and one-150 ml. portion of ethyl acetate. The combined organic phases were dried over magnesium sulfate, then stripped of solvent, yielding an amber colored foam. It was dissolved in 50 ml.
of ethyx acetate, seeded with the intended product, and hel' in a refrigerator overnight. Crystals had formed; they were separated by filtration, rinsed with cold isopropyl acetate, and vacuum dried at 50°C., 3.2 grams (14 percent yield).
NMR confirmed the identity of the product, 3 2.00 (s, 3,
3-rH?SCH3), 3.74 (m, 3-CHgii-, 2-CHg, and -CHgCONH-), 5.14 (d, 1, Cg-H, J-5 Hz), 6.64 (q, 1, Cg-H, J=5 Hz, J=9 Hz),
7.15 (m, 3, thiophene H), and 9.12 (d, 1, -CHgCONH-, J=9 Hz) .
EXAMPLE 46; PREPARATION OF 7-(2-FORMYLOXY-2-PHENYLACET15 AMIDO)-3-(1-METHYL-1H-TETRAZOL-5-YL)THIO)METHYL)-3-CEPHEM4- CARBOXYLIC ACID SODIUM SALT IN BENZENE
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid (2.17 grams; 4.65 mmoles) and 1-methyl-lH-tetrazole5- thiol (0.87 gram; 7.5 mmole) in 25 ml. of benzene were refluxed (about 80°C.) for 12 hours. A layer of soft plastic deposited on the glass vessel during the reaction.
On cooling, the plastic hardened to a glassy solid. TLC showed that the solution contained only a trace of product and that the plastic was mostly product with some deformylated product. The reaction mixture was evaporated with added acetone to a foam which was dissolved in 35 ml. of dry acetone and treated with 10 ml. of a solution of 1.25 grams of sodium 2-ethylhexanoate (7.5 mmole) in acetone. The product crystallized as the sodium salt. After an hour, the
-6546437 product was filtered, washed with 20 ml. of acetone and dried, 1.38 grams (58 percent yield). The identity of the product was confirmed by TLC and NMR. NMR (D2O) ® 3.48 (q, 2, 2-CH2, J=18 Hz), 4.00 (s, 3, -CHg of tetrazolyl), 4.10 (m, 2, 3-CH2S-), 5.05 (d, 1, Cg-H, J=5 Hz), 5.70 (d, 1, CgH, J=5 Hz), 6.24 (s, 1, -CHCONH-), 7.50 (m, 5, phenyl Η), and 8.33 (a, 1, -OCH).
EXAMPLE 47: PREPARATION OF 7-(2-FORMYLOXY-2-PHENYLACET10 AMIDO)-3-(((1-METHYL-1H-TETRAZQL-1-YL)THIO)METHYL)-3CEPHEM-4-CARBOXYLIC ACID IN CARBON TETRACHLORIDE
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid (2.17 grams; 4-65 mmole) and l-methyl-lH-tetrazole-5thiol (0.87 gram; 7.5 mmoles) in 25 ml. of carbon tetra15 chloride were refluxed (about 77°C.) for 12 hours. The reaction mixture was then cooled to room temperature and the supernatant Recanted from a hardened semi-solid. To the solid was added 25 ml, of 1,2-dichloroethane, with warming. The product crystallize^, The mixture was cooled to room f
temperature and stirred for about an hour, then the product was separated by filtrat|on, washed with 10 ml. of 1,2dichloroethane, and vacuum' dried overnight at 45°C., 1.54 grams of white crystals (65 percent yield). Identity of the product was confirmed by NMR and TLC, the latter of which
3o showed a small trace of defqrmyiated product. The NMR was identical with the NMR of the product of Example 16.
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PREPARATION 48: PREPARATION OP 3-METHYL-l,2,4-OXADIAZOLE5-THIOL
Acetamide oxime (30 grams; 0.4 mole), carbon disulfide MOO ml.; 1.66 mole) and triethylam4ne '56 ml.;
0.4 mole) were mixed and stirred in 1 liter of pyridine. A stream of nitrogen gas was bubbled through a carbon disulfide solution and then passed over the reaction mixture. The mixture was heated in an oil bath at 70°C. for three days, then evaporated to an oil, to which ethyl acetate and saturated sodium carbonate were added. The layers were separated and the organic layer was again washed with saturated sodium bicarbonate. The combined sodium bicarbonate washes were extracted with ethyl acetate and the ethyl acetate extracts were discarded. The aqueous portion wa® layered with fresh ethyl acetate and cooled in an ice bath. The pH was adjusted to 2.5 with 20 percent HCl and sodium chloride was added to saturate the solution. It was then extracted with ethyl acetate, rinsed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solution was filtered and evaporated to one-half its original volume. An equal volume of carbon tetrachloride was added and evaporation was continued until the product crystallized, 24.8 grams (52 percent yield).
EXAMPLE 49: PREPARATION OF 3-(((3-METHYL-l,2,4-OXADIAZOL5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl)acetamido)-3-(carbamoyloxymethyl)3-cephem-4-carboxylic acid (100 mg.; 0.25 mmole) was suspended in 25 ml. of 1,2-dichloroethane and stirred while 3-methyl-671,2,4-oxadiazole-5-thiol (35 mg.; 0.30 mmole) was added.
The reaction mixture was heated on an oil bath at 110°C., to distill off 5 ml. of solvent including any trace amount of water. The oil bath temperature was lowered to 90-95°C. and the reaction mixture maintained for 19 hours, then cooled to room temperature. Insoluble material was removed by filtration and rinsed with 1,2-dichloroethane and diethyl ether. It was determined by TLC to be unreacted starting material with only a trace amount of product.
The filtrate was evaporated and the residual oil partitioned between sodium bicarbonate solution and ethyl acetate. The aqueous solution was layered with fresh ethyl acetate, cooled in an ice bath, and the pH adjusted to 2.5 with 20 percent HCl. The organic layer was removed. The aqueous layer was extracted with fresh ethyl acetate and the combined ethyl acetate solutions were washed with saturated NaCl solution, dried over magnesium sulfate, filtered, and evaporated to an oil. Crystallization from a 1:1 solution containing hexane and diethyl ether gave 13 mg. of product, (11.5 percent yield). The identity of the product was confirmed by NMR and IR, which were identical with the same compound prepared as reported In Example 32.
EXAMPLE 50: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(tert-BUTOXYCARBONYL)-2-PHENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(tert-Butoxycarbonyl)-2-phenylacetamido)cephalosporanic acid (490 mg.; 1 mmole) and 1-methyl-lHtetrazole-5-thiol (145 mg.; 1.25 mmole) in 15 ml. of dry nitromethane were heated at 85-90°C. for 8 hours under
-6846437 nitrogen. TLC showed product, excess thiol reactant, and decarboxylated product, but no cephalosporanic acid starting material. The nitromethane was removed by evaporation. The residual orange foam was dissolved in 10 ml. of saturated sodium bicarbonate, 20 ml. of water was added, and the mixture was washed successively with ethyl acetate until the washes were clear. The ethyl acetate washes were combined, ml. of water was added, and the mixture cooled to 0°C. and adjusted to pH 2.2 with 20 percent HCl. The layers were separated and the aqueous layer washed with ethyl acetate.
The ethyl acetate portions were combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated to a brown foam, 455 mg. ¢83 percent yield). TLC was excellent, showing the presence of product, a trace of thiol, and a trace of decarboxylated product.
The 455 mg. of product (0.833 mmole) were dissolved in 7 ml. of ethyl acetate and lithium acetate (0.833 ml.) was added dropwise with stirring, resulting in a brown precipitate, the lithium salt. It was separated by filtration, washed with ethyl acetate, and dried overnight under vacuum at room temperature, 368 mg. (80 percent yield). The identity of the product was confirmed by TLC, NMR, bioautogram, elemental analysis, IR, and UV. TLC showed a trace of decarboxylated material. NMR (CDClg) δ 1.4 (s,
9, -COOtertC^Hg) , 3.6 (s, 2, 2-¾) , 3.85 (s, 3, CHg of tetrazole), 4.3 (s, 2, 3-CHgS-), 4.44 and 4.45 (2s, 1,
0CH-) , 4.9 (d, 1, J=6 Hz, Cg-H) , 5.8 (q, 1, J=6 Hz, C-j-H) ,
7.35 (s, 5, 0), 8.2 and 7.8 (2d, 1, J=9 Hz, -CONH-), and 9.3 (s, 1, -COOH).
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EXAMPLE 51: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(N-((1,3-DIMETHYLUREIDO)CARBONYL)-2PHENYLGLYCYLAMlNO)-3-CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(N-((1,3-Dimethylureido)carbonyl)-2-phenyl5 glycylamino)cephalosporanic acid (130 mg.; 0.25 mmole) was suspended in 5 ml. of nitromethane and 1-methyl-lH-tetrazole-5-thiol (43.5 mg.; 0.375 mmole) was added. The reaction mixture was heated at 85° under nitrogen for 12 hours, then held at room temperature over a weekend. The reaction mixture was then filtered and the solid washed with a small amount of nitromethane and dried in a vacuum oven at 35°, mg. (58 percent yield). The identity of the product was confirmed by TLC, NMR, IR, UV, elemental analysis and bioautogram. NMR (DMSO-dg) 5 2.65 (d, 3, J=4 Hz, -CONHCHg),
3.15 (s, 3, CONCHgCO-), 3.6 (s, 2, 2-CHg), 3.9 (s, 3, CHg on tetrazole), 4.3 (s, 2, 3-CHgS-), 5.0 (d, 1, J=5 Hz, Cg-H),
.5 (d, 1, J=7 Hz, 0CHCO), 5.7 (q, 1, Cy-H) , 5.8 (q, 1,
N1
-CONHCHg), 7.4 (s, 5, 0) , 9.3 (d, 1, J=8 Hz, 0CHCONH-), and 10 (d, 1, J=8 Hz, 0CH-CO-).
NH r
EXAMPLE 52: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE, TETRABUTYLAMMONIUM IODIDE ADDED
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole), 1-methyl-lH-tetrazole-5-thiol (1.2 grams;
mmole), and tetrabutylammonium iodide (0.2 gram) were mixed in 25 ml. of dry acetonitrile, heated to reflux, and refluxed for 8 hours. The reaction mixture was then cooled
-7046437 to room temperature and solvent removed on a rotary evaporator. The residue was treated with a hot mixture of 25 ml. of isopropyl acetate and 5 ml. of acetonitrile, filtered, and allowed to rno’ -lowly. The product ’-'tecipitatri a- liaht cream colored crystals and was filtered, washed with isopropyl acetate, and dried, 1.30 grams (57.5 percent yield). The NMR was identical with the NMR on the product of Example 5. EXAMPLE 53: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC
ACID IN 1,2-DICHLOROETHANE (TETRABUTYLAMMONIUM IODIDE ADDED)
The reaction reported in Example 52 was repeated except that 1,2-dichloroethane was employed as solvent. Dicyclohexylamine (2 ml.) was added to obtain the product as the dicyclohexylamine salt, 1.55 grams (48.9 percent yield).
The NMR was identical with the NMR on the product of Example 1.
EXAMPLE 54: PREPARATION OF 3-((PHENYLTHIO)METHYL)-7(2-(2-THIENYL)ACETAMIDO)-3-CEPIIEM-4-CARBOXYL1C ACID IN 1,2-DICHLOROETHANE, l-METHYL-5-(METHYLTHIO)-1H-TETRAZOLE 20 ADDED
7-(2-(2-Thienyl)acetamido)cephalosporanic acid '2.0 grams; 5 mmole), benzenethiol (0.75 ml.; 7.5 mmole), and 0.65 gram of l-methyl-5-(methylthio)-ΙΗ-tetrazole were mixed in 25 ml. of 1,2-dichloroethane and heated to reflux.
The reaction was followed by TLC and appeared to be complete in 14 hours. Solvent was removed on a rotary evaporator and the residue was extracted repeatedly with diethyl ether. Exhaustive removal of solvent left 1.66 grams of tan solid product (74 percent yield). IR and NMR were identical with the same product prepared as described in preceding examples.
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EXAMPLE 55: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYLACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN ISOPROPANOL
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) an'4 1-methyl-lH-tetrazole-5-thiol (0.87 gram; 7.5 mmole) in 25 ml. of isopropanol were placed in a flask (equipped with a condenser, with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite). The flask was immersed in an oil bath at 84-85°C
The reaction was followed by TLC. After 40 hours at 82-83°C only half of the cephalosporanic acid had reacted.
EXAMPLE 56: PREPARATION OF 3-((2-OXAZOLYLTHIO)METHYL)-7(2-(1H-TETRAZOL-1-YL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID
IN NITROMETHANE
A suspension of 7-(2-(IH-tetrazol-l-yl)acetamido)cephalosporanic acid (0.38 gram; 1.0 mmole) and 2-oxazolethiol (0.11 gram; 1.1 mmole) in 5 ml. of nitromethane was immersed in an oil bath at 90-91°C. An atmosphere of dry nitrogen was maintained over the reaction mixture. After 20 minutes, all of the reactants had dissolved, and after 35 minutes, product began to crystallize. After 6 hours the reaction mixture was cooled to room temperature and the product was filtered, washed with 7 ml. of nitromethane, air dried, and vacuum dried for 3 hours at 40°C., yielding 0.36 gram (85.7 percent yield of off white crystals, m.p. 196°C. (dec). NMR Showed the product to be 70 percent of the desired product and 30 percent of the cephalosporanic acid starting material.
-7246437
The product was recrystallized from 5 ml. of
DMSO-d, and 10 ml, of water, separated by filtration, washed 0 with 5 ml. of 2:1 water:DMSO-dg, air dried, and vacuum dried at 50°C. for 6 hours, yielding 0.26 gram. NMR showed that the product contained 87 percent of the desired product and 13 percent of starting cephalosporanic acid. The recrystallization was repeated with 3 ml. of DMSO-dg and 6 ml. of water, stirring for 1 hour, resulting in 0.21 gram. NMR (DMSO-d,) indicated that the starting cephalosporanic acid o had been reduced to 5 percent, and confirmed the identity of the desired product: δ 3.75 (s, 2, 2-CH2)» 4.34 (q, 2, 3-CH2S-, J=14 Hz), 5.16 (d, 1, Cg-H, J=5 Hz), 5.76 (q, 1, C?-H, J=5 Hz, J=9 Hz), 5.44 (s, 2, -CH^CONH-) , 7.28 (s, 1, oxazole C^-H), 8.14 (s, 1, oxazole Cg-H), 9.37 (s, 1, tetrazole Η) , and 9.53 (d, 1, -CONH-, J=9 Hz).
EXAMPLE 57: PREPARATION OP 3-((2-OXAZOLYLTHIO)METHYL)7-(2-FORMYLOXY-2-PHENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
A solution of 7-(2-formyloxy-2-phenylacetamido)cephalosporanic acid methylene chloride solvate (0.52 gram;
mmole) and 2-oxazolethiol ' (0.12 gram; 1.1 mmole) in 20 ml. of 1,2-dichloroethane was refluxed for about 16 hours and then cooled to room temperature. TLC showed clear conversion to product. The reaction mixture was concentrated on a rotary evaporator to 10 ml.; and upon standing, somewhat gelatinous crystals formed. They were filtered, washed with 1,2-dichloroethane, and dried, yielding 0.12 gram of gray solid.
-7346437
Exhaustive removal of solvent from filtrate left 0.45 gram of light yellow foam. It was triturated with 25 ml. of diethyl ether, filtered, washed with diethyl ether, and dried yielding 0.21 gram of light yellow powder.
The identity of the product was confirmed by NMR, δ 3.56 (m,
2, 2-CH2), 4.24 (g, 2, 3-CH2S~), J=13 Hz), 5.00 (d, 1,
Cg-H, J=5 Hz), 5.70 (q, 1, C?-H, J=5 Hz, J=9 Hz), 6.14 (s,
1, ·ζ —CH-), 7.25 (s, 1, oxazole C^-H), 7.45 (m, 5, phenyl
H), 8.12 (s, 1, oxazole Cg-H), 8.35 (s, 1, -CHO), and 9.40 (d, 1, -CONH-, J=9 Hz).
EXAMPLE 58: PREPARATION OF 3-({(4-PHENYL-2-THIAZOLYL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE
A mixture of 7-(2-(2-thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 4-phenyl-2thiazolethiol (1.44 grams; 7.5 mmole) in 35 ml. of acetonitrile was refluxed for 16 hours, protected from atmospheric moisture with a drying tube containing anhydrous calcium sulfate sold under the trademark Drierite. TLC showed clean conversion to a new spot.
Upon cooling the reaction mixture to room temperature and stirring it for 2 hours, the product crystallized and was filtered, washed with acetonitrile, and dried, 2.25 gram (85.6 percent yield, m.p. 180°C. (dec.).
NMR confirmed the identity of the product.
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EXAMPLE 59: PREPARATION OF 3-(((5-METHYL-l,3,4-THIADIAZOL2-YL)THIO)METHYL)-7-(2-(lH-TETRAZOL-l-YL)ACETAMIDO)-3CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(lH-Tetrazol-i-yl)acetamido)cephalosporanic acid (1.92 grams; 5 mmole) and 5 methyl-1,3,4-thiadiazole2-thiol (0.79 gram; 6 mmole) were added to 25 ml. of aluminatreated nitromethane and the reaction mixture heated to
95°C. in an oil bath and allowed to stir for a total of 4 hours. TLC showed conversion except for a trace of cepha10 losporanic acid starting material (less than 2 percent).
The reaction mixture was cooled to room temperature filtered, washed with nitromethane, and vacuum dried, 2.11 grams (92.5 percent yield), m.p. 183.5°C. (dec.). NMR confirmed the identity of the product.
EXAMPLE 60: PREPARATION OF 3-(((5-METHYL-l,3,4-THIADIAZOL2-YL)THIO)METHYL)-7-(2-(lH-TETRAZOL-l-YL)ACETAMIDO)-3CEPHEM-4-CARBOXYLIC ACID IN PROPIONITRILE
7-(2-(ΙΗ-Tetrazol-l-yl)acetamido)cephalosporanic acid (1.92 grams; 5 mmole) and 5-methyl-l,3,4-thiadiazole20 2-thiol (0.99 grams; 7.5 mmole) were added to 25 ml. of propionitrile (treated over neutral alumina) and heated to reflux (97°C.). The reaction mixture was refluxed with stirring for 9 hours. TLC showed only a trace of cephalosporanic acid starting material. The reaction mixture was cooled to room temperature, filtered, washed with propionitrile, and vacuum dried, 2.04 grams (89.5 percent yield), m.p.
186.5°C. (dec.). NMR confirmed the identity of the product.
-75EXAMPLE 61: PREPARATION OF 3-( ( (l-METlIYL-lIl-TETRAZOL-5YL)THIO)METHYL)-7-(2-FORMYLOXY-2-PHENYLACETAMIDO)-3-CEPHEM4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-ACA (7-aminocephalosporanic acid) (13.62 grams; 0.05 mole) was suspended in 100 ml. of 1,2-dichloroethane and N-trimethylsilyl-acetamide (26.25 grams; O.2OO mole) was added. The reaction mixture was heated to 40°C. and the solid dissolved to yield a cloudy solution, which was cooled to 20°C.
A solution of 2-formyloxy-2-phenylacetyl chloride (10.92 grams; 0.055 mole) in 25 ml. of 1,2-dichloroethane was added dropwise over 20 minutes, with a temperature rise to 30°C. The reaction mixture was stirred for 2 hours,
100 ml. of 1,2-diehloroethane were added, and the reaction mixture was washed with three 100-ml. portions of water.
The water washes were combined and extracted with two 50-ml. portions of I,2-dichloroethane, which were back washed with 40 ml. of water. The 1,2-dichloroethane layers were combined, stirred 20 minutes with 2.0 grams of activated carbon sold under the trademark 'barco G-60“, and filtered through a diatomaceous earth sold under the trademark “Hyflo Total volume was 375 ml. of solution containing the desired 7-(2-formyloxy-2-phenylacetamido)cephalosporanic acid.
This solution was evaporated at 30°C. to 336 grams, estimated to be 250 ml. of 1,2-dichloroethane and 22 grams of the 7-(2-formyloxy-2-phenylacetamido)cephalosporanic acid. 1-Methyl-lH-tetrazole-5-thiol (6.39 grams; 55 mmole) in 250 ml. of 1,2-dichlorothane was added and the reaction mixture heated to reflux. Water (apparently remaining from
-7646437 earlier washes) was azeotroped into the condenser and began returning into the vessel; a trap was employed to intercept water. TLC after 12 hours of reflux showed near normal reaction. The reaction mixture was cooled to room tem5 perature and seeded to precipitate the product, 3-(((1methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-formyloxy)2-phenylacetamido)-3-cephem-4-carboxylic acid. After two hours, the product was filtered and washed with 63 ml. of 1,2dichloroethane, 13.90 grams (56.7 percent yield based on
7-ACA). TLC of the product was clean. The NMR confirmed the identity of the product and was identical with the NMR of the product prepared as reported in Example 16.
EXAMPLE 62: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-FORMYLOXY-2-PHENYLACETAMIDO)-315 CEPHEM-4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid (2.33 grams; 5 mmole) and l-methyl-lH-tetrazole-5thiol (0.64 gram; 5.5 mmole) were added to 25 ml. of 1,2dichloroethane and the mixture refluxed for 12 hours. The reaction mixture was cooled to room temperature, then reheated to reflux and 10 ml. of solvent distilled off.
Then 10 ml. of carbon tetrachloride was added dropwise near the reflux temperature (77°c.). The resulting mixture was allowed to cool to room temperature and stirred for 1 hour.
The product was separated by filtration, washed with 14 ml. of 40 percent carbon tetrachloride in 1,2-dichloroethane, and dried at 50°C. under vacuum, 2.12 grams of light colored solid (86.5 percent yield). The NMR was identical with the NMR on the product prepared as reported in Example 16.
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EXAMPLE 63: PREPARATION OF 3-(((3-(BENZYLOXYCARBONYLAMINOMETHYL) -1,2,4-TRIAZOL-5-YI.) THIO) METHYL) -7- (2- (2-TIIIENYL) ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(2-Thienyl) acetamido)cephalosporanic acid (2 grams; 5 mmole) and 3-(benzyloxycarbonylaminomethyl)l,2,4-triazole-5-thiol (2 grams; 7.6 mmole) in 35 ml. of nitromethane were heated at 80-90°C. for 6 hours, with stirring. The reaction mixture was cooled and filtered to separate the product. It was recrystailized twice from aqueous acetone, 1.2 grams of cream colored crystals, m.p. 174-178°C. (dec.) (40 percent yield).
Anal., Calc, for C25H24N6°6S3: C, 49.99; H, 4.03; N, 13.99;
S, 16.01.
Found : C, 50.20; H, 4.03; N, 13.76;
S, 15.68.
EXAMPLE 64: PREPARATION OF 3-(((1-(CARBOXYMETHYL)-1HTETRAZOL-5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (1.0 gram; 2.5 mmole) and 1-(carboxymethyl)-IH-tetrazole5-thiol (0.61 gram; 3.8 mmole) in 75 ml. of acetonitrile was heated to boiling and 35 ml. of the solvent distilled off.
The reaction mixture was then refluxed for 13 hours, cooled, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with IN HCl and brine, and dried over sodium sulfate. Hexane was added, resulting in a precipitate which was separated and triturated with ether, 0.475 gram of tan solid (38 percent yield). The identity of the product was established by comparison with an authentic sample prepared by another synthetic route.
-7846437
EXAMPLE 65; PREPARATION OP 3-(((5-METHYL-l,3,4-THIADIAZOL2-YL)THIO)METHYL)-7-(3-CHLOROPROPIONAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN NITROMETHANE
A stirred suspension of 7-(3-chloropropionamido)5 cephalosporanic acid (1.0 gram; 2.5 mmole) and 5-methyll,3,4-thiadiazole-2-thiol (0.4 gram; 3 mmole) in 20 ml. of nitromethane was immersed in an oil bath at 95-96°C.
According to TLC, reaction was complete in 3 hours. The reaction mixture was cooled to room temperature, filtered,
JO and evaporated under vacuum, leaving a light red oil which crystallized on standing at room temperature for 2 hours.
It was then triturated with 15 ml. of ethyl acetate, filtered, washed with ethyl acetate, and dried, 0.64 gram (55.2 percent yield). Identity of the product was confirmed by IR, UV, titration, microanalysis, and NMR.
Anal., Calc, for cigHigclN4°4S3: C, s, 41.51; 20.78; H, 4.14; Cl, 7.66 N, 12.10; Found : c, 41.70; H, 4.23; N, 11.84; s, 20.51; Cl, 7.88
EXAMPLE 66: PREPARATION OF 3-(((1-BENZYL-1H-1,2,3-TRIAZOL5-YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-(2-Thienyl) acetamido)cephalosporanic acid (200 mg.; 0.5 mmole) and 1-benzyl-IH-l,2,3-triazole-515 thiol (140 mg.; 0.7 mmole) were mixed in 15 ml. of 1,2dichloroethane and heated at 65-70°C. for 21 hours. Solvent was removed under reduced pressure, 25 ml. of a saturated sodium bicarbonate solution was added, and the mixture was extracted with two portions of ethyl acetate. Fresh ethyl
-7946437 acetate was added to the remaining aqueous solution which was cooled in an ice bath and the pH adjusted to 2.5 with 20 percent HCl solution. The acidic product was extracted with two portions of ethyl acetate, and the combined ethyl acetate was washed with saturated NaCl solution and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered and ethyl acetate removed under reduced pressure, mg. Thin layer chromatography showed it to be a mixture of starting material and product by comparison with an authentic sample of product and starting materials.
EXAMPLES 67-72: DISPLACEMENT BY VARIOUS THIOLS OF 7METHOXY-7-(2-(1H-TETRAZOL-1-YL)ACETAMIDO)CEPHALOSPORANIC
ACID IN NITROMETHANE
7-Methoxy-7-(2-(IH-tetrazol-l-yl)acetamido)cephalo15 sporanic acid was reacted with various thiols in nitromethane. The procedures were essentially the same as reported above, except that high pressure liquid chromatography was employed to purify the products from unreacted starting material. The products and identification were as follows:
3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)7-methoxy-7-(2-(IH-tetrazol-l-yl)acetamido)-3-cephem-4carboxylic acid, uv max (ethanol) 273 mp (e 9,082).
3-(((5-methyl-l,3,4-thiadiazol-2-yl)thio)methyl)25 7-methoxy-7-(2-(IH-tetrazol-l-yl)acetamido)-3-cephem-4carboxylic acid, uv max (ethanol) 273 my (e 12,785).
Anal., Calc, for ^Η-^ΝθΟ^: C, 37.18? H, 3.33? N, 23.13.
Pound : C, 36.99; II, 3.31; N, 22.86.
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3-(((5-methyl-l,3,4-oxadiazol-2-yl)thio)methyl)7-methoxy-7-(2-(lH-tetrazol-l-yl)acetamido)-3-cephem-4carboxylic acid, uv max (ethanol) 269 my (e 8,910).
Anal., Calc. for C- ^gNgO^S,: C, 38.46; H, 3.44; N, 23.9?
Found : C, 38.58; H, 3.69; N, 23.91.
3-(((1-(carboxymethyl)-lH-tetrazol-5-yl)thio ) methyl)-7-methoxy-7-(2-(ΙΗ-tetrazol-l-yl)acetamido)-3cephem-4-carboxylic acid, uv max (ethanol) 269 mu (e 7669). Anal., Calc, for C15H16N10O7S2: C, 35.16; H, 3.15; N, 27.33.
Found : C, 35.42; H, 3.38; N, 27.39.
3-(((4,5-dihydro-6-hydroxy-4-methyl-5-oxo-l,2,4triazin-3-yl)thio)methyl)-7-methoxy-7-(2-(lH-tetrazol-1yl)acetamido)-3-cephem-4-carboxylic acid, uv max (ethanol)
274 (e 11,967).
Anal., Calc, for C16H17NgO7S2: C, 37.57; H, 3.35; N, 24.65.
Found : C, 36.96; H, 3.80; N, 27.63.
3-( ((l,3,4-triazol-5-yl)thio)methyl)-7-methoxy7-(2-(ΙΗ-tetrazol-l-yl)acetamido)-3-cephem-4-carboxylic acid Anal., Calc, for ci4H15N9°5S2 ! c' 37·08? H, 3.33; N, 27.80.
Found : C, 36.98; H, 3.43; N, 27.79.
EXAMPLE 73: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5-YL)THIO)METHYL)-7-(2-(4-ETHYL-2,3-DIOXO-l-PIPERAZINYLCARBONYLAMINO) -2-PHENYLACETAMIDO) -3-CEPHEM-4-CARBOXYLIC ACID IN
NITROMETHANE
7-(2-(4-Ethyl-2,3-dioxopiperazinylcarbonylamino)2-phenylacetamido)cephalosporanic acid hydrate (0.3 gram;
0.5 mmole) and l-methyl-lH-tetrazole-5-thiol (0.0725 gram; 0.625 mmole) were added to 6 ml. of nitromethane which had been dried over alumina and the mixture was heated at 85°C.,
-814 6 4 3 7 under nitrogen, for 12 hours. The nitromethane was then evaporated and the residual brown foam redissolved in sodium bicarbonate solution and washed twice with ethyl acetate. Fresh ethyl acetate was added and the mixture cooled to 0°C. and adjusted to pH 2.3. The layers were separated and the aqueous layer was washed with ethyl acetate. The ethyl acetate portions were combined, washed with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered, and evaporated, yielding a pale yellow powder, 130 mg. (40% of theoretical). Identity of the product was confirmed by NMR δ 1.2 (t, 3, -NCH2CH3, J = 7 HZj,'3.65 (m, 6, N-CHgCHg and piperazinyl H), 4.0 (s, 3, -CHg of tetrazole), 4.4 (s,
2, 3-CH2S->, 5.1 (d, 1, Cg-H, J = 6 Hz) , 5.8 (d, 1, C?-H, ,β—e.
J = 8 Hz), 6.0 (d, 1, / S-CH- , J = 6 Hz) , 7.4 (m, 5,
I
N phenyl-H),.8.4 (d, 1, -CHCONH- , J = 8 Hz) , and 10.0 (d,
1, -CHCONH- , J = 6 Hz).
NH
EXAMPLE 74: PREPARATION OF 3-(((1-CARBOXYMETHYL)-1H-TETRAZOL-5-YL)THIO)METHYL)-7-(2-(4-ETHYL-2,3-DIOXO-l-PIPERAZINYLCARBONYLAMINO)-2-PHENYLACETAMIDO)-3-CEPHEM-4-CARBOXYLIC
I
ACID IN 1,2-DICHLOROETHANE
7-(2-(4-Ethyl-2,3-dioxopiperazinylcarbonylamino)2-phenylacetamido)cephalosporanic acid hydrate (0.3 gram;
0.5 mmole) was dissolved in 45 ml. of 1,2-dichloroethane .
which had been dried over alumina and the solution was heated to 95° to azeotrope off water. After 40 ml. of solvent had been collected, nitromethane (10 ml.) and 1(carboxymethyl)-lH-tetrazole-5-thiol (Q.160 gram; 1 mmole)
-8246437 were added and the reaction mixture maintained at 90°C. for 12 hours under nitrogen. The reaction mixture was then filtered and solvent evaporated, yielding a gum to which ethyl acetate and saturated sodium bicarbonate solution were added. The mixture was washed twice with etnyx acetate, then fresh ethyl acetate was added and the mixture cooled to 0°C. and adjusted to pH 2.3 with 20% HCl. The layers were separated and the aqueous layer was washed with ethyl acetate. The ethyl acetate layers were combined and washed with saturated HCl, dried over anhydrous magnesium sulfate, filtered, evaporated, and dried at room temperature, 123 mg. The identity of the product was confirmed by NMR, 6 1.2 (t,
3, -NCHgCHg, J = 7 Hz), 3.6 (m, 4, N-CHgCHg and piperazinyl
- H), 4.1 (m, 2, piperazinyl 4-H), 4.4 (s, 2, S-CHgS-), 5.1 (d, 1, Cg-H, J = 5 Hz), 5.3 (s, 2, tetrazole 1“CHgCOOH), ·-5.75 (d, 1, C--H, J = 6 Hz), 5.9 (d, 1, / >CH- ) , 7.4 ·=· ι (m, 5, phenyl H) , and 9.9 (d, 1, / X,«-CH- , J = 7 Hz) .
\=·' I
NH
Γ
EXAMPLE 75: PREPARATION OF 3-(((4,5-DIHYDRO-4-METHYL6- HYDROXY-5-OXO-1,2,4-TRIAZIN-3-YL)THIO)METHYL)-7-(2-(42THYL-2,3-DIOXO-l-PIPERAZINYLCARBONYLAMINO)-2-PHENYLACETAMXDO)-3-CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(4-Ethy1-2,3-dioxo-l-piperazinylcarbonylamino,-2-phenylacetamido)cephalosporanic acid hydrate (0.3 gram; 0.5 mmole) and 4,5-dihydro-4-methyl-6-hydroxy5-oxo-l,2,4-triazine-3-thiol (0.111 gram; 0.625 mmole) were dissolved in 10 ml. of nitromethane under nitrogen at room
-8346437 temperature, and the reaction mixture heated at 85°C. Cor about 12 hours. A brown gummy precipitate formed and was discarded. Solvent was evaporated slowly, and a yellow precipitate formed. The residue was cooled, filtered, and washed with diethyl ether, yielding two crops, identical on TLC, of off-white solid. Total yield was 80 mg. (24 percent yield). Identity of the product was confirmed by NMR δ 1.1 (t, 3, -NCH2CH_3, J= 6 Hz), 3.3 (s, 3, triazine-CH3), 3.65 (m, 4, N-CH2CH3 and piperazinyl 5-H), 4.0 (m, 2, piperazinyl
6-H), 4.6 (s, 2, 3-CH2S~), 5.1 (d, 1, Cg-H, J = 5 Hz), 5.75
Λ-S.
(m, 2, of fo-CH-and C7-H) , 7.45 (m, 5, phenyl H) , 9.5 acre Γ ' ί \ /e~*\ (d, 1, -CHCONH-, J = 8 Hz) and 10.0 (d, 1, #f , '9—· |
-NH
J = Hz) .
EXAMPLE 76: PREPARATION OP 3-{((5-METHYLTHIO-l,3,4-THIADIAZOL-2-YL)THIO)METHYL)-7-(2-(1H-TETRAZOL-1-YL)ACETAMIDO)3-CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(lH-Tetrazol-l-yl)acetamido)cephalosporanic acid (15.0 grams; 39.2 mmole) and 5-(methylthio)-1,3,4thiadiazole-2-thiol (6.43 grams; 39.2 mmole) were suspended in 500 ml. of nitromethane which had been passed through a column of neutral alumina. The mixture was heated to 95°C.
and the reaction mixture was maintained at 95°C. for 6 hours, then cooled overnight, filtered, washed with 250 ml. of nitromethane, and dried at 45°C. for 4 hours, 18.08 gram (94.9% yield).
-8446437
This product was added to 150 ml. of water and 4.0 ml. of acetic acid. The pH was adjusted to 6.3 with IN NaOH (required 107 ml.) and the mixture was stirred for 1 hour. A solution of 257 ml. of 60% sodium lactate and s 05 ml. of ethanol was then added, and the restating mixture allowed to stand for 45 minutes. It was then stirred for 45 minutes, filtered, washed three times with ethanol and dried, 18.1 grams.
The product was reslurried in 300 ml. of ethanol 10 for 3 hours, filtered, washed with ethanol, and dried, 14.85 grams. The identity of the product was confirmed by HPLC. EXAMPLES 77-84: PREPARATION OP 3-{((5-METHYL-l,3,4-THIADIAZOL-2-YL)THIO)METHYL)-7-(2-(1H-TETRAZOL-1-YL)ACETAMIDO)3-CEPHEM-4-CARBOXYLIC ACID IN VARIOUS SOLVENTS 15 7-(2-(ΙΗ-Tetrazol-l-yl)acetamido)cephalosporanic acid was reacted with 5-methyl-l,3,4-thiadiazole-2-thiol in various solvents. The key details of the reactions are summarized below (all other aspects of the reaction being typical of the preceding examples).
-8546437
UJ e ♦rl co co • 00 • O a. r~1 u rH 0 0 J Φ (fl O rH CN d ch 00 CO 3 t—I Γ—1 I—l
,t. of Cephalosporanic acid Amt, of Thiol _Solverr r>
Γ· i—l
CN
CN in
ω CQ CQ Ui CQ CQ tn Ui k k k k k k k M fi 3 fi fi fi fi fi fi o 0 0 0 0 O o 0 Λ 45 45 45 45 45 45 45 VO CN kO 00 TO in CN rH r- r-H r-H
Ό
C iff tf α
rH
ΜΗ
Φ
Μ
Q O O u Q a u 0 0 o o o o 0 in o in o in in in oo o 00 σι στ στ co
cn fi ω ·η ο 45 ιη ΓΩ
Φ 44 Φ fi (fl 44 1 (fl Φ fi (fl t‘P τί 0 45 fi 0 fi in fi k UH 44 (fl Λ 0 • rfl Ch 0 Φ45 k 45 CN 0 GO Φ 0 -P (fl k in Φ k rH Φ fi Φ k Φ Φ 0 (fl fi 44 •Η Ή Φ k 0 g c υ •ri UH (fl •rH k k N fi rH o (fl Φ ϋ O 45 fi 44 *0 fi «Ρ 45 k 45 fi φ (fl 44 I •rl Φ tf 0 44 44 Φ fi Φ Φ CN fi Φ Λ •rl »rl -rH Φ rH φ □ y § 0 t> 0 6 Ό fi 0 >1 r-H •»H fi 0 &> +J Φ k 1 k CU >1 44 44 k in 0 *rl 44 rH CN *d 44 0 43 Φ tf -P • 0 Ui •H ·* * fi •rl k 44 ϋ •rl «rl r- (fl fi r*1 rH (fl fi CU Φ fi g fi
Cn m
kO η
ο
Cn in ο
σ» ω
cn ο
rH
Cn
CN •Η
Cn cn
CN as the sodium salt στ ο
-864643?
EXAMPLE 85; PREPARATION OF LITHIUM 3-(((1-METHYL-1HTETRAZOL-5-YL)THIO)METHYL)-7-(2-HYDROXY-2-PHENYLACETAMIDO)3-CEPHEM-4-CARBOXYLATE IN GLACIAL ACETIC ACID
7-(2-Hydroxy-2-phenylacetamido)cephalosporanic acid {□.<>& gram; ι mmole) and 1 -methyi-iH-i.e^.iazole-5thiol (0.5 gram; 4.3 mmole) were reacted in 15 ml. of glacial acetic acid at 84-86°C. for 8 hours. The reaction mixture was cooled to room temperature and iodine (0.4 gram; 1.6 mmole) added to convert unreacted thiol to the disulfide.
The mixture was stirred 20 minutes at room temperature, then poured into 100 ml. of ethyl acetate and 50 ml. of water and excess lg removed by addition of sodium sulfite. The layers were separated and the ethyl acetate layer washed with two 100 ml. portions of water and one 50 ml. portion of 20% NaCl solution and dried over anhydrous sodium sulfate. Ethyl acetate was removed on a rotary evaporator, and the residue dissolved in 10 ml. of methanol. Lithium acetate dihydrate (0.21 gram; 2 mmole) was added and the mixture stirred for 20 minutes at room temperature. The product crystallized and was separated by filtration, washed with 5 ml. of methanol and dried, yielding 0.34 gram of white cyrstals (69.4% yield). The identity of the product was confirmed by NMR: δ 3.50 (ABq, J - 17 Hz), 3.92 (s, -CHg of tetrazole), 4.20 (s, 3-CHgS-), 5.04 (d, Cg-H, J = 5 Hz), 5.24 (s,
0CHCONH-), 5.64 (d, C?-H, J = 5 Hz) , and 7.44 (s, 0-H).
The NMR spectrum was identical with an NMR spectrum on an authentic sample of the product prepared by aqueous displacement.
-874 S 4 3 7
EXAMPLE 86: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL5-YL)THIO)METHYL)-7-(2-(o-(TERT-BUTOXYCARBONYLAMINOMETHYL)PHENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(o-(tert-Butoxycarbonylaminomethyl)phenyl)acetamido)cephalosporanic acid (0.2 gram; 0.386 mmole) and l-methyl-lH-tetrazole-5-thiol (0.047 gram; 0.405 mmole) were reacted in 5 ml. of nitromethane at 85°C., under nitrogen, for 12 hours, yielding 3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-(o-(tert-butoxycarbonylaminosnethyl)phenyl)acetamido)-3-cephem-4-carboxylic acid. Identity of the product was confirmed by NMR, δ 1.45 (s, 9, -C(CHg)g, 3.65 (s, 4, 2-CH2 and -CHgCONH-), 3.85 (s, 3, -CHg of tetrazole), 4.3 (m, 4, 3-CHgS- and -CHgNHCOO-tert-C^Hg), 5.0 (d, 2,
Cg-H, J = 4 Hz), 5.7 (q, 1, Cg-H), 7.25 (s, 5, phenyl -H and -CONH-), and 8.9 (s, 1, -COOH).
EXAMPLE 87: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-ORBIDO-2-PHENYLACETAMIDO)-3-CEPHEM4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-Ureido-2-phenylacetamido)cephalosporanic acid (0.224 gram; 0.5 mmole) and l-methyl-lH-tetrazole-5-thiol (0.061 gram; 0.525 mmole) were reacted in 8 ml. of nitromethane at 85°C., for 12 hours, yielding 3-(((1-methyl-lHtetrazol-5-yl)thio)methyl)-7-(2-ureido-2-phenylacetamido)3-cephem-4-carboxylic acid. Identity of the product was confirmed by NMR, δ 3.5 (d, 2, 2-CHg, J = 3 Hz), 3.83 (s,
3, -CHg of tetrazole), 4.17 (d, 2, 3-CHgS-, J = 3 Hz), 4.9 (d, 1, Cg-H, J = 5 Hz), 5.4 (d,l, -CHgCONH-, J = 8 Hz) 5.6 (m, 3, Cg-H and -NHg), 6.7 (d, 1, 0CH- , J = 8 Hz), 7.25 (m, NH
, phenyl H), and 9.2 (d, 1, -CHgCONH- , J = 8 Hz).
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EXAMPLE 88: PREPARATION OF 3-(({l-METHYL-lH-TETRAZOL-5YL)THIO)METHYL)-7-(2-CYANOACETAMIDO)-3-CEPHEM-4-CARBOXYLIC
ACID IN NITROMETHANE
7-(2-Cyanoacetamido)cephalosporanic acid ¢0.339 gram; 1 nuuoie) and l-methyl-lH-tetrazole-5-thiol (0.122 gram; 1.05 mmole were reacted in 10 ml. of nitromethane at 85°C., under nitrogen, for 12 hours, yielding 3-(((1methyl-lH-tetra2ol-5-yl)thio)methyl)-7-(2-cyanoacetamido)3-cephem-4-carboxylic acid. Identity of the product was confirmed by NMR, δ 3.5 (s, 2, 2-CH2), 3.65 (s, 2, CNCH_2CONH-), 3.95 (s, 3, -CH3 of tetrazole), 5.35 (s, 2, 3-CH2S-), 5.1 (d, 1, Cg-H, J = 6 Hz), 5.75 (q, 1, C?-H, J = 4 Hz, 7.8 (s,
1, -COOH), and 8.7 (d, 1, -CH2CONH-, J = 9 Hz).
EXAMPLE 89: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(m-CHLOROPHENYLTHIO)ACETAMIDO)-3CEPHEM-4-CARBOXYLIC ACID IN NITROMETHANE
7-(2-(m-Chlorophenylthio)acetamido)cephalosporanic acid (0.390 gram; 0.855 mmole) and 1-methyl-lH-tetrazole5-thiol (0.104 gram; 0.9 mmole) were reacted in 10 ml. of nitromethane at 85°C., under nitrogen, for 12 hours, yielding
3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-(m-chlorophenylthio)acetamido)-3-cephem-4-carboxylic acid. Identity of the product was confirmed by NMR δ 3.6 (s, 2, 2-CH2, 3.75 (s, 2, -CH2CONH-), 3.9 (s, 3, -CH3 of tetrazole), 4.4 (s, 2,
3-CH2S-), 5.0 (d, 1, Cg-H, J = 5 Hz), 5.8 (q, 1, C?-H, J =
Hz), 7.15 (m, 4, pheny1-H) , 7.7 (d, 1, -CH2CONH-, J =
Hz), and 8.5 (s, 1, COOH).
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EXAMPLE 90: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(PHENYLTHIO)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN NITROMETHANE
7-(2-Phenylthio)acetamido)cephalosporanic acid (0.422 gram; 1 mmole) and l-methyl-lH-tetrazole-5-thiol (0.122 gram; 1.05 mmole) were reacted in 10 ml. of nitromethane at 85°C., under nitrogen, for 12 hours, yielding
3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-(phenylthio) acetamido) -3-cephem-4-carboxylic acid. Identity of the product was confirmed by NMR, δ 3.7 (s, 4, -CHgCONH- and
2- CHg), 3.9 (s, 3, “CHg of tetrazole), 4.35 (s, 2, 3-CHgS-),
4.9 (d, 1, Cg-H, J = 6 Hz), 5.8 (q, 1, Cg-H, J = 4 Hz), 7.25 (s, 5, pheny1-H), 7.7 (d, 1, -CHgCONH-, J = 8 Hz), and 9.4 (s, 1, -COOH).
EXAMPLE 91: PREPARATION OF .3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN n-BUTYLFORMATE
7-(2-(2-Thienyl)acetamido)cephalosporanic acid (3.96 gram; 10 mmole) and l-methyl-lH-tetrazole-5-thiol (1.28 gram, 11 mmole) were reacted in 98 ml. of n-butyl formate at 84-86°C. for 48 hours, yielding 3-(((1-methyllH-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)3- cephem-4-carboxylic acid, m.p. 167.5-168°C., yield 79.9%. The NMR spectrum on the product was identical with the NMR spectrum on the product of Example 5.
-904643?
EXAMPLE 92: PREPARATION OF 3-({(1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(2-THIENYL)ACETAMIDO)-3-CEPHEM-4CARBOXYLIC ACID IN TOLUENE
The reaction reported in Example 91 was repeated on the same scale but in 150 ml. of toluene at 84-86°C., for 136 hours. The product melted at 163-163.5°C. and was obtained in 88.5% yield. The NMR spectrum on the product was identical with the NMR spectrum on the product of Example 5.
EXAMPLE 93: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(tert-BUTOXYCARBONYLAMINO)-3-CEPHEM-4CARBOXYLIC ACID IN NITROMETHANE
7-(tert-Butoxycarbonylamino)cephalosporanic acid (0.372 gram; 1 mmole) and l-methyl-lH-tetrazole-5-thiol (0.122 gram; 1.05 mmole) were reacted in 10 ml. of nitromethane at 80°C. for 12 hours, yielding 3-(((l-methylIH-tetrazol-5-yl) thio)methyl)-7-(tert-butoxycarbonylamino)3-cephem-4-carboxylic acid. The identity of the product^was confirmed by NMR, δ 1.45 (s, 9, -C(CH3)3), 3.7 (s, 2,
2-CH2) , 3.95 (s, 3, -CH3 of tetrazole), 4.4 (s,.'2, 3-CHgS-) , 5.0 (s, 1, Cg-H), 5.6 (s, 2, C7-H and -CHjCONH), and 13 (s,
1, -COOH).
EXAMPLE 94: PREPARATION OF 3-(((1-METHYL-1H-TETRAZOL-5YL)THIO)METHYL)-7-(2-(4-ETHYL-2,3-DIOXOPIPERAZINYLCARBONYLAMINO)-2-(P-HYDROXYPHENYL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC
ACID
7-(2-(4-Ethyl-2,3-dioxopiperazinylcarbonylamino)2-(p-hydroxyphenyl)acetamido)cephalosporanic acid (0.180 gram; 0.306 mmole) and l-raethyl-lH-tetrazole-5-thiol (0.0374
-9146437 gram; 0.322 mmole) were reacted in 6 ml. of nitromethane at 80°C. for 12 hours, yielding 3-(((1-methyl-lH-tetrazol5- yl)thio)methyl)-7-(2-(4-ethyl-2,3-dioxopiperazinylcarbonylamino)-2-(p-hydroxyphenyl)acetamido)-3-cephem-4carboxylic acid. The identity of the product was confirmed by NMR, δ 1.2 (t, 3, N-CHgCHg), 3.6 (nt, 6, 2-CHg, piperazinyl
6- H and Ν-CHgCHg), 3.9 (m, 2, piperazinyl 5-H), 3.95 (s,
3, -CHg of tetrazole), 4.4 (s, 2, 3-CHgS-), 5.0 (d, 1,
Cg-H, J = 6 Hz), 5.6 (d, 1, C?-H, J = 6 Hz) , 5.8 (d, 1, CHCONH-, J = 8 Hz), 6.8 (d, 2, phenyl-H, J= 8 Hz), 7.3 (d,
2, phenyl-H, J = 8 Hz), 8.3 (d, 1, -CHCONH-, J = 8 Hz), and
9.9 (d, 1, -CHCONH-, J = 6 Hz.
-NH
EXAMPLE 95: PREPARATION OF 3-(((1,3,4-THIADIA2OL-2-YL)THIO)METHYL)-7-(2-(1H-TETRAZOL-1-YL)ACETAMIDO)-3-CEPHEM-4-CARBOXYLIC ACID IN ACETONITRILE
7-(2-(lH-Tetrazol-l-yl)acetamido)cephalosporanic acid (0.38 gram; 1 mmole) and l,3,4-thiadiazole-2-thiol (0.15 gram; 1.27 mmole) were reacted in 15 ml. of acetonitrile at reflux, under nitrogen, for 24 hours, yielding 3-(((l,3,4-thiadiazol-2-yl)thio)methyl)-'?-(2-(lK-tetrazol1-yl)acetamido)-3-cephem-4-carboxy13» acid,. The identity of the product was confisffted by itMft, δ 3.7# (nt, 2, 2-CHg-) ,
4.48 (q, 2, 3-CHgS-, - l4), 5.16 (d, 1, Cg-H, J = 5),
.42 (s, 2, -CHg of tetrazolyl), 5.76 (q, 1, C^-H, Jg 7 5, J?NH = 8), 8.87 (s, 1, tetrazole ring), 9.40 (s, 1, thiadiazolethiol starting material), 9.53 (d, 1, -CHgCONH-, J=
Hz), and 9.57 (s, 1, thiadiazole ring).
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EXAMPLE 96: PREPARATION OF 3-(((5-METHYL-l,3,4-THIADIAZOL2- YL)THIO)METHYL)-7-(5-CARJ3OMETHOXY-5-(2,4-DICHLOROBENZAMIDO) VALERAMIDO) -3-CEPHEM-4-CARBOXYLIC ACID IN 1,2DICHLOROETHANE
7-(5-Carbomethoxy-5-(2,4-dichlorobenzamido)valeramido) cephalosporanic acid (0.3 gram; 0.5 mmole) and 5methyl-l,3,4-thiadiazole-2-thiol (0.1 gram; 0.75 mmole) were reacted in 1,2-dichloroethane at reflux for 16 1/2 hours, yielding 3-(((5-methyl-l,3,4-thiadiazol-2-vl)thio)methyl)10 7-(5-carbomethoxy-5-(2,4-dichlorobenzamido)valeramido)3- cephem-4-carboxyiic acid.
EXAMPLE 97: PREPARATION OF LITHIUM 3-(((1-METHYL-1HTETRAZOL-5-YL)THIO)METHYL)-7-(2-(1H-TETRAZOL-1-YL)ACETAMIDO) -3-CEPHEM-4-CARBOXYLATE IN ACETONITRILE
7-(2-(lH-Tetrazol-l-yl)acetamido)cephalosporanic acid (1.91 grams; 5 mmole) and l-methyl-lH-tetrazole-5thiol (0.7 gram; 6 mmole) in 50 ml. of acetonitrile were refluxed for 24 hours and cooled to room temperature.
Solvent was removed on a rotary evaporator, to about 10 ml.
Ethanol (40 ml.) was added; followed by a solution of 0.3 gram of lithium hydroxide in 10 ml. of methanol. The product, lithium 3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)· 7-(2-(lH-tetrazol-l-yl)acetamido)-3-cephem-4-carboxylate, crystallized. After the reaction mixture was stirred for 45 minutes at room temperature, the product was separated by filtration, washed with ethanol, and vacuum dried at 40°C., 1.60 grams (72% yield). The identity of the product was confirmed by NMR.
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EXAMPLE 98: PREPARATION OP 3-(((5-METHYL-l,3,4-THIADIAZOL2-YL)THIO)METHYL)-7-(2-PORMYLOXY-2-PHENYLACETAMIDO)-3CEPHEM-4-CARBOXYLIC ACID IN 1,2-DICHLOROETHANE
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid (4.6 grams; 8.8 mmole) and 5-methy1-1,3,4-thiadiazole2-thiol (1.52 grams; 11.5 mmole) in 50 ml. of 1,2-dichloroethane were refluxed for 12 hours and cooled to room temperature. The product, 3-(((5-methyl-l,3,4-thiadiazol2-yl)thio)methyl)-7-(2-formyloxy-2-phenylacetamido)—ΒΙΟ cephem-4-carboxylic acid, precipitated ar; a thick paste.
The mixture was diluted with an additional 50 ml. oi 1,2dichloroethane and stirred 4 hours at room temperature. The product was then separated by filtration, washed with 1,2dichloroethane until the filtrate was clear, and vacuum dried at 40-45°C., 2.8 grams (635 yield). The identity of the product was confirmed by NMR.
EXAMPLE 99: PREPARATION OF 3-(((4,5-DIHYDRO-6-HYDROXY-4METUYL-5-OXO-1,2,4-TRIAZIN-3-YL)THIO)METHYL)-7-(2-(IHTETRAZOL-l-YL)ACETAMIDO)-3-CEPIIEM-4-CARBOXYI,rC ACID ΓΝ
ACETONITRILE
7-(2-(lH-Tetrazol-l-yl)acetamido)cephalosporanic acid (8.9 grams; 23.2 mmole) and 4,5-dihydro-6-hydroxy-4methyl-5-oxo-l,2,4-triazine-3-thiol (4.1 grams; 25.8 mmole) in 200 ml. of acetonitrile were refluxed 23 hours then cooled to room temperature. Product had crystallized during the course of the reaction and was separated by filtration, washed with 50 ml. of acetonitrile, and vacuum dried at 40-50°C., 9.70 grams (86.65 yield). The identity of the product 3-(((4,5-dihydro-6-hydroxy-4-mothy1-5-oxo-l,2,4iO triazin-3-yl)thio)methyl)-7-(2-(ili-tetrazol-l-yl) acetamido)J-cephem-4-carboxylic acid, was confirmed by NMR.
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EXAMPLES 100-144
Yet other reactions in accordance with the present process can be conducted as follows:
7-(2-Sulfo-2-phenylacetamido)cephalosporanic acid, 5 sodium salt, is reacted with 1-methyl-lll-tetrazole-5thiol, yielding 3- (((l-methyl-lII-tetrazol-5-yl) thi.o)mothyl) 7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid, sodium salt.
7-(2-(4-Pyridylthio)acetamido)cephalosporanic acid LO is reacted with l-methyl-lH-tetrazole-5-thiol, yielding
3- (((1-methy1-1H-tetrazol-5-yl)thio)methyl)-7-(2-(4pyridylthio)acetamido)-3-cephem-4-carboxylic acid.
7-(5-Carbo-n-butoxy-5-(2,4-dichlorobenzamido)valeramido)cephalosporanic acid and 5-methyl-l,3,4-thia15 diazole-2-thiol are reacted, yielding 3-(((5-methyl-l,3,4thiadiazol-2-yl)thio)methyl)-7-(5-carbo-n-butoxy-5-(2,4dichlorobenzamido)valeramido)-3-cephem-4-carboxylic acid.
7-(5-Carbo-n-butoxy-5-(2,4-dichlorobenzamido)valeramido)cephalosporanic acid and 1-methyl-lH-tetrazole20 5-thiol are reacted yielding 3-(((1-methyl-lii-tetrazol5-yl)thio)methyl)-7-(5-carbo-n-butoxy-5-(2,4-dichlorobenzamido)valeramido)-3-cephem-4-carboxylic acid.
7-(2-(2-(p-Nitrobenzyloxycarbonylamino)thiazol4- yl)-2-(methoxyimino)acetamido)cephalosporanic acid is 25 reacted with l-methyl-lH-tetrazole-5-thiol, yielding 3(((l-methyl-lH-tetrazol-5-yl)thiojmethyl)-7-(2-(2-(pnitrobenzvloxycarbonylamino)thiazol-4-yl)-2-(methoxyimino)acetamido)-3-cephem-4-carboxylic acid.
-954 6 4 3 7
7-(2-(2-(p-Nitrobenzyloxycarbonylamino)thiazol4-yl)acetamido)cephalosporanic acid is reacted with 1-methyl lH-tetrazole-5-thiol yielding 3-(((l-methyl-lH-tetrazol-5yl)thio)methyl)-7-(2-(2-(p-nitrobenzyloxycarbonylamino)5 thiazol-4-yl)acetamido)-3-cephem-4-carboxylic acid.
7-((2,2,2-Trichloroethoxy)carbonylamino)cephalosporanic acid is reacted with 6-hydroxypyridazine-3-thiol, yielding 3-(((6-hydroxypyridazin-3-yl)thiojmethyl)-7((2,2,2-trichloroethoxy)carbonylamino)-3-cephem-4-carboxylic acid.
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with 6-hydroxypyridazine-3-thiol, yielding 3(((6-hydroxypyridazin-3-yl)thiojmethyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid.
7-((2,2,2-Trichloroethoxy)carbonylamino)cephalosporanic acid is reacted with tetrazolo[1,5-b]pyridazine-6thiol, yielding 3-(((tetrazolo[1,5-b]pyridazin-6-yl)thio)methyl)-7-((2,2,2-trichloroethoxy)carbonylamino)-3-cephem4-carboxylic acid.
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with tetrazolo[1,5-b]pyridazine-6-thiol, yielding
3-(((tetrazolo[1,5-b]pyridazin-6-yl)thio)methyl)-7-(2(2-thienyl)acetamido)-3-cephem-4-carboxylic acid.
7-((2,2,2-Trichloroethoxy)carbonylamino)cephalosporanic acid is reacted with 1-(sulfomethyl)-lll-tetrazole25 5-thiol, sodium salt, yielding 3-(((1-(sulfomethyl)-llltetrazol-5-yl)thiojmethyl)-7-((2,2,2-trichloroethoxy)carbonylamino) -3-cephem-4-carboxylic acid, sodium salt.
-9646437
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with 1-(sulfomethyl)-lH-tetrazole-5-thiol, sodium salt, yielding 3-(((1-(sulfomethyl)-lH-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid, sodium salt.
7-((2,2,2-Trichloroethoxy)carbonylamino)cephalosporanic acid is reacted with 1-(2-(dimethylamino)ethyl)lH-tetrazole-5-thiol, yielding 3-(((l-(2-(dimethylamino)ethyl)-lH-tetrazol-5-yl)thio)methyl)-7-((2,2,2-trichloroethoxy)carbonylamino)-3-cephem-4-carboxylic acid.
7-(2-(2-Thienyl) acetamido)cephalosporanic acid is reacted with 1-(2-(dimethylamino)ethyl)-lH-tetrazole-5thiol, yielding 3-(((1-(2-(dimethylamino)ethyl)-lH-tetrazol5-yl)thiojmethyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4carboxylic acid.
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with p-methoxybenzenethiol, yielding 3-(((pmethoxyphenyl)thiojmethyl)-7-(2-(2-thienyl)acetamido)3-cephem-4-carboxylic acid.
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with p-chlorobenzenethiol, yielding 3-(((p-chlorophenyl) thiojmethyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4carboxylic acid.
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with o-toluenethiol, yielding 3-(((o-tolyl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid.
-9746437
7-(2-(lH-Tetrazol-1-yl)acetamido)cephalosporanic acid is reacted with l,3,4-thiadiazole-2-thjol, yielding
3- (((1,3,4-thiadiazol-2-y 1) thio) methy 1) -7- (2- (111-l et razo I 1-yl)acetamido)-3-cephem-4-carboxylic acid.
7-Phthalimidocephalosporanic acid is reacted with
-methyl-l,3,4-thiadiazole-2-thiol, yielding 3-(((5-methyl1,3,4-thiadiazol-2-yl)thio)methyl)-7-phthalimido-3-cephem4- carboxylic acid.
7-(2-Hydroxy-2-phenylacetamido)cephalosporanic 10 acid is reacted with 5-methyl-l,3,4-thiadiazole-2-thiol, yielding 3-(((5-methyl-l,3,4-thiadiazol-2-yl)thio)methyl)7-(2-hydroxy-2-phenylacetamido)-3-cephem-4-carboxylic acid.
7-(2-Acetoxy-2-phenylacetamido)cephalosporanic acid is reacted with 5-methyl-l,3,4-thiadiazole-2-thiol>
yielding 3-(((5-methyl-l,3,4-thiadiazol-2-yl)thio)methyl)7-(2-acetoxy-2-phenylaCetamido)-3-cephem-4-carboxylic acid.
7-(2-(Trifluoromethylthio)acetamido)cephalosporanic acid is reacted vzith l-methyl-lH-tetrazole-5-thiol, yielding
3- (((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-(trifluoro20 methylthio)acetamido)-3-cephem-4-carboxylic acid.
7-(2-(2-(p-Nitrobenzyloxycarbonylamino)thiazol4- yl)-2-(methoxyimino)acetamido)cephalosporanic acid is reacted with 4,5-dihydro-6-hydroxy-4-methyl-5-oxo-l,2,4triazine-3-thiol, yielding 3-(((4,5-dihydro-6-hydroxy-425 methy1-5-oxo-l,2,4-triazin-3-yl)thio)methyl)-7-(2-(2—(p— nitrobenzyloxycarbonylamino)-3-cephem-4-carboxylic acid.
7-(2-(2-(p-Nitrobenzyloxycarbonylamino)thiazol-4yl)acetamido)cephalosporanic acid is reacted with 1-(2(dimethylamino)ethyl)-lH-tetrazole-5-thiol, yielding 3-9846437 (((1-(2-(dimethylamino)ethyl)-lH-tetrazol-5-yl)thio)methyl)7-(2-(2-(p-nitrobenzyloxycarbonylamino)thiazol-4-ylj acetamido) -3-cephem-4-carboxylic acid.
7-(2-(o—(tert-Butoxycarborylaminomethyl)phenyl)acetamido)cephalosporanic acid is reacted with tetrazolo[1,5-b]pyridazine-6-thiol, yielding 3-(((tetrazolo[1,5-b]pyridazin-6-yl)thio)methyl)-7-(2-(o-(tert-butoxycarbonylaminomethyl) phenyl)acetamido)-3-eephem-4-earboxylic acid.
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid is reacted with 1-(sulfomethyl)-lH-tetrazole-5-thiol, sodium salt, yielding 3-(((1-(sulfomethyl)-lll-tetrazol-5yl)thio)methyl)-7-(2-formyloxy-2-phenylacetamido)-3cephem-4-carboxylic acid.
7-(2-Hydroxy-2-phenylacetamido)cephalosporanic acid is reacted with 1-(sulfomethyl)-lH-tetrazole-5-thiol, sodium salt, to produce 3-(((1-(sulfoinethyi)-IH-tetrazol5-yl)thio)methyl)-7-(2-hydroxy-2-phenvlacetamido)-3cephem-4-carboxylic acid.
7-(2-(2-Thienyl)acetamido)cephalosporanic acid is reacted with 2-oxazolethiol to yield 3-(((oxazol-2-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-)-cephem-4-carboxylic acid.
7-(2-Formyloxy-2-phenylacetamido)cephalosporanic acid and 1-(carboxymethyl)-lH-tetrazole-5-thiol are reacted to produce 3-(((1-(carboxymethyl)-W-tetrazol-5-yl) thio) methyl)-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4carboxylic acid.
-994643*?
7-(2-(Trifluoromethylthio)acetamido)cephalosporanic acid and 1-methyl-lH-tetrazole-5-thiol are reacted to prepare 3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2(trif]uoromethylthio)acetamido)-3-cephem-4-carboxylic acid.
7-(2-(Cyanomethylthio)acetamido)cephalosporanic acid is reacted with l-methyl-lH-tetrazole-5-thiol to produce 3-(((l-methyl-lH-tetrazol-5-yl)thiojmethyl)-7(2-(cyanomethylthio)acetamido)-3-cephem-4-carboxylic acid.
7.-Methoxy-7-(2-(cyanomethylthio)acetamido)cepha10 losporanic acid is reacted with 1-methy1-lH-tetrazole5-thiol to obtain 3-(((1-methyl-lH-tetrazol-5-yl)thio)methyl) 7-methoxy-7-(2-(cyanomethylthio)acetamido)-3-cephem-4carboxylic acid.
7-(2-(o-Benzoylaminomethylphenyl)acetamido)cepha15 losporanic acid and 1-(carboxymethyl)-lH-tetrazole-5-thiol are reacted to prepare 3-(((1-(carboxymethyl)-W-tetrazol5-yl)thio)methyl)-7-(2-(o-benzoylaminomethylphenyl)acetamido) -3-cephem-4-carboxylic acid.
7-(2-Oreido-2- (2-thienyl):acetamido) cephalosporanic acid is reacted with l-methyl-lH-tetrazole-5-thiol to obtain 3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-ureido2-(2-thienyl)acetamido)-3-cephan-4-carboxylic acid.
7-(2-(2-Amino-4-thiazolyl)acetamido)cephalosporanic acid is reacted 1-(2-(dimethylamino)ethyl)-lH-tetrazole25 5-thiol to produce 3-(((1-(2-dimethylamino)ethyl)-1Htetrazol-5-yl)thio)methyl)-7-(2-(2-amino-4-thiazolyl)acetamido) cephalosporanic acid.
-1007- (5-Benzoylamino-5-carboxyvaleramido) cephalosporanic acid is reacted with 4,5-dihydro-b-liydroxy-4methyl-5-oxo-l,2,4-triazine-3-thiol to prepare 3-(((4,5dihydro-6-hydroxy-4-methyl-5-oxo-l,2 -4-triazin-3-yl)thio)5 methyl)-7-(5-benzoylamino-5-carboxyvaleramido)-3-cephem4-carboxylic acid.
7-(5-Benzoylamino-5-carboxyvaleramido)cephalosporanic acid is reacted with l-methyl-lH-1,2,3-triazole-5-thiol to prepare 3-(((l-methyl-lH-1,2,3-triazol-5-yl)thio)methyl;10 7-(5-benzoylamino-5-carboxyvaleramido)-3-cephem-4-carbOxylic acid.
7-(5-Benzoylamino-5-carboxyvaIeramidoj cephalosporani c acid and 1-(oarboxymethyl)-lH-tetrazole-5-thiol are reacted to produce 3-(((1-(carboxymethyl)-lH-tetrazol-5-yl)thio)15 methyl)-7-(5-benzoylamino-5-carboxvvaleramido)-3-cephem4-carboxylic acid.
7-(5-Benzoylamino-5-carboxyvaleramido;cephalosporanic acid is reacted with 5-methyl-l,3,4-oxadiazole-2-thiol to obtain 3-(((5-methyl-l,3,4-oxadiazol-2-yl)thio)methyl)-720 (5-benzoylamino-5-carboxyvaleramido)-3-cephem-4-carboxylic acid.
7-(5-Benzoylamino-5-carboxyvaleramido)cephalosporanic acid is reacted with l-benzyl-lH-tetrazole-5-thiol to obtain 3-(((l-benzoyl-lH-tetrazol-5-yl)thiojmethyl)-7-(5-benzoyl25 ami.no-5-carboxyvaleramido)cephalosporanic acid.
7-(5-Benzoylamino-5-carboxyvaleramido)cephalosporanic acid is reacted with thiourea to obtain 3amidinothiomethyl-7-(5-benzoylamino-5-carboxyvaleramido)3-cephem-4-carboxylic acid.
-10146437
7-Methoxy-7-(5-benzoylamino-5-carboxyvaleramido)cephalosporanic acid is reacted with 1-methy 1-lII-tetrazole'j-thiol to obtain 3-(((l-methyl-lH-tetrazol-5-yl)thio)methyl)-7-methoxy-7~(5-benzoylamino-5-carboxyvaleramido)5 3-cephem-4-carboxylic acid.
7-Methoxy-7-(5-benzoylamino-5-carboxyvaleramido)cephalosporanic acid is reacted with 5-methyl-l,3,4thiadiazole-2-thiol to obtain 3-(((5-methyl-l,3,4-thiad i azo1-2-yl) thio) me thyl)-7-methoxy-7-(5-ben zoylamino-510 carboxyvaleramido)-3-cephem-4-carboxylic acid.
7-Methoxy-7-(5-benzoylamino-5-carboxyvaleramido)cephalosporanic acid is reacted with 4,5-dihydro-6-hydroxy4-methyl-5-oxo-l,2,4-triazine-3-thiol to obtain 3-(((4,5dihydro-6-hydroxy-4-methyl-5-oxo-l,2,4-tri.izin-3-yl)thio)15 methyl)-7-methoxy-?-(5-benzoylamino-5-carboxyvaleramido)3-cephem-4-carboxylic acid.
7-Methoxy-7-(5-benzoylamino-5-carboxyvaleramido)cephalosporanic acid and thiourea are reacted to obtain 3amidinothiomethyl-7-methoxy-7- (5-benzoylamino-5-carboxy20 valeramido)-3-cephem-4-carboxylic acid.
7-(5-Butoxycarbonylamino-5-carboxyvaleramido)3-carbamoyloxymethyl-3-cephem-4-carboxylic acid is reacted with thiourea to prepare 3-amidinothioinetbyl-7-(5-butoxycarbonylamino-5-carboxyvaleramido)-3-cephem-4-carboxylie acid.
7-(5-Butoxycarbonylamino-5-carboxyvaleramido)3-carbamoyloxymethyl-3-cephem-4-carboxylic acid is reacted with 1-inethyl-ill-tetrazole-5-thiol to obtain 3-(((1mr.'i hy 1 - I ll-tot razol -5-y 1) th io) methy I )-7-( 5-buLoxyearbony I 10 ;imino-5-c
-10246437
7-(5-Butoxycarbonylamino-5-carboxyvaleramido)-3carbamoyloxymethyl-3-cephem-4-carboxylic acid and 5-methyl.1, j,4-thiadiazole-2-thiol are reacted to prepare 3-(((5methyl-I,3,4-thiadiazol-2-yl)thiojmethyl)-7-(5-butoxy5 carbonylamino-5-carboxyvaleramido)-3-cephem-4-carboxylic acid.
7-(5-Butoxycarbonylamino-5-carboxyvaleramido)3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 1(carboxymethyl)-lH-tetrazole-5-thiol are reacted to prepare
3-(((1-(carboxymetnyl)-IH-tetrazol-5-yl) thio)methyl)-7( 5-butoxycarbony1ami rio-5-carboxyvaloramiuo) - )-cephem-4carboxylic acid.
-103>46437
CIAIMS:1. A process for preparing a cephalosporin compound of the formula
. 13 .
wherein R is
-C-C alkyl, '
1, or ζ, or
formula
R3 is hydrogen or methoxy;
R is phthalimido, suocinimido, a radical of the /~\ • · CH—c wherein L is hydrogen or nitroso, \=/Τί
Λ.Λ
CH Z \h δ 3
-10446437 or a radical of the formula
3
R -C-NH-;
(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) hydrogen,
C^-Cg alkyl,
-CHg—(ci“c3 chloroalkyl),
-CHg—(ci“C·, fluoroalkyl), oyanoalkyl,
C^-C^ hydroxyalkyl, ρ-nitrobenzyioxy, tart-butoxy,
2,2,2-trichloroethcxy, a protected 4-amino-4-carboxybutyl radical of the formula
R12O-C-CH-(CHg)2-CHgA1 wherein A1 is a protected amino group 12 and R is hydrogen or C^-C^ alkyl; 4-oxo-4-carboxybutyl;
3-carboxypropyl; a radical of the formula
a.
,x=/
-(Z) -CH m 2 in which each of a and a1 is independently hydrogen, C^-C^ alkyl, C^-C^ alkoxy, . 1 halogen, hydroxy, or A CHg- wherein A
-10546437 (14) (a) (b) (c) is, as above, protected amino; Z is 0 or S; and m is 0 or 1; a radical of the formula
P-CHI
Q wherein P is
2- thienyl,
3- thienyl, or a phenyl group of the formula (a) (b) (c) id) (e) (f) tg)
in which a and a^ are as defined above; and wherein Q is hydroxy, formyloxy, acetoxy, carboxy of the formula -C-O-A wherein 2
A is diphenylmethyl, p-nitrobenzyl, benzyl, 2,2,2-trichloroethyl, tert-butyl,' or p-methoxybenzyl;
alkali metal oxysulfonyl, a protected amino group, an acylated amino group of the formula
II
-NH-C-T wherein T represents amino,
-10646437
NH R7 0 11 1 p
-NH-C-NH2, -N—C-R8,
R7 0
-N—C-CH=CHR9, ιΎ ,10
wherein R 13 hydrogen or C^-C3 alkyl;
g
R is phenyl, halophenyl, furyl, monomethylamino, dimethylamino, monoethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, diisopropyl9 amino, phenylamino, or diphenylamino; R is hydrogen, C^-C^ alkyl, or phenyl; R19 is hydrogen, C^-Cj alkyl, or methylsulfonyl; and R11 is ethylene, trimethylene, or vinylene;
(15) a radical of the formula , r°H' ?
P1 -C-C— , — OCH3 or— OCCH3
-1074-64 3 7 wherein P' is P as defined above, projected 2-amino-4-thiazolyl, or 2-furyl;
(16) a radical of the formula V-S(O)n-CH2~ wherein V represents CFg or -CH^-X .wherein X represents hydrogen, methyl,
CFg, CN, or Ng, and n represents 0, 1, or 2; or (17) a radical of the formula Υ-CHg- in which Y is
2- thienyl,
3- thienyl,
2-furyl,
2-oxazolyl,
2-thiazolyl,
1-tetrazolyl,
1- benzotriazolyl,
2- oxazolylthio,
2- thiazolylthio,
1.2.3- triazol-5-ylthio,
1.3.4- triazol-2-ylthio,
1.3.4- thiadiazol-2-ylthio, protected 5-amino-l,.3,4-thiadiazol-2-ylthio,
-methyl-l,3,4-thiadiazol-225 ylthio,
1.2.4- thiadiazol-5-ylthio,
3- methy1-1,2,4-thiadiazol-5ylthio,
1.2.5- thiadiazol-3-ylthio, l,3,4-oxadiazol-2-ylthio,
-methyl-l,3,4-oxadiazol-2ylthio,
-10846437 l-methyl-5-tetrazolylthio, pyridylthio,
4-cyano-l,2,3-triazol-l-yl,
3-cyano-l,2,4-triazol-l-yl, or protected 2-amino-4-thiazolyl;
each R is independently hydrogen, ci-c4
Cg-Cg alkenyl, cyclohexyl, or phenyl;
each R5 is independently C1-C4 alkyl, C1~C4 alkoxy, halo, hydroxy, nitro, cyano, methanesulfonamido, or trifluoromethyl; and a unit which with the -¾_ , comprises an unsubstituted or substituted, five or six-membered, heteroaromatic ring having a total of from 1 to 4 hetero atoms selected from the following combinations:
nitrogen and 0 or 1 oxygen or sulfur, nitrogens and 0 or 1 oxygen or sulfur, nitrogens, and 0 or 1 oxygen, or nitrogens, all other ring atoms being carbon; or a unit which with the -Ci_ , comprises
2-benzoxazolyl, or a radical of the formula
which process comprises reacting a compound of the formula
-10946437 R1 /\ “ΓΙ I >—N. ,·—CH OCOR / \/ 2 CO
COOH
2 wherein R and R are as defined above, and
R is alkyl,
C^-Cg cycloalkyl, amino, mono- or difC^-C^ alkyl)amino,
-C = CH—/ OH k ·=7 / \0H -C = CH— 2 ;·—OH 'OCH . X-=“Z ,·-·.
-C = CH—< >—OSO H ' \=z ·
OCH a
XI , or with a sulfur nucleophile of the formula
R13-S-R14
III
14 wherein R is as defined above, and R is hydrogen, or
Claims (74)
1. when and only when R is a methyleneaminium group, R combines with R d3 and the S atom to form a thiourea; in an organic solvent under essentially anhydrous conditions. -110
2. A process of claim 1 wherein the temperature is from 50 e C. to 140°C.
3. A process of claim 2 wherein the temperature ia from 70°C. to 120°C.
4. 5 4. A process of any of claims 1-3 wherein the solvent is a hydrocarbon, an alcohol, an amide, an ether, a ketone, a carboxylic acid, a carboxylic acid ester, a halogenated hydrocarbon, a nitro compound, a nitrile or a thioether. 10 5. A process of claim 4 wherein the solvent is acetonitrile, 1,2-dichloroethane, methylene chloride, propionitrile, nitromethane, nitroethane, acetic acid, isopropyl acetate, butyl acetate or methyl isobutyl ketone.
5.
6. A process of claim 4 wherein the solvent is 15 fluorobenzene, thiophene, methyl ethyl ketone, 1,1,2-trichloroethane, chloroform, benzene, carbon tetrachloride, isopropanol, nitrobenzene, propylene carbonate, ethylene carbonate, 2-nitropropane, or n-butyl formate.
7. A process of claim 5 wherein the solvent is 2 0 nitromethane.
8. A process of claim 5 wherein the solvent is propionitrile
9. A process of claim 5 wherein. the solvent is acetonitrile. 25
10. A process of claim 5 wherein the solvent is acetic acid.
11. A process of claim 5 wherein the solvent is 1,2-dichloroethane. -Ill46437
12. A process of any of claims 1-11 for preparing a compound of Formula I wherein a compound of Formula II wherein R is alkyl, C^-Cg cycloalkyl, amino, or monoor di(C^-C 3 alkyl)amino is reacted with a compound of Formula 5 III.
13. A process of claim 12 for preparing a compound of Formula I wherein a compound of Formula II wherein R is methyl is reacted with a compound of Formula III.
14. A process of claim 12 for preparing a compound 10 of Formula I wherein a compound of Formula II wherein R is amino is reacted with a compound of Formula III.
15. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is hydrogen and R is 2-(2-thienyl)acetamido wherein a compound of Formula II 1 2 15 wherein R and R are as defined above is reacted with a compound of Formula III.
16. A process of claim 15 for preparing 3-amidinothiomethyl-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido)cephalosporanic acid is reacted with thiourea.
17. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is hydrogen, R is 213 (2-thienyl)acetamido and R is a heteroaryl group wherein a 1 2 compound of Formula II wherein R and R are as defined above 25 is reacted with a compound of Formula III wherein R 11 is a heteroaryl group.
18. A process of claim 17 for preparing 3-(((1methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acet-11246437 amido)-3-cephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido)cephalosporanic acid is reacted with 1-methyl-1Htetrazole-5-thiol.
19. A process of claim 17 for preparing 3-(((4,55 dihydro-6-hydroxy-4-methyl-5-oxo-l,2,4-triazin-3-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido)cephalosporanic acid is reacted with 4,5-dihydro-S-hydroxy-4-methyl-5-oxo-l,2,4triazine-3-thiol. 10
20. A process of claim 17 for preparing 3-(((5methyl-l,3,4-oxadiazol-2-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-oarboxylio acid wherein 7-(2-(2thienyl)acetamido)cephalosporanic acid is reacted with 5methyl-1,3,4-oxadiazole-2-thiol. 15
21. A process of claim 17 for preparing 3-(((5methyl-1,3,4-thiadiazol-2-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-(2thienyl)acetamido)cephalosporanic acid is reacted with 5methyl-1,3,4-thiadiazole-2-thiol. 20
22. A process of claim 17 for preparing 3-(((benzothiazol-2-yl)thiojmethyl)-7-(2-(2-thienyl)acetamido)-3cephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido)cephalosporanic acid is reacted with 2-mercaptobenzothiazole.
23. A process of claim 17 for preparing 3-(((525 (N-methylacetamido)-l,3,4-thiadiazol-2-yl)thiojmethyl)-7(2-(2-thienyl)acetamido)-3-oephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido)cephalosporanic acid is reacted with 5-(N-methylacetamido)-1,3,4-thiadiazole-2-thiol. -11346437
24. A process of claim 17 for preparing 3-(((3methyl-1,2,4-oxadiazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-(2thienyl)acetamido)cephalosporanic acid is reacted with 35 methyl-1,2,4-oxadiazole-5-thiol.
25. A process of claim 17 for preparing 3-(((3methy1-1,2,4-thiadiazol-5-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-(2thienyl)acetamido)cephalosporanic acid is reacted with 310 methyl-1,2,4.-thiadiazole-5-thiol.
26. A process of claim 17 for preparing 3(((pyrimidin-2-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)3-cephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido) cephalosporanic acid is reacted with 2-mercaptopyr15 imidine.
27. A process of claim 17 for preparing 3-(((4phenylthiazol-2-yl)thio)methyl)-7-(2-(2-thienyl)acetamido)3-eephem-4-carboxylic acid wherein 7-(2-(2-thienyl)acetamido) cephalosporanic acid is reacted with 4-phenyl-2-thia20 zolethiol. ·
28. A process of claim 17 for preparing 3-(((1(carboxymethyl)-lH-tetrazol-5-yl)thio)methyl)-7-(2-(2thienyl)acetamido)-3-cephem-4-carboxylie acid wherein 7(2-(2-thieny-l) acetamido) cephalosporanic acid is reacted with 25 1-(carboxymethyl)-lH-tetrazole-5-thiol. -1144 6 4 3 7
29. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is hydrogen and R is 2-(lH-tetrazol-l-yl)acetamido wherein a compound of Formula 1 2 II wherein R and R are as defined above is reacted with a 5 compound of Formula III.
30. A process of claim 29 for preparing a compound 1 2 of Formula I wherein R and R are as defined m claim 30 13 and R is a heteroaryl group wherein a compound of Formula 1 2 II wherein R and R are as defined in ciaim 29 is reacted 10 with a compound of Formula III which is a heteroarylthiol.
31. A process of claim 30 for preparing 3-(((5methyl-1,3,4-thiadiazol-2-y1)thio)methyl)-7-(2-(IH-tetra20l-l-yl)acetamido)-3-cephem-4-carboxylic acid wherein 6. 7-(2-(ΙΗ-tetrazol-l-yl)acetamido)cephalosporanic acid is 15 reacted with 5-methyl-l,3,4-thiadiazole-2-thiol.
32. A process of claim 30 for preparing 3(((l,3,4-thiadiazol-2-yl)thio)methyl)-7-(2-(lH-tetrazol1-yl)acetamido)-3-cephem-4-carboxylie acid wherein 7-(2(IH-tetrazol-l-yl)acetamido)cephalosporanic acid is reacted 20 with 1,3,4-thiadiazole-2-thiol.
33. A process of claim 30 for preparing 3-(((1methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-(lH-tetrazol-1yl)acetamido)-3-cephem-4-carboxylie acid wherein 7-(2(ΙΗ-tetrazol-l-yl)acetamido)cephalosporanic acid is reacted 25 with l-methyl-lH-tetrazole-5-thiol.
34. A process of claim 30 for preparing 3(((oxazol-2-yl)thio)methyl)-7-(2-(lH-tetrazol-l-yl)acetamido) -3-cephem-4-carboxylic acid wherein 7-(2-(lH-tetrazol-l-yl)acetamido)cephalosporanic acid is reacted with 30 2-oxazolethiol. -11546437
35. A process of any of claims 1-14 for preparing 1 2 . a compound of Formula I wherein R is hydrogen and R is 2-hydroxy-2-phenylacetamido wherein a compound of Formula II· 1 2 wherein R and R are as defined above is reacted with a 5 compound of Formula III.
36. A process of claim 35 for preparing 3-(((1methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-hydroxy-2-phenylacetamido) -3-cephem-4-carboxylic acid wherein 7-(2-hydroxy2-phenylacetamido)cephalosporanic acid is reacted with ΙΙΟ methyl-lK-tetrazoIe-5-thiol.
37. A process of any of claims 1-14 for preparing 7. 1 2 a compound of Formula I wherein R is hydrogen and R is 2-formyloxy-2-phenylacetamido wherein a compound of Formula 1 2 II wherein R and R are as defined above is reacted with a 15 compound of Formula III.
38. A process of claim 37 for preparing 3-(((1methyl-lH-tetrazol-5-yl)thio)methyl)-7-(2-formyloxy-2phenylacetamido)-3-cephem-4-carboxylic acid wherein 7-(2formyloxy-2-phenylacetamido)cephalosporanic acid is reacted 20 with l-methyl-lH-tetrazole-5-thiol.
39. A process of claim 37 for preparing 3(((oxazol-2-yl)thio)methyl)-7-(2-formyloxy-2-phenylacetamido) -3-cephem-4-earboxylic acid wherein 7-(2-formyloxy2-phenylacetamida)cephalosporanic acid, is reacted with 25 2-oxazolethiol. . -11646437
40. A process of any of claims 1-14 for preparing 1 2 a compound of Formula X wherein R is hydrogen and R is 1 2 formamido wherein a compound of Formula II wherein R and R are as defined above is reacted with a compound of Formula 5 III.
41. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is hydrogen and R is 1 2 acetamido wherein a compound of Formula II wherein R and R are as defined above is reacted with a compound of Formula 10 III.
42. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is hydrogen and R is 2-phenylacatamido wherein a compound of Formula II wherein 1 2 R and R are as defined above is reacted with a compound of 15 Formula III.
43. A process of claim 42 for preparing 3-(((5methyl-l,3,4-thiadiazol-2-yl)thiojmethyl)-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid wherein 7-(2-phenylacetamido)cephalosporanic acid is reacted with 5-methyl-l,3,420 thiadiazole-2-thiol.
44. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is methoxy and R is 2-phenylacetamido wherein a compound of Formula II wherein R 1 2 and R are as defined above is reacted with a compound of 25 Formula III.
45. A process of any of claims 1-14 for preparing 1 2 . a compound of Formula I wherein R is hydrogen and R is 2-phenoxyacetamido wherein a compound of Formula II wherein 1 2 R and R are as defined above is reacted with a compound of 30 Formula III. -11746437
46. A process of any of claims 1-14 for preparing a compound 1 2 of Formula I wherein R is hydrogen and R is 2-(protected amino) -2-phenylacetamido wherein a compound of Formula II wherein R 1 and R are as defined above is reacted with a compound of 5 Formula III.
47. A process of claim 1-14 for preparing 3-(((1-methyllH-tetrazol-5-yl)thio)methyl)-7-(N-((1,3-dimethyl-ureido), carbonyl)-2-phenylglycylamino )-3~eephem-4-carboxylic acid wherein 7-(N-((1,3-dimethylureido)carbonyl)-2-phenyl10 i glycylamino )cephalosporanic acid is reacted with. 1-methy1lH-tetrazole-5-thiol.
48. A process of any of claims 1-14 for preparing a 1 2 compound of Formula I wherein R is hydrogen and R is 2-((4ethyl-2,3-dioxo-l-piperazinyl)carbonylamino)-2-(£-hydroxy15 phenyl) acetamido wherein a compound of Formula II wherein 1 2 R and R are as defined above is reacted with a compound of Formula III.
49. A process of claim 48 for preparing 3-(((1-methyl-lHtetrazol-5-yl)thiojmethyl)-7-(2-((4-ethyl-2,3-dioxo-l20 pipera2inyl)carbonylamino)-2-(p-hydroxyphenyl)-acetamido)-3cephem-4-carboxylic acid wherein 7-(2-((4-ethyl-2,3-dioxo-lpiperazinyl)carbonylamino)-2-(p-hydroxyphenyl)acetamido) cephalosporanic acid is reacted with l-methyl-lH-tetrazole-5thiol. 25
50. A process of any of claims 1-14 for preparing a compound 1 2 of Formula I wherein R is methoxy and R is 2-(lH-tetrazol-1yl)acetamido wherein a compound of Formula II wherein R 1 and R are as defined above is reacted with a compound of Formula III. 30
51. A process of any of claims 1-14 for preparing a compound of Formula I wherein R is a heteroaryl group wherein a 1 2 compound of Formula II wherein R, R and R are as defined in any of claims 1 or 12-14 is reacted with a compound of Formula III wherein R 11 III is a heteroaryl group. 118
52. A process of claim 51 for preparing a compound of Formula I wherein R is lH-tetrazol-5-yl wherein a 1 2 compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with lH-tetrazole-5-thiol.
53. A process of claim 51 for preparing a compound of Formula I wherein R is l-methyl-lH-tetrazol-5-yl 1 2 wherein a compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with 1-methyl-lH-tetrazole-5-thiol.
54. A process of claim 51 for preparing a compound of Formula I wherein R is 1-(carboxymethyl)-lH-tetrazol1 2 5-yl wherein a compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with 1-(carboxymethyl)lH-tetrazole-5-thiol.
55. A process of claim 51 for preparing a compound of Formula I wherein R is l,3,4-thiadiazol-5-yl wherein a 1 2 compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with l,3,4-thiadiazole-5-thiol.
56. A process of claim 51 for preparing a compound of Formula I wherein R is 5-methyl-l,3,4~thiadiazol-2-yl 1 2 wherein a compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with 5-methyl-l,3,4thiadiazole-2-thiol.
57. A process of claim 51 for preparing a compound of Formula I wherein R is t triazolyl wherein a compound of Formula II wherein R, R 1 and R 2 are as defined in claim 51 is reacted with a triazolylthiol.
58. A process of claim 51 for preparing a compound of Formula I wherein R is 4,5-dihydro-6-hydroxy-4-methyl5-oxo-l,2,4-triazin-3-yl wherein a compound of Formula II 119 1 2 wherein R, R and R are as defined in claim 51 is reacted with 4,5-dihydro-6-hydroxy-4-methyl-5-oxo-l,2,4-triazine3-thiol.
59. A process of claim 51 for preparing a compound 5 of Formula I wherein R is tetrazolo[l,5-b]pyridazin-6-yl 1 2 wherein a compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with tetrazolo[1,5-b]pyridazine-6-thiol.
60. A process of claim 17 for preparing 3-(((oxazol10 2-yl) thio)methyl-7-(2-(2-thienyl)acetamido)-3-cephem-4carboxylic acid wherein 7-(2-(2-thienyl)acetamido)eephalosporanic acid is reacted with 2-oxazolethiol.
61. A process of claim 37 for preparing 3-(((1(carboxymethyl)-lH-tetrazol-5-yl)thio)methyl)-7-(2-formyloxy15 2-phenylacetamido)-3-cephem-4-carboxylic acid wherein 7-(2formyloxy-2-phenylacetamido)cephalosporanic acid is reacted with l-carboxymethyl-lH-tetrazole-5-thiol.
62. A process of any of claims 1-14 for preparing a 1 2 compound of Formula I wherein R is hydrogen and R is 220 trifluoromethylthioacetamido wherein a compound of Formula II 1 2 wherein R and R are as defined above is reacted with a compound of Formula III.
63. A process of claim 62 for preparing 3-(((1methy1-1H-tetrazol-5-yl)thio)methyl)-7-(2-trifuloromethyl25 thioacetamido-3-cephem-4-carboxylic acid wherein 7-(2-trifluoromethylthioacetamido) cephalosporanic acid is reacted with l-methyl-lH-tetrazole-5-thiol. - 120 46437
64. A process of any of claims 1-14 for praparing 1 2 a compound of Formula I wherein R is hydrogen and R is 2-cyanomethylthioacetamido wherein a compound of Formula II 1 2 wherein R and R are as defined above is reacted with a compound of Formula III.
¢5. A process of claim 64 for preparing 3-(((1methyl-lH-tetrazol-5-yl)thiojmethyl)-7-(2-cyanomethylthioacetamido) -3-cephem-4-carboxylic acid wherein 7-(2-cyanomethylthioacetamido)cephalosporanic acid is reacted with 1- methyl-lH-tetrazole-5-thiol.
66. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is methoxy and R is cyanomethylthioacetamido wherein a compound of Formula II 1 2 wherein R and R are as defined above is reacted with a compound of Formula III.
67. A process of claim 66 for preparing 3-(((1methyl-lH-tetrazol-5-yl)thiojmethyl)-7-methoxy-7-(2-cyanomethylthioacetamido)-3-cephem-4-carboxylic acid wherein 7-methoxy-7-(2-cyanomethylthioacetamido)cephalosporanic acid is reacted with 1-methyl-IH-tetrazole-5-thiol.
63. A process of any of claims 1-14 for preparing 1 2 a compound of Formula I wherein R is hydrogen and R is 2- (o-protected aminomethylphenyl)acetamido wherein a comI 2 pound of Formula II wherein R and R are as defined above is reacted with a compound of Formula III. 121
69. A process of claim 1-14 for preparing 3.-( ((1-methyllH-tetrazol-5-yl)thio)methyl)-7 -(2-ureido-2-(2-thienyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-ureido2-(2“-thienyl)acetamido)cephalosporanic acid is reacted with ·· s. 1-methyl-lH-tetrazole-5-thiol.
70. A process of claim 1-14 for preparing 3-(((1-(2(dimethylamino)ethyl)-lH-tetrazol-5-yl)thio)methyl)-7-(2-(2amino-4-thiazolyl)acetamido)-3-cephem-4-carboxylic acid wherein 7-(2-(2-amino-4-thiazolyl)acetamido)cephalosporanic acid is reacted with 1-(2-(2-diemthylamino)ethyl-lH-tetrazole-5-thiol.
71. A process of any of claims 1-12 or 14 for preparing a compound of Formula I wherein a compound of Formula II wherein R is amino is reacted with a compound of Formula III.
72. A compound of Formula I as defined in any of claims 1 and 12-71 whenever prepared by the process of any of claims 1-71.
73. A process as claimed in claim 1 substantially as hereinbefore described with particular reference to any one of the Examples.
74. ' A compound of Formula I whenever prepared by the process claimed in claim 73.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US77501877A | 1977-03-07 | 1977-03-07 | |
US05/862,871 US4144391A (en) | 1977-03-07 | 1977-12-27 | Cephalosporin displacement reaction |
Publications (2)
Publication Number | Publication Date |
---|---|
IE780453L IE780453L (en) | 1978-09-07 |
IE46437B1 true IE46437B1 (en) | 1983-06-15 |
Family
ID=27118982
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE453/78A IE46437B1 (en) | 1977-03-07 | 1978-03-06 | Cephalosporin synthesis |
Country Status (30)
Country | Link |
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JP (1) | JPS53130689A (en) |
AT (1) | AT366696B (en) |
AU (1) | AU515428B2 (en) |
BG (1) | BG31379A3 (en) |
CA (1) | CA1083141A (en) |
CH (1) | CH637964A5 (en) |
CS (1) | CS205115B2 (en) |
CY (1) | CY1196A (en) |
DD (1) | DD137356A5 (en) |
DE (1) | DE2809058A1 (en) |
DK (1) | DK97378A (en) |
EG (1) | EG13454A (en) |
ES (1) | ES467637A1 (en) |
FI (1) | FI69309C (en) |
FR (1) | FR2383189A1 (en) |
GB (1) | GB1597036A (en) |
GR (1) | GR68893B (en) |
HK (1) | HK49083A (en) |
HU (1) | HU179967B (en) |
IE (1) | IE46437B1 (en) |
IL (1) | IL54181A (en) |
IT (1) | IT1093504B (en) |
MX (1) | MX5142E (en) |
NL (1) | NL190703C (en) |
NZ (1) | NZ186610A (en) |
PH (1) | PH14596A (en) |
PL (1) | PL122152B1 (en) |
PT (1) | PT67732A (en) |
SE (1) | SE437991B (en) |
YU (1) | YU51478A (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5543043A (en) * | 1978-09-22 | 1980-03-26 | Sankyo Co Ltd | Preparation of 3-substituted thiomethylcephalosporin derivative |
US4576937A (en) * | 1984-02-29 | 1986-03-18 | Smithkline Beckman Corporation | 7-D-Mandelamido-3(1-sulfomethyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid monosodium salt |
GB8519606D0 (en) * | 1985-08-05 | 1985-09-11 | Fujisawa Pharmaceutical Co | 3 7-d substituted-3-cephem compounds |
JP2503500B2 (en) * | 1986-04-14 | 1996-06-05 | 萬有製薬株式会社 | Novel cefalosporin derivative and method for producing the same |
JPS62281881A (en) * | 1986-09-08 | 1987-12-07 | Sankyo Co Ltd | Production of 3-substituted thiomethylcephalosporin derivative |
EP2539348A4 (en) * | 2010-02-26 | 2013-07-24 | Gary Igor Dmitrienko | Cephalosporin derivatives useful as -lactamase inhibitors and compositions and methods of use thereof |
GB201818410D0 (en) * | 2018-11-12 | 2018-12-26 | Imperial Innovations Ltd | Compounds |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3641021A (en) * | 1969-04-18 | 1972-02-08 | Lilly Co Eli | 3 7-(ring-substituted) cephalosporin compounds |
JPS5116436B1 (en) * | 1971-05-31 | 1976-05-24 | ||
JPS5143785A (en) * | 1974-10-11 | 1976-04-14 | Yamanouchi Pharma Co Ltd | Shinsefuarosuhorinkanrenkagobutsuno goseiho |
JPS612674B2 (en) * | 1974-06-20 | 1986-01-27 | Meiji Seika Co | |
CA1100129A (en) * | 1974-08-02 | 1981-04-28 | William H.W. Lunn | Cephalosporin compounds |
FI761035A (en) * | 1975-04-21 | 1976-10-22 | Erba Carlo Spa |
-
1978
- 1978-03-02 CY CY1196A patent/CY1196A/en unknown
- 1978-03-02 GB GB8224/78A patent/GB1597036A/en not_active Expired
- 1978-03-02 CA CA298,070A patent/CA1083141A/en not_active Expired
- 1978-03-02 IL IL54181A patent/IL54181A/en unknown
- 1978-03-02 DE DE19782809058 patent/DE2809058A1/en active Granted
- 1978-03-02 PT PT67732A patent/PT67732A/en unknown
- 1978-03-02 AT AT0150778A patent/AT366696B/en not_active IP Right Cessation
- 1978-03-02 NZ NZ186610A patent/NZ186610A/en unknown
- 1978-03-03 PH PH20847A patent/PH14596A/en unknown
- 1978-03-03 GR GR55608A patent/GR68893B/el unknown
- 1978-03-03 FI FI780716A patent/FI69309C/en not_active IP Right Cessation
- 1978-03-03 CH CH236178A patent/CH637964A5/en not_active IP Right Cessation
- 1978-03-03 AU AU33828/78A patent/AU515428B2/en not_active Expired
- 1978-03-03 DK DK97378A patent/DK97378A/en not_active Application Discontinuation
- 1978-03-03 NL NL7802376A patent/NL190703C/en not_active IP Right Cessation
- 1978-03-03 HU HU78EI784A patent/HU179967B/en unknown
- 1978-03-03 FR FR7806158A patent/FR2383189A1/en active Granted
- 1978-03-06 YU YU00514/78A patent/YU51478A/en unknown
- 1978-03-06 SE SE7802530A patent/SE437991B/en not_active IP Right Cessation
- 1978-03-06 MX MX786901U patent/MX5142E/en unknown
- 1978-03-06 IE IE453/78A patent/IE46437B1/en not_active IP Right Cessation
- 1978-03-06 IT IT20912/78A patent/IT1093504B/en active
- 1978-03-07 BG BG7838941A patent/BG31379A3/en unknown
- 1978-03-07 PL PL1978205135A patent/PL122152B1/en unknown
- 1978-03-07 ES ES467637A patent/ES467637A1/en not_active Expired
- 1978-03-07 JP JP2646878A patent/JPS53130689A/en active Granted
- 1978-03-07 CS CS781436A patent/CS205115B2/en unknown
- 1978-03-07 DD DD78204007A patent/DD137356A5/en not_active IP Right Cessation
- 1978-03-07 EG EG149/78A patent/EG13454A/en active
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1983
- 1983-10-27 HK HK490/83A patent/HK49083A/en not_active IP Right Cessation
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