GB1597036A - Cephalosporin synthesis - Google Patents

Cephalosporin synthesis Download PDF

Info

Publication number
GB1597036A
GB1597036A GB8224/78A GB822478A GB1597036A GB 1597036 A GB1597036 A GB 1597036A GB 8224/78 A GB8224/78 A GB 8224/78A GB 822478 A GB822478 A GB 822478A GB 1597036 A GB1597036 A GB 1597036A
Authority
GB
United Kingdom
Prior art keywords
methyl
formula
compound
acetamido
reacted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB8224/78A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US05/862,871 external-priority patent/US4144391A/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of GB1597036A publication Critical patent/GB1597036A/en
Expired legal-status Critical Current

Links

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

Landscapes

  • 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 <IMAGE> 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

(54) CEPHALOSPORIN SYNTHESIS (71) We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention provides a process for the displacement of the acetoxy group of a cephalosporanic acid by a sulfur nucleophile, 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 displacements 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--70"C.), 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. Keactions 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 formula
wherein R13 is
-C1-C4 alkyl,
Rl is hydrogen or methoxy; R2 is a phthalimido, succinimido, a radical of the formula
wherein L is hydrogen or nitroso, or a radical of the formula
R3 iS: (1) hydrogen, (2) C1-C6 alkyl, (3) -CH2-(C1-C3 chloroalkyl), (4) -CH4-(C1-C3 fluoroalkyl), (5) C1-C4 cyanoalkyl, (6) C1-C4 hydroxyalkyl, (7) p-nitrobenzyloxy, (8) tert.-butoxy, (9) 2,2,2-trichloroethoxy, (10) a protected 4-amino-4-carboxybutyl radical of the formula
wherein Al is a protected amino group and Rl2 is hydrogen or C1-C4 alkyl; (11) 4-oxo-4-carboxybutyl; (12) 3-carboxypropyl; (13) a radical of the formula
in which each of a and a is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, or ACH2- wherein A is, as above, protected amino; Z is O or S; and m is 0 or 1; (14) a radical of the formula wherein P is
(a) 2-thienyl, (b) 3-thienyl, or (c) a phenyl group of the formula
in which a and a' are as defined above; and wherein Q is (a) hydroxy, (b) formyloxy, (c) acetoxy, (d) carboxy of the formula
wherein A2 is diphenylmethyl, p-nitrobenzyl, benzyl, 2,2, 2-trichloroethyl, tert butyl, or p-methoxybenzyl; (e) alkali metal oxysulfonyl, (f) a protected amino group, (g) an acylated amino group of the formula
wherein T represents amino,
wherein R7 is hydrogen or C1-C alkyl; RB is phenyl, halophenyl, furyl, monomethylamino, dimethylamino, monoethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, diisopropylamino, phenylamino, or diphenylamino; R9 is hydrogen, C1-C4 alkyl, or phenyl; R10 is hydrogen, C1-C3 alkyl, or methylsulfonyl; and R11 is ethylene, trimethylene, or vinylene; (15) a radical of the formula
wherein P' is P as defined above, protected 2-amino-4-thiazolyl, or 2-furyl; (16) a radical of the formula V-S(O),,-CH2- wherein V represents -CF3 or -CH2-X wherein X represents hydrogen, methyl, CF3, CN, or N3, and n represents 0, 1, or 2; or (17) a radical of the formula Y-CH2- in which Y is 2-thienyl, 3-thienyl, 2furyl, 2-oxazolyl, 2-thiazolyl, 1-tetrazolyl, 1-benzotriazolyl, 2-oxazolylthio, 2thiazolylthio, 1,2,3 - triazol - 5 - ylthio, 1,3,4 - triazol - 2 - ylthio, 1,3,4 thiadizol - 2 - ylthio, protected 5 - amino - 1,3,4 - thiadiazol - 2 - ylthio, 5 methyl - 1,3,4 - thiadiazol - 2 - ylthio, 1,2,4 - thiadiazol - 5 - ylthio, 3 - methyl 1,2,4 - thiadiazol - 5 - ylthio, 1,2,5 - thiadiazol - 3 - ylthio, 1,3,4 - oxadiazol - 2 ylthio, 5 - methyl - 1,3,4 - oxadiazol - 2 - ylthio, 1 - methyl - 5 - tetrazolylthio, pyridylthio, 4 - cyano - 1,2,3 - triazol - 1 - yl, 3 - cyano - 1,2,4 - triazol - 1 - yl, or protected 2 - amino - 4 - thiazolyl; each R4 is independently hydrogen, C1-C4 alkyl, C2-C3 alkenyl, cyclohexyl, or phenyl; each R5 is independently C1-C4 alkyl, C1-C4 alkoxy, halo, hydroxy, nitro, cyano, methanesulfonamido, or trifluoromethyl; and R6 is a unit which with the
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: 1 nitrogen and 0 or 1 oxygen or sulfur, 2 nitrogens and 0 or 1 oxygen or sulfur, 3 nitrogens, and 0 or 1 oxygen, or 4 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
which process comprises reacting a compound of the formula
wherein R' and R2 are as defined above, and R is C1-C3 alkyl, C4-C6 cycloalkyl, amino, mono- or di(C1-C3 alkyl)amino,
with a sulfur nucleophile of the formula R13-S-R14 III wherein R'3 is as defined above, and Rl4 is hydrogen, or when and only when R'3 is a methyleneaminium group, R14 combines with R13 and the S atom to form a thiourea; in an organic solvent under essentially anhydrous conditions.
The term C1-C3 alkyl, representing R, may for example be methyl.
The products of the present process exhibit antibacterial activity; in addition, many of them serve as intermediates to yet other cephalosporin products which also exhibit antibacterial activity, see, 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 of R3 as "C1-C6 alkyl", alkyl refers to groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, alkyl, isoamyl, hexyl and 2,3-dimethylbutyl. The terms "-CH3-(C1-C3 chloroalkyl)" and '-CH3-(C1-C3 fluoroalkyl)" refer to such groups as chloroethyl, fluoroethyl, 2-chloroethyl, 2-chloropropyl, 3-fluoropropyl and 4-chlorobutyl. The term "C1-C4 cyanoalkyl" refers to such groups as cyanomethyl, 2-cyanoethyl, 3cyanopropyl and 2-cyanopropyl. The term "C1-C4 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). In 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
which is subsequently to be cleaved from the cephalosporin. Suitable protecting groups for this radical include C2-C4 alkanoyl, C3-C4 chloro- or fluoroalkanoyl, benzoyl, and substituted benzoyl. The term "C3-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 4-chlorobenzoyl, 4-bromobenzoyl, and 2,4dichlorobenzoyl. 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, pnitrobenzyloxycarbonyl, 2,2,2 - trichloroethoxycarbonyl, tert-butoxycarbonyl, p methoxybenzyloxycarbonyl, and diphenylmethoxycarbonyl. The amino group of the formula
can also be protected as described in Belgian patent 771,694.
As used herein, the term "halogen" and the term "halo" refer to fluoro, chloro, bromo, or iodo. The term "C1-C4 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
wherein R3 is any of moieties (1) to (12): formamido, acetamido, propionamido, butyramido, a - methylpropionamido, valeramido, a - methylbutyramido, trimethylacetamido, hexanamido, heptanamido, 3-chloropropionamido, 3chlorobutyramido, 4-fluorobutyramido, 5-chlorovaleramido, cyanoacetamido, 2cyanopropionamido, 3-cyanopropionamido, 4-cyanobutyramido, hydroxyacetamido, 2- hydroxypropionamido, 3 - hydroxybutyramido, pnitrobenzyloxycarbonylamino, tert - butoxycarbonylamino, (2,2,2 trichloroethoxy)carbonylamino, 5- (2,5 - dichlorobenzamido) - 5 carboxyvaleramido, 5 - acetamido - 5 - 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 - 5carboxyvaleramido, 5 - oxo - 5 - carboxyvaleramido and 4 - carboxybutyramido.
The following are illustrative of the groups
in the above definition in which R3 is
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- (2,4 - 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 - isopropoxyphenyl)acetamido, 2 - (m - ethoxyphenyl)acetamido, 2 - (p methoxyphenyl)acetamido, 2 - (3,4 - dimethoxyphenyl)acetamido, 2 - (p - tert 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 - 4 - methylphenyl)acetamido. When, in the above formula, ml and Z represents -0-, illustrative groups include the following: phenoxyacetamido, 2 (p - methylphenoxy)acetamido, 2 - (m - ethylphenoxy)acetamido, 2- (p isopropylphenoxy)acetamido, 2- (o - methylphenoxy)acetamido, 2- (p chlorophenoxy)acetamido, 2- (p - bromophenoxy)acetamido, 2- (2,4 dichlorophenoxy)acetamido, 2- (m - bromophenoxy)acetamido, 2- (p fluorophenoxy)acetamido, 2 - (o - fluorophenoxy)acetamido, 2- (2,6 dimethoxyphenoxy)acetamido, 2 - (m - ethoxyphenoxy)acetamido, 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 (o - chlorophenoxy)acetamido, 2 - (p - isopropoxyphenoxy)acetamido, 2 - (o - acetamidomethyl)phenoxy)acetamido and 2 - (p - (tert - butoxycarbonylaminomethyl)phenoxy)acetamido. When in the foregoing formula, m=l 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 - (2,6 dimethoxyphenylthio)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 difluorophenylthio)acetamido, 2 - (m - fluorophenylthio)acetamido, 2 - (o (acetamidomethyl)phenylthio)acetamido and 2 - (p - (tert - butoxycarbonylaminomethyl)phenylthio)acetamido.
When R3 represents a group of the formula
illustrative groups having the overall formula
include 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; the protected 2- amino - 2phenylacetamido group; in which the protected amino group is, for example, a carbonylamino group such as tert - butoxycarbonyl - amino, trichloroethoxycarbonylamino, or p - nitrobenzyloxy - carbonylamino; and the 2 - (acylated amino) - 2 - phenylacetamido group. Also included are those 2substituted 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, p methoxymandelamido, m - bromomandelamido, p- chloromandelamido, 3 methyl - 4 - fluoromandelamido, o- fluoromandelamido, p - fluoromandelamido, p - isopropylmandelamido, 3,4 - dimethyl - O - formylmandelamido, p - chloro O - formylmandelamido, m - isopropoxy - O - formylmandelamido, m - bromo O - formylmandelamido, O-formylmandelamido, 3,4 - dimethoxy - O formylmandelamido, O-acetylmandelamido, p - hydroxy - 0 - acetylmandelamido, p - (acetamidomethyl)mandelamido, p - hydroxy - 0 - formylmandelamido, 2 - hydroxy - 2 - (2 - thienyl)acetamido, 2 - hydroxy - 2 (3 - thienyl)acetamido, 2 - formyloxy - 2 - (2 - thienyl)acetamido, 2 - acetoxy 2 - (2 - thienyl)acetamido, 2 - formyloxy - 2 - (3 - thienyl)acetamido, 2acetoxy - 2 - (3 - thienyl)acetamido, 2 - (tert - butoxycarbonyl) - 2 phenylacetamido, 2 - (2,2,2 - trichloroethoxycarbonyl) - 2 - (p methylphenyl)acetamido, 2 - (benzyloxycarbonyl) - 2 - (p hydroxyphenyl)acetamido, 2 - (tert - butoxycarbonyl) - 2 - (p hydroxyphenyl)acetamido, 2- (p - nitrobenzyloxycarbonyl) - 2 - (m hydroxyphenyl)acetamido, 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 isoprophenyl)acetamido, 2 - (tert - butoxycarbonyl) - 2 - (3,4 dimethylphenyl)acetamido, 2 - (tert - butoxycarbonyl) - 2 - (m isopropoxyphenyl)acetamido, 2 - (diphenylmethoxycarbonyl) - 2 - (3,4 dimethoxyphenyl)acetamido, 2 - 8tert - 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 - (p hydroxyphenyl)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 - 4fluorophenyl)acetamido, 2 - (sodiooxysulfonyl) - 2 - (o - fluorophenyl)acetamido, 2 - (sodiooxysulfonyl) - 2 - (p - fluorophenyl)acetamido, 2 - (sodiooxysulfonyl) 2 - (p - acetamidomethylphenyl)acetamido, 2- (sodiooxysulfonyl)- 2 - (p - isopropylphenyl)acetamido, 2 - (sodiooxysulfonyl) - 2 - (3,4 dimethylphenyl)acetamido, 2 - (sodiooxysulfonyl) - 2 - (m isopropoxyphenyl)acetamido, 2 - (sodiooxysulfonyl) - 2 - (3,4 dimethoxyphenyl)acetamido, 2 - (sodiooxysulfonyl) - 2 - (2 - thienyl)acetamido, 2 - (potassiooxysulfonyl) - 2 - (3 - thienyl)acetamido, 2 - (p - nitrobenzyloxycarbonylamino) - 2 - phenylacetamido, 2 - (tert - butoxycarbonylamino) - 2 (2 - thienyl)acetamido, 2 - (benzyloxycarbonylamino) - 2 - (m hydroxyphenyl)acetamido, 2- (tert - butoxycarbonylamino) - 2- (p hydroxyphenyl)acetamido, 2 - ureido - 2 - phenylacetamido, 2 - ureido - 2 - (2 thienyl)acetamido, 2 - (3 - guanyl - 1 - ureido) - 2 - phenylacetamido, 2 - (3 methylaminocarbonyl - 1 - ureido) - 2- phenylacetamido, 2- (3 dimethylaminocarbonyl - 3 - methyl - 1 - ureido) -2 - phenylacetamido, 2 - [N (imidazolidin - 2 - one - 1 - ylcarbonyl)amino] - 2 - phenyl - acetamido, 2 - [N - (3 - methylimidazolidin - 2- one - I - ylcarbonyl)- amino] - 2phenylacetamido; 2 - [N - (hexahydropyrimidin - 2 - one - I ylcarbonyl)aminoi - 2 - phenylacetamido; 2 - [N - (3 methylhexahydropyrimidin - 2 - one - 1 - ylcarbonyl)amino] - 2phenylacetamido; 2 - [N - (3 - methanesulfonylhexahydropyrimidin - 2 - one 1 - ylcarbonyl)amino] - 2 - phenylacetamido; 2 - (3 - di - n propylaminocarbonyl - 1 - ureido) - 2 - phenylacetamido, 2 - ((4 - ethyl - 2,3 dioxo - 1 - piperazinyl)carbonylamino) - 2 - phenylacetamido, 2 - (3 (methylsulfonyl) - 2 - oxo - 1 - imidazolidinyl)carbonylamino) - 2 phenylacetamido, 2 - (2 - oxo - 4 - imidazolin - 1 - yl)carbonylamino) - 2 phenylacetamido, 2 - ((4 - oxo - 4H - thiopyran - 3 - yl)carbonylamino) - 2 phenylacetamido, 2- (3 - methyl - 3- (methylcarbamoyl)ureido) - 2phenylacetamido, 2 - (3 - methyl - 3 - (cinnamoylureido)) - 2 - phenylacetamido, 2 - (3 - methyl - 3 - (acryloylureido)) - 2 - phenylacetamido, 2 - ((4 - ethyl 2,3 - dioxo - 1 - piperazinyl)carbonylamino) - 2 - thienylacetamido, 2 - ((4 ethyl - 2,3 - dioxo - 1 - piperazinyl)carbonylamino) - 2 - (p hydroxyphenyl)acetamido, 2 - ((4 - ethyl - 2,3 - dioxo - I piperazinyl)carbonylamino) - 2 - phenylacetamido, 2 - ((2 - oxoimidazolidin - 1 yl)carbonylamino) - 3 - thienylacetamido and 2- ((2 - oxo - 3 (methylsulfonyl) - 4- imidazolin - 1 - yl)carbonylamino) - 2- (p hydroxyphenyl)acetamido.
The following are illustrative of the group
wherein R is moiety (15): 2 - (hydroxyimino) - 2 - phenylacetamino, 2 (metoxyimino) - 2 - phenylacetamido, 2 - (acetoxyimino) - 2 phenylacetamido, 2 - (hydroxyimino)- 2 - (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 - (p nitrobenzyloxycarbonylamino) - 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
wherein R3 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
in the above definition in which R3 is Y-CH2- are the following: 2 - (2 thienyl)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, 2 - (1,2,3 - triazol - 5 - ylthio)acetamido, 2 - (1,3,4 triazol - 2 - yl - 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 - thiadiazol - 2- ylthio)acetamido, 2- (1,2,4 - thiadiazol - 5 ylthio)acetamido, 2 - (3 - methyl - 1,2,4 - thiadiazol - 5 - ylthio)acetamido), 2 (1,2,5 - thiadiazol - 3 - ylthio)acetamido, 2- (1,3,4 - oxadiazol - 2ylthio)acetamido, 2 - (5 - methyl - 1,3,4 - oxadiazol - 2 - ylthio)acetamido, 2 (1 - methyl - 5 - tetrazolylthio)acetamido, 2 - (pyridylthio)acetamido, 2 - (4 cyano - 1,2,3 - triazol - I - yl)acetamido, 2 - (3 - cyano - 1,2,4 - triazol - 1 - yl)acetamido, and 2 - (2 - (protected amino) - 4 - thiazolyl)acetamido (tautomeric with 2 - (2 - protected imino - 4 - thiazolin - 4 - yl)acetamido).
Many of the cephalosporanic acids to be 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 R'3 is of the formula
Suitable five-membered heteroaromatic rings of said formula include the following: pyrrole oxazole isoxazole thiazole isothiazole pyrazole imidazole 1 ,2,3-oxadiazole I ,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 I ,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 - 1,3,4 - thiadiazole 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 the 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 C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C5-C6 cycloalkyl, benzyl, phenethyl, aryl including phenyl and substituted phenyl as defined hereinabove, halo -CF3, -OH, protected amino or C1-C4 alkylamino, -COOH, -COOA2, -CONH2, protected aminomethyl or C1C4 alkylaminomethyl, -CH2SO3-alkali metal, -CH2COOH, -CM2COOA2, or -(CH2)2N(CH3)2.
Representative sulfur nucleophiles of Formula III include the following: Thioureas allylthiourea N,N'-di-n-butylthiourea N,N'-di-tert-butylthiourea N,N'-dicyclohexylthiourea N,N'-diisopropylthiourea N,N'-dimethylthiourea N-methylthiourea N,N,N',N'-tetraethylthiourea N,N,N1,N'4etramethylthiourea thiourea N-phenylthiourea N,N'-diphenylthiourea N,N-dimethylthiourea Thiobenzoic acid Alkylthiols methanethiol ethanethiol 1- or 2-propanethiol 1- or 2-butanethiol 2-methyl- 1 -propanethiol Benzenethiols benzenethiol 4-bromo-3-methylbenzenethiol p-bromobenzenethiol p-chlorobenzenethiol 2,5-dichlorobenzenethiol 3,4-dichlorobenzenethiol 4-fluorobenzenethiol m-methoxybenzenethiol p-methoxybenzenethiol p-nitrobenzenethiol p-methylbenzenethiol Heteroarylthiols 2-pyrrolethiol 3-pyrazolethiol 2-methyl-3-pyrazolethiol 2-methyl-4-imidazolethiol 2-imidazolethiol 4-oxazolethiol 3-isoxazolethiol 2-thiazolethiol 3-isothiazolethiol l-methyl-l ,2,3-triazole-5-thiol 1 -benzyl- 1 ,2,3-triazole-4-thiol 2-methyl-l ,2,3-triazole-4-thiol 3,5-dimethyl-1 ,2,3-triazole-4-thiol 1,2,4-triazole-3-thiol 4-methyl-1,2,4-triazole-5-thiol 3-methyl-1,2,4-triazole-5-thiol 3,4-dimethyl-1,2,4-triazole-5-thiol 2-methyl-1,2,4-triazole-5-thiol 2-benzyl-1,2,4-triazole-5-thiol 2,3-dimethyl 1 ,2,4-triazole-5-thiol 4-methyl-3-(trifluoromethyl)- 1 ,2, 4-triazole-5-thiol 3-carbamoyl-4-methyl- 1 ID= 1 -(2-dimethylaminoethyl)tetrazole-5-thiol 1 ,2,3,4-oxatriazole-5-thiol 2-pyridinethiol 2-pyridinethiol, I-oxide 3-pyridazinethiol 2-pyrimidinethiol 2-pyrazinethiol 1 ,2,3-triazine-4-thiol 1,2,4-triazine-3-thiol 4,5-dihydro-6-hydroxy-4-methyl-5-oxo- 2,4-triazine 34hiol 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, halogenated 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 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, o-, m-, or p-xylene, cumene, mesitylene, p-cymene, l-pentene, isopropanol diethyl ether, butyl ethyl ether, diamyl ether, benzyl ethyl ether, acetone, methyl ethyl ketone, 2butanone, 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, o-, m- or p-fluorotoluene, o-, m-, or pchlorotoluene, o-, m-, orp-bromotoluene, 2-chloroethane, 1- or 2-chloropropane, 1 or 2-chlorobutane, I-chloro-2-methylpropane, 1, 2, or 3-chloropentane, 1chloronaphthalene, methylene chloride, chloroform, carbon tetrachloride, 1,1 - dichloroethane, I ,2-dichloroethane, 1,1,1 -trichloroethane, 1,1 ,2-trichloroethane, 1 ,2,2-tetrachloroethane, o-, 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 o-, m-, or p-xylene cumene mesitylene Halogenated Hydrocarbons: chloroethane 1- or 2-chloropropane 1- or 2-ehlorobutane isobutyl chloride 1, 2, or 3-chloropentane methylene chloride chloroform 1 ,2-dichloroethane carbon tetrachloride 1,1,1 -trichloroethane 1,1 ,2-trichloroethane 1 1 ,2,2-tetrachloroethane fluorobenzene chlorobenzene bromobenzene o-, m-, or p-fluorotoluene o-, m-, or p-chlorotoluene o-, m-, or p-bromotoluene o-, m-, or p-dichlorobenzene Acids: acetic acid propionic acid butyric acid isobutyric acid valeric acid Esters: 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 are acetonitrile, 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 (acyloxymethyl)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 accordance with known procedures, including azeotroping and the use of drying agents such as alumina, silica gel or anhydrous calcium sulfate.
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 usually achieved 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 3-heteroarylthio groups: 5-methyl- 1 ,3,4-thiadiazol-2-ylthio I -methyl- I H-tetrazol-5-ylthio 1 -carboxymethyl- 1 H-tetrazol-5-ylthio 4-methyl-6-hydroxy-5-oxo- 1 ,2,4-triazin-3-ylthio 1-methyl- 1 ,3,4-triazol-2-ylthio 2-methyl- 1 ,3,4-triazol-5-ylthio 1 ,2-dimethyl- 1 ,3,4-triazol-5-ylthio- 3-methyl-l ,3,4-triazol-5-ylthio 2,3-dimethyl- 1 ,3,4-triazol-5-ylthio 1-methyl-2-trifluoromethyl-1 ,3,4-triazol-5-ylthio 1 -methyl-2-carbamoyl- 1,3 ,4-triazol-5-ylthio 1 -methyl-2-carboxymethyl- 1 ,3,4-triazol-5-ylthio 1 -methyl-2-carboalkoxy- 1 ,3,4-triazol-5-ylthio 1 -methyl-2-(protected aminomethyl)- 1,3 ,4-triazol 5-ylthio 1 -methyl-2(protected amino)- 1 ,3,4-triazol-5- ylthio l-methyl-2-hydroxy-l ,3,4-triazol-5-ylthio 1 H-tetrazol-5-ylthio 1 -(2-dimethylaminoethyl)- 1 H-tetrazol-5-ylthio 1-(sulfomethoxyl)-1H-tetrazol-5-ylthio, alkali metal salt 5-methyl- 1 ,3,4-oxadiazol-2-ylthio 1,3 ,4-thiadiazol-2-ylthio- 3-methyl-l ,2,4-thiadiazol-5-ylthio- and 2-(proteeted aminomethyl)-1,3,4-thiadiazol-5-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:
cefamandole nafate:
cefazolin: ceftezole: cefazaflur:
The products of the present invention, their deblocked derivatives, and the pharmaceutically acceptable salts of the same are useful in combating infections in 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 practise the same.
EXAMPLE 1 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Acetonitrile 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.2 grams; 5.5 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (1.0 gram; 8.6 mmol) 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 thin-layer 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 400C for 2 hours, 2.50 grams (76.1 percent yield), m.p. 1834"C. (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-d6) S 3.52 (m, 2, 2-CH2), 3.76 (s, 2, -CH2CONH-), 3.92 (s, 3, H3 of tetrazole), 4.35 (s, 2, 3-CH2S), 5.00 (d, 1, C6-H, J=5 Hz), 5.55 (q, 1, C7-H, J=5 Hz, J=9 Hz), 6.95 (d, 2, thiophene 3 and H, J=3 Hz), 7.35 (t, 1, thiophene 5-H, J=3 Hz), and 8.75 (d, 1, -CH2CONH-, J=9 Hz).
EXAMPLE 2 Preparation of 3 - (((1 - methyl - I H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Acetonitrile 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (4.0 grams; 10 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (5.8 grams; 50 mmole) were refluxed in 50 ml of dry acetonitrile (treated over an 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 - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in 1,2 Dichloroethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (1.2 grams; 10 mmole) in 25 ml of 1,2dichloroethane 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 dicyclohexylamine salt and was stirred for 20 minutes at room temperature, then filtered, washed with 25 ml of ethanol, and dried at 400C 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 - lH - tetrazol - 5 - yl)thio)methyl)- 7 formamido - 3 - cephem - 4 - carboxylic Acid in 1 2-Dichloroethane 7 - Formamidocephalosporanic acid (3.0 grams; 10 mmole) and 1 - methyl 1H - 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 HCI 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. NMR(D2O, NaHCO3) a 3.65 (q, 2, 2-CH2, JAB=16.5 Hz), 4.08 (s, 3, -CH3 on tetrazole), 4.16 (q, 2, 3-CH2S-, JAB=12.5 Hz), 5.05 (d, 1, C6-H, J=5 Hz), and 5.45 (dl, C7-H, J=5 Hz).
EXAMPLE 5 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Isopropyl Acetate 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (1.2 grams; 10 mmole) in 25 ml of isopropyl acetate were refluxed (900 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-d6) # 3.72 (s, 2, 2-CH2), 3.80 (s, 2, -CH2CONH-), 3.95 (s, 3, -CH3 of tetrazole), 4.30 (s, 2, 3-CH2S-), 5.10 (d, 1, C6-H,J=5 Hz), 5.70 (q, 1, C7 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 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Propionitrile 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grmas; 5 mmol) and 1 - methyl - 1H - 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 - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Acetonitrile, 3,5-Dichlorophenyl Dihydrogen Phosphate Added 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole), 1 - methyl - 1H - tetrazole - 5- thiol (0.87 gram; 7.5 mmole), and 3,5dichlorophenyl dihydrogen phosphate (0.122 grams; 0.5 mmole) were heated overnight in 25 ml of dry acetonitrile at 700 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 during 1/2 hour to effect 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 Preparation of 3 - (((I - methyl - 1H - 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 1 - methyl - 1H - tetrazole - 5 - thiol (0.87 grams; 7.5 mmole) were added to glacial acetic acid (25 ml). The reaction mixture was heated to 600C and held at this temperature for an hour. Only a trace of product was evident on TLC. The reaction mixture was heated to 800C 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 - 4 - methyl - 5 - oxo - 1,2,4 triazin - 3 - yl)thio)methyl) - 7 - (2 - (2 - thienyl)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 - methyl - 5 - oxo - 1,2,4 - 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--850C. 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 offwhite crystals, m,p. 1610C (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 1610C (dec).
Total yield was therefore 83.1 percent.
EXAMPLE 10 Preparation of 3 - (((5 - methyl - 1,3,4 - oxadiazol - 2 - yl)thio)methyl) - 7 - (2 (2 - thienyl)acetamido)- 3- cephem - 4- carboxylic Acid in 1,2 Dichloroethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 5 - methyl - 1,3,4 - oxadiazole - 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--850C 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 15 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 of 3 - (((1 - methyl - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1 - methyl - 1H - 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 10S 101"C 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 filtration, washed with diethyl ether, and dried, 1.27 gram (56.2 percent yield), offwhite crystals, m.p. 156-1590C. (dec.). The identity of the product was confirmed by NMR.
EXAMPLE 12 Preparation of 3 - (((I - methyl - 1H - tetrazol .- 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Methylene Chloride 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (11.9 grams; 30 mmole) and 1 - methyl - 1H - 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 83-860C., 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 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 - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Fluorobenzene 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5.04 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (1.2 grams; 10 mmole) in 75 ml of fluorobenzene (b.p. 85.10C)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 400C 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 - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido - 3 - cephem - 4 - carboxylic Acid in Thiophene 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1 - methyl - IH - 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--1630C (dec.). TLC showed that the filtrate contained additional product.
EXAMPLE 15 Preparation of 3 - (((5 - methyl - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (2 (1H - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Acetonitrile 7 - (2 - (lH - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (0.76 gram; 2 mmole) and 5 - methyl - 1,3,4 - thiadiazole - 2 - 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 C under vacuum, 0.61 gram (67 percent yield). The identity of the product was confirmed by NMR, # 2.68 (s, 3, -CH3 of tetrazole), 3.72 (s, 2, 2-CH2), 4.40 (q, 2, 3H2S-, JAR=13 Hz), 5.12 (d, 1, C6-H, J=5 Hz), 5.38 (s, 2, -CH2CONII-), 5.72 (q, 1, C7-H, J=5 Hz), 9.00 (s, 1, tetrazole 5-H), and 9.17 (d, 1, -C2CONH-).
EXAMPLE 16 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 formyloxy - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylic Acid in 1,2-Dichloroethane 7 - (2 - Formyloxy - 2 - phenylacetamido)cephalosporanic acid (2.17 grams; 5 mmole) and 1 - methyl - IH - tetrazole - 5 - thiol (0.87 grams; 7.5 mmole) were added to 25 ml of 1 ,2-dichloroethane, 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-d6 a 3.52 (s, 2, 2-CH2), 3.88 (s, 3, -CH3 of tetrazole), 4.10 (s, 2, 3 CH2S-), 4.92 (d, 1, C6-H), 5.62 (q, 1, C-H, J=5 Hz, J=9 Ha), 6.06 (s, 1 -CHCONII-), 7.26 (s, 5 phenyl-H), and 8.28 (s, 1,
EXAMPLE 17 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)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 - methyl - 1H - 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 - dichlorobenzamido)valeramido)cephalosporanic acid (2.9 grams; 5 mmole), 1 - methyl - IH - 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 chain), 3.66 (m; 2, 2-CH2), 3.95 (s, 3, H3 of tetrazole), 4.30 (m, 2, 3-CH3S-), 5.08 (d, 1, C6-H, J=5 Hz), 5.68 (q, 1, C7-H, J=5 Hz), 7.50 and 7.62 (each s, 2,4dichlorophenyl), and 9.00 (m, 2, two -CONH).
EXAMPLE 18 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido)- 3- cephem - 4- carboxylic Acid in 1,2 Dichloroethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (0.99 gram; 2.5 mmole) and 1 - methyl - 1H - 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 1,2dichloroethane 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 - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (2 (2 - thienyl)acetamido)- 3 cephem - 4- carboxylic Acid in Acetonitrile 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 5 - methyl - 1,3,4 - thiadiazole - 2 - thiol (2.64 grams; 20 mmole) in 25 ml. of acetonitrile were refluxed overnight at 790 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, UV, NMR, MS, and elemental analyses, NMR (DMSO-dS) a 2.68 (s, 3, -CH3 of tetrazole), 3.68 (s, 2, 2-CH2), 3.76 (s, 2, -CH2CONH-), 4.38 (q, 2, 3-CH2S-, J=13 Hz), 5.10 (d, 1, C6-H, J=5 Hz), 5.70 (q, 1, C7-H,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 - 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 (2.0 grams; 5 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (1.2 grams; 10 mmole) were added to 25 ml of 1,1,2-trichloroethane and heated to 1010C. The reaction was followed by TLC; after 4 hours at 100--1"C., with stirring, TLC showed no cephalosporanic acid starting material remaining. The reaction mixture was cooled to room temperature, with stirring. A 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 - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid, m.p. 1580C (dec) (43.4 percent yield).
EXAMPLE 21 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic 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 1 - methyl - 1H - tetrazole - 5 - thiol (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 I 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 wtih the NMR of the product of Example 5.
(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 mixture was refluxed for 16 hours, at which time 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 - 5 - yl)thio)methyl) - 7 - (2 phenylacetamido) - 7 - methoxy - 3 - cephem - 4 - carboxylic Acid in 1 ,2-Dichloroethane 7 - (2 - Phenylacetamido) - 7 - methoxycephalosporanic acid (210 mg; 0.5 mmole), 1 - methyl - 1H - 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 I - methyl - 1H - 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 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 NaCI, 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 (CDCl3+1d acetone-d6) a 3.45 (s, 3, -OCH3), 3.55 (s, 2, 2-CH2), 3.75 (s, 2, CH2CO-), 3.9 (s, 3, CH3 on tetrazole), 4.4 (s, 2, 3-CH2S-), 5.15 (s, 1, C6-H), 7.35 (s, 5, ), 8.0 (s, I, -CH2CONH-), and ,v 11.2 (s, 1, J=0 Hz, -COOH).
EXAMPLE 23 Preparation of 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 of 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 off-white 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, W, mass spectroscopy, IR, and elemental analysis. NMR (DMSO-d6) a 3.74 (s, 2, 2-CH2), 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, C7-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 of 3 - (((5 - (N - methylacetamido)1,3,4 - thiadiazol - 2 yl)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 carboxylic Acid 1,2-Dichloroethane 7 - (2 - (2 - Thienylacetamido)cephalosporanic acid (2.0 grams; 5 mmole)and 5 - (N - methylacetamido) - 1,3,4 - thiadiazole - 2 - thiol (1.42 grams; 7.5 mmole) were added to 50 ml of 1 ,2-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--90C. The identity of the product was confirmed by IR, UV, NMR, mass spectroscopy, and elemental analysis. NMR (DMSO-d6) 2.42 (s, 3, -COCH3), 3.74 (m, 7, 2-CH2, -CH3 of tetrazole, and-CH,CONH-), 4.35 (q, 2, 3-CH3,j=13 Hz), 5.10(d, 1, C8-H,J=5 Hz), 5.70 (q, 1, C7-H, J=5 Hz, J=9 Hz), 6.96 and 7.36 (each m, 3, thiophene H), and 9.10 (d, 1, -CR2CONH-, J=9 Hz).
EXAMPLE 25 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (N tert - butoxycarbonyl)- 2- phenylglycylamido)- 3 - cephem - 4 - carboxylic Acid in 1,2-Dichloroethane I ,2-Dichloroethane (45 ml) was refluxed to remove water-solvent azeotropes, then distilled down to 30 ml which was permitted to cool. 7 - (N - tert Butoxycarbonyl- 2- phenylglycylamido)cephalosporanic acid (253 mg; 0.5 mmole) was added and the solution distilled further, down to 15 ml and again cooled. 1 - Methyl - 1H - 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 tp pH 2.4 with 20 percent HCl. The layers were separated. The aqueous layer was washed with ethyl acetate.
The ethyl acetate layers were combined, washed with saturated NaCI, 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 (CDCl3) # 1.45 (s, 9, -COO tert C4H9), 3.6 (s, 2, 2-CH2), 3.95 (s, , CH3 on tetrazole), 4.3 (s, 2, 3-CH2S-), 4.9 (d, 1, J=6 Hz, C6-H), 5.4 (d, 1, J=8 Hz, #CH-), 5.75 (q, 1, J=4 Hz, C7-H), 6.2 (d, 1, J=8 Hz,
7.4 (s, 5, #), 7.65 (d, 1, J=8 Hz, -CONH), and N9.3 (s, 1, COOH).
EXAMPLE 26 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (N (tert - butoxycarbonyl) - 2 - (p - hydroxyphenyl)glycylamido) - 3 cephem - 4 - carboxylic Acid in 1,2-Dichloroethane 1,2-Dichloroethane (45 ml) was refluxed with a trap and 15 ml solvent removed. The remaining 30 ml was cooled. 7 - (N - (tert - butoxycarbonyl) - 2 (p - hydroxyphenyl) - glycylamido)cephalosporanic acid (260.5 mg; 0.5 mmole) was added and the solution distilled further, down to 15 ml and cooled again. 1 Methyl - 1H - tetrazole - 5 - thiol (87 mg; 0.75 mmole) was added and the reaction mixture heated to 65--700C. 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 as described in the preceding example. The yield was 189 mg of crude product (65.5 percent) and 46 mg of purified product (about 16 percent). NMR (CDCl3+2d acetone d8) 1.45 (s, 9, -COOtertC4H9), 3.35 (s, 2, 2-CH2), 3.85 (s, 3, CH3 on tetrazole), 4.3 (s, 2, 3- CH2S-), 4.9 (d, 1, J=6 Hz, C6-H) 5.3 (q, 1, J=3 Hz, C7-H), 5.4 (s, 1, H=-#CH-), 5.75 (d, 1, J=6 Hz,
6.4 (s, 1, COOH), 6.8 (d, 2, J=8 Hz,
and 7.9 (d, 1, -CONH).
EXAMPLE 27 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 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. 1 - Methyl - I H tetrazole - 5 - thiol (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. TLC of the final product showed it to be identical with an authentic sample of product prepared by prior art methods. NMR (CDCl3) a 3.65 (s, 2, 2-CH2), 3.9 (s, 3, CH3 of tetrazole), 4.35 (s, 2, 3-CH2S-), 4.65 (s, 2, OCH3-), 5.1 (d, 1, J=4 Hz, C6-H), 5.9 (q, 1, J=4 Hz, C7-H), 7.1 (m, 5, F), 7.6 (d, 1, J=10 Hz, -CONH-), and N9 (s, 1, -COOH).
EXAMPLE 28-31 Preparation of 3 - (((1 - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Fluorobenzene 3 - (((1 - Methyl - lR - 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) - 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) 30: 3 - (n - butyryloxymethyl)- 7 - (2 - (2 - thienyl)acetamido)- 3cephem - 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 in 10 ml of fluorobenzene (which had been dried over an aluminosilicate desiccant sold under the term 4-A Linde (Registered Trade Mark) molecular sieve). 1 - Methyl - 1H - 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 NMR of each product was consistent with that of an authentic sample of the product prepared by aqueous displacement.
EXAMPLE 32 Preparation of 3 - (((3 - Methyl - 1,2,4 - oxadiazol - 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 40 ml of 1,1,2-trichloroethane and 3 - methyl - 1,2,4 - oxadiazole 5 - thiol (116 mg; 1 mmole) added. The reaction mixture was heated to 1 130C 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 HC1. 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-d6) a 2.35 (s, 3, CH3 on oxadiazole), 3.7 (q, 2, J=18 Hz, 2-CH2), 3.8 (s, 2, -CH2CONH-), 4.4 (q, 2, J=14 Hz, 3-CH2S-), 5.1 (d, 1, J=5 Hz, C6-H), 5.6 (q, 1, J=4 Hz, C7-H), 6.9, 7.3 (t, d, 3, thiophene H), and 9.1 (d, 1, J=8 Hz, -CH2CONH-).
EXAMPLE 33 Preparation of 3 - (((1H - 1,3,4 - 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 ml of 1,1,2-trichloroethane and 1H - 1,3,4 - triazole - 5 - thiol (100 mg; 1 mmole) added. The reaction mixture was heated to 1050C. 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 l,l,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-d6 a 3.7 (s, 2. 2-CU2), 3.8 (s, 2, -CH2CONH-), 4.2 (q, 2, J=5 Hz, ACH2S), 5.1 (d, 1, J=5 Hz, C-H), 5.J(q, 1, J=4 Hz, C7-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 - 5 - yl)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 I - methyl - 1H - tetrazole - 5 - thiol (75 mg; 0.65 mmole) added. The reaction mixture was heated in an oil bath at 8085 C for 3 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-d6) a 3.6 (s, 2, 2-CH3), 3.7 (s, 2, -CH2CONH-), 4.0 (s, 3, CH3 on tetrazole), 4.3 (s, 2, 3-CH2S-), 5.1 (d, 1, J=5, Hz, C6-H), 5.7 (q, 1, J=4 Hz, C7-H), 7.3 (s, 5, #), and 9.13 (s, 1, J=8 Hz, -CH2CONH-).
EXAMPLE 35 Preparation of 3 - (((1- Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 acetamido - 3 - cephem - 4 - carboxylic Acid in 1,2-Dichloroethane 7-Acetamidocephalosporanic acid (314 mg; 1 mmole) and 1 - methyl - IH tetrazole - 5- thiol (98 mg; 0.65 mmole) were mixed in 70 ml of 1,2dichloroethane: 50 ml were distilled off and the reaction mixture then 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-d6) # 1.97 (s, 3, CH3CONH-), 3.7 (s, 2, 2-CH2), 4.0 (s, 3, CH3 on tetrazole), 4.35 (s, 2, 3-CH2S-), 5.1 (d, 1, J=5 Hz, C6H), 5.7 (q, 1, J=4 Hz, C7-H), and 8.8 (d, 1, J=8 Hz, -CH3CONH).
EXAMPLE 36 Preparation of 3 - (((3 - Methyl - 1,2,4 - thiadiazol - 5 - yl)thio)methyl) - 7 - (2 (2 - thienyl)acetamido)- 3 - cephem - 4- carboxylic Acid in 1,2 Dichloroethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (200 mg; 0.5 mmole) and 3 - methyl - 1,2,4 - thiadiazole - 5 - thiol (85 mg; 0.65 mmole) were mixed in 50 ml of 1 ,2-dichloroethane and heated to 950C 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 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 acetyl 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-d6) a 3.7 (s, 2, 2-CH2), 3.8 (s, 2, -CH2CONH), 4.5 (q, 2, J=15 Hz, 3- CH2S-), 5.1 (d, 1, J=5 Hz, C6-H), 5.7 (q, 1, J=4 Hz, C7-H), 6.96, 7.38 (t, d, 3, thiophene H), and 9.13 (d, 1, J=8 Hz, -CH2CONH).
EXAMPLE 37 Preparation of 3 - (((2 - Pyrimidinyl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Acetonitrile 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 2-mercaptopyrimidine (0.62 grams; 5.5 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 500C for 4 hours, 1.86 grams of off-white crystals (83.0 percent yield), m.p. 2170C (dec). NMR in DMSO-d6 showed neither starting material. The identity of the product was confirmed by IR, UV, and NMR.
NMR (DMSO6-d6) a 3.55 (q, 2, 2-CH2, J=18 Hz), 3.74 (s, 2,-CH2CONH), 4.28 (q, 2, 3-CH2S-, J=13 Hz), 5.00 (d, 1, C6-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 H), and 9.00 (d, 1, -CHCONH-, 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), 2mercaptopyrimidine (0.6 gram; 5.4 mmole), and sodium acetate (0.41 gram; 5 mmole) in 25 ml of glacial acetic acid were heated to 850C 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 dried, 1.58 grams (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 - 1 H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido)cephalosporanic Acid in Acetic Acid 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole), 1 - methyl - 1H - 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 75-770C 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 40450C 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 H2SO4. 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 for 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.
EXAMPLE 40 Preparation of 3 - (((1 - Benzyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido)- 3- cephem - 4- carboxylic Acid in 1,2 Dichloroethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1 - benzyl - IH - tetrazole - 5 - thiol (1.44 grams; 7.5 mmole) were added to 25 ml of l,2-dichloroethane and the reaction mixture heated to 850C 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 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 - (2 - thienyl)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 15 ml of acetonitrile (which had been dried over an aluminosilicate desiccant sold under the term 4-A Linde molecular sieve) were heated at 870C 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 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 prod
The reaction mixture was cooled to O--SOC and filtered, and the product washed with cold 1 ,2-dichloroethane and vacuum dried, 1.82 grams (78.8 percent yield), m.p. 171--20C. NMR (DMSO-d6) S 2.70 (s, 3, -CH3 of thiadiazolyl), 3.58 (s, 2, -CH2CONH-), 3.70 (broad s, 2, 2-CH3), 4.40 (q, 2, 3-CH2S-, J=l3 Hz), 5.12 (d, 1, C6-H, J=5 Hz), 5.72 (q, 1, C7-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 of 3 - ((Methylthio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 cephem - 4 - carboxylic Acid in Methylene Chloride 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (24 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 8" 860C. 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 HCI. The organic phase was separated 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 ethyl acetate, seeded with the intended product, and held in a refrigerator overnight. Crystals had formed; they were separated by filtration, rinsed with cold isopropyl acetate, and vacuum dried at 500C., 3.2 grams (14 percent yield). NMR confirmed the identity of the product, a 2.00 (s, 3, 3-CH2SCH3), 3.74 (m, 3 CH2S-, 2-CH2, and -CH2CONH-), 5.14 (d, 1, C6-H, J=5 Hz), 6.64 (q, 1, C7- H, J=5 Hz, J=9 Hz), 7.15 (m, 3, thiophene H), and 9.12 (d, I, -CH2CONH-, J=9 Hz).
EXAMPLE 46 Preparation of 7 - (2 - formyloxy - 2 - phenylacetamido) - 3 - (I - methyl - 1H tetrazol - 5 - yl)thio)methyl) - 3 - cephem - 4 - carboxylic Acid Sodium Salt in Benzene 7 - (2 - Formyloxy - 2 - phenylacetamido)cephalosporanic acid (2.17 grams; 4.65 mmole) and 1 - methyl - 1H - tetrazole - 5 - 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 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 (D20) â 3.48 (q, 2, 2-CH3, J=18 Hz), 4.00 (s, 3, -CH3 of tetrazolyl), 4.10 (m, 2, 3-CH2S-), 5.05 (d, 1, C6-H, J=5 Hz), 5.70 (d, 1, C7-H), J=5 Hz), 6.24 (s, 1, -CHCONH-) 7.50 (m, 5, phenyl H), and 8.33 (s, 1,
EXAMPLE 47 Preparation of 7 - (2 - Formyloxy - 2 - phenylacetamido) - 3 - (((I - methyl 1H - tetrazol - 1 - yl)thio)methyl) - 3 - cephem - 4 - carboxylic Acid in Carbon Tetrachloride 7 - (2 - Formyloxy - 2 - phenylacetamido)cephalosporanic acid (2.17 grams; 4.65 mmole) and I - methyl - 1H - tetrazole - 5 - thiol (0.87 gram; 7.5 mmoles) in 25 ml of carbon tetrachloride were refluxed (about 77"C) for 12 hours. The reaction mixture was then cooled to room temperature and the supernatant decanted from a hardened semi-solid. To the solid was added 25 ml of 1,2dichloroethane, with warming. The product crystallized. The mixture was cooled to room temperature and stirred for about an hour, then the product was separated by filtration, washed with 10 ml of 1,2-dichloroethane, 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 showed a small trace of deformylated product. The NMR was identical with the NMR of the product of Example 16.
PREPARATION 48 Preparation of 3 - Methyl - 1,2,4 - oxadiazole - 5 - thiol Acetamide oxime (30 grams; 0.4 mmole), carbon disulfide (100 ml; 1.66 mole) and triethylamine (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 700C 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 was layered with fresh ethyl acetate and cooled in an ice bath. The pH was adjusted to 2.5 with 20 percent HCI 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 - 1,2,4 - oxadiazol - 5 - yl)thio)methyl) - 7 - (2 (2 - thienyl)acetamido) - 3 - cephem - 4- carboxylic 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 1,2dichloroethane and stirred while 3 - methyl - 1,2,4 - oxadiazole - 5 - thiol (35 mg; 0.30 mmole) was added. The reaction mixture was heated on an oil bath at 1100C to distill off 5 ml of solvent including any trace amount of water. The oil bath temperature was lowered to 9e950C 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 NaCI 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 - 5 - yl)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 - 1H - tetrazole - 5 - thiol (145 mg; 1.25 mmole) in 15 ml of dry nitromethane were heated at 85-900C for 8 hours under 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, 20 ml of water was added, and the mixture cooled to OOC and adjusted to pH 2.2 with 20 percent HC1. 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 (CDCl3) # 1.4 (s, 9, -COOtertC4H9), 3.6 (s, 2, 2 CH2), 3.85 (s, 3, CH3 of tetrazole), 4.3 (s, 2, 3-CH2S-), 4.44 and 4.45 (2s, 1, #CH-), 4.9 (d, 1, J=6 Hz, C6-H), 5.8 (q, 1, J=6 Hz, C7-H), 7.35 (s, 5, #), 8.2 and 7.8 (2d, 1, J=9 Hz, -CONH-), and 9.3 (s, 1, -COOH).
EXAMPLE 51 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (N ((1,3 - dimethylureido)carbonyl) - 2- phenylglycylamido) - 3 cephem - 4 - carboxylic Acid in Nitromethane 7 - (N - ((1,3 - Dimethylureido)carbonyl) - 2 phenylglycylamido)cephalosporanic acid (130 mg; 0.25 mmole) was suspended in 5 ml of nitromethane and 1 - methyl - 1H - tetrazole - 5 - thiol (43.5 mg; 0.375 mmole) was added. The reaction mixture was heated at 850C 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 350C, 83 mg (58 percent yield). The identity of the product was confirmed by TLC, NMR, IR, UV, elemental analysis and bioautogram. NMR (DMSO-d8) a 2.65 (d, 3, J=4 Hz, -CONHCH3), 3.15 (s, 3, CONCH3CO-), 3.6 (s, 2, 2-CH2), 3.9 (s, 3, CH3 on tetrazole), 4.3 (s, 2, 3-CH2S-), 5.0 (d, 1, J=5 Hz, C6- n), 5.5 (d, 1, J=7 Hz,
5.7 (q, 1, C7-H), 5.8 (q, 1, -CONHCH3), 7.4 (s, 5, #), 9.3 (d, 1, J=8 Hz, #CHCONH-), and 10 (d, 1, J=8 Hz,
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; 10 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 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 cool slowly. The product precipitated as light 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 - 5 - yl)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 1,2dichloroethane 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 cephem - 4 - carboxylic Acid in 1,2-Dichloroethane, 1 - Methyl - 5 (methylthio) - 1 H - tetrazole 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 1 - methyl - 5 - (methylthio) IH - 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.
EXAMPLE 55 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienylacetamido) - 3 - cephem - 4 - carboxylic Acid in Isopropanol 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2.0 grams; 5 mmole) and 1 - methyl - 1H - 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--850C. The reaction was followed by TLC. After 40 hours at 82-830C only half of the cephalosporanic acid had reacted.
EXAMPLE 56 Preparation of 3- ((2- Oxazolylthio)methyl) - 7 - (2 - (1 H - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane A suspension of 7 - (2 - (lH - tetrazol - 1 - 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--910C. 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 400C, yielding 0.36 gram (85.7 percent yield of off white crystals, m.p. 1960C (dec). NMR showed the product to be 70 percent of the desired product and 30 percent of the cephalosporanic acid starting material.
The product was recrystallized from 5 ml of DMSO-d6 and 10 ml of water, separated by filtration, washed with 5 ml of 2:1 water:DMSO-d6, air dried, and vacuum dried at 500C 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-d6 and 6 ml of water, stirring for 1 hour, resulting in 0.21 gram. NMR (DMSO-d6) indicated that the starting cephalosporanic acid had been reduced to 5 percent, and confirmed the identity of the desired product: a 3.75 (s, 2, 2-CH2), 4.34 (q, 2, 3 CH2S-, J=14 Hz), 5.16 (d, 1, C6-H, J=5 Hz), 5.76 (q, 1, C7-H, J=5 Hz, J=9 Hz), 5.44 (s, 2, -CH2CONH-), 7.28 (s, 1, oxazole C4-H), 8.14 (s, 1, oxazole Cs-H), 9.37 (s, 1, tetrazole H), and 9.53 (d, 1, --CONHH-, J=9 Hz).
EXAMPLE 57 Preparation of 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; 1 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.
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, a 3.56 (m, 2, 2-CH2), 4.24 (q, 2, 3--CH,SS-), J-13 Hz), 5.00 (d, 1, C6-H, J=5 Hz), 5.70 (q, 1, C7-H, J=5 Hz, J=9 Hz), 6.14 (s, 1,
7.25 (s, 1, oxazole C4-H), 7.45 (m, 5, phenyl H), 8.12 (s, 1, oxazole C5-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 - 2 - thiazolethiol (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 converson 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.
EXAMPLE 59 Preparation of 3 - (((5 - Methyl - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (2 (1H - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7 - (2 - (1 H - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (1.92 grams; 5 mmole) and 5 - methyl - 1,3,4 - thiadiazole - 2 - thiol) 0.79 gram; 6 mmole) were added to 25 ml of alumina-treated 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 cephalosporanic 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 - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (2 (1H - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Propionitrile 7 - (2 - (1H - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (1.92 grams; 5 mmole) and 5 - methyl - 1,3,4 - thiadiazole - 2 - thiol (0.99 grams; 7.5 mmole) were added to 25 ml of propionitrile (treated over neutral alumina) and heated to reflux (970C). 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.
EXAMPLE 61 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 formyloxy - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylic Acid in 1 ,2-Dichloroethane 7-ACA (7-aminocephalos oranic acid) (13.62 grams; 0.05 mole) was suspended in 100 ml of 1,2-dichloroethane and N-trimethylsilyl acetamide (26.25 grams; 0.200 mole) was added. The reaction mixture was heated to 400C and the solid dissolved to yield a cloudy solution, which was cooled to 200 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 300C. The reaction mixture was stirred for 2 hours, 100 ml of 1 ,2-dichloroethane 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 1,2-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 "Darco 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 300C 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 - 1H - tetrazole - 5 - thiol (6.39 grams; 55 mmole) in 250 ml of 1,2-dichloroethane was added and the reaction mixture heated to reflux. Water (apparently remaining from 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 temperature and seeded to precipitate the product, 3 - (((I - methyl - IH - 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 1,2-dichloroethane, 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 - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 formyloxy - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylic Acid in 1,2-Dichloroethane 7 - (2 - Formyloxy - 2 - phenylacetamido)cephalosporanic acid (2.33 grams; 5 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (0.64 gram; 5.5 mmole) were added to 25 ml of 1,2-dichloroethane 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 (770C). 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 500C 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.
EXAMPLE 63 Preparation af 3 - (((3 - (Benzyloxycarbonylaminomethyl) - 1,2,4 - triazol - 5 yl)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 carboxylic Acid in Nitromethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (2 grams; 5 mmole) and 3 - (benzyloxycarbonylaminomethyl) - 1,2,4 - triazole - 5 - thiol (2 grams; 7.6 mmole) in 35 ml of nitromethane were heated at 80--900C for 6 hours, with stirring. The reaction mixture was cooled and filtered to separate the product. It was recrystallized twice from aqueous acetone, 1.2 grams of cream colored crystals, m.p. 174--178"C (dec.) (40 percent yield).
Anal., Calc. for C25H34N6O6S3: 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) - 1H - tetrazol - 5 - yl)thio)methyl) 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Acetonitrile 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (1.0 gram; 2.5 mmole) and 1 - (carboxymethyl) - 1H - tetrazole - 5 - 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 1N HCI 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.
EXAMPLE 65 Preparation of 3 - (((5 - Methyl - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (3 chloropropionamido) - 3 - cephem - 4- carboxylic Acid in Nitromethane A stirred suspension of 7 - (3 - chloropropionamido)cephalosporanic acid (1.0 gram; 2.5 mmole) and 5 - methyl - 1,3,4 - 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, 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 C16H19ClN4O4S3: C, 41.51; H, 4.14; N, 12.10; S, 20.78; Cl, 7.66 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 - triazol - 5 - yl)thio)methyl) - 7 (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in 1,2 Dichloroethane 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (200 mg; 0.5 mmole) and 1 - benzyl - 1H - 1,2,3 - triazole - 5 - thiol (140 mg; 0.7 mmole) were mixed in 15 ml of 1,2-dichloroethane 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 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 HCI 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, 76 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 7 - Methoxy - 7 -
Anal., Calc. for Cl8Hl7NgO7S2 C, 37.57; H, 3.35; N, 24.65 Found: C, 36.96; H, 3.80; N, 27.63 3 - (((1,3,4 - triazol - 5 - yl)thio)methyl) - 7 - methoxy - 7 - (2 - (IR - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic acid Anal., Calc. for C14H15N9O5S2: 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 - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (4 ethyl - 2,3 - dioxo - I - piperazinylcarbonylamino) - 2 phenylacetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7- (2 - (4 - Ethyl - 2,3 - dioxopiperazinylcarbonylamino) - 2phenylacetamido)cephalosporanic acid hydrate (0.3 gram; 0.5 mmole) and I methyl - IH - 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 85CC., 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 NaCI 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 a 1.2 (t, 3, -NCH2CH3, J=7 Hz), 3.65 (m, 6, N-CH2CH3 and piperazinyl H), 4.0 (s, 3, -CH3 of tetrazole), 4.4 (s, 2, 3-CH2S-), 5.1 (d, 1, C8-H, J=6 Hz), 5.8 (d, 1, C7-H, J=8 Hz), 6.0 (d, 1,
J=6 Hz), 7.4 (m, 5, phenyl-H), 8.4 (d, 1, -CHCONH-, J=8 Hz), and 10.0 (d, 1,
J=6 Hz).
EXAMPLE 74 Preparation of 3 - ((( I - Carboxymethyl) - I H - tetrazol - 5 - yl)thio)methyl) - 7 (2 - (4 - ethyl - 2,3 - dioxo - 1 - piperazinyl - carbonylamino) - 2 phenylacetamido) - 3 - cephem - 4 - carboxylic 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 C to azeotrope off water. After 40 ml of solvent had been collected, nitromethane (10 ml) and 1 - (carboxymethyl) - 1H - tetrazole - 5 thiol (0.160 gram; 1 mmole) were added and the reaction mixture maintained at 90 C for 12 hours under nitrogen. The reaction mixture was filtered and solvent evaporated, yielding a gum to which ethyl acetate and saturated sodium bicarbonate solution were added. The mixture was washed twice with ethyl acetate, then fresh ethyl acetate was added and the mixture cooled to 0 C and adjusted to pH 2.3 with 20% HCI. The layers were separated and the aqueous layer was washed with ethyl acetate. The ethyl acetate layers were combined and washed with saturated HCI, dried over anhydrous magnesium sulfate, filtered, evaporated, and dried at room temperature, 123 mg. The identity of the product was confirmed by NMR, a 1.2 (t, 3, -NCH2CH3, J=7 Hz), 3.6 (m, 4, N-CH2CH3 and piperazinyl 5 H), 4.1 (m, 2, piperazinvl-4H), 4.4 (s, 2, 3--CH2S-), 5.1 (d, 1, C6-H, J=5 Hz), 5.3 (s, 2, tetrazole l-CH2COOH), 5.75 (d, 1, C7-H. J=6 Hz), 5.9 (d, 1,
7.4 (m, 5, phenyl H), and 9.9 (d, 1,
J=7 Hz).
* EXAMPLE 75 Preparation of 3 - (((4,5 - Dihydro - 4 - methyl - 6 - hydroxy - 5 - oxo - 1,2,4 triazin - 3 - yl)thio)methyl) - 7 - (2 - (4 - ethyl - 2,3 - dioxo - I - piperazinylcarbonylamino) - 2 - phenylacetamido) - 3 - cephem - 4 carboxylic Acid in Nitromethane 7 - (2 - (4 - Ethyl - 2,3 - dioxo - 1 - piperazinylcarbonylamino) - 2 phenylacetamido)cephalosporanic acid hydrate (0.3 gram; 0.5 mmole) and 4,5 dihydro - 4 - methyl - 6 - hydroxy - 5 - oxo - 1,2,4 - triazine - 3 - thiol (0.111 gram; 0.625 mmole) were dissolved in 10 ml of nitromethane under nitrogen at room temperature, and the reaction mixture heated at 850C for 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 either, 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 a 1.1 (t, 3, -NCH2CH3), 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, C6-H, J=5 Hz), 5.75 (m, 2,
and C7-H), 7.45 (m, 5, phenyl H),9.5 (d, 1, -CHCONH-, J=8 Hz) and 10.0 (d, 1,
J=Hz).
EXAMPLE 76 Preparation of 3 - (((5 - Methylthio - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 (2 - (1H - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7 - (2 - (1H - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (15.0 grams; 39.2 mmole) and 5 - (methylthio) - 1,3,4 - thiadiazole - 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 950C and the reaction mixture was maintained at 950C for 6 hours, then cooled overnight, filtered, washed with 250 ml of nitromethane, and dried at 450C for 4 hours, 18.08 gram (94.9% yield).
This product was added to 150 ml of water and 4.0 ml of acetic acid. The pH was adjusted to 6.3 with 1N NaOH (required 107 ml) and the mixture was stirred for 1 hour. A solution of 257 ml of 60% sodium lactate and 65 ml of ethanol was then added, and the resulting 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 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 of 3 - (((5 - Methyl - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (2 (1H - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylic Acid in Various Solvents 7 - (2 - (1H - Tetrazol - 1 - yl)acetamido)cephalosporanic acid was reacted with 5 - methyl - 1,3,4 - 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).
Amt. of Cephalo Temperature Time %Yield sporanic acid Analysis Amt. of Thiol Solvent reflux 24 hours 87 190 C 1.91 g 0.86 g acetonitrile (sieve dried) 85 C and 16 hours 83 181 C (dec.) 0.96 g 0.363 g nitrobenzene 100 C 72 hours 0.96 g 0.5 g 1:1 mixture of 85 C 14 hours 88 182-183 C (dec.) 1,2-dichloroethane and nitromethane nitroethane 0.96 g 0.5 g 90 C 16 hours 84 177 C (dec.) 3.82 g 1.98 g propylene carbonate 95 C 8 hours 68 1.91 g 0.99 g ethylene carbonate 95 C 6 hours 22 2.02 g* 1.0 g acetic acid 85 C 5 hours 55 1.92 g 0.79 g mixture of 52.5% 95 C 3 hours 89 nitromethane and 50 mins 47.5%2-nitropropane *as the sodium salt EXAMPLE 85 Preparation of Lithium 3 - (((1 - Methyl - IH - tetrazol - 5 - yl)thio)methyl) - 7 (2 - hydroxy - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylate in Glacial Acetic Acid 7 - (2 - Hydroxy - 2 - phenylacetmido)cephalosporanic acid (0.48 gram; 1 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (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 I2 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% NaCI 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 crysrals (69.4% yield). The identity of the product was confirmed by NMR: # 3.50 (ABq, J#17 Hz), 3.92 (s, -CH3 of tetrazole), 4.20 (s, 3-CH2S-), 5.04 (d, C6-H, J=5 Hz), 5.24 (s, #CHCONH-), 5.64 (d, C7-H, J=5 Hz), and 7.44 (s, #-H). The NMR spectrum was identical with an NMR spectrum on an authentic sample of the product prepared by aqueous displacement.
EXAMPLE 86 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (o (tert - butoxycarbonylaminomethyl)phenyl)acetamido) - 3 - cephem 4 - carboxylic Acid in Nitromethane 7 - (2 - (o - (tert - Butoxycarbonylaminomethyl)phenyl)acetmido)cephalosporanic acid (0.2 gram; 0.386 mmole) and 1 - methyl - IH - tetrazole 5 - thiol (0.047 gram; 0.405 mmole) were reacted in 5 ml of nitromethane at 850C under nitrogen, for 12 hours, yielding 3 - (((1 - methyl - IH - tetrazol - 5 yl)thio)methyl) - 7 - (2 - (o - (tert - butoxycarbonylaminomethyl)phenyl)- acetamido) - 3 - cephem - 4 - carboxylic acid. Identity of the product was confirmed by NMR, a 1.45 (s, 9, -C(CH3)3, 3.65 (s, 4, 2-CH2 and -CH2CONH-), 3.85 (s, 3, -CH3 of tetrazole), 4.3 (m, 4, 3-CH2S- and -CH2NHCOO-tert-C4H9), 5.0 (d, 2, C6-H, J=4 Hz), 5.7 (q, 1, C7-H), 7.25 (s, 5, phenyl-H and -CONH-), and 8.9 (s, 1, -COOH).
EXAMPLE 87 Preparation of 3 - (((1 - Methyl - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 ureido - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7 - (2 - Ureido - 2 - phenylacetamido)cephalosporanic acid (0.224 gram; 0.5 mmole) and 1 - methyl - 1H - 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 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - ureido - 2 - phenylacetamido) - 3 cephem - 4 - carboxylic acid. Identity of the product was confirmed by NMR, # 3.5 (d, 2, 2-CH2, J=3 Hz), 3.83 (s, 3, -CH3 of tetrazole), 4.17 (d, 2, 3-CH2S-, J=3 Hz), 4.9 (d, 1, C6-H, J=5 Hz), 5.4 (d, 1, -CH2CONH-, J=8 Hz) 5.6 (m, 3, C7-H and -NH2), 6.7 (d, 1,
J=8 Hz), 7.25 (m, 5, phenyl H), and 9.2 (d, 1, -CH2CONH-, J=8 Hz).
EXAMPLE 88 Preparation of 3 - (((I - Methyl - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 cyanoacetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7 - (2 - Cyanoacetamido)cephalosporanic acid (0.339 gram; 1 mmole) and 1 methyl - 1H - tetrazole - 5 - thiol (0.122 gram; 1.05 mmole were reacted in 10 ml of nitromethane at 85 C inder nitrogen, for 12 hours, yielding 3 - (((1 - methyl 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - cyanoacetamido) - 3 - cephem - 4 carboxylic acid. Identity of the product was confirmed by NMR, # 3.5 (s, 2, 2- CH2), 3.65 (s, 2, CNCH2CONH-), 3.95 (s, 3, -CH3 of tetrazole), 5.35 (s, 2, 3 CH2S-), 5.1 (d, 1, C6-H, J=6 Hz), 5.75 (q, 1, C7-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 - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 (m - chlorophenylthio)acetamido) - 3 - cephem - 4 - carboxylic Acid in Nitromethane 7 - (2 - (m - Chlorophenylthio)acetamido)cephalosporanic acid (0.390 gram; 0.855 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (0.104 gram; 0.9 mmole) were reacted in 10 ml of nitromethane at 850C under nitrogen, for 12 hours, yielding 3 - (((I - methyl - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (m chlorophenylthio)acetamido) - 3 - cephem - 4 - carboxylic acid. Identity of the product was confirmed by NMR # 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, C6-H, J=5 Hz), 5.8 (q, 1, C7-H, J=4 Hz), 7.15 (m, 4, phenyl-H), 7.7 (d, 1, -CH2CONH-, J=8 Hz), and 8.5 (s, 1, COOH).
EXAMPLE 90 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl - 7 - (2 (phenylthio)acetamido) - 3 - cephem - 4- carboxylic Acid in Nitromethane 7 - (2 - Phenylthio)acetamido)cephalosporanic acid (0.422 gram; 1 mmole) and I - methyl - 1H - tetrazole - 5 - thiol (0.122 gram; 1.05 mmole) were reacted in 10 ml of nitromethane at 850C under nitrogen, for 12 hours, yielding 3 - (((I - methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (phenylthio)acetamido) - 3 cephem - 4 - carboxylic acid. Identity of the product was confirmed by NMR, # 3.7 (s, 4, -CH2CONH- and 2-CH2), 3.9 (s, 3, -CH3 of tetrazole), 4.35 (s, 2, 3 CH2S-), 4.9 (d, 1, C6-H, J=6 Hz), 5.8 (q, 1, C7-H, J=4 Hz), 7.25 (s, 5, phenyl H), 7.7 (d, I, -CH2CONH-, J=8 Hz), and 9.4 (s, 1, -COOH).
EXAMPLE 91 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic Acid in n-Butylformate 7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid (3.96 gram; 10 mmole) and 1 - methyl - 1H - 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 - methyl - 1H 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.
EXAMPLE 92 Preparation of 3 - (((I - Methyl - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic 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 - 5 - yl)thio)methyl - 7 - (tert butoxycarbonylamino) - 3 - cephem - 4- carboxylic Acid in Nitromethane 7 - (tert - butoxycarbonylamino)cephalosporanic acid (0.372 gram; 1 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (0.122 gram; 1.05 mmole) were reacted in 10 ml of nitromethane at 800C for 12 hours, yielding 3 - (((1 - methyl - IH tetrazol - 5 - yl)thio)methyl - 7 - (tert - butoxycarbonylamino) - 3 - cephem 4 - carboxylic acid. The identity of the product was confirmed by NMR, # 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-CH2S-), 5.0 (s, 1, C6-H), 5.6 (s, 2, C7-H and -CH2CONH), and 13 (s, 1, -COOH).
EXAMPLE 94 Preparation of 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)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)cehalosporanic acid (0.180 gram; 0.306 mmole) and 1 methyl - 1H - tetrazole - 5 - thiol (0.0374 gram; 0.322 mmole) were reacted in 6 ml of nitromethane at 800C for 12 hours, yielding 3 - (((1 - methyl - 1H - tetrazol 5 - yl)thio)methyl) - 7 - (2 - (4 - ethyl - 2,3 - dioxopiperazinylcarbonylamino) 2 - (p - hydroxyphenyl)acetamido) - 3 - cephem - 4 - carboxylic acid. The identity of the product was confirmed by NMR, # 1.2 (t, 3, N-CH2CH3), 3.6 (m, 6, 2-CH2, piperazoinyl 6-H and N-CH2CH3), 3.9 (m, 2, piperazinyl 5-H), 3.95 (s, 3, -CH3 of tetrazole), 4.4 (s, 2, 3-CH2S-), 5.0 (d, 1, C6-H, J=6 Hz), 5.6 (d, 1, C7 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, phenyI-H, J=8 Hz), 8.3 (d, 1, -CHCONH-, J=8 Hz), and 9.9 (d, 1, J=6 Hz.
EXAMPLE 95 Preparation of 3 - (((1,3,4 - thiadiazol - 2 - yl)thio)methyl)- 7 - (2 - (1H tetrazol- 1 - yl)acetamido)- 3 - cephem - 4- carboxylic Acid in Acetonitrile 7 - (2 - (1H - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (0.38 gram; I mmole) and 1,3,4 - 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 - (((1,3,4 thiadiazol - 2 - yl)thio)methyl) - 7 - (2 - (lH - tetrazol - 1 - yl)acetamido) - 3 cephem - 4 - carboxylic acid. The identity of the product was confirmed by NMR, # 3.74 (m, 2, 2-CH2-), 4.48 (q, 2, 3-CH2S-, JAB=14), 5.16 (d, 1, C6-H, J=5), 5.42 (s, 2, -CH3 of tetrazolyl), 5.76 (q, 1, C7-H, J6.7=5, J7NH=8), 8.87 (s, 1, tetrazole ring), 9.40 (s, 1, thiadiazolethiol starting material), 9.53 (d, 1, -CH2CONH-, J=8 Hz), and 9.57 (s, 1, thiadiazole ring).
EXAMPLE 96 Preparation of 3 - (((5 - Methyl - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (5 carbomethoxy - 5- (2,4 - dichlorobenzamido)valeramido) - 3 cephem - 4 - carboxylic Acid in 1,2-Dichloroethane 7 - (5 - Carbomethoxy - 5 - (2,4 dichlorobenzamido)valeramido)cephalosporanic acid (0.3 gram; 0.5 mmole) and 5 - methyl - 1,3,4 - 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 - 1,3,4 thiadiazol- 2- yl)thio)methyl)- 7- (5 - carbomethoxy - 5- (2,4 dichlorobenzamido)valeramido) - 3 - cephem - 4 - carboxylic acid.
EXAMPLE 97 Preparation of Lithium 3 - (((1 - Methyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 (2 - (IH - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 - carboxylate in Acetonitrile 7 - (2 - (lH - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (1.91 gram; 5 mmole) and 1 - methyl - 1H - tetrazole - 5 - thiol (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 - (((I - methyl - lH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 (1H - tetrazol - 1 - 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 400 C., 1.60 grams (72% yield). The identity of the product was confirmed by NMR.
EXAMPLE 98 Preparation of 3 - (((5 - Methyl - 1,3,4 - thiadiazol - 2 - yl)thio)methyl) - 7 - (2 formyloxy - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylic Acid in 1,2-Dichloroethane 7 - (2 - Formyloxy - 2 - phenylacetamido)cephalosporanic acid (4.6 grams; 8.8 mmole) and 5 - methyl - 1,3,4 - thiadiazole - 2 - 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 - 1,3,4 - thiadiazol - 2 yl)thio)methyl) - 7 - (2 - formyloxy - 2 - phenylacetamido) - 3 - cephem - 4 carboxylic acid, precipitated as a thick paste. The mixture was diluted with an additional 50 ml of 1,2-dichloroethane and stirred 4 hours at room temperature.
The product was then separated by filtration, washed with 1,2-dichloroethane until the filtrate was clear, and vacuum dried at 40-45 C., 2.8 grams (63% yield). The identity of the product was confirmed by NMR.
EXAMPLE 99 Preparation of 3 - (((4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 triazin - 3 - yi)thio)methyl) - 7 - (2 - (lH - tetrazol - 1 - yl)acetamido) 3 - cephem - 4 - carboxylic Acid in Acetonitrile 7 - (2 - (lH - Tetrazol - 1 - yl)acetamido)cephalosporanic acid (8.9 grams; 23.2 mmole) and 4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 triazine - 3 - thiol (4.1 grams; 25.8 mmole) in 200 ml of acetonitrile were refluxed for 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 (86.6% yield). The identity of the product 3 - (((4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 triazin - 3 - yl)thio)methyl) - 7 - (2 - (lH - tetrazol - 1 - yl)acetamido) - 3 cephem - 4 - carboxylic acid, was confirmed by NMR.
EXAMPLES 100-144 Yet other reactions in accordance with the present process can be conducted as follows: 7 - (2 - Sulfo - 2 - phenylacetamido)cephalosporanic acid, sodium salt, is reacted with 1 - methyl - IH - tetrazole - 5 - thio, yielding 3 - (((I - methyl 1 H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - sulfo - 2 - phenylacetamido) - 3 cephem - 4 - carboxylic acid, sodium salt.
7 - (2 - (4 - Pyridylthio)acetamido)cephalosporanic acid is reacted with 1 methyl -H - tetrazole - 5 - thiol, yielding 3 - (((1 - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - (4 - pyridylthio)acetamido) - 3 - cephem - 4 carboxylic acid.
7 - (5 - Carbo - n - butoxy - 5 - (2,4 dichlorobenzamido)valeramido)cephalosporanic acid and 5- methyl - 1,3,4 - thiadiazole - 2 - thiol are reacted, yielding 3 - (((5 - methyl - 1,3,4 - thiadiazol 2- yl)thio)methyl) - 7 - (5 - carbo - n - butoxy - 5 - (2,4 dichlorobenzamido)valeramido) - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Carbo - n - butoxy - 5 - (2,4 dichlorobenzamido)cephalosporanic acid and 1 - methyl - 1H tetrazole - 5 - thiol are reacted yielding 3 - (((1 - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (5 - carbo - n - butoxy - 5 - (2,4 dichlorobenzamido)valeramido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (2 - (p - Nitrobenzyloxycarbonylamino)thiazol - 4 - yl) - 2 (methoxyimino)acetamido)cephalosporanic acid is reacted with 1 - methyl - 1H tetrazole - 5 - thiol, yileding 3 - (((1 - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - (2 - (p - nitrobenzyloxycarbonylamino)thiazol -4 - yl) 2 - (methoxyimino)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (2 - (p - Nitrobenzyloxycarbonylamino)thiazol - 4 yl)acetamido)cephalosporanic acid is reacted with 1 - methyl 1H - tetrazole 5 - thiol yielding 3 - (((1 - methyl - 1H - terazol - 5 - yl)thio)methyl) - 7 - (2 (2 - (p - nitrobenzyloxycarbonylamino)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)thio)methyl) - 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)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - ((2,2,2 - Trichloroethoxy)carbonylamino)cephalosporanic acid is reacted with tetrazolo[l,5-blpyridazine - 6 - thiol, yielding 3 - (((tetrazolo[l,5- b]pyridazin - 6 - yl)thio)methyl) - 7 - ((2,2,2 - trichloroethoxy)carbonylamino) 3 - cephem - 4 - carboxylic acid.
7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid is reacted with tetrazolo[1,5-b]pyridazine - 6 - thio, 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) - 1H - tetrazole - 5 - thiol, sodium salt, yielding 3 - (((I (sulfomethyl) - IH - tetrazol - 5 - yl)thio)methyl)- 7 - ((2,2,2 trichloroethoxy)carbonylamino) - 3 - cephem - 4 - carboxylic acid, sodium salt.
7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid is reacted with 1 - (sulfomethyl)- iR - tetrazole - 5- thiol, sodium salt, yielding 3 - (((1 - (sulfomethyl) - 1H - 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) - 1H - tetrazole - 5 - thiol, yielding 3 - (((1 (2 - (dimethylamino) - ethyl) - 1H - 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 I - (2 (dimethylamino)ethyl - 1H - tetrazole - 5 - thiol, yielding 3 - (((1 - (2 (dimethylamino)ethyl - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid is reacted with p methoxybenzenethiol, yielding 3 - (((p - methoxyphenyl)thio)methyl) - 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)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid is reacted with otoluenethiol, yielding 3- (((o - tolyl)thio)methyl)- 7- (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (IH - Tetrazol - 1 - yl)acetamido)cephalosporanic acid is reacted with 1,3,4- thiadiazole - 2- thiol, yielding 3 - (((1,3,4 - thiadiazol- 2yl)thio)methyl) - 7 - (2 - (lH - tetrazol - I - yl)acetamido) - 3 - cephem - 4 carboxylic acid.
7 Phthalimidocephalosporanic acid is reacted with 5 - methyl - 1,3,4 - thiadiazole - 2 thiol, yielding 3 - (((5 - methyl - 1,3,4 - thiadiazol- 2yl)thio)methyl) - 7 - phthalimido - 3 - cephem - 4 - carboxylic acid.
7 - (2 - Hydroxy - 2 - phenylacetamido)cephalosporanic acid is reacted with 5 - methyl - 1,3,4 - thiadiazole - 2 - thiol, yielding 3 - (((5 - methyl - 1,3,4 thiadiazol - 2 - yl)thio)methyl) - 7 - (2 - hydroxy - 2 - phenylacetamido) - 3 cephem - 4 - carboxylic -acid.
7 - (2 - Aceto (sulfomethyl) - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - formyloxy - 2 phenylacetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - Hydroxy - 2 - phenylacetamido)cephalosporanic acid is reacted with 1 - (sulfomethyl) - 1H - tetrazole - 5 - thiol, sodium salt, to produce 3 - (((1 (sulfomethyl) - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - hydroxy - 2 phenylacetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (2 - Thienyl)acetamido)cephalosporanic acid is reacted with 2oxazolethiol to yield 3 - (((oxazol - 2 - yl)thio)methyl) - 7 - (2 - (2 thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - Formyloxy - 2- phenylacetamido)cephalosporanic acid and I (carboxymethyl) - 1 H - tetrazole - 5 - thiol are reacted to produce 3 - (((I - (carboxymethyl) - I H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - formyloxy - 2 phenylacetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (Trifluoromethylthio)acetamido)cephalosporanic acid and 1 methyl - 1H - tetrazole - 5 - thiol are reacted to prepare 3 - (((1 - methyl - 1H tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (trifluoromethylthio)acetamido) - 3 cephem - 4 - carboxylic acid.
7 - (2 - (Cyanomethylthio)acetamido)cephalosporanic acid is reacted with 1 methyl - 1H - tetrazole - 5 - thiol to produce 3 - (((1 - methyl - 1H - tetrazol 5 - yl)thio)methyl) - 7 - (2 - (cyanomethylthio)acetamido) - 3 - cephem - 4 carboxylic acid.
7 - Methoxy - 7 - (2 - (cyanomethylthio)acetamido)cephalosporanic acid is reacted with 1 - methyl - 1H - tetrazole - 5 - thiol to obtain 3 - (((1 - methyl 1H - tetrazol - 5 - yl)thio)methyl) - 7 - methoxy - 7 - (2 (cyanomethylthio)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - (o - Benzylaminomethylphenyl)acetamido)cephalosporanic acid and 1 - (carboxymethyl) - 1H - tetrazole - 5 - thiol are reacted to prepare 3 - (((1 (carboxymethyl) - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (o benzoylaminomethylphenyl)acetamido) - 3 - cephem - 4 - carboxylic acid.
7 - (2 - Ureido - 2 - (2 - thienyl)acetamido)cephalosporanic acid is reacted with 1 - methyl - 1H - tetrazole - 5 - thiol to obtain 3 - (((1 - methyl - 1H tetrazol - 5 - yl)thio)methyl) - 7 - (2 - ureido - 2 - (2 - thienyl)acetamido) - 3 cephem - 4 - carboxylic acid.
7 - (2 - (2 - Amino - 4 - thiazolyl)acetamido)cephalosporanic acid is reacted I -(2 - (dimethylamino)ethyl) - 1H - tetrazole - 5 - thiol to produce 3 - (((I - (2 dimethylamino)ethyl) - 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 - amino 4 - thiazolyl)acetamido)cephalosporanic acid.
7 - (5 - Benzoylamino - 5 - carboxyvaleramido)cephalosporanic acid is reacted with 4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 - triazine 3 - thiol to prepare 3 - (((4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo 1,2,4 - triazin - 3 - yl)thio)methyl)- 7 - (5 - benzoylamino - 5 carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Benzoylamino - 5 - carboxyvaleramido)cephalosporanic acid is reacted with 1 - methyl - 1H - 1,2,3 - triazole - 5 - thiol to prepare 3 - (((I methyl - IH - 1,2,3 - triazol - 5 - yl)thio)methyl) - 7 - (5 - benzoylamino - 5 carboxyvaleramido), - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Benzoylamino - 5 - carboxyvaleramido)cephalosporanic acid and 1 (carboxymethyl) - 1H - tetrazole - 5 - thiol are reacted to produce 3 - (((1 (carboxymethyl) - 1 H - tetrazol - 5 - yl)thio)methyl) - 7 - (5 - benzoylamino 5 - carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Benzoylamino - 5- carboxyvaleramido)cephalosporanic acid is reacted with 5 - methyl - 1,3,4 - oxadiazole - 2 - thiol to obtain 3 - (((5 - methyl 1,3,4 - oxadiazol - 2 - yl)thio)methyl) - 7 - (5 - benzoylamino - 5 carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Benzoylamino - 5 - carboxyvaleramido)cephalosporanic acid is reacted with 1 - benzyl - 1H - tetrazole - 5 - thiol to obtain 3 - (((1 - benzoyl 1H - tetrazol - 5 - yl)thio)methyl) - 7 - (5 - benzoyl - amino - 5 carboxyvaleramido)cephalosporanic acid.
7 - (5 - Benzoylamino - 5 - carboxyvaleramido)cephalosporanic acid is reacted with thiourea to obtain 3 - amidinothiomethyl - 7 - (5 - benzylamino 5 - carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.
7 - Methoxy - 7 - (5 - benzoylamino - 5 carboxyvaleramido)cephalosporanic acid is reacted with 1 - methyl - 1H tetrazole - 5 - thiol to obtain 3 - (((1 - methyl - lH - tetrazol- 5 yl)thio)methyl) - 7 - methoxy - 7 - (5 - benzoylamino - 5 - carboxyvaleramido) 3 - cephem - 4 - carboxylic acid.
7 - Methoxy - 7 - (5 - benzoylamino - 5 carboxyvaleramido)cephalosporanic acid is reacted with 5 - methyl - 1,3,4 - thiadiazole - 2- thiol to obtain 3 - (((5 - methyl - 1,3,4 - thiadiazol- 2yl)thio)methyl) - 7 - methoxy - 7 - (5 - benzoylamino - 5 - carboxyvaleramido) 3 - cephem - 4 - carboxylic acid.
7 - Methoxy - 7 - (5 - benzoylamino - 5 carboxyvaleramido)cephalosporanic acid is reacted with 4,5 - dihydro - 6hydroxy - 4 - methyl - 5 - oxo - 1,2,4 - triazine - 3 - thiol to obtain 3 - (((4,5 dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 - triazin - 3yl)thio)methyl) - 7 - methoxy - 7 - (5 - benzoylamino - 5 - carboxyvaleramido) 3 - cephem - 4 - carboxylic acid.
7 - Methoxy - 7 - (5 - benzoylamino - 5 carboxyvaleramido)cephalosporanic acid and thiourea are reacted to obtain 3 amidinothiomethyl - 7 - methoxy - 7 - (5 - benzoylamino - 5 carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Butoxycarbonylamino - 5 - carboxyvaleramido) - 3 carbamoyloxymethyl - 3 - cephem - 4 - carboxylic acid is reacted with thiourea to prepare 3 - amidinothiomethyl - 7 - (5 - butoxycarbonylamino - 5 carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.
7 - (5 - Butoxycarbonylamino - 5 - carboxyvaleramido) - 3 carboamoyloxymethyl - 3 - cephem - 4 - carboxylic acid is reacted with I methyl - 1H - tetrazole - 5 - thiol to obtain 3 - ((( I - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (5 - butoxycarbonyl - amino - 5 - carboxyvaleramido) - 3 cephem - 4 - carboxylic acid.
7 - (5 - Butoxycarbonylamino - 5 - carboxyvaleramido) - 3 carbamoyloxymethyl - 3 - cephem - 4 - carboxylic acid and 5 - methyl - 1,3,4 thiadiazole - 2 - thiol are reacted to prepare 3 - (((5 - methyl - 1,3,4 - thiadiazol 2 - yl)thio)methyl) - 7 - (5 - butoxycarbonylamino - 5 - carboxyvaleramido) - 3 cephem - 4 - carboxylic acid.
7 - (5 - Butoxycarbonylamino - 5 - carboxyaleramido) - 3 carbamoyloxymethyl - 3 - cephem - 4 - carboxylic acid and 1 (carboxymethyl) - 1H - tetrazole - 5 - thiol are reacted to prepare 3 - (((I (carboxymethyl) - 1H - tetrazol- 5- yl)thio)methyl)- 7- (5 butoxycarbonylamino - 5 - carboxyvaleramido) - 3 - cephem - 4 - carboxylic acid.

Claims (74)

WHAT WE CLAIM IS:
1. A process for preparing a cephalosporin compound of the formula
wherein R13 is
-C1-C4 alkyl,
R' is hydrogen or methoxy; R2 is phthalimido, succinimido, a radical of the formula
wherein L is hydrogen or nitroso, or a radical of the formula
R3 iS: (1) hydrogen, (2) C1-C6 alkyl, (3)-CH2-(C1-C3 chloroalkyl), (4)-CH2-(C1-C3 fluoroalkyl), (5) C1-C4 cyanoalkyl, (6) C1-C4 hydroxyalkyl, (7) p-nitrobenzyloxy, (8) tert-butoxy, (9) 2,2,2-trichloroethoxy, (10) a protected 4-amino-4-carboxybutyl radical of the formula
wherein A is a protected amino group and R12 is hydrogen or C1-C4 alkyl; (11) 4-oxo-4-carboxybutyl; (12) 3-carboxypropyl; (13) a radical of the formula
in which each of a and a is independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, or ACH2-wherein A is, as above, protected amino; Z is O or S; and m is 0 or 1; (14) a radical of the formula
wherein P is (a) 2thienyl, (b) 3-thienyl, or (c) a phenyl group of the formula
in which a and a' are as defined above; and wherein Q is (a) hydroxy, (b) formyloxy, c) acetoxy, (d) carboxy of the formula
wherein A2 is diphenylmethyl, p-nitrobenzyl, benzyl, 2,2,2-trichloroethyl, tert-butyl, or p-methoxybenzyl; (e) alkali metal oxysulfonyl, (f) a protected amino group (g) an acylated amino group of the formula
wherein T represents amino,
wherein R7 is hydrogen or C1-C3 alkyl; R8 is phenyl, halophenyl, furyl, monomethylamino, dimethylamino, monoethylamino, diethylamino, methylethylamino, propylamino, dipropylamino, diisopropylamino, phenylamino, or diphenylamino; R9 is hydrogen, C1-C4 alkyl, or phenyl; R10 is hydrogen, C1-C3 alkyl, or methylsulfonyl; and R11 is ethylene, trimethylene, or vinylene; (15) a radical of the formula
wherein P' is P as defined above, protected 2 - amino - 4 - thiazolyl, or 2-furyl; (16) a radical of the formula V-S(O)n-CH2-wherein V represents -CF3 or -CH2-X wherein X represents hydrogen, methyl, CF3, CN, or N3, and n represents 0, 1, or 2; or (17) a radical of the formula Y-CH2- in which Y is 2-thienyl, 3-thienyl, 2furyl, 2-oxazolyl, 2-thiazolyl, I-tetrazolyl, I-benzotriazolyl, 2-oxazolylthio, 2thiazolylthio, 1,2,3-triazol-5-ylthio, 1,3,4-triazol-2-ylthio, 1,3 ,4-thiadiazol-2-ylthio, protected 5 - amino - 1,3,4 - thiadiazol - 2 - ylthio, 5 - methyl - 1,3,4 thiadiazol - 2 - ylthio, 1,2,4 - thiadiazol - 5 - ylthio, 3 - methyl - 1,2,4 thiadiazol - 5 - ylthio, 1,2,5 - thiadiazol - 3 - ylthio, 1,3,4 - oxadiazol - 2 - ylthio, 5 - methyl - 1,3,4 - oxadiazol - 2 - ylthio, 1 - methyl - 5 - tetrazolylthio, pyridylthio, 4-cyano-1,2,3-triazol-1-yl, 3 - cyano - 1,2,4 - triazol - 1 - yl, or protected 2 - amino - 4 - thiazolyl; each R4 is independently hydrogen, C1-C4 alkyl, C3-C3 alkenyl, cyclohexyl, or phenyl; each R5 is independently C1-C4 alkyl, C1-C4 alkoxy, halo, hydroxy, nitro, cyano, methaesulfonamido, or trifluoromethyl; and R6 is a unit which with the
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: 1 nitrogen and 0 or 1 oxygen or sulfur, 2 nitrogens and 0 or 1 oxygen or sulfur, 3 nitrogens, and 0 or 1 oxygen, or 4 nitrogens, all other ring atoms being carbon; or a unit which with the
comprises 2-benzoxazolyl, or a radical of the formula
which process comprises reacting a compound of the formula
wherein R and R are as defined above, and R is C1-C3 alkyl, C4-C6 cycloalkyl, amino, mono- or di(C1-C3 alkyl) amino,
with a sulfur nucleophile of the formula R13-S-R14 III wherein R'3 is as defined above, and R'4 is hydrogen, or when and only when R'3 is a methyleneaminium group, R'4 combines with R'3 and the S atom to form a thiourea; in an organic solvent under essentially anhydrous conditions.
2. A process of claim I wherein the temperature is from 50"C to 1400C.
3. A process of claim 2 wherein the temperature is from 70"C to 1200C.
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.
5. A process of claim 4 wherein the solvent is acetonitrile, 1,2-dichloroethane, methylene choride, propionitrile, nitromethane, nitroethane, acetic acid, isopropyl acetate, butyl acetate or methyl isobutyl ketone.
6. A process of claim 4 wherein the solvent is fluorobenzene, thiophene, methyl ethyl ketone, l,l,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 nitromethane.
8. A process of claim 5 wherein the solvent is propionitrile.
9. A process of claim 5 wherein the solvent is acetonitrile.
10. A proces of claim 5 wherein the solvent is acetic acid.
11. A process of claim 5 wherein the solvent is 1,2-dichloroethane.
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 C1-C3 alkyl, C4-C6 cycloalkyl, amino, or mono- or di(C1-C3 alkyl) amino is reacted with a compound of Formula 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 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 a compound of Formula I wherein R' is hydrogen and R2 is 2 - (2 - thienyl)acetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
16. 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 a compound of Formula I wherein R' is hydrogen, R2 is 2 - (2 - thienyl)acetamido and R'3 is a heteroaryl group wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III wherein R'3 is a heteroaryl group.
18. A process of claim 17 for preparing 3 - (((I - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid wherein 7 - (2 - (2 - thienyl)acetamido)cephalosporanic acid is reacted with 1 - methyl - 1H - tetrazole - 5 - thiol.
19. A process of claim 17 for preparing 3 - (((4,5 - dihydro - 6 - hydroxy - 4 methyl - 5 - oxo - 1,2,4 - 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 - 6hydroxy - 4 - methyl - 5 - oxo - 1,2,4 - triazine - 3 - thiol.
20. A process of claim 17 for preparing 3 - ((((5 - methyl - 1,3,4 - oxadiazol 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 5 - methyl - 1,3,4 - oxadiazole - 2 - thiol.
21. A process of claim 17 for preparing 3 - (((5 - methyl - 1,3,4 - thiadiazol 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 5 - methyl - 1,3,4 - thiadiazole - 2 - thiol.
22. A process of claim 17 for preparing 3 - (((benzothiazol- 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-mercaptobenzothiazole.
23. A process of claim 17 for preparing 3 - (((5 - (N - methylacetamido) 1,3,4 - thiadiazol - 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 5 - (N methylacetamido) - 1,3,4 - thiadiazole - 2 - thiol.
24. A process of claim 17 for preparing 3 - (((3 - methyl - 1,2,4 - oxadiazol 5 - yl)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 - carboxylic acid wherein 7 - (2 - (2 - thienyl)acetamido)cephalosporanic acid is reacted with 3 - methyl - 1,2,4 - oxadiazole - 5 - thiol.
25. A process of claim 17 for preparing 3 - (((3 - methyl - 1,2,4 - thiadiazol 5 - yl)thio)methyl) - 7 - (2 - (2 - thienyl) - acetamido)- 3 - cephem - 4 - carboxylic acid wherein 7 - (2 - (2 - thienyl)acetamido)cephalosporanic acid is reacted with 3 - 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 - carboxlic acid wherein 7 - (2 (2 - thienyl)acetamido)cephalosporanic acid is reacted with 2mercaptopyrimidine.
27. A process of claim 17 for preparing 3- (((4- phenylthiazol - 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 4 - phenyl - 2 - thiazolethiol.
28. A process of claim 17 for preparing 3 - (((1 - (carboxymethyl) - 1H tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 - thienyl)acetamido) - 3 - cephem - 4 carboxylic acid wherein 7 - (2 - (2 - thienyl)acetamido)cephalosporanic acid is reacted with 1 - (carboxymethyl) - 1H - tetrazole - 5 - thiol.
29. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2 - (1H - tetrazol - I - yl)acetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
30. A process of claim 29 for preparing a compound of Formula I wherein R' and R2 are as defined in claim 30 and R'3 is a heteroaryl group wherein a compound of Formula II wherein R' and R2 are as defined in claim 29 is reacted with a compound of Formula III which is a heteroarylthiol.
31. A process of claim 30 for preparing 3 - (((5 - methyl - 1,3,4 - thiadiazol 2 - yl)thio)methyl) - 7 - (2 - (lH - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 carboxylic acid wherein 7 - (2 - (lH - tetrazol - 1 - yl)acetamido)cephalosporanic acid is reacted with 5 - methyl - 1,3,4 - thiadiazole - 2 - thiol.
32. A process of claim 30 for preparing 3 - (((1,3,4 - thiadiazol - 2 yl)thio)methyl) - 7 - (2 - (lH - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 carboxylic acid wherein 7 - (2 - (lH - tetrazol - 1 - yl)acetamido)cephalosporanic acid is reacted with 1,3,4 - thiadiazole - 2 - thiol.
33. A process of claim 30 for preparing 3 - (((1 - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - (lH - tetrazol - 1 - yl)acetamido) - 3 - cephem - 4 carboxylic acid wherein 7 - (2 - (1H - tetrazol - 1 - yl)acetamido)cephalosporanic acid is reacted with I - methyl - 1H - tetrazole - 5 - thiol.
34. A process of claim 30 for preparing 3 - (((oxazol - 2 - yl)thio)methyl) - 7 (2 - (lH - tetrazol - I - yl)acetamido) - 3 - cephem - 4 - carboxylic acid wherein 7 - (2 - (lH - tetrazol - 1 - yl)acetamido)cephalosporanic acid is reacted with 2oxazolethiol.
35. A process of any of claims 1-14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2 - hydroxy - 2 - phenylacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
36. A process of claim 35 for preparing 3 - (((I - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - hydroxy - 2 - phenylacetamido) - 3 - cephem - 4 - carboxylic acid wherein 7 - (2 - hydroxy - 2 - phenylacetamido)cephalosporanic acid is reacted with 1 - methyl - 1H - tetrazole - 5 - thiol.
37. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2 - formyloxy - 2 - phenylacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
38. A process of claim 37 for preparing 3 - (((1 - methyl - IH - tetrazol - 5 yl)thio)methyl) - 7 - (2 - formyloxy - 2 - phenylacetamido) - 3 - cephem - 4 carboxylic acid wherein 7 - (2 - formyloxy - 2 phenylacetamido)cephalosporanic acid is reacted with I - 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 - arboxylic acid wherein 7 - (2 - formyloxy - 2 - phenylacetamido)cephalosporanic acid is reacted with 2oxazolethiol.
40. A process of any of claims 1-14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is formamido wherein a compound of Formula II wherein R1 and R2 are as defined above, is reacted with a compound of Formula III.
41. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is acetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
4i!. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2-phenylacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
43. A process of claim 42 for preparing 3 - (((5 - methyl - 1,3,4 - thiadiazol 2 - yl)thio)methyl) - 7 - (2 - phenylacetamido) - 3 - cephem -4 - carboxylic acid wherein 7- (2 - phenylacetamido)cephalosporanic acid is reacted with 5methyl - 1,3,4 - thiadiazole - 2 - thiol.
44. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is methoxy and R2 is 2-phenylacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
45. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2-phenoxyacetamido wherein a compound of Formula II wherein R1 and R2 are as defined above is reacted with a compound of Formula III.
46. A process of any of claims 1--14 for preparing a compound of Formula I wherein R1 is hydrogen and R2 is 2 - (protected amino) - 2 - phenylacetamido wherein a compound Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
47. A process of claim 1--14 for preparing 3 - (((1 - methyl - 1H - tetrazol 5 - yl)thio)methyl) - 7- (N- ((1,3- dimethyl- ureido)carbonyl)- 2phenylglycylamido) - 3 - cephem - 4 - carboxylic acid wherein 7 - (N - ((1,3 dimethylureido)carbonyl) - 2- phenylglycylamido) cephalosporanic acid is reacted with 1 - methyl - 1H - tetrazole - 5 - thiol.
48. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2 - ((4 - ethyl - 2,3 - dioxo - 1 - piperazinyl)carbonylamino) - 2 (p - hydroxyphenyl)acetamido wherein a compound of Formula II wherein R' and R2 are as defined above, is reacted with a compound of Formula III.
49. A process of claim 48 for preparing 3 - (((I - methyl - IH - tetrazol - 5 yl)thio)methyl) - 7 - (2 - ((4 - ethyl - 2,3 - dioxo - 1 piperazinyl)carbonylamino) - 2 - (p - hydroxyphenyl)acetamido) - 3 - cephem 4 - carboxylic acid wherein 7 - (2 - ((4 - ethyl - 2,3 - dioxo - 1 piperazinyl)carbonylamino) - 2 - (p - hydroxyphenyl)acetamido)cephalosporanic acid is reacted with 1 - methyl - IH - tetrazole - 5 - thiol.
50. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is methoxy and R2 is 2 - (lH - tetrazol - 1 - yl)acetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
51. A process of any of claims 1--14 for preparing a compound of Formula I wherein R'3 is a heteroaryl group wherein a compound of Formula II wherein R, R' and R2 are as defined in any of claims 1 or 12-14 is reacted with a compound of Formula III wherein R'3 is a heteroaryl group.
52. A process of claim 51 for preparing a compound of Formula I wherein R'3 is 1H - tetrazol - 5 - yl wherein a compound of Formula II wherein R, R' and R2 are as defined in claim 51 is reacted with 1 H-tetrazole-5-thiol.
53. A process of claim 51 for preparing a compound of Formula I wherein R13 is 1 - methyl - 1H - tetrazol - 5 - yl wherein a compound of Formula II wherein R, R and R are as defined in claim 51 is reacted with 1 - methyl - 1H tetrazole - 5 - thiol.
54. A process of claim 51 for preparing a compound of Formula I wherein R'3 is 1 - (carboxymethyl) - 1H - tetrazol - 5 - yl wherein a compound of Formula II wherein R, R' and R2 are as defined in claim 51 is reacted with 1 - (carboxymethyl) - 1H - tetrazole - 5 - thiol.
55. A process of claim 51 for preparing a compound of Formula I wherein R13 is 1,3,4 - thiadiazol - 5 - yl wherein a compound of Formula II wherein R, R1 and R2 are as defined in claim 51 is reacted with 1,3,4 - thiadiazole - 5 - thiol.
56. A process of claim 63 for preparing a compound of Formula I wherein R'3 is 5 - methyl - 1,3,4 - thiadiazol - 2 - yl wherein a compound of Formula II wherein R, R' and R2 are as defined in claim 51 is reacted with 5 - methyl - 1,3,4 thiadiazole - 2 - thiol.
57. A process of claim 51 for preparing a compound of Formula I wherein R'3 is triazolyl wherein a compound of Formula II wherein R, R' and R2 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'3 is 4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 - triazin - 3 - yl wherein a compound of Formula II wherein R, R' and R2 are as defined in claim 51 is reacted with 4,5 - dihydro - 6 - hydroxy - 4 - methyl - 5 - oxo - 1,2,4 triazine - 3 - thiol.
59. A process of claim 51 for preparing a compound of Formula I wherein R13 is tetrazolo[1,5-b]pyridazin - 6 - yl 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 - (((oxazol - 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-oxazolethiol.
61. A process of claim 37 for preparing 3 - (((I - (carboxymethyl) - 1H tetrazol - 5 - yl)thio)methyl) - 7 - (2 - formyloxy - 2 - phenylacetamido) - 3 cephem - 4 - carboxylic acid wherein 7 - (2 - formyloxy - 2 phenylacetamido)cephalosporanic acid is reacted with 1 - carboxymethyl - 1H tetrazole - 5 - thiol.
62. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2-trifluoromethylthioacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
63. A process of claim 62 for preparing 3 - (((1 - methyl - 1H - tetrazol - 5 yl)thio)methyl) - 7 - (2 - trifluoromethyl - thioacetamido - 3 - cephem - 4 carboxylic acid wherein 7 - (2 - trifluoromethylthioacetamido)cephalosporanic acid is reacted with I - methyl - IH - tetrazole - 5 - thiol.
64. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2-cyanomethylthioacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
65. A process of claim 64 for preparing 3 - (((I - methyl - 1H - tetrazol - 5 yl)thio)methyl)- 7 - (2 - cyanomethylthioacetamido) - 3 - cephem - 4carboxylic acid wherein 7 - (2 - cyanomethylthioacetamido)cephalosporanic acid is reacted with I - methyl - 1H - tetrazole - 5 - thiol.
66. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is methoxy and R2 is cyanomethylthioacetamido wherein a compound of Formula II wherein R' and R2 are as defined above is reacted with a compound of Formula III.
67. A process of claim 66 for preparing 3 - (((I - methyl - 1H - tetrazol - 5 yl)thio)methyl)- 7 - methoxy - 7 - (2 - cyanomethylthioacetamido) - 3 cephem - 4 - carboxylic acid wherein 7 - methoxy - 7 - (2 cyanomethylthioacetamido)cephalosporanic acid is reacted with I - methyl - 1H tetrazole - 5 - thiol.
68. A process of any of claims 1--14 for preparing a compound of Formula I wherein R' is hydrogen and R2 is 2 - (o - protected aminomethylphenyl)acetamido wherein a compound of Formula II wherein R1 and R2 are as defined above is reacted with a compound of Formula III.
69. A process of claim 1--14 for preparing 3 - (((I - methyl - 1H - tetrazol 5 - yl)thio)methyl) - 7 - (2 - ureido - 2 - (2 - thienyl)acetamido) - 3 - cephem 4 - carboxylic acid wherein 7 - (2 - ureido - 2 - (2 thienyl)acetamido)cephalosporanic acid is reacted with 1 - methyl - IH tetrazole - 5 - thiol.
70. A process of claim 1--14 for preparing 3 - (((1 - (2 (dimethylamino)ethyl) - IH - tetrazol - 5 - yl)thio)methyl) - 7 - (2 - (2 - amino 4 - thiazolyl)acetamido) - 3 - cephem - 4 - carboxylic acid wherein 7 - (2 - (2 amino - 4 - thiazolyl)acetamido)cephalosporanic acid is reacted with 1 - (2 - (2 dimethylamino)ethyl) - lR - 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 I 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.
GB8224/78A 1977-03-07 1978-03-02 Cephalosporin synthesis Expired GB1597036A (en)

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 (1)

Publication Number Publication Date
GB1597036A true GB1597036A (en) 1981-09-03

Family

ID=27118982

Family Applications (1)

Application Number Title Priority Date Filing Date
GB8224/78A Expired GB1597036A (en) 1977-03-07 1978-03-02 Cephalosporin synthesis

Country Status (30)

Country Link
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)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020099858A1 (en) * 2018-11-12 2020-05-22 Imperial College Of Science, Technology And Medicine Cephalosporin ciprofloxacin hybrid compounds

Families Citing this family (6)

* Cited by examiner, † Cited by third party
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
CA2828114A1 (en) * 2010-02-26 2011-09-01 Gary Igor DMITRIENKO Cephalosporin derivatives useful as .beta.-lactamase inhibitors and compositions and methods of use thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
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
AU1303576A (en) * 1975-04-21 1977-10-20 Erba Carlo Spa Cephalosporins

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020099858A1 (en) * 2018-11-12 2020-05-22 Imperial College Of Science, Technology And Medicine Cephalosporin ciprofloxacin hybrid compounds

Also Published As

Publication number Publication date
CS205115B2 (en) 1981-04-30
IL54181A0 (en) 1978-06-15
BG31379A3 (en) 1981-12-15
GR68893B (en) 1982-03-15
NL190703B (en) 1994-02-01
FR2383189B1 (en) 1981-06-26
AU515428B2 (en) 1981-04-02
AT366696B (en) 1982-04-26
NL190703C (en) 1994-07-01
SE437991B (en) 1985-03-25
NL7802376A (en) 1978-09-11
DD137356A5 (en) 1979-08-29
IT1093504B (en) 1985-07-19
CY1196A (en) 1983-12-31
DE2809058C2 (en) 1989-02-09
FR2383189A1 (en) 1978-10-06
DE2809058A1 (en) 1978-09-14
CA1083141A (en) 1980-08-05
AU3382878A (en) 1979-09-06
IL54181A (en) 1981-03-31
PT67732A (en) 1978-04-01
FI69309B (en) 1985-09-30
ES467637A1 (en) 1980-04-01
PL205135A1 (en) 1979-06-04
IE780453L (en) 1978-09-07
JPH025758B2 (en) 1990-02-05
FI69309C (en) 1986-01-10
IE46437B1 (en) 1983-06-15
YU51478A (en) 1982-10-31
SE7802530L (en) 1978-09-08
DK97378A (en) 1978-09-08
IT7820912A0 (en) 1978-03-06
MX5142E (en) 1983-03-30
HK49083A (en) 1983-11-04
PH14596A (en) 1981-10-02
EG13454A (en) 1981-12-31
FI780716A (en) 1978-09-08
NZ186610A (en) 1979-11-01
ATA150778A (en) 1981-09-15
HU179967B (en) 1983-01-28
CH637964A5 (en) 1983-08-31
PL122152B1 (en) 1982-06-30
JPS53130689A (en) 1978-11-14

Similar Documents

Publication Publication Date Title
CA1316171C (en) Cephalosporin derivatives
US4470983A (en) Cephalosporin derivatives
HU177441B (en) Process for preparing syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid derivatives
US4144391A (en) Cephalosporin displacement reaction
EP0293771A2 (en) Cephalosporin compound and pharmaceutical composition thereof
CA1083141A (en) Cephalosporin displacement reaction
CA1273628A (en) Antibacterial compounds
US4091211A (en) Cephalosporins
CA1130278A (en) Production of cephalosporins
US4117125A (en) 7-Acylamino-3-[1-[2-(carboxymethylamino]ethyl) tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids
US4093723A (en) 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl) cephalosporins
KR830001278B1 (en) Process for preparing cephalosporin compound
US4117124A (en) 7-Acylamino-3-[[3-(carboxymethyl)thio-1H-1,2,4-triazol-5-yl]thiomethyl]-3-cephem-4-carboxylic acids
US4239758A (en) Cephalosporins
US4117123A (en) 7-Acylamino-3-[1-(2-sulfamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids
US4079134A (en) 7-Acylamino-3-(5-sulfomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acids
US4174323A (en) 1-(2-Sulfamidoethyl)-1,4-dihydro-5H-tetrazole-5-thione
US4229573A (en) 7α-Methoxycephalosporin derivatives
GB1589881A (en) Cephalosporin compounds
US4210587A (en) 7-Acylamino-3-[1-[2-(carboxymethylamino)ethyl]tetrazol-5-ylthio methyl]-3-cephem-4-carboxylic acids
CA1057738A (en) (((alkylthiocarbonyl)oxy) acetyl) cephalosporins
US4174324A (en) 3-(Carboxymethyl)thio-1H-1,2,4-triazol-5-thione
JP2975949B2 (en) Novel cephalosporin derivatives and their salts
US4963542A (en) Cephalosporin derivatives
KR810000759B1 (en) Process for preparing cephalosporin derivatives

Legal Events

Date Code Title Description
PS Patent sealed [section 19, patents act 1949]
704A Declaration that licence is not available as of right for an excepted use (par. 4a/1977)
PCNP Patent ceased through non-payment of renewal fee

Effective date: 19970302