CA1050531A - Process for preparing cephalosporin derivatives - Google Patents
Process for preparing cephalosporin derivativesInfo
- Publication number
- CA1050531A CA1050531A CA214,609A CA214609A CA1050531A CA 1050531 A CA1050531 A CA 1050531A CA 214609 A CA214609 A CA 214609A CA 1050531 A CA1050531 A CA 1050531A
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- group
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
7.alpha.-Methoxycephalosporin derivatives having a 7.beta. substituent of formula R1 - S - A - CO.NH -(in which: R1 represents a hydrogen atom, an acyclic hydro-carbon group, a monocyclic alicyclic hydrocarbon group having a 5- or 6- membered ring, a monocyclic or bicyclic aromatic group, an alkanoyl group, a benzoyl group, or a monocyclic or bicyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom, any of which groups may be substituted or unsubstituted; and A is a straight or branched-chain alkylene group) are prepared by reacting a 7.alpha.-methoxycephalosporin derivative having a 7.beta. substituent of formula X - A - CO.NH -(in which: A is as defined above; and X is a halogen atom) with a thiol compound of formula R1 - SH (I) or with a metal salt thereof.
7.alpha.-Methoxycephalosporin derivatives having a 7.beta. substituent of formula R1 - S - A - CO.NH -(in which: R1 represents a hydrogen atom, an acyclic hydro-carbon group, a monocyclic alicyclic hydrocarbon group having a 5- or 6- membered ring, a monocyclic or bicyclic aromatic group, an alkanoyl group, a benzoyl group, or a monocyclic or bicyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom, any of which groups may be substituted or unsubstituted; and A is a straight or branched-chain alkylene group) are prepared by reacting a 7.alpha.-methoxycephalosporin derivative having a 7.beta. substituent of formula X - A - CO.NH -(in which: A is as defined above; and X is a halogen atom) with a thiol compound of formula R1 - SH (I) or with a metal salt thereof.
Description
~S3~
The present invention relates to a novel process for the preparation of certain 7,B-acylamino-7c~-me$hoxycephalosporin . derivatives.
In one known process for preparing 7,B-acylamino-7~-methoxycephalo~porin derivatives, 7,B-(~-aminoadipo~l~amino-. 7~-methoxycephalosporin compounds are produced by ferrnentation and then acylated to form the corresponding diac~ ated compounds.
The aminoadipoyl group is then split off (see Japanese Patent Provisional Publication No. 931/~2). The same Japanese I'atent Publieation also describes a process in which a 7-amino-7-methoxy-.i eephalosporin compound obtained by chemieal synthesis is aeylated to give the corresponding 7~-acylamino-7O~ ethoxycephalosporir ~; : eompo~md. In these processes, the acylation at the 7~B-poi,ition- ~ ~ is effeeted by the use of an active derivative of the acid whose . residue it Is desired to incorporate at the 7,B-position, such as the acid chloride. II, however, the aeyl group to be introduced , derived from a substituted thioalkanoic aeid ~such as 1, 3, 4-thiadia-:
i, ~ zolylthioaeetic aeid or I,2,4-tria~olylthioacetic),this proeess .
is not praetical, since it :is often difficult or, in some cas.es, impossible to prepare an active derivative OI sueh an acid; in other cases, this active derivative may be unstable or may not , , :
. ' ' .
~5~53~
be obtainable in a good yield. In any case, the yield of the acylation reaction is extremely poor.
, Another process is described in Japanese Patent Provisional Publication No. ~;2791/73 In this process, a cephalosporin compound, unsubstituted at the 7~- position, is converted to an acylimine intermediate, which is then methoxylated to give the desired 7~-methoxycephalosporin derivative, This process however, also has disadvantages in that it cannot be carried out economically and, in any case, still leaves unsolved the problem of introducing the desired 7,B-acyl substituent in ~e starting material.
We hàve now discovered a process for the preparation of 7cY-methoxycephalosporir. derivatives having a substituled thio-~i alkanoylamino group at the 7~- position, which enables these derivatives to be obtained under mild conditions, in very high -~ ~ 15 yields compared with known processes and without any of the disadvantages desFribed above. The process of the invention may be used to prepare a wide variety of cephalosporin derivatives.
, . . .
Thus, in accordance with the present invention, there is provided a process for preparing a 7~-methoxycephalosporin , , ' . ':
.
. ~ . , .. . .... , ... . . .... .. , ~ ..
3~
derivative having a 713 substituent of formula R -- S--A-- CO.NH--.
(in which: Rl represents a hydrogen atom, a substituted or unsubstituted acyclic hydrocarbon group, a substituted or unsubstituted monocyclic alicyclic hydrocarbon group having a 5- or 6-membered ring~ a monocyclic or bicyclic aromatic group - (whose benzene ring may be substituted or unsubstituted), a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted benzoyl group, or a substituted or unsubstituted monocyclic or bicyclic heterocycli.c group having at least one ring nitrogen, oxygen or sulphur atom; and A is a straight or branched- chain alkylene group), wherein a 7~-methoxycephalosporin 5 ~ ' derivative having a 7~ substituent of formula :. ~
,~ ~ X--A--CO,NH--.
(in which: A is as defined above; and X is a halogen atom) , IS reacted with a thiol compound of formula:
Rl _ SH
, . .
'. , ' .
,' ,~ ', ` ' :' or with a metal salt thereof.
The 7~x-methoxycephalosporin derivative }arepared is preferably a compound of formula (II):
B -S--A- CO.NH ~S~ (11) o N~S~ R
~, . .
R
(in which: R is as defined above; R 1S a group which does not participate in the reaction, suc:h as those groups exemplified below; and R3 is a carboxyl group or an esterified carboxyl group), Examples of acyclic hydrocarbon groups which may be represented by Rl are straight or branched- chain hydrocarbon groups having from l to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, vinyl, aLlyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl or propargyl. These hydrocarbon groups may be unsubstituted or they may be substituted with such substituents as: hydroxy groups, azido group~; cyano groups; nitro groups; acylamino groups, e.g. acetylamino; alkoxycarbonylamino groups, such as as t -butoxycarbonylamino; alkoxy groups9 e.g. methoxy or ; ' ~ ' ' . .
.
~SiCI 53~
ethoxy; the phenyl group; the cyclohexadienyl group; the cyclohexyl group; or alkoxycarbonyl groups, e,g. methoxy-carbonyl or ethoxycarbonyl.
Where the group R represents a mono-- cyclic or bicyclic aromatic group, it may be, for example, a substituted or unsubstituted phenyl and naphthyl group, Examples of suitable substituents include, for example: halogen .
atoms, such as chlorine or bromine; alkyl groups, such as methyl or ethyi groups, alkoxy groups, such as methoxy or ethoxy; the cyano group; the nitro group; acylamino groups, such as acetylamino; or alkoxycarbonylamino groups, such as t-butoxycarbonylamino. If the group :Rl is a benzoyl group, it may be unsubstituted or substituted and, if substitut`ed, the ~ substituents may be any of those exempllfied above with lS respect to the phenyl and naphthyl groups.
Rl may also be a monocyclic alicyclic group having a 5- or 6-membered ssturated or unsaturated ring; examples of such groups include: cyclopentyl, cyclo-I ~
penten~rl, cyclohexyl, cyclohexenyl and cyclohexadienyl.
The present invention relates to a novel process for the preparation of certain 7,B-acylamino-7c~-me$hoxycephalosporin . derivatives.
In one known process for preparing 7,B-acylamino-7~-methoxycephalo~porin derivatives, 7,B-(~-aminoadipo~l~amino-. 7~-methoxycephalosporin compounds are produced by ferrnentation and then acylated to form the corresponding diac~ ated compounds.
The aminoadipoyl group is then split off (see Japanese Patent Provisional Publication No. 931/~2). The same Japanese I'atent Publieation also describes a process in which a 7-amino-7-methoxy-.i eephalosporin compound obtained by chemieal synthesis is aeylated to give the corresponding 7~-acylamino-7O~ ethoxycephalosporir ~; : eompo~md. In these processes, the acylation at the 7~B-poi,ition- ~ ~ is effeeted by the use of an active derivative of the acid whose . residue it Is desired to incorporate at the 7,B-position, such as the acid chloride. II, however, the aeyl group to be introduced , derived from a substituted thioalkanoic aeid ~such as 1, 3, 4-thiadia-:
i, ~ zolylthioaeetic aeid or I,2,4-tria~olylthioacetic),this proeess .
is not praetical, since it :is often difficult or, in some cas.es, impossible to prepare an active derivative OI sueh an acid; in other cases, this active derivative may be unstable or may not , , :
. ' ' .
~5~53~
be obtainable in a good yield. In any case, the yield of the acylation reaction is extremely poor.
, Another process is described in Japanese Patent Provisional Publication No. ~;2791/73 In this process, a cephalosporin compound, unsubstituted at the 7~- position, is converted to an acylimine intermediate, which is then methoxylated to give the desired 7~-methoxycephalosporin derivative, This process however, also has disadvantages in that it cannot be carried out economically and, in any case, still leaves unsolved the problem of introducing the desired 7,B-acyl substituent in ~e starting material.
We hàve now discovered a process for the preparation of 7cY-methoxycephalosporir. derivatives having a substituled thio-~i alkanoylamino group at the 7~- position, which enables these derivatives to be obtained under mild conditions, in very high -~ ~ 15 yields compared with known processes and without any of the disadvantages desFribed above. The process of the invention may be used to prepare a wide variety of cephalosporin derivatives.
, . . .
Thus, in accordance with the present invention, there is provided a process for preparing a 7~-methoxycephalosporin , , ' . ':
.
. ~ . , .. . .... , ... . . .... .. , ~ ..
3~
derivative having a 713 substituent of formula R -- S--A-- CO.NH--.
(in which: Rl represents a hydrogen atom, a substituted or unsubstituted acyclic hydrocarbon group, a substituted or unsubstituted monocyclic alicyclic hydrocarbon group having a 5- or 6-membered ring~ a monocyclic or bicyclic aromatic group - (whose benzene ring may be substituted or unsubstituted), a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted benzoyl group, or a substituted or unsubstituted monocyclic or bicyclic heterocycli.c group having at least one ring nitrogen, oxygen or sulphur atom; and A is a straight or branched- chain alkylene group), wherein a 7~-methoxycephalosporin 5 ~ ' derivative having a 7~ substituent of formula :. ~
,~ ~ X--A--CO,NH--.
(in which: A is as defined above; and X is a halogen atom) , IS reacted with a thiol compound of formula:
Rl _ SH
, . .
'. , ' .
,' ,~ ', ` ' :' or with a metal salt thereof.
The 7~x-methoxycephalosporin derivative }arepared is preferably a compound of formula (II):
B -S--A- CO.NH ~S~ (11) o N~S~ R
~, . .
R
(in which: R is as defined above; R 1S a group which does not participate in the reaction, suc:h as those groups exemplified below; and R3 is a carboxyl group or an esterified carboxyl group), Examples of acyclic hydrocarbon groups which may be represented by Rl are straight or branched- chain hydrocarbon groups having from l to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, vinyl, aLlyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl or propargyl. These hydrocarbon groups may be unsubstituted or they may be substituted with such substituents as: hydroxy groups, azido group~; cyano groups; nitro groups; acylamino groups, e.g. acetylamino; alkoxycarbonylamino groups, such as as t -butoxycarbonylamino; alkoxy groups9 e.g. methoxy or ; ' ~ ' ' . .
.
~SiCI 53~
ethoxy; the phenyl group; the cyclohexadienyl group; the cyclohexyl group; or alkoxycarbonyl groups, e,g. methoxy-carbonyl or ethoxycarbonyl.
Where the group R represents a mono-- cyclic or bicyclic aromatic group, it may be, for example, a substituted or unsubstituted phenyl and naphthyl group, Examples of suitable substituents include, for example: halogen .
atoms, such as chlorine or bromine; alkyl groups, such as methyl or ethyi groups, alkoxy groups, such as methoxy or ethoxy; the cyano group; the nitro group; acylamino groups, such as acetylamino; or alkoxycarbonylamino groups, such as t-butoxycarbonylamino. If the group :Rl is a benzoyl group, it may be unsubstituted or substituted and, if substitut`ed, the ~ substituents may be any of those exempllfied above with lS respect to the phenyl and naphthyl groups.
Rl may also be a monocyclic alicyclic group having a 5- or 6-membered ssturated or unsaturated ring; examples of such groups include: cyclopentyl, cyclo-I ~
penten~rl, cyclohexyl, cyclohexenyl and cyclohexadienyl.
2~ ~ Examples of alkanoyl groups, preferably having from 2 to 18 caFbon stomsj which may be represented by , ~a~5DS3~
R include acetyl, propionyl, butyroyl and stearoyl groups, which may be substituted or unsubstituted. If substituted, suitable substituents include: cyano groups; nitro groups;
acylamino groups, e.g. acetylamino; alkoxycarbonylamino groups, such as t-butoxycarbonylamino; and alkoxycarbonyl gralps, e. g. ethoxycarbonyl or methoxycarbonyl.
Alternatively, Rl may be a monocycli c or bicyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom; the heterocyclic group may be 1~ aromatic or non-aromatic in character and examples include:
2-imidazolyl; 1, 2, 4-triazol-3-;yl; 1, 3, 4 -thiadiazol- 2-yl; 2-pyridyl; 2-pyrimidyl; purin-6--yl; 2-benzothiaz~lyl; 2-benzoxazolyl; s-triazolo[ 4,3-a] pyridin-3-yl; and 2-thiazolyl.
.
The group A is a straight or branched-chain alkylene group, preferably a lower alkylene group having from 1 to 6 carbon atoms, Examples include: methylene, trimethylene, propylene, tetramethylene, 2-methyltetramethylene, pentamethylene and hexamethylene groups.
The group R does not participate in the reaction of the process of the present invention and its nature is, there~ore, not critical to the present invention, ....
' :, , ,", , ~ , ~ , .. ...
, " . . .. . ... ..
5~;i3~
However, preferred groups R include: hydrogen atoms; lower alkyl groups, e.g. methyl; acyloxymethyl groups, e.g. acetoxymethyl;
carbamoyloxymethyl groups; and thiomethyl groups which are S-substituted by aromatic monocyclic heterocyclic groups, S containing at least one nitrogen, oxygen or sulphur ring atom, e . g . (l -methyl - lH - tetra zol - 5 - yl) thiom ethyl or (l, 3, 4 - thi adiazol - 2 -yl)thiomethyl .
In formula (II), the group R is a carboxyl or esterified carboxyl group. When R is an esterified carboxyl group, the nature of the ester is not particularly critical, provided that it does not destroy the cephem ring during or after the condensation reaction and provided that it can readily be split off from the cephem ring. Suitable esters include, for example:
alkylsilyl esters, such as trimethylsilyl esters; lower alkyl esters, such as methyl, ethyl or t-butyl esters; benzyl esters; p-methoxy-benzyl esters, ben~hydryl esters; phenacyl esters; ~-bromophen-acyl esters; and 2, 2, 2-trichloroethyl esters. When R is an esterified carboxy1 group, the process of the invention preferably comprises the additional step of deesterifying the reaction .
product, - Where, as is preferred, the 7~ mFthoxycephalosporin to be produced is a compoundof formula (II), defined above, the , :.
~53~
preferred 7~-methoxyceph~losporin starting material is a compound of formula (III):
O~I3 ~ S~ (III) X - ~- CC~ 2 s~ N ~ R
.. O
`- !
;
~, .
(in which X, R and R are as deiined above)~. In this compoundJ
` X is a halogen atom, preferably chlorine or bromine.
''' - The thiol compound of formula (I) may be :`
employed as such or may be~ and preferably iB, employed in the form of a metal salt, e. g. an all~ali metal or alkaline earth metal salt, such as a sodium, potassium, lithium, calcium or barium salt. Of these, the sodium, potassium and lithium salts are preferred.
'' ' '.
The process c~f the present invention can easily be carried out simply by contacting the 7a-metho~ycephalosporin .,~ .
.
. .
i3~
derivative used as starting material, e. g. the compound of formula (III) with the thiol compound of formula (I), or with a metal salt thereoi. In order that the reaction should proceed smoothly,~we prefer that it should be carried out in the presence OI a solvent, particularly if a metal salt of the thiol (I) is employed.
Any solvent which does not participate in the reaction can be used in the process of the present invention, including water and ~ . .
many organic solvents. Examples of suitable organic solvents include dialkyl ketones, e. g. acetone or methyl ethyl ketone;
10 halogenated alkanes, e.g. chloroform9 methylene chloride or dichloroethane; lower alkanols, e.g. methanol or ethanol; and dimethylformamide. Mixtures of two or more solvents can also be employed. If the 7Q-methoxycephalosporin derivative of ., .
formula (III) has a carboxyl group in the 4-position, we preîer .
15 to employ a mixture of water and an organic solvent as the reaction medlum.
The thiol (I) or metal salt thereof will normally be used in an amount equimolar to the 7~-methoxycephalosporin derivative or in a slight excess; thu~, for example, the molar 20 ratio of thioi (I) to ~a-methoxycephalosporin starting material 1: ' ~: .
may be from 1: 1 to 1.1: 1.
., .
~ 9 .; ' .
R include acetyl, propionyl, butyroyl and stearoyl groups, which may be substituted or unsubstituted. If substituted, suitable substituents include: cyano groups; nitro groups;
acylamino groups, e.g. acetylamino; alkoxycarbonylamino groups, such as t-butoxycarbonylamino; and alkoxycarbonyl gralps, e. g. ethoxycarbonyl or methoxycarbonyl.
Alternatively, Rl may be a monocycli c or bicyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom; the heterocyclic group may be 1~ aromatic or non-aromatic in character and examples include:
2-imidazolyl; 1, 2, 4-triazol-3-;yl; 1, 3, 4 -thiadiazol- 2-yl; 2-pyridyl; 2-pyrimidyl; purin-6--yl; 2-benzothiaz~lyl; 2-benzoxazolyl; s-triazolo[ 4,3-a] pyridin-3-yl; and 2-thiazolyl.
.
The group A is a straight or branched-chain alkylene group, preferably a lower alkylene group having from 1 to 6 carbon atoms, Examples include: methylene, trimethylene, propylene, tetramethylene, 2-methyltetramethylene, pentamethylene and hexamethylene groups.
The group R does not participate in the reaction of the process of the present invention and its nature is, there~ore, not critical to the present invention, ....
' :, , ,", , ~ , ~ , .. ...
, " . . .. . ... ..
5~;i3~
However, preferred groups R include: hydrogen atoms; lower alkyl groups, e.g. methyl; acyloxymethyl groups, e.g. acetoxymethyl;
carbamoyloxymethyl groups; and thiomethyl groups which are S-substituted by aromatic monocyclic heterocyclic groups, S containing at least one nitrogen, oxygen or sulphur ring atom, e . g . (l -methyl - lH - tetra zol - 5 - yl) thiom ethyl or (l, 3, 4 - thi adiazol - 2 -yl)thiomethyl .
In formula (II), the group R is a carboxyl or esterified carboxyl group. When R is an esterified carboxyl group, the nature of the ester is not particularly critical, provided that it does not destroy the cephem ring during or after the condensation reaction and provided that it can readily be split off from the cephem ring. Suitable esters include, for example:
alkylsilyl esters, such as trimethylsilyl esters; lower alkyl esters, such as methyl, ethyl or t-butyl esters; benzyl esters; p-methoxy-benzyl esters, ben~hydryl esters; phenacyl esters; ~-bromophen-acyl esters; and 2, 2, 2-trichloroethyl esters. When R is an esterified carboxy1 group, the process of the invention preferably comprises the additional step of deesterifying the reaction .
product, - Where, as is preferred, the 7~ mFthoxycephalosporin to be produced is a compoundof formula (II), defined above, the , :.
~53~
preferred 7~-methoxyceph~losporin starting material is a compound of formula (III):
O~I3 ~ S~ (III) X - ~- CC~ 2 s~ N ~ R
.. O
`- !
;
~, .
(in which X, R and R are as deiined above)~. In this compoundJ
` X is a halogen atom, preferably chlorine or bromine.
''' - The thiol compound of formula (I) may be :`
employed as such or may be~ and preferably iB, employed in the form of a metal salt, e. g. an all~ali metal or alkaline earth metal salt, such as a sodium, potassium, lithium, calcium or barium salt. Of these, the sodium, potassium and lithium salts are preferred.
'' ' '.
The process c~f the present invention can easily be carried out simply by contacting the 7a-metho~ycephalosporin .,~ .
.
. .
i3~
derivative used as starting material, e. g. the compound of formula (III) with the thiol compound of formula (I), or with a metal salt thereoi. In order that the reaction should proceed smoothly,~we prefer that it should be carried out in the presence OI a solvent, particularly if a metal salt of the thiol (I) is employed.
Any solvent which does not participate in the reaction can be used in the process of the present invention, including water and ~ . .
many organic solvents. Examples of suitable organic solvents include dialkyl ketones, e. g. acetone or methyl ethyl ketone;
10 halogenated alkanes, e.g. chloroform9 methylene chloride or dichloroethane; lower alkanols, e.g. methanol or ethanol; and dimethylformamide. Mixtures of two or more solvents can also be employed. If the 7Q-methoxycephalosporin derivative of ., .
formula (III) has a carboxyl group in the 4-position, we preîer .
15 to employ a mixture of water and an organic solvent as the reaction medlum.
The thiol (I) or metal salt thereof will normally be used in an amount equimolar to the 7~-methoxycephalosporin derivative or in a slight excess; thu~, for example, the molar 20 ratio of thioi (I) to ~a-methoxycephalosporin starting material 1: ' ~: .
may be from 1: 1 to 1.1: 1.
., .
~ 9 .; ' .
-3 " .
~' .
.
- . ',' ',: :' ' ' ' ' ', ,, ~.
:' ' ' ' , , ' ' i ' i 1~5~i3~
Although the reaction will proceed at an approximately neutral pH, it proceeds more smoothly under weak:Ly alkaline conditions. ~ccordingly, if the thiol (I) itself iæ employed, we prefer to add an alkali to the reaetion mixture in order that the reaction should be carried out under weakly alkaline conditions. Suitable alkalis which may be used include:
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bi-earbonate.
The reaetion temperature is not !~
eritical to the process of the invention and the reaetion is, .: .
aeeordingly, normally effeetedat approximately ambient temperature, ` although the reaetion will proceed at temperatures higher ~f and lower than ambient. The time required for the reaction will vary dependingupon the reaetion temperature, the reagents and other conditions, but the reaction will normally be eomplete , . . .within ~rom 2 to 30 hours; if X in the 7a-rnethoxyeephalosporin starting material is a ehlorine atom, the reactlon will normally ' take a relatively long time~ i. e. from 10 to 30 hours.
. , .
When the r eaetion is eomplete, the - - ,.
.
.
~L~50t~i3~
des;red compound, e.gO the compound of formula (lI),may be recovered from the reaction mixture by conventional methods. For example, if a carboxyl group is present in the 4- position of the compound, the reaction mixture is first acidified and, if a solvent other than water is employed for the reaction, the solvent is removed by distillation, after which the reaction product is extracted with a suitable solvent (e.g. ethyl acetate) and the extract is washed with water and dried. The solvent is then removed by distillation, giving the desired product.
.
If necessary, this may be further purified by conventional means, .
e.g. by chromatography.
' If the compound pro~ucedby the pr ocess of the invention has an csterified carboxyl group at the 4- positionJ
the reaction medium is, as stated above, preferably a mi~ture 1 S; of water and a miscible organic solvent. This organic solvent ie flrst removed from the reaction mixture by distillation, after which the residue is extracted with a water-immiscible solvent.
. . ~
The extract is then washed with water and the solvent removed i ~y distillation to give the ester~fied compound. This compound~, 20 may be further purified by conventional methods, e.g.
chromatography, but, in general, we prefer that it should be .
~[35C~3~
swbjected directly to deesterification to give the desired compound. This deesterification can be carried out by any conventional method, depending upon the nature of the ester, Suitable deesterification processes include: alkaline hydrolysis, acid hydrolysis and reduction with hydrogen.
AMer completion of the deesterification, the desired product is reeovered from the reaction mixture in the manner described .
above.
Many of the 7~-methoxycephalosporin :. . .
derivatives of formula (II) have valuable antibacterial activlty against various pathogenie bacteria. Representative exarnples , of these compounds and their antibacterial activities (expressed as m~nimiu~ ;nhibitory concentrations) are shown in the following Table. Also shown, for purposes of comparisonj ~ are the minimum inhibitory con entrations against the same baeteria of two known compounds, 3 - earbamoyloxym ethyl -7~-methoxy- 7,B -phenylac etamido- 3 - c ephem -4 - carboxylic ac;d ,~ ~
'; and Cephalothin.
As will be seen from the Table, the most , 20 preferred eompounds of the invention are those in which:R represents a eyanomethyl, l-eyanoethyl, 2-hydroxyethyl, propargyl, azidomethyl or 3-isoxazolyl group; R represents a (l-methyl-iH-tetrazol-5-yl)thio-methyl, earbamoyloxymethyl or acetoxymethyl group;
and A represents a methylene group.
' ' .
. .
1, i3~L
~1 ~ ~
, .. _ ~_ h ¦ ~ ~ a~
~ . ~ ~
., ~ ~1 o o o c o , ~ . . _ . , ~ . . ~.
Eoil ,~ I~ 1 Ic~
~ U~_ _ . .. . . _ . ~
..~ V ~ ~^ CO - .
. ~ ~ o~ :~o ~ CO, : ~ ~ ~ V,~ " ~
,~ ~ ~, ~1 ~ ~ i ~ O
~ w wl ~o _ .-_ C~ ~
~ m~ ~ m~
~ ;`-~
.,. ~
- 13 - :~
.. . . . . . . . . ..
3~
.._ _ ~1 . ~ 0~ ID U~ ' C~
~ ~, U O O O ~i ,i C`J CD
~ .. . . _ .~
o i td ~ "~ I u~ c~
CO ~ N CD
._ _ _ .. _ _ . _ ._ __ ~ O o O o O O g ~ CO ~ ~ ~
., bq . . _ ...... _ . ,___ ,Q ~Oo ~ U~ C~
.` ~....... ~! C~ C~ U~ i .. .. __ .__ _ . ,_ ___ .
~1 ~ ~ .
.. _ O p~ ._ ~ ... _ ~1 ;c~l ~D_ _ CO_ .~ 11~ C~
.l _ ~1 C~ Ir) C~
~ ~ _ ~ _ __ .. _ --__ ___~__ ~' l ~ O O O ' ~ C~ C~ ~
I _ ~ _ _~
~ P~ c~ ol~ ~
Uil o o . o, o o o o ~9 , _ _ .. . . _ ~
,: ~ ~, ¦ P~ ¦ I v c Is ~ .,1 1 ~ .. _ . . . . , ~ q ~ , ~ ~ ~
~ ~ _E ~L~I
, . . . . . . . ........... . . . . . ... .... . . . . .. . . ...
.. . ; .. , .... ,`. .. .... ` . . .. . .. . .
OS3~L
The compounds thus show excellent activity against both Gram- positive and Gram- negative bacteria, especially against Gram- negative bacteria.
The compounds of formula (III) which are used as starting materials in the process of the present invention are also novel compounds, but these can easily be prepared by known mlethods. Although they themselves have a . .
- certain antibacterial activity, they are more valuable as starting materials for the compounds of formula (II),which have lO ~ much higher antibacterial activil;ies.
.. .
The invention is ~Lrther iLlustrated with reference to the following Examples. The preparation of certain novel starting m~Lterials is also illustrated in the following ~- Preparations 1 to 4.
, .
., .
, :''; .
,:
:
5i3:~
Example 1 3Sarbamoyloxymethyl-7~-methoxy-7~ 2,4-triazol-3-yl-thioacetamido) - 3 - cephem -4 -carboxylic acid 12 mg of 3-mercapto-l, 2,4-triazole were ~' 5 dissolved in 0.12 ml of a lN aqueous sol~ltion of sodium hydroxide;
to the resulting solution was added an aqueous solution of sodium hydrogen carbonate containing 42 mg of 7,B-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-oephem-4-carboxylic acid.
The mixture was agitated at room temperature for 2 hours, and the pH was adjusted to about 2. 5 by addition of lN hydrochloric acid. The mixture was then extrElcted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulphate.
The solvent was then distilled off under reduced pressure, yielding 4B mg of a crystalline residue. This residue was chromatographed on a silica gel plate, employing a 50: 50 by volume mixture of methanol and chloroform. The solvent was then distilled of E, giving 33 mg of pure 3-carbamoyloxymethyl-7~-methoxy-7,B-(l, 2,4-triazol-3-yl-thioacetamido)-3-cephem-4-carboxylic acld.in the form of a powder.
Nuclear magnetic resonance spectrum (CD3CN ~ D20), ô ppm:
5.00 (singlet, H at 6-position) ' i ~., .
.
3~
3 . 90 ~singlet, -S- CH2-CO- ) 3. 37 (singlet, OCH3 at 7 position).
Ultraviolet absorption spectrum (CH30H), ~ aX m~u:
263.
Infrared absorption spectrum (KBr), ~cm 1770.
Thin layer chromatography (silica gel~:
(a) Developing solvent (n- butanol/acetic acid/water , 5: 4: 1 by volume) :
Rf value = 0 . 37 .
(b) Developimg solvent (methanol/chloroform, :;
1 : 1 by volume):
Rf value = O . 28 .
~ ~ When this procedure was repeated except ; ~ 15 that the 7,B-bromoacetamido-3-carbamoyloxymethyl-7a!-methoxy-3-cephem-4-carboxylic acid was replaced by the corresponding 7,8-chloroacetamido derivative, similar results were obtained.
~',:~
~ - Example 2 i~ 20 3-Carbamoyloxymeth~1-7,~ midazol-2-yl-thioacetamido)-7~-methoxy-3-cephem-4-carboxylic acid .~ ~
~ ,, , :
j , , ' !
~G~5~i3~
20 mg OI 2-mercaptoimidazole were dissolved in 0. 2 ml of lN sodium hydroxide, and a solution of 117 mg of 7,B-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-cephem-4-carboxylic acid in 0. 2ml OI lN sodium hydroxide was added to the resulting solution, The mixture was a31owed to stand at room temperature for 2 hours, after which the pH was adjusted to 2. 5 by addition of 2N phosphoric acid. The mixture - was then extracted with ethyl acetate and the aqueous phase was freeze-dried and extracted with methanol. The methanol-soluble portion was separated on a silica gel plate using a 50: 50 ~ ~ by volume mixture of methanol and chloroform and extracted -` with methanol. The solvent was distilled from the extract, glving 80 mg of pure 3-carbamoyloxymethyl-7~3-(imidazol-2-yl-i~ this~acetamido)-7~-methoxy-3-cephem-4-carboxylic acid in the form ;, 15 of a powder .
Nuclear magnetic resonance spectrum ~CD3CN f D20), ~ ppm:
7 . 09 (singlet, H of iIrlidazole) 5.0Z (singlet, H at 6-position) 3.75 (singlet, -S-CH2-CO-) 2~ 3,39 (singlet, OCE13 at 7-position).
- Ultraviolet absorption spectrum (phosphoric acid buffer, pH
' 6, 86)~ max ~u:
257 .
, 56~53~L
Infrared absorption spectrum (KBr)~cm 1765.
Thin layer chromatography (silica gel):
(a) Developing solvent (n-butanol/acetic acid/water, 5: 4: 1 by volume):
Rf value = 0. 21.
(b) Developing solvent (methanol/chloroform, 1 :1 .
- by volume):
.~ ~ ...
: Rf ~ 0. 31.
, . ~
, ......................................................................... .
When this procedure was repeated except that the 7~B-bromoacetamido-3-carbamoyloxymethyl-7~-metho2~y-3-cephem-4-carboxylic acid was replaced by the corresponding 7,B-chloroacetamido derivativeJ similar results were obtained.
:; :
Example 3 ~ 3-Carbamoylo~ymethyl-7c~-methoxy-7,B-~lJ 3J4-thiadiazol-2-yl-thioacetamldo)- 3 -cephem-4 -carboxylic acid '':~ ' ~ ' :
A solution of 117 mg of 713-b~omoacetamido-:
3 -carbamoyloxymethyl- 7ar-methoxy- 3 -cephem-4 -carboxylic acid in 0, 2 ml of lN sodium hydroxide was added to a solution of : ' ' .' ''~ .'.
,. , ' . I
!
:~ , , . ,., , , ~ , . , : , - .,, -i3~L
23.6 mg of 2-mercapto-1,3,4-thiadiazole in 0,2 ml of lN sodium hydroxide, and the mixture was agitated at room temperature for 2 hours. The pE was then adjusted to 2. 5 by addition of 2N phosphoric aeid. The solution was then extracted 5 times, each time with 15 ml of ethyl acetate, and the combined ethyl acetate extracts were dried over sodium sulphate; the solvent was then distilled off, giVillg 69 mg of an amorphous crude product. This was separated .
on a silica gel plate using a 50: 50 by volume mixture of methanol and chloroform and then extracted with methanol. The solvent :, .
was distilled off from the extract, giving 34 mg of 3-carbamoyloxy-methyl-7~-methoxy-7,B-(1, 3,4-thiadiazol-2-yl-thioaeetamido)-:
3-eephem-4-carboxylic acid in the form of a powder.
` Nuclear magnetic resonance spectrum (CD3CM ~ D2O), ô ppm:
9. 30 (singlet, H of thlazole) 5. 03 (singlet, H at 6 -position) .. ~ .
; 4,16 (singlet, S-CH2-CO-) . 3.46 (singlet, OCH3 at 7-position), Ultraviolet absorption spectrum (phosphorie acid buffer, pH 6. 86), , , max m~
~6 3, :
Imr ared absorption speetrum (~3r), ~ cm 1 1~60, .
.1 , 1 i3~
Thin layer chromatography (silica gel):
(a) Developing solvent (n-butanol/acetic acid/water, 5: 4 : 1 by volume):
Rf value = 0, 4 9, -; 5 (b) Developing solvent (methanol/chloroform~ 1 :1 ,;
by volume~:
Rf value = 0. 29 .
When thls procedure was repeated except that the 7~-bromoacetamido-3-carbamoyloxymethyl-7cY-methoxy-3-cephem-4-carboxylic acid was replaced by the corresponding 7,~-ch]oroacetamido derivative, similar result6 were obtained.
Examples of compounds prepared in ~ .
the ame rnanner as in the foregoing Examples and their properties are shown below.
~ ' ' ' Except where otherwise indicated,the physical properties were measured as follows:
Nuclear magnetic resonance spectrum (in CD3CN-~
; ~ D2)9 ~ ppm Ultraviolet absorption spectrum ~in phosphoric acid buffer of pH 6 . 86), ~max m~u.
.
;. ,, - , : . , . , ,- :
.
~56~3~
Infrared absorption spectrum (in KBr), ~J cm D: Thin layer chromatography (TLC) on silica gel:
(a) Rf value obtained employing a 5: 4: 1 by volume mixture of n-butanol/acetic acid/water.
(b) Rf value obtained employing a 1: 1 by volume mixture of methanol/chloroform.
3-Carbamoyloxymethyl-7a!-methoxy-7~-(5-methyl-1, 3,4-thiadiazol-2 -yl -thioacetamido) - 3 -c ephem -4 - carboxylic acid NMR spectrum, ~ ppm:
5,02 (singlet, H at 6-position) `, 4.05 (singlet, S-CH2CO-) 3.43 (singlet, OCH3 at 7-position) 2.64 (singlet, H of thiadiazole)~
IJV spectrum ~ max }~:
" . .
263.
IR spectrum~ cm 1770.
.. . . .
, TLC, Rf value:
(a)=0,45, (b)=0. 38, 3-Carbamoyloxymeth~yl-70~-methoxy-7,B-propargylthioacetamido-3-cephem-4-carboxylic acid ~,' ' -.
353~L
NMR spectrum ~ dimethylsulphoxide (~MSO)-d6], ~ ppm:
5.15 (singlet, H at 6-position~
3.40 (multiplet, -CH2-S~CH2 and OCH3 at 7-position), UV spectrum.~ max ~lu:
2~2, 265.
IR spectrum~ cm 1 178~.
3~ arbamoyl xymethyl-7,B-cyanomethylthioacetamido-7a-methoxy-3-cephem-4-carboxylic acid NMR spectrum (DMSO-d6), ~ ppm:
5. 06 (singlet, H at 6 -position) 3, 58 (singlet, NC -CE2SCH2) UV spectrum.~
246, 26 5, l:R spectrum,~cm 1 ~: 15 1720, 1776, :. .
; 3-yl-thioacetamido)-3-cephem-4-carboxylic acid ~-~ NMR spectrum ~ ppm:
5.02 (singlet, H at 6-position) ~,05 (singlet, SCH2C~-~
.. ... . : . ~
~s~
3.43 (singlet, OCH3 at 7-position) 2 . 64 (CH3 of imidazole).
UV spectrum ;~ m~ m,u:
263, IR spectrum~) cm - 17~00 TLC, Rf value:
(a)= O. 39, (b)- O. 29.
. . . `
3-Carbamoyloxymethyl-7~3-(5-ethyl-1, 2,4-triazol-3-yl-thioacetamido)-7cr-methoxy-3-cephem-4-carboxylic acid NMR spectrum ~ ppm:
5,13 (singlet, H at 6-position)
~' .
.
- . ',' ',: :' ' ' ' ' ', ,, ~.
:' ' ' ' , , ' ' i ' i 1~5~i3~
Although the reaction will proceed at an approximately neutral pH, it proceeds more smoothly under weak:Ly alkaline conditions. ~ccordingly, if the thiol (I) itself iæ employed, we prefer to add an alkali to the reaetion mixture in order that the reaction should be carried out under weakly alkaline conditions. Suitable alkalis which may be used include:
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bi-earbonate.
The reaetion temperature is not !~
eritical to the process of the invention and the reaetion is, .: .
aeeordingly, normally effeetedat approximately ambient temperature, ` although the reaetion will proceed at temperatures higher ~f and lower than ambient. The time required for the reaction will vary dependingupon the reaetion temperature, the reagents and other conditions, but the reaction will normally be eomplete , . . .within ~rom 2 to 30 hours; if X in the 7a-rnethoxyeephalosporin starting material is a ehlorine atom, the reactlon will normally ' take a relatively long time~ i. e. from 10 to 30 hours.
. , .
When the r eaetion is eomplete, the - - ,.
.
.
~L~50t~i3~
des;red compound, e.gO the compound of formula (lI),may be recovered from the reaction mixture by conventional methods. For example, if a carboxyl group is present in the 4- position of the compound, the reaction mixture is first acidified and, if a solvent other than water is employed for the reaction, the solvent is removed by distillation, after which the reaction product is extracted with a suitable solvent (e.g. ethyl acetate) and the extract is washed with water and dried. The solvent is then removed by distillation, giving the desired product.
.
If necessary, this may be further purified by conventional means, .
e.g. by chromatography.
' If the compound pro~ucedby the pr ocess of the invention has an csterified carboxyl group at the 4- positionJ
the reaction medium is, as stated above, preferably a mi~ture 1 S; of water and a miscible organic solvent. This organic solvent ie flrst removed from the reaction mixture by distillation, after which the residue is extracted with a water-immiscible solvent.
. . ~
The extract is then washed with water and the solvent removed i ~y distillation to give the ester~fied compound. This compound~, 20 may be further purified by conventional methods, e.g.
chromatography, but, in general, we prefer that it should be .
~[35C~3~
swbjected directly to deesterification to give the desired compound. This deesterification can be carried out by any conventional method, depending upon the nature of the ester, Suitable deesterification processes include: alkaline hydrolysis, acid hydrolysis and reduction with hydrogen.
AMer completion of the deesterification, the desired product is reeovered from the reaction mixture in the manner described .
above.
Many of the 7~-methoxycephalosporin :. . .
derivatives of formula (II) have valuable antibacterial activlty against various pathogenie bacteria. Representative exarnples , of these compounds and their antibacterial activities (expressed as m~nimiu~ ;nhibitory concentrations) are shown in the following Table. Also shown, for purposes of comparisonj ~ are the minimum inhibitory con entrations against the same baeteria of two known compounds, 3 - earbamoyloxym ethyl -7~-methoxy- 7,B -phenylac etamido- 3 - c ephem -4 - carboxylic ac;d ,~ ~
'; and Cephalothin.
As will be seen from the Table, the most , 20 preferred eompounds of the invention are those in which:R represents a eyanomethyl, l-eyanoethyl, 2-hydroxyethyl, propargyl, azidomethyl or 3-isoxazolyl group; R represents a (l-methyl-iH-tetrazol-5-yl)thio-methyl, earbamoyloxymethyl or acetoxymethyl group;
and A represents a methylene group.
' ' .
. .
1, i3~L
~1 ~ ~
, .. _ ~_ h ¦ ~ ~ a~
~ . ~ ~
., ~ ~1 o o o c o , ~ . . _ . , ~ . . ~.
Eoil ,~ I~ 1 Ic~
~ U~_ _ . .. . . _ . ~
..~ V ~ ~^ CO - .
. ~ ~ o~ :~o ~ CO, : ~ ~ ~ V,~ " ~
,~ ~ ~, ~1 ~ ~ i ~ O
~ w wl ~o _ .-_ C~ ~
~ m~ ~ m~
~ ;`-~
.,. ~
- 13 - :~
.. . . . . . . . . ..
3~
.._ _ ~1 . ~ 0~ ID U~ ' C~
~ ~, U O O O ~i ,i C`J CD
~ .. . . _ .~
o i td ~ "~ I u~ c~
CO ~ N CD
._ _ _ .. _ _ . _ ._ __ ~ O o O o O O g ~ CO ~ ~ ~
., bq . . _ ...... _ . ,___ ,Q ~Oo ~ U~ C~
.` ~....... ~! C~ C~ U~ i .. .. __ .__ _ . ,_ ___ .
~1 ~ ~ .
.. _ O p~ ._ ~ ... _ ~1 ;c~l ~D_ _ CO_ .~ 11~ C~
.l _ ~1 C~ Ir) C~
~ ~ _ ~ _ __ .. _ --__ ___~__ ~' l ~ O O O ' ~ C~ C~ ~
I _ ~ _ _~
~ P~ c~ ol~ ~
Uil o o . o, o o o o ~9 , _ _ .. . . _ ~
,: ~ ~, ¦ P~ ¦ I v c Is ~ .,1 1 ~ .. _ . . . . , ~ q ~ , ~ ~ ~
~ ~ _E ~L~I
, . . . . . . . ........... . . . . . ... .... . . . . .. . . ...
.. . ; .. , .... ,`. .. .... ` . . .. . .. . .
OS3~L
The compounds thus show excellent activity against both Gram- positive and Gram- negative bacteria, especially against Gram- negative bacteria.
The compounds of formula (III) which are used as starting materials in the process of the present invention are also novel compounds, but these can easily be prepared by known mlethods. Although they themselves have a . .
- certain antibacterial activity, they are more valuable as starting materials for the compounds of formula (II),which have lO ~ much higher antibacterial activil;ies.
.. .
The invention is ~Lrther iLlustrated with reference to the following Examples. The preparation of certain novel starting m~Lterials is also illustrated in the following ~- Preparations 1 to 4.
, .
., .
, :''; .
,:
:
5i3:~
Example 1 3Sarbamoyloxymethyl-7~-methoxy-7~ 2,4-triazol-3-yl-thioacetamido) - 3 - cephem -4 -carboxylic acid 12 mg of 3-mercapto-l, 2,4-triazole were ~' 5 dissolved in 0.12 ml of a lN aqueous sol~ltion of sodium hydroxide;
to the resulting solution was added an aqueous solution of sodium hydrogen carbonate containing 42 mg of 7,B-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-oephem-4-carboxylic acid.
The mixture was agitated at room temperature for 2 hours, and the pH was adjusted to about 2. 5 by addition of lN hydrochloric acid. The mixture was then extrElcted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulphate.
The solvent was then distilled off under reduced pressure, yielding 4B mg of a crystalline residue. This residue was chromatographed on a silica gel plate, employing a 50: 50 by volume mixture of methanol and chloroform. The solvent was then distilled of E, giving 33 mg of pure 3-carbamoyloxymethyl-7~-methoxy-7,B-(l, 2,4-triazol-3-yl-thioacetamido)-3-cephem-4-carboxylic acld.in the form of a powder.
Nuclear magnetic resonance spectrum (CD3CN ~ D20), ô ppm:
5.00 (singlet, H at 6-position) ' i ~., .
.
3~
3 . 90 ~singlet, -S- CH2-CO- ) 3. 37 (singlet, OCH3 at 7 position).
Ultraviolet absorption spectrum (CH30H), ~ aX m~u:
263.
Infrared absorption spectrum (KBr), ~cm 1770.
Thin layer chromatography (silica gel~:
(a) Developing solvent (n- butanol/acetic acid/water , 5: 4: 1 by volume) :
Rf value = 0 . 37 .
(b) Developimg solvent (methanol/chloroform, :;
1 : 1 by volume):
Rf value = O . 28 .
~ ~ When this procedure was repeated except ; ~ 15 that the 7,B-bromoacetamido-3-carbamoyloxymethyl-7a!-methoxy-3-cephem-4-carboxylic acid was replaced by the corresponding 7,8-chloroacetamido derivative, similar results were obtained.
~',:~
~ - Example 2 i~ 20 3-Carbamoyloxymeth~1-7,~ midazol-2-yl-thioacetamido)-7~-methoxy-3-cephem-4-carboxylic acid .~ ~
~ ,, , :
j , , ' !
~G~5~i3~
20 mg OI 2-mercaptoimidazole were dissolved in 0. 2 ml of lN sodium hydroxide, and a solution of 117 mg of 7,B-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-cephem-4-carboxylic acid in 0. 2ml OI lN sodium hydroxide was added to the resulting solution, The mixture was a31owed to stand at room temperature for 2 hours, after which the pH was adjusted to 2. 5 by addition of 2N phosphoric acid. The mixture - was then extracted with ethyl acetate and the aqueous phase was freeze-dried and extracted with methanol. The methanol-soluble portion was separated on a silica gel plate using a 50: 50 ~ ~ by volume mixture of methanol and chloroform and extracted -` with methanol. The solvent was distilled from the extract, glving 80 mg of pure 3-carbamoyloxymethyl-7~3-(imidazol-2-yl-i~ this~acetamido)-7~-methoxy-3-cephem-4-carboxylic acid in the form ;, 15 of a powder .
Nuclear magnetic resonance spectrum ~CD3CN f D20), ~ ppm:
7 . 09 (singlet, H of iIrlidazole) 5.0Z (singlet, H at 6-position) 3.75 (singlet, -S-CH2-CO-) 2~ 3,39 (singlet, OCE13 at 7-position).
- Ultraviolet absorption spectrum (phosphoric acid buffer, pH
' 6, 86)~ max ~u:
257 .
, 56~53~L
Infrared absorption spectrum (KBr)~cm 1765.
Thin layer chromatography (silica gel):
(a) Developing solvent (n-butanol/acetic acid/water, 5: 4: 1 by volume):
Rf value = 0. 21.
(b) Developing solvent (methanol/chloroform, 1 :1 .
- by volume):
.~ ~ ...
: Rf ~ 0. 31.
, . ~
, ......................................................................... .
When this procedure was repeated except that the 7~B-bromoacetamido-3-carbamoyloxymethyl-7~-metho2~y-3-cephem-4-carboxylic acid was replaced by the corresponding 7,B-chloroacetamido derivativeJ similar results were obtained.
:; :
Example 3 ~ 3-Carbamoylo~ymethyl-7c~-methoxy-7,B-~lJ 3J4-thiadiazol-2-yl-thioacetamldo)- 3 -cephem-4 -carboxylic acid '':~ ' ~ ' :
A solution of 117 mg of 713-b~omoacetamido-:
3 -carbamoyloxymethyl- 7ar-methoxy- 3 -cephem-4 -carboxylic acid in 0, 2 ml of lN sodium hydroxide was added to a solution of : ' ' .' ''~ .'.
,. , ' . I
!
:~ , , . ,., , , ~ , . , : , - .,, -i3~L
23.6 mg of 2-mercapto-1,3,4-thiadiazole in 0,2 ml of lN sodium hydroxide, and the mixture was agitated at room temperature for 2 hours. The pE was then adjusted to 2. 5 by addition of 2N phosphoric aeid. The solution was then extracted 5 times, each time with 15 ml of ethyl acetate, and the combined ethyl acetate extracts were dried over sodium sulphate; the solvent was then distilled off, giVillg 69 mg of an amorphous crude product. This was separated .
on a silica gel plate using a 50: 50 by volume mixture of methanol and chloroform and then extracted with methanol. The solvent :, .
was distilled off from the extract, giving 34 mg of 3-carbamoyloxy-methyl-7~-methoxy-7,B-(1, 3,4-thiadiazol-2-yl-thioaeetamido)-:
3-eephem-4-carboxylic acid in the form of a powder.
` Nuclear magnetic resonance spectrum (CD3CM ~ D2O), ô ppm:
9. 30 (singlet, H of thlazole) 5. 03 (singlet, H at 6 -position) .. ~ .
; 4,16 (singlet, S-CH2-CO-) . 3.46 (singlet, OCH3 at 7-position), Ultraviolet absorption spectrum (phosphorie acid buffer, pH 6. 86), , , max m~
~6 3, :
Imr ared absorption speetrum (~3r), ~ cm 1 1~60, .
.1 , 1 i3~
Thin layer chromatography (silica gel):
(a) Developing solvent (n-butanol/acetic acid/water, 5: 4 : 1 by volume):
Rf value = 0, 4 9, -; 5 (b) Developing solvent (methanol/chloroform~ 1 :1 ,;
by volume~:
Rf value = 0. 29 .
When thls procedure was repeated except that the 7~-bromoacetamido-3-carbamoyloxymethyl-7cY-methoxy-3-cephem-4-carboxylic acid was replaced by the corresponding 7,~-ch]oroacetamido derivative, similar result6 were obtained.
Examples of compounds prepared in ~ .
the ame rnanner as in the foregoing Examples and their properties are shown below.
~ ' ' ' Except where otherwise indicated,the physical properties were measured as follows:
Nuclear magnetic resonance spectrum (in CD3CN-~
; ~ D2)9 ~ ppm Ultraviolet absorption spectrum ~in phosphoric acid buffer of pH 6 . 86), ~max m~u.
.
;. ,, - , : . , . , ,- :
.
~56~3~
Infrared absorption spectrum (in KBr), ~J cm D: Thin layer chromatography (TLC) on silica gel:
(a) Rf value obtained employing a 5: 4: 1 by volume mixture of n-butanol/acetic acid/water.
(b) Rf value obtained employing a 1: 1 by volume mixture of methanol/chloroform.
3-Carbamoyloxymethyl-7a!-methoxy-7~-(5-methyl-1, 3,4-thiadiazol-2 -yl -thioacetamido) - 3 -c ephem -4 - carboxylic acid NMR spectrum, ~ ppm:
5,02 (singlet, H at 6-position) `, 4.05 (singlet, S-CH2CO-) 3.43 (singlet, OCH3 at 7-position) 2.64 (singlet, H of thiadiazole)~
IJV spectrum ~ max }~:
" . .
263.
IR spectrum~ cm 1770.
.. . . .
, TLC, Rf value:
(a)=0,45, (b)=0. 38, 3-Carbamoyloxymeth~yl-70~-methoxy-7,B-propargylthioacetamido-3-cephem-4-carboxylic acid ~,' ' -.
353~L
NMR spectrum ~ dimethylsulphoxide (~MSO)-d6], ~ ppm:
5.15 (singlet, H at 6-position~
3.40 (multiplet, -CH2-S~CH2 and OCH3 at 7-position), UV spectrum.~ max ~lu:
2~2, 265.
IR spectrum~ cm 1 178~.
3~ arbamoyl xymethyl-7,B-cyanomethylthioacetamido-7a-methoxy-3-cephem-4-carboxylic acid NMR spectrum (DMSO-d6), ~ ppm:
5. 06 (singlet, H at 6 -position) 3, 58 (singlet, NC -CE2SCH2) UV spectrum.~
246, 26 5, l:R spectrum,~cm 1 ~: 15 1720, 1776, :. .
; 3-yl-thioacetamido)-3-cephem-4-carboxylic acid ~-~ NMR spectrum ~ ppm:
5.02 (singlet, H at 6-position) ~,05 (singlet, SCH2C~-~
.. ... . : . ~
~s~
3.43 (singlet, OCH3 at 7-position) 2 . 64 (CH3 of imidazole).
UV spectrum ;~ m~ m,u:
263, IR spectrum~) cm - 17~00 TLC, Rf value:
(a)= O. 39, (b)- O. 29.
. . . `
3-Carbamoyloxymethyl-7~3-(5-ethyl-1, 2,4-triazol-3-yl-thioacetamido)-7cr-methoxy-3-cephem-4-carboxylic acid NMR spectrum ~ ppm:
5,13 (singlet, H at 6-position)
- 4.00 (singlet, S-CH2-CO) lS ~ ~ ~ 3. 52 (singlet, OCH3 at 7-position) 2. 83 and 1. 31 (quartet and triplet, CH3CH2 of triazole).
J: : `
UV spectrum . ~max mJl , : . .
26 2.
, , ~ IR spectrum,^Ycm 1 ~ ;
.j~ :
1765.
TLC, Rf value:
(a)=0.46, ~b)SO.33.
' .
i3~L
3-Carbamoyloxymethyl-7~-methoxy-7~ (5-propyl-1, 2,4-triazol-3-yl-thioacetamido)-3-cephem-4-carboxylic acid NMR æp ectrum 9 ~ ppm:
J: : `
UV spectrum . ~max mJl , : . .
26 2.
, , ~ IR spectrum,^Ycm 1 ~ ;
.j~ :
1765.
TLC, Rf value:
(a)=0.46, ~b)SO.33.
' .
i3~L
3-Carbamoyloxymethyl-7~-methoxy-7~ (5-propyl-1, 2,4-triazol-3-yl-thioacetamido)-3-cephem-4-carboxylic acid NMR æp ectrum 9 ~ ppm:
5.07 (singlet, H at 6-position) 3, 95 (singlet, S-CH2CO-) 3.49 ~singlet, OCH3 at 7-position).
IJV spectrum;l max m~
263.
IR spectrum,~ cm 1 176 5 .
TLC, Rf value;
(a)=0. 51, (b)=0.44.
3-Carbamoyloxymethyl-7a-metlloxy-7~-~5-phenyl-1, 2,4-tria~ol-3-~1-thioacetamido)-3-cephem-4-carboxylic acid `~ ``
15~ NMR spectrum ~ ppm:
4 . 94 (singlet, H at 6 -position) 3. 92 (singlet, S-CH2-CO-) , :
3.38 (singlet, OCH3 at 7-position) 7.3 - 8.0 (H of benzene).
U~ spectrum~maX ~:
, 253, 235.
IR spectrum,~cm:
,....
' ':
5~)53~
176 5 .
TLC, Rf value:
( a~=0 . 61, (b)0 . 53 .
3-Carbamoyloxy~ ethyl- 7~- methoxy-~3-(4-phenyl-1, 2, 4 -triazol-3-yl-thioacetamido~-~cephem-4-carboxylic acid acid NM:R spectrum, ~ ppm:
4 . 99 ( singlet, H at 6 -position) ` 3.99 (singlet, SCH2CO-) 3~41 (singlet, OCH3 at 7-position).
- UV spectrum ~ max ~:
260.
. IR spectrum,~Jcm 7 6 5 .
., -: TLC, Rf value:
(a)=0.43, (b)- 0. 38.
3 -Carbamoyloxymethyl- 7~-methoxy- 7,B - (4 -phenyl- 5 -methyl-l, 2, 4 -tri~a~ol-3-yl-thi em-4-carboxylic acid NMR spectrum, ô ppm:
;, :
5. 0V tsinglet, H at 6-position) ~ 3.92 (singlet, SCH2CO-) , 3.42 (singlet, OC~I3 at 7-position) ~ - , ' . .
.
2.19 (singlet, CH3 OI trlazole).
UV spectrum, ~max ~:
260.
IR spectrum,)~cm l 1765, TLCJ Rf value:
(a)=0 . 41, (b)=0 . 41.
... 3-Carbamo~methyl-7a-methoxy-7,B-(2-pyridylthioacetamido)- ;
3-cephem-4-carboxylic acid NMR spectrum ~ ppm:
f , , 5, 02 (singlet, H at 6 -position) 3.89 (~inglet, SCH2CO-) 3.39 (singlet, OCEI3 at 7-position) . . 7, 0 - 8. 5 (H of pyridi~le).
UVspectrum,~ m,~:
266, 239.
IR spectrumy cm l 1770.
TLC~R val~le: ~ ` . .
f (a)=0. 57, (b)=0.43, 3-Carbamoylox~rm thyl-7~Y-methox~-7f3-(4-met lyl-2-pyrimi~lthio-. ~ acetamido)-3-cephe~ 4-carboxylic acid 'f. ~' f .
.
- 27- :
5~
.
NMR spectrum, ~ ppm:
5 . 02 (singlet, H at 6 -position) 3. 93 (singlet, SCH2CO-) ~; 3.43 (singlet, OCH3 at 7-position) 2.42 (singlet, CH3 of pyrimidine).
UV spectrum. ~ maX m~U:
242, 270.
IR spectrum,~cm :`
1780.
.1 :
TLC,Rf value:
(a~=0. 51, (b)-b. 39.
3-Car amoyloxymethyl-7~-methox;~7~imidylthioacetamido~-;` 3-cephem-4-carboxylic acid .
NMR spectlr~li~, ô pprn:
.
15 ~ 5.04 (singlet, H at 6^position) 3.96 (singlet, SCH2CO-) '~ - 3.46 (singlet, OCH3 at 7-position) 7. 22 and 8, 58 (triplet and douhlet, H of pyrimidine).
UV spectrum,~maX rryu:
,' 20 242, 26~.
.
IR spectrum, ~ cm 1 1760, 1700.
;'' ~ ' .
, ............................................................. .
TLC, Rf value:
(a)=0,43, (b)=0.43.
3-Carbamoyloxymethyl-7~-methoxy-7~-(8-purinylthioacetamido)-3-cephem-4-carboxylic acid NMR spectrum, ~ ppm:
4. 99 (singlet, H at 6-position) 3 . 37 (singlet, OCH3 at 7 -position) 8.65 and 8.70 (H of purine).
UV spectrum,~maX mp - 10 2~7.
IR spectrum,~cm 1770.
, TLC, Rf value:
(a)=0. 35, (b~=0.18.
~- 15 3-Carbamoyloxymethyl-7~-methoxy-7~-(6-purlnylthioacetamido)-3-cephem-4-carboxylic acid NMR spectrum, i~ ppm:
5.01 (singlet, H at 6-position) 4.14 (singlet, SCH2CO-) 2û 3.43 (singlet, OCH3 at 7-position) 8. 31 and 8. 63 (E of purine) .
.
.
.
. , . . , ~ , ~ , . .
3~.
UV spectrum~maX m~
278.
IR spectrum,V cm:
176 5.
TLC, Rf value:
(a)=0.40~ (b) 0. 20.
7,B-(2-Benzimidazolylthioacetamido)-3-carbamoyloxymethyl-7ar-- methoxy-3-_ephem-4-carboxylic acid ~ . .
NMR spectrumJ ~ ppm:
., 4 . 95 (singlet, :H at 6 -position) 4.16 (singlet, SCH2CO-) 3.41 tsingletJ OCH3 at 7-position).
UV spectrum~ma ~:
2~1, 287.
IR spectrum, ~ cm : -1780, 1680.
~ TLC, Rf value:
.; - (a)=0.48, ~b)=0. 51.
-7~3-(2 1S~A~tamido)-3-carba~noyloxymethyl-7~-metho~ ~em-4-carboxylic acid , ~
~ ~ NMR spectrum, ~ ppm:
- .
., .
:, .
, ~, ~ ....... . . . . . . .
~5~i3~L
5 . 05 (singlet, H at 6 -position) - 4.14 (singlet, SCH2CO-) 3. 50 (singlet, OCH3 at 7-position).
UV spectrumJ ;~ max m~
283, 276J 245.
IR spectrum ~ cm : .
1~80J 172~.
~; TLC J Rf value:
. (a)=0, 61J (b)=0.48.
: 10 7~ - ( 2 -B enzthla7.olylthioac etamido) - 3 - carbamoyloxymethyl - 7~-methoxy-3-cephem-4-carboxylic acid NMR spectrum (CD3OD)J ~ ppm:
5. 04 (singletJ H at 6 -position) 3,45 (singletJ OCH3 at 7-position), : lS UV spectrumJ~ maX
: : 2~7, ~71.
,j~: - , IR spectrumJ ~ cm 1770.
TLC, Rf value:
ao (a)-0 . 58 J (b) =0 . 48, .: , ' , .
53~L
3 - Carbamo~oxymethyl- 7~-m ethoxy- 7,e - ( s -tria zolo~ 4, 3 -a] pyridin-3 -yl-thioac etamido) - 3 - cephem -4 -carboxylic acid NMR spectrum, ~ ppm:
4. 94 (singlet, H at 6-position) 3.95 (singlet, SCH~CO-) 3.40 tsinglet, O(:H3 at 7-position~.
UV ~;pectrum,~maxrr~:
269.
IR spectrum,~cm l 1770, 1690.
TL(, R value:
(a)=0. 29, (b)=0. 39.
,: :
3-Carbamoyloxymethyl-~-methoxy-7~-t2-naphth~hioacetamido)-- ~ 3-cephem-4-carboxylic acid ":
l~ ~ NMR spectrum, ~ ppm:
-4. 92 (singlet, H at 6-position) 3.72 (singlet, SCH2-CO-) 3.29 (singlet, OCH3 at 7-position) 7. 3 - 7. 9 (H of naphthalene).
., .
(~ UV spectrum,~ ma~
248, 270 (Sh.).
.
, , S3~
IR sp ectrum, ~ cm 176 5.
TLC, Rf ualue:
(a)=0. 61, (b)=0. 60.
~ "Sh"= "shoulder"]
3-Carbamoyloxymethyl-7a-methoxy-7~-(2-thiazolinylthioacetamido~-: ~ 3 - cephem -4 - carboxylic acid :' " i NMR sp ec1; rum 9 ~ ppm:
5. 08 (singlet, H at 6-position) ~ - 10 3, 92 ~singlet, SCH2CO-) ~ .
! 3. 50 (singlet, OCH3 at 7-position).
UV spectrurn,~max m}
258, 239.
IR spectrum )~cm 1;
S~ 1770, 1690.
TLC, Rf ~ralue:
. (a)=0.49, ~b)=0.49, ~ , .
3-Carbamoyloxymethyl-7~-cyclohexylthioacetamido-7~-methoxy-3-cephem-4-carboxylic acid .;
:~ Z0 NMR spectrum, ~ ppm:
5. 08 (singlet, H at 6-positlon) 3 . 81 (einglet, SCH2CO-) ,, .
, , .
" ~'.' 3~
3.48 (æinglet, OCH3 at 7-position) 1. O - 2. (CH2 f cyclohexane) .
UV spectrum,~ a ~:
266.
TLC, Rf value:
(a)=O, 56, (b)=O. 50.
... 3-C:arbamoyloxymethyl-7~-methoxy-7,B-(rl-~ropylthioacetamido) 3-ceRhem-4-carboxylic acid ~ ' , .
N~R spectrum (CD30D), ~ ppm:
5, 04 (singlet, H at b-position) 3.45 (singlet, OCH,~ at 7-position3.
UV spectrum,~maX rryu;
26 5.
.~ ~ IR spectrum,~cm 1 ': : . 1771~.
., TLC, R~ value:
`` (a)=O. 55, (b)=O. 55.
3-Carbamo;sr~oxymethyl-q~-methoxy-7~,_-pent2~ioacetamido)-3-cel?hem-4~ ~ d ,. ~ .
. ~ .
:? :
.' - . , ' ' . ,. , , .. , .,, .. : : ' .
i3~
NMR spectrum (CD30D), ~ ppm:
5, 04 (singlet, El at 6 -position) 3.46 (singlet, OCH3 at 7-position).
UV spectrum. ~ max rryu:
265.
IR spectrum,~)cm 1 1770.
TLC, Rf value:
(a)=O, 60, (b)=O. 54, ';i . , - 10 Example 4 :i ~;~ 7~B-(2-Butylthioacetamido)-3-carbamoyloxyrreth~rl-7~-methoxy- 3-cel?hem-4-carboxylic acid 45 mg of sec-butanethiol were dissolved with 0. 5 ml of a lN aqueous solution of sodium hydroxide in 50% aqueous methanol, and 0. 5 ml of benzhydryl 7,B-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-cephem-4-carboxylate ~ras added to the resulting solution, The mixture was agitated for 2 hours, after which methanol was distilled off under reduced pressure. The aqueous phase waæ extracted three times with ~; 20 ethyl acetate and the extracts were dried over sodium sulphate.
The solvent was then distilled off, giving crude benz~ydryl 7~-,' .
- 35 - ~
' ' , .
.
~ 533L
(2-butylthioacetamido) - 3 - carbamoyloxym ethyl- 7~-methoxy- 3 -cephem-4-carboxylate. This crude product was dissolved in 1. 0 ml of anisole, and 1, 5 ml of trifluoroacetic acid were added to the resulting solution. The mixture was allowed to stand at room temperature for 6 minutes and then evaporated to dryness under reduced pressure. The solid residue was dissolved in 20 ml of ethyl acetate and 20 ml of 0. 2M phosphoric acid buffer (pH 7. 5) and the mixture was agitated and then allowed to stand to allow phase separation. The aqueous phase was washed once again with ethyl acetate and its pH was then adjusted to 2. 5. The aqueous layer was then extracted 4 times with 20 ml of ethyl acetate, and the combined extracts were dried over sodium sulphate and evaporated to dryness under reduced pressure giving an amorphous crude product, This product was separated and purified on a silica gel plate emplo~ying a 50 : 50 mixture of methanol and chloroform. 115 mg of the desired product were obtained in the form of a powder.
~, Nuclear magnetic resonance spectrum (CD30D), ~ ppm:
5.08 5singlet, H at 6-position~
.
3. 58 (singlet, OC~13 at 7-position).
Ultraviolet absorption spectrum (CH30H) 1 maX ~:
- ` 26~ (= 9i40).
.
~ - 36- -:
' ~ . . . . . . .. . . . . . . . . . .. .
S(~S3~L
Ihrared absorption spectrum (KBr), Y cm 1 1795, 1720, 1680.
Thin layer chromatography (silica gel):
(a) Developing solvent (n-butanol /acetic acid/water, -5: 4: 1 by volume):
` :Rf value = 0. 59.
~` (b~ Developing solvent (chloroform/methanol, 1 ~ 1 by volume):
Rf value = 0 . 6 0 .
. . .
`; 10 ~5 3-Acetoxymethyl-7~-methoxy-7~ 3, 4-thiadiazol-2-yl-thioacetamido)-3-cephem-4-carboxylic acid . .
~. . 33 mg of 2-mercapto-1, 3, 4-thiadia~.ole were di.~solved .~: .
: in 0. 24 ml of lN aqueous sodium hydroxide, and a solution of ~: 15 0.27 mmole ~100 mg) of 3-acetoxyrnethyl-7~-chloroacetamido-7~- :
methoxy-3-cephem-4-carboxylic acid m 0, 5N sodium bicarbonate : was added to the resulting solution. The mixture was agitated :.
at room temperature for 3 hours and the p~I was then adjusted .
to 2. 5 by addition of O.lN phosphoric acid. The mixt7lre was then extracted 3 times with ethyl acetate and the combined ethyl - . acetate extracts were dried over sodium sulphate. The solvent .,'" ~"
.-' .
- ~S~53~
.
was distilled off from the dried ethyl acetate solution, giving 113 mg of an arnorphous crude product. This was separated on a silica gel plate employing chloroform containing 40% methanol as a solvent and was then extracted with methanol. The solvent vvas distilled off from the extract, giving 69 mg of the desired - ~ product .
.,~ .
Nuclear magnetic resonance spectrum (CD3CN -~ D2O), ~ ppm:
9 . 23 (singlet, H of thiadiazole) 5. 00 (singlet, H at 6-position) 4.73 (doublet, CH2 at 3-position) ~r 4.11 (smglet, S-CH2-CO-) ~' 3.42 (singlet, OCH3 at 7-position) 1. 98 (singlet, O-CO-CH3).
IJltrav~olet absorption spectrum ~phosphoric acid buffer of pH 6, ~6j, ; ~ ~ lS ~ max P
26 3 m~ =87 89) .
Infrar ed absorption spectrum (KBr), ~ cm 1 1760.
.:: .
Thin layer chromatography (silica gel):
~ Developing solvent (methanol/chloroform, 1: 1 by volume):
R value = 0.45.
f Examples of other compounds prepared .
in the same manner as in the foregoing Example, together with .
' , , ' ' . ..
, , , , . . .:
`, : : ' , ~ ! `
~L~S~53~L
their properties (determined as described in Example 3) are shown below:
3 -Ac etoxym ethyl - 7~ - cyanom ethylthioac etamido - 7a -methoxy-3-cephem-4-carboxylic acid NMR spectrum (CD3CN), ~ ppm:
5 . 06 (singlet, H at 6 -position) 4.76 - 5.06 (quartet, -CH2OCO- at 3-position~
3,60 (singlet, NCCH2S or SCH2CO) 3. 52 (singlet, OCH3 at 7-position) 3,42 ~singlet, NCCH2S or SCH2CO) 3, 32 - 3, 55 (quartet, H2 at 2-position) 2,02 (singlet, OCOCH3).
UV spectrum ~
247 ( ~ = 8000) 267 ( '~ -8400).
IR spectrum,2J cm 1 177 5, 3-Acetoxymethyl-7~-methoxy-?~B-pro~argylthioacetamiào-3-cephem-4-carboxylic acid N~R spectrum ~DMSO-d6j, ~ ppm:
5.05 (singlet, H at 6-position) 4.9 - 4.6 (quartet, -CH2OCO- at 3-position) i3~
3. 36 (singlet, OCH3 at 7-position) 3. 2 - 3. 5 (multiplet, 2-position, H2, -C:H2 and -S-C~2 ) 3.05 (triplet, HC_C) 1.98 (singlet, OCOCH3).
UV spectrum,;~max ~yU:
245 (~ =7800) .
~... 268 (~ =8200).
IR spectrum,lJ cm 1 1775.
When 83 mg of the carboxylic acid thus obtained were added to 8 m]. of water, 17 mg of sodium bicarbonate were gradually added thereto and the resulting homogeneous solution was freeze-dried, a sodium salt of tlle carboxylic acid was obtained in the form of an amorphous powder.
, 3-Acetoxymethyl-7,B-azidomethylthioacetamido 7~-methox~sr-3-cephem-4-carboxylic acid P~MR spectrum (DMSO-d6), ~ ppm:
5.14 (singlet, H at 6-position) 4.69 - 4.98 (quartet, -CH2-OCO- at 3-position) ' 3~. -4. 51 (singlet, N3CH2S-) 3.40 (singlet, 7-position, OCH3, S-CH2-CO) 3.3 - 3.6 (quartet, H2 at 2-position) 2 00 (singlet, OCO-CH3).
5 UV spectrum,~max m~:
` 247 ( =57800) 269 ( = 8000).
IR spectrum, 1J cm 1 1775.
. 10 3 -Acetoxymethyl-7~3- (imidazol-2-yl-thioacetamido) - 7a-methoxy-3-cephem-4-carboxylic acid N.MR spectrum ~ ppm:
7.11 (singlet, H at 4- an~d 5-position of imidazole) 5 . 0 2 tsinglet, H at 6 -position~
4.78 (broad singlet, H2 at 3-position) 3.78 (singlet, -S-CH2CO-) 3 38 (singlet, OCH3 at 7-position) 2.02 (singlet, -O-COCH3).
UV spectrUm,,J~ max 265.
IR spectrum, 2~ cm . 1760.
TLC, Rf ~alue:
(b) =0. 46 .
_ 41 -~ ' .
Example 6 7a-Methoxy- 3 - (l-m ethyl -lH-tetrazol- 5 -yl)thiomethyl- 7~3-(1, 3, 4 -thiadiazol-2-yl-thioacetamido)-3-ceE~hem-4-carboxylic acid 33 mg of 2-mercapto-1, 3, 4 -thiadiazole were dissolved in 0. 24 ml of lN sodium hydroxide and a solution of 117 mg (0.27 mmole) of 7,B-chloroacetamido-7~-methoxy-3-(1-methyl-lH tetrazol- 5-yl)thiomethyl- 3 -cephem-4 -carboxylic acid in 0. 5N sodium hydrogen carbonate was added to the resulting solution. The mixture was agitated at room temperature for 3 hours, and the pH was then adjusted to 2. 5 by addition of 0,lN phosphoric acid. The mixture was extracted 3 times with ethyl acetate, and the combined extracts were dried over sodium sulph~te. The solvent was then distilled off, giving 125 mg OI an amorphous product. This was separated on a silica gel plate employing a 50: 50 mixture of methanol and chloroform and extracted with methanol. The solvent was distillèd off from the extract, giving 70 mg of the desired product in the form of , an amorphous powder.
Nuclear magnetic resonance spectrum (CD3CN + D2O), ~ ppm:
ZO 9, 28 (singlet, H at 5-position of thiadiaæole).
Ultraviolet absorption spectrum (phosphoric acid buffer of pH
IJV spectrum;l max m~
263.
IR spectrum,~ cm 1 176 5 .
TLC, Rf value;
(a)=0. 51, (b)=0.44.
3-Carbamoyloxymethyl-7a-metlloxy-7~-~5-phenyl-1, 2,4-tria~ol-3-~1-thioacetamido)-3-cephem-4-carboxylic acid `~ ``
15~ NMR spectrum ~ ppm:
4 . 94 (singlet, H at 6 -position) 3. 92 (singlet, S-CH2-CO-) , :
3.38 (singlet, OCH3 at 7-position) 7.3 - 8.0 (H of benzene).
U~ spectrum~maX ~:
, 253, 235.
IR spectrum,~cm:
,....
' ':
5~)53~
176 5 .
TLC, Rf value:
( a~=0 . 61, (b)0 . 53 .
3-Carbamoyloxy~ ethyl- 7~- methoxy-~3-(4-phenyl-1, 2, 4 -triazol-3-yl-thioacetamido~-~cephem-4-carboxylic acid acid NM:R spectrum, ~ ppm:
4 . 99 ( singlet, H at 6 -position) ` 3.99 (singlet, SCH2CO-) 3~41 (singlet, OCH3 at 7-position).
- UV spectrum ~ max ~:
260.
. IR spectrum,~Jcm 7 6 5 .
., -: TLC, Rf value:
(a)=0.43, (b)- 0. 38.
3 -Carbamoyloxymethyl- 7~-methoxy- 7,B - (4 -phenyl- 5 -methyl-l, 2, 4 -tri~a~ol-3-yl-thi em-4-carboxylic acid NMR spectrum, ô ppm:
;, :
5. 0V tsinglet, H at 6-position) ~ 3.92 (singlet, SCH2CO-) , 3.42 (singlet, OC~I3 at 7-position) ~ - , ' . .
.
2.19 (singlet, CH3 OI trlazole).
UV spectrum, ~max ~:
260.
IR spectrum,)~cm l 1765, TLCJ Rf value:
(a)=0 . 41, (b)=0 . 41.
... 3-Carbamo~methyl-7a-methoxy-7,B-(2-pyridylthioacetamido)- ;
3-cephem-4-carboxylic acid NMR spectrum ~ ppm:
f , , 5, 02 (singlet, H at 6 -position) 3.89 (~inglet, SCH2CO-) 3.39 (singlet, OCEI3 at 7-position) . . 7, 0 - 8. 5 (H of pyridi~le).
UVspectrum,~ m,~:
266, 239.
IR spectrumy cm l 1770.
TLC~R val~le: ~ ` . .
f (a)=0. 57, (b)=0.43, 3-Carbamoylox~rm thyl-7~Y-methox~-7f3-(4-met lyl-2-pyrimi~lthio-. ~ acetamido)-3-cephe~ 4-carboxylic acid 'f. ~' f .
.
- 27- :
5~
.
NMR spectrum, ~ ppm:
5 . 02 (singlet, H at 6 -position) 3. 93 (singlet, SCH2CO-) ~; 3.43 (singlet, OCH3 at 7-position) 2.42 (singlet, CH3 of pyrimidine).
UV spectrum. ~ maX m~U:
242, 270.
IR spectrum,~cm :`
1780.
.1 :
TLC,Rf value:
(a~=0. 51, (b)-b. 39.
3-Car amoyloxymethyl-7~-methox;~7~imidylthioacetamido~-;` 3-cephem-4-carboxylic acid .
NMR spectlr~li~, ô pprn:
.
15 ~ 5.04 (singlet, H at 6^position) 3.96 (singlet, SCH2CO-) '~ - 3.46 (singlet, OCH3 at 7-position) 7. 22 and 8, 58 (triplet and douhlet, H of pyrimidine).
UV spectrum,~maX rryu:
,' 20 242, 26~.
.
IR spectrum, ~ cm 1 1760, 1700.
;'' ~ ' .
, ............................................................. .
TLC, Rf value:
(a)=0,43, (b)=0.43.
3-Carbamoyloxymethyl-7~-methoxy-7~-(8-purinylthioacetamido)-3-cephem-4-carboxylic acid NMR spectrum, ~ ppm:
4. 99 (singlet, H at 6-position) 3 . 37 (singlet, OCH3 at 7 -position) 8.65 and 8.70 (H of purine).
UV spectrum,~maX mp - 10 2~7.
IR spectrum,~cm 1770.
, TLC, Rf value:
(a)=0. 35, (b~=0.18.
~- 15 3-Carbamoyloxymethyl-7~-methoxy-7~-(6-purlnylthioacetamido)-3-cephem-4-carboxylic acid NMR spectrum, i~ ppm:
5.01 (singlet, H at 6-position) 4.14 (singlet, SCH2CO-) 2û 3.43 (singlet, OCH3 at 7-position) 8. 31 and 8. 63 (E of purine) .
.
.
.
. , . . , ~ , ~ , . .
3~.
UV spectrum~maX m~
278.
IR spectrum,V cm:
176 5.
TLC, Rf value:
(a)=0.40~ (b) 0. 20.
7,B-(2-Benzimidazolylthioacetamido)-3-carbamoyloxymethyl-7ar-- methoxy-3-_ephem-4-carboxylic acid ~ . .
NMR spectrumJ ~ ppm:
., 4 . 95 (singlet, :H at 6 -position) 4.16 (singlet, SCH2CO-) 3.41 tsingletJ OCH3 at 7-position).
UV spectrum~ma ~:
2~1, 287.
IR spectrum, ~ cm : -1780, 1680.
~ TLC, Rf value:
.; - (a)=0.48, ~b)=0. 51.
-7~3-(2 1S~A~tamido)-3-carba~noyloxymethyl-7~-metho~ ~em-4-carboxylic acid , ~
~ ~ NMR spectrum, ~ ppm:
- .
., .
:, .
, ~, ~ ....... . . . . . . .
~5~i3~L
5 . 05 (singlet, H at 6 -position) - 4.14 (singlet, SCH2CO-) 3. 50 (singlet, OCH3 at 7-position).
UV spectrumJ ;~ max m~
283, 276J 245.
IR spectrum ~ cm : .
1~80J 172~.
~; TLC J Rf value:
. (a)=0, 61J (b)=0.48.
: 10 7~ - ( 2 -B enzthla7.olylthioac etamido) - 3 - carbamoyloxymethyl - 7~-methoxy-3-cephem-4-carboxylic acid NMR spectrum (CD3OD)J ~ ppm:
5. 04 (singletJ H at 6 -position) 3,45 (singletJ OCH3 at 7-position), : lS UV spectrumJ~ maX
: : 2~7, ~71.
,j~: - , IR spectrumJ ~ cm 1770.
TLC, Rf value:
ao (a)-0 . 58 J (b) =0 . 48, .: , ' , .
53~L
3 - Carbamo~oxymethyl- 7~-m ethoxy- 7,e - ( s -tria zolo~ 4, 3 -a] pyridin-3 -yl-thioac etamido) - 3 - cephem -4 -carboxylic acid NMR spectrum, ~ ppm:
4. 94 (singlet, H at 6-position) 3.95 (singlet, SCH~CO-) 3.40 tsinglet, O(:H3 at 7-position~.
UV ~;pectrum,~maxrr~:
269.
IR spectrum,~cm l 1770, 1690.
TL(, R value:
(a)=0. 29, (b)=0. 39.
,: :
3-Carbamoyloxymethyl-~-methoxy-7~-t2-naphth~hioacetamido)-- ~ 3-cephem-4-carboxylic acid ":
l~ ~ NMR spectrum, ~ ppm:
-4. 92 (singlet, H at 6-position) 3.72 (singlet, SCH2-CO-) 3.29 (singlet, OCH3 at 7-position) 7. 3 - 7. 9 (H of naphthalene).
., .
(~ UV spectrum,~ ma~
248, 270 (Sh.).
.
, , S3~
IR sp ectrum, ~ cm 176 5.
TLC, Rf ualue:
(a)=0. 61, (b)=0. 60.
~ "Sh"= "shoulder"]
3-Carbamoyloxymethyl-7a-methoxy-7~-(2-thiazolinylthioacetamido~-: ~ 3 - cephem -4 - carboxylic acid :' " i NMR sp ec1; rum 9 ~ ppm:
5. 08 (singlet, H at 6-position) ~ - 10 3, 92 ~singlet, SCH2CO-) ~ .
! 3. 50 (singlet, OCH3 at 7-position).
UV spectrurn,~max m}
258, 239.
IR spectrum )~cm 1;
S~ 1770, 1690.
TLC, Rf ~ralue:
. (a)=0.49, ~b)=0.49, ~ , .
3-Carbamoyloxymethyl-7~-cyclohexylthioacetamido-7~-methoxy-3-cephem-4-carboxylic acid .;
:~ Z0 NMR spectrum, ~ ppm:
5. 08 (singlet, H at 6-positlon) 3 . 81 (einglet, SCH2CO-) ,, .
, , .
" ~'.' 3~
3.48 (æinglet, OCH3 at 7-position) 1. O - 2. (CH2 f cyclohexane) .
UV spectrum,~ a ~:
266.
TLC, Rf value:
(a)=O, 56, (b)=O. 50.
... 3-C:arbamoyloxymethyl-7~-methoxy-7,B-(rl-~ropylthioacetamido) 3-ceRhem-4-carboxylic acid ~ ' , .
N~R spectrum (CD30D), ~ ppm:
5, 04 (singlet, H at b-position) 3.45 (singlet, OCH,~ at 7-position3.
UV spectrum,~maX rryu;
26 5.
.~ ~ IR spectrum,~cm 1 ': : . 1771~.
., TLC, R~ value:
`` (a)=O. 55, (b)=O. 55.
3-Carbamo;sr~oxymethyl-q~-methoxy-7~,_-pent2~ioacetamido)-3-cel?hem-4~ ~ d ,. ~ .
. ~ .
:? :
.' - . , ' ' . ,. , , .. , .,, .. : : ' .
i3~
NMR spectrum (CD30D), ~ ppm:
5, 04 (singlet, El at 6 -position) 3.46 (singlet, OCH3 at 7-position).
UV spectrum. ~ max rryu:
265.
IR spectrum,~)cm 1 1770.
TLC, Rf value:
(a)=O, 60, (b)=O. 54, ';i . , - 10 Example 4 :i ~;~ 7~B-(2-Butylthioacetamido)-3-carbamoyloxyrreth~rl-7~-methoxy- 3-cel?hem-4-carboxylic acid 45 mg of sec-butanethiol were dissolved with 0. 5 ml of a lN aqueous solution of sodium hydroxide in 50% aqueous methanol, and 0. 5 ml of benzhydryl 7,B-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-cephem-4-carboxylate ~ras added to the resulting solution, The mixture was agitated for 2 hours, after which methanol was distilled off under reduced pressure. The aqueous phase waæ extracted three times with ~; 20 ethyl acetate and the extracts were dried over sodium sulphate.
The solvent was then distilled off, giving crude benz~ydryl 7~-,' .
- 35 - ~
' ' , .
.
~ 533L
(2-butylthioacetamido) - 3 - carbamoyloxym ethyl- 7~-methoxy- 3 -cephem-4-carboxylate. This crude product was dissolved in 1. 0 ml of anisole, and 1, 5 ml of trifluoroacetic acid were added to the resulting solution. The mixture was allowed to stand at room temperature for 6 minutes and then evaporated to dryness under reduced pressure. The solid residue was dissolved in 20 ml of ethyl acetate and 20 ml of 0. 2M phosphoric acid buffer (pH 7. 5) and the mixture was agitated and then allowed to stand to allow phase separation. The aqueous phase was washed once again with ethyl acetate and its pH was then adjusted to 2. 5. The aqueous layer was then extracted 4 times with 20 ml of ethyl acetate, and the combined extracts were dried over sodium sulphate and evaporated to dryness under reduced pressure giving an amorphous crude product, This product was separated and purified on a silica gel plate emplo~ying a 50 : 50 mixture of methanol and chloroform. 115 mg of the desired product were obtained in the form of a powder.
~, Nuclear magnetic resonance spectrum (CD30D), ~ ppm:
5.08 5singlet, H at 6-position~
.
3. 58 (singlet, OC~13 at 7-position).
Ultraviolet absorption spectrum (CH30H) 1 maX ~:
- ` 26~ (= 9i40).
.
~ - 36- -:
' ~ . . . . . . .. . . . . . . . . . .. .
S(~S3~L
Ihrared absorption spectrum (KBr), Y cm 1 1795, 1720, 1680.
Thin layer chromatography (silica gel):
(a) Developing solvent (n-butanol /acetic acid/water, -5: 4: 1 by volume):
` :Rf value = 0. 59.
~` (b~ Developing solvent (chloroform/methanol, 1 ~ 1 by volume):
Rf value = 0 . 6 0 .
. . .
`; 10 ~5 3-Acetoxymethyl-7~-methoxy-7~ 3, 4-thiadiazol-2-yl-thioacetamido)-3-cephem-4-carboxylic acid . .
~. . 33 mg of 2-mercapto-1, 3, 4-thiadia~.ole were di.~solved .~: .
: in 0. 24 ml of lN aqueous sodium hydroxide, and a solution of ~: 15 0.27 mmole ~100 mg) of 3-acetoxyrnethyl-7~-chloroacetamido-7~- :
methoxy-3-cephem-4-carboxylic acid m 0, 5N sodium bicarbonate : was added to the resulting solution. The mixture was agitated :.
at room temperature for 3 hours and the p~I was then adjusted .
to 2. 5 by addition of O.lN phosphoric acid. The mixt7lre was then extracted 3 times with ethyl acetate and the combined ethyl - . acetate extracts were dried over sodium sulphate. The solvent .,'" ~"
.-' .
- ~S~53~
.
was distilled off from the dried ethyl acetate solution, giving 113 mg of an arnorphous crude product. This was separated on a silica gel plate employing chloroform containing 40% methanol as a solvent and was then extracted with methanol. The solvent vvas distilled off from the extract, giving 69 mg of the desired - ~ product .
.,~ .
Nuclear magnetic resonance spectrum (CD3CN -~ D2O), ~ ppm:
9 . 23 (singlet, H of thiadiazole) 5. 00 (singlet, H at 6-position) 4.73 (doublet, CH2 at 3-position) ~r 4.11 (smglet, S-CH2-CO-) ~' 3.42 (singlet, OCH3 at 7-position) 1. 98 (singlet, O-CO-CH3).
IJltrav~olet absorption spectrum ~phosphoric acid buffer of pH 6, ~6j, ; ~ ~ lS ~ max P
26 3 m~ =87 89) .
Infrar ed absorption spectrum (KBr), ~ cm 1 1760.
.:: .
Thin layer chromatography (silica gel):
~ Developing solvent (methanol/chloroform, 1: 1 by volume):
R value = 0.45.
f Examples of other compounds prepared .
in the same manner as in the foregoing Example, together with .
' , , ' ' . ..
, , , , . . .:
`, : : ' , ~ ! `
~L~S~53~L
their properties (determined as described in Example 3) are shown below:
3 -Ac etoxym ethyl - 7~ - cyanom ethylthioac etamido - 7a -methoxy-3-cephem-4-carboxylic acid NMR spectrum (CD3CN), ~ ppm:
5 . 06 (singlet, H at 6 -position) 4.76 - 5.06 (quartet, -CH2OCO- at 3-position~
3,60 (singlet, NCCH2S or SCH2CO) 3. 52 (singlet, OCH3 at 7-position) 3,42 ~singlet, NCCH2S or SCH2CO) 3, 32 - 3, 55 (quartet, H2 at 2-position) 2,02 (singlet, OCOCH3).
UV spectrum ~
247 ( ~ = 8000) 267 ( '~ -8400).
IR spectrum,2J cm 1 177 5, 3-Acetoxymethyl-7~-methoxy-?~B-pro~argylthioacetamiào-3-cephem-4-carboxylic acid N~R spectrum ~DMSO-d6j, ~ ppm:
5.05 (singlet, H at 6-position) 4.9 - 4.6 (quartet, -CH2OCO- at 3-position) i3~
3. 36 (singlet, OCH3 at 7-position) 3. 2 - 3. 5 (multiplet, 2-position, H2, -C:H2 and -S-C~2 ) 3.05 (triplet, HC_C) 1.98 (singlet, OCOCH3).
UV spectrum,;~max ~yU:
245 (~ =7800) .
~... 268 (~ =8200).
IR spectrum,lJ cm 1 1775.
When 83 mg of the carboxylic acid thus obtained were added to 8 m]. of water, 17 mg of sodium bicarbonate were gradually added thereto and the resulting homogeneous solution was freeze-dried, a sodium salt of tlle carboxylic acid was obtained in the form of an amorphous powder.
, 3-Acetoxymethyl-7,B-azidomethylthioacetamido 7~-methox~sr-3-cephem-4-carboxylic acid P~MR spectrum (DMSO-d6), ~ ppm:
5.14 (singlet, H at 6-position) 4.69 - 4.98 (quartet, -CH2-OCO- at 3-position) ' 3~. -4. 51 (singlet, N3CH2S-) 3.40 (singlet, 7-position, OCH3, S-CH2-CO) 3.3 - 3.6 (quartet, H2 at 2-position) 2 00 (singlet, OCO-CH3).
5 UV spectrum,~max m~:
` 247 ( =57800) 269 ( = 8000).
IR spectrum, 1J cm 1 1775.
. 10 3 -Acetoxymethyl-7~3- (imidazol-2-yl-thioacetamido) - 7a-methoxy-3-cephem-4-carboxylic acid N.MR spectrum ~ ppm:
7.11 (singlet, H at 4- an~d 5-position of imidazole) 5 . 0 2 tsinglet, H at 6 -position~
4.78 (broad singlet, H2 at 3-position) 3.78 (singlet, -S-CH2CO-) 3 38 (singlet, OCH3 at 7-position) 2.02 (singlet, -O-COCH3).
UV spectrUm,,J~ max 265.
IR spectrum, 2~ cm . 1760.
TLC, Rf ~alue:
(b) =0. 46 .
_ 41 -~ ' .
Example 6 7a-Methoxy- 3 - (l-m ethyl -lH-tetrazol- 5 -yl)thiomethyl- 7~3-(1, 3, 4 -thiadiazol-2-yl-thioacetamido)-3-ceE~hem-4-carboxylic acid 33 mg of 2-mercapto-1, 3, 4 -thiadiazole were dissolved in 0. 24 ml of lN sodium hydroxide and a solution of 117 mg (0.27 mmole) of 7,B-chloroacetamido-7~-methoxy-3-(1-methyl-lH tetrazol- 5-yl)thiomethyl- 3 -cephem-4 -carboxylic acid in 0. 5N sodium hydrogen carbonate was added to the resulting solution. The mixture was agitated at room temperature for 3 hours, and the pH was then adjusted to 2. 5 by addition of 0,lN phosphoric acid. The mixture was extracted 3 times with ethyl acetate, and the combined extracts were dried over sodium sulph~te. The solvent was then distilled off, giving 125 mg OI an amorphous product. This was separated on a silica gel plate employing a 50: 50 mixture of methanol and chloroform and extracted with methanol. The solvent was distillèd off from the extract, giving 70 mg of the desired product in the form of , an amorphous powder.
Nuclear magnetic resonance spectrum (CD3CN + D2O), ~ ppm:
ZO 9, 28 (singlet, H at 5-position of thiadiaæole).
Ultraviolet absorption spectrum (phosphoric acid buffer of pH
6 . 86 ) ~ max m~:
266 (~ ~ 9270).
~'' ' , . ' . ~
3~L
; Infrared absorption spectrum (K~r), ~Jcm . 176 0 .
Thin layer chromatography ~ silica gel):
I)eveloping solvent (chloroform/methanol, 1:1 by volume) Rf value ~ 0. 38.
:'' Examples of compounds prepared in the same manner as in the foregoing Example and their properties (measured as described in Example 3) are shown below:
"
266 (~ ~ 9270).
~'' ' , . ' . ~
3~L
; Infrared absorption spectrum (K~r), ~Jcm . 176 0 .
Thin layer chromatography ~ silica gel):
I)eveloping solvent (chloroform/methanol, 1:1 by volume) Rf value ~ 0. 38.
:'' Examples of compounds prepared in the same manner as in the foregoing Example and their properties (measured as described in Example 3) are shown below:
"
7,8-(Imidazol-2-ylthioacetamido)-7a!-methoxy-3-(1-methyl-lH-. .
~ :l0 tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid :
NMR spectrum ~ ppm:
`~ 7.03 (singlet, H at 4- and 5-position of imidazole~
: 4. 95 ~singlet, H at 6-position) 3 . 84 (singlet, CH3 at l-posltion of tetrazole ring) : 15 3. 36 (singlet, OCH3 at 7-positionj .
1 . :
UV spectrum, ~max : 265 (~= 7200).
- IR spectrum, ~J cm l .~ 1760.
TLC, Rf value:
(b) = 0 . 36 .
: :
~ ~ -43 , . . . .
,. .. . . . . .
~CI Sq~153~il 7,B=cyanomethylthioacetamido-7~methoxy-3-(l-methyl-lH
tetra zol - 5 - yl)thiom ethyl - 3 - c eph em - 4 - c arboxylic acid NMR spectrum, ~ ppm:
5.10 (singlet, EI at 6-position) 4.3 - 4.6 (quartet, CH2-S at 3-position) 3. 98 (singlet, CH3 at l-position of tetrazole ring) 3 . 70 (singlet, -NCCH2S or -SCH2CO) 3.5 - 3.7 (quartet, H2 at 2-position~
3.60 (singlet, -NCCH2S or -SCH2CO) 3 . 50 ¦sin~let, OCEI3 at 7 -position) .
` UV spectrum ~ mp:
274 ( = 9ooo), 7a-~$ethoxy- 3 - (l-methyl -lH-tetrazol- 5 -yl)thiomethyl- 7,~ -propargyl-thioacetamido-3-cephem-4-carboxylic acid NMR spectrum (DMSO-d6), ~ ppm:
. ~ ~.05 (singlet, EI at 6-position) 4 . 2 - 4 . 3 (quartet, CH2-S at 3 -position) 3. 90 (singlet, CH3 at l-position of tetrazole ring) about 3. 5 (multiplet, OCH3 at 7-position, H2, -CEI2-S-CH2CO at 2-position) 3,20 (triplet, HC_C-).
.
.
, , , . ~ . : .
1~5~53~
Example 7 7~-Methoxy-3-(1-methyl-lH-tetrazol-5-yl )thiomethyl-7,B-(1, 3,4-_ thiadiazol- 2-yl-thioacetamido)- 3-cephem-4 -carboxylic acid To a solution of 596 mg of 2-[ 7,B-bromoacetamido-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-:~ 4-carbonyl] -s-triazolo[ 4,3-a] pyrid-3-one in 30 ml of acetone was added a solution of 86 mg of 2-mercapto-1, 3,4-thiadiazole and 84 mg of sodium hydrogen carbonate in 8 ml of water; the resulting mixture was stirred at room temperature for 1 hour, -1 lû The solvent was then distilled off under reduced pressure and 50 ~ ml of ethyl acetate were added to the residue, which was then washed ~ with water and dried over anhydrous magnesium sulphate. The solvent was distilled o~, giving crude 2 [7a-metho~y-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl 7~3-(1, 3,4-thiadiazol-2-yl-thioacetamido)-3 - cephem-~ -carbonyl~ - s - triazolo[ 4, 3 - a] pyrid- 3 -one as a powder .
Nuclear magnetic resonance spectrum (CDC13), ~ ppm:
3.43 (singlet, O-CH3 at 7-position) 3. ~0 (singlet, N-CH3 at 3-position of tetrazole) 4, 25 (singletJ -S-CH2-CO at 7-position) . 5,24 (singlet, 6-position, ~
--N~ H
'~ 6,3 - 7~9 (multlplet, 4-position -CO-N~
O H
.' ' ' .
, :
.
. .
5~3~
9,08 (7-position, thiadiazole) Ultraviolet absorption spectrum (THF), max nm:
227, 261, 359.
Infrared absorption spectrum (Nujol-trade mark), L~cm l 1770, 1700, 1650, Thin layer chromatography ( silica gel):
(a) Developing solvent (chloroform containing 10%
. methanol~:
' R E value = O . 56 .
; 10 (b) Developing solv~ent (n-butanol/acetic acid/water, . 4: 1 :1 by volunne): ;
Rf value - 0 . 47 .
To a ~olution of the compound obta~ned above in a mi~ture of 15 ml of tetrahydrofuran and 7. 5 ml of water were .
- . 15 added 600 mg of copper acetate monohydrate. The resulting ~' ~ mixture was stirred at room "emperature for 5 hours, after , .
which 50 ml of ethyl acetate and 7. 5 ml OI a 0. 5M citric acid , .
solution were added thereto. Insolubles were filtered off .' and the organic phase was washed three times with 50 ml OI
an aqueous solution of sodium chloride and then dried over anhydrous magneslum sulphate, The solvent was distilled off~
under reduced pressure to give a crude amorphous product, :. . ' .
~' ,: ~
., .. ' ' 53~
which was purified by thin layer chromatography, using as solvent a mixture of n-butanol/acetic acid/water (4: 1 :1 by volume), to give the desired product.
Nuclear rnagnet;c resonance spectrum (CD3CN + D20), ~ ppm:
3.46 (singlet, O-CH3 at 7-position) 3.94 (singlet, 3-position, tetrazole N--CH3) 6.02 (singlet, 6-position, Hy . ~ . ~N~
.. ..
9,28 (singlet, 7-position, ~J~S3~ ) Infrared absorption spectrum (KBr) 1~ cm 1:
:, 176 0 .
~, Ultraviolet absorption spectrurn (in phosphoric acid buffer of : ! pH 6, 86)~max nm ; 2~6, ' : Thin layer chromatography (~ilica gel):
eveloping solvent (chloroform/methanol,l :1 by J ~ volume):
Rf value = 0, 38, ' ~8 i 7,B (2-Carbo~y4henylthioacetamido)-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid , ~ '.
. .
3~a To a solution of 596 mg of 2-[ 7,B-bromoacetamido-7~-methoxy- 3 - (1-methyl -lH -tetrazol- 5 -yl)thiomethyl- 3 -cephem -4 -carbonyl] -s-triazolo[ 4, 3-a] pyrid-3-one in 30 ml of acetone was added a solution OI 152 mg of thiosalicylic acid and 173 mg of ' 5 sodium bicarbonate in 8 ml of water. The resulting mixture was stirred at room temperature for 30 minutes, The solvent was ` then distilled off under reduced pressure and 50 ml of ethyl ' acetate were added to the residue. The resulting solution was then washed with water and dried over anhydrous magnesium æulphate. The solvent was then distilled off under reduced pressure, giving crude 2-[ 7,B-(2-carboxyphenylthioacetamidoj-7,x-methoxy-, :
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl] -s-tria~olo-1 4, 3-a] pyrid-3-one as a powdery residue, . . .
, This product was dissolved in a mixture of 15 ml oi tetrahydrofuran and 7. 5 ml of water and then 500 mg of copper ,, '~ ~ acetate monohydrate were added thereto. The resulting mixture ~ : . :
',, was stirred at room temperature for 5 hours, after which 50 ml ,~ .
of ethyl acetate and 7~ 5 ml of a 0. 5M citric acid solution were !~- added thereto. I~isolubles were filtered off and the organic phase 2~ was was,hed three times with an aqueous solution of sodium .
~` ~ chloride and then dried over anhydrous magnesium sulphate.
:
:, ' ' ,, - 48 -:;
.
. .
~5~3~
~; After the solvent had been distilled off under reduced pressure, the residue was purified by thin layer chromatography on silica gel, using as solvent a mixture OI n-butanol/acetic acid/water (4: 1: 1 by volume), to give the desired product.
Nuclear magnetic resonance spectrum (CD3CN ~ D20), ô ppm:
- 7. 2 - 7.6 (multiplet, proton in phenyl moiety) 5.13 (singlet, 6-position, ~~ ) ~N~
.:. ~ ' i 4.07 (singlet, 3-position tetrazole ,,N-CH3) 3.47 (singlet, 7-position, -O-C~H3), rared absorption spectrum (KBr) ~Jcm 1 1775.
.
Ultraviolet absorption spectrum (phosphoric acid buffer, pH
6. 86)J A nm:
: 15 253 ~'' .
~` Thin layer chromatography (silica gel):
.
- (a) Developing solvent (n-butanol/acetic acid/
water , 4 :1 :1 by volume) :
;: : Rf value = 0. 36.
(~) Developing solvent (chlorolorm/methanol/
water, 6: 4: 1 by volume):
'- Rf value = 0. 20.
, . 49 . , .
... . .
Example 9 7,,~ - ( 2 - H~droxyethylthioac etamido) - 7~- m ethoxy- 3 - (1- m ethyl -lH -tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 434 mg of 7,~-chloroacetamido-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid were ~igsolved in 20 ml of water containing 84 mg of sodium ` bicarbonate and 156 mg of thioglycol were added thereto. The - ~ resulting mixture was then stirred at room temperature for 3 hours, while maintaining the pH at 8. 0-3. 5 by addition of a lN sodium hydroxide solution, The pH was then adjuslted to 2. 0 - 2, 5 by addition of lN
hydrochloric acid and the mi~ture was freeze-dried. The residue 1: was extracted with methanol and the olvent was distilled off. The resulting residue was then purified by preparative silica gel chromatography u~ing as developing solvent a mixture of n-butanolJ
15 ~ acetic acid/water (4 :1: 1 by volume)9 to give 360 mg of the desired product as a powder.
: i I` Nuclear magnetic resonance spectrum (CD3CN + D2)J ~ ppm:
5.2G (singlet, 6-position, .i ,N~
4,15 - 4.25 (quartet, 3-position, \1CH2-S-) '' ' .
3.90 (~inglet, 3-position, tetr~zole , ~ ) , ' .
.
533~
3.44 (singlet, 7-position, -O-CH3) 3. 30 (singlet, 7-position, -S-CH2-C-) 3.68 and 2.74 (triplet, 7-position, HO-CH2CH2-S-).
Infrared absorption spectrum (KBr), lJcm 1 1740, 1675.
. .
Ultra~iolet absorption spectrum (phosphoric acid buffer, pH
6. ~6)~ ~max m~:
270 ( = 9450) Preparation 1 7,B-Bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-~'~ 10 cephem-4-carboxylic acid Into a beaker were charged 808 mg of bromoacetyl bromide and 1.030 g of bis-(trimethylsil~)triElworoacet~ id~
~-~ and the resulting m~xture was allowed to stand at room , :
temperature for 20 minutes. 5 ml of methylene chloride were then added to the mixture, followed by a solution of 879 mg of dibenzhydryl 7,B-(D-5-t-butoxycarbonylarnino-5-carboxyvaler-amido) - 3 -carbamoyloxymethyl- 7~-methoxy- 3-cephem-4 -carboxylate in 5 ml of methylene chloride. Thebeaker was washed with 10 ml of methylene chloride and the washings were combined , with the mixture. The mixture was aLlowed to stand at . .i room temperature under moist conditions for 2 hours. 1 g of sodium bicarbonate was then added to the reaction mixture, :~ .
whilst cooling with ice/sodium chloride, and then 20 ml of a 5% aqueous solution of sodium bicarbonate was added to the reaction mixture, which was agitated for 30 minutes.
The methylene chloride phase was combined with the washings obtained by washing the water phase wlth 10 ml of methylene chloride, and the mixture was washed twice with 20 ml of a 20% aqueous solution of sodium chloride. The organic phase was dried over sodium sulphate and the solvent was distilled off under reduced pressure, giving 1.194 g of crude diben~hydryl 7,B-[ (D- 5-t -butoxycarbonylamino- 5-carboxyvaleryl)-bromo-ac etylamino~ - 3 - carbamoyloxym ethyl - 7a - m ethoxy- 3 - c ephem -~, 4-carboxylate in the form of a yellow amorphous product.
, .
This ye:Uow pr~duct was dissolved in 1 rnl ~; of anisole and 2 ml of trifluoroacetic acid, and the resulting ' .
~ solution was allowed to stand at room temperature for 5 minutes, ;
after which the solvent was distilled off under reduced pressure.
, .
The r esulting yellow viscous paste was dissolved in 20 ml .,j ' of ethyl acetate and 20 ml of a 0. 2M phosphoric acid buffer ~pH 7~ 5), and the solutlon was then transferred into a separating funnel and well shaken. After phase separation, the pH of the aqueous phase was adjusted to 2. 5 with lN hydrochloric . ' , .
~. -52 -,. .
~ .
~ L~5~3~3~
acid and the aqueous phase was extracted 5 times with 20 ml of ethyl acetate, The extracts were dried over sodium sulphate, after which the solvent was distilled off under reduced ~`
pressure. 300 mg of the desired compound were obtained S ~n the`form of a crude amorphous product.
Nuclear magnetic resonance spectrum (CD3CN ~ D20), ~ ppmL
5.12 (singlet, H at 6-position) 3.95 (singlet, BrCH2CO) ~, . . .
3. 53 (singlet, OCH3 at 7-posltion), IJltraviolet absorptlon spectrum (CH30H), lmaX, mJl:
263.
Infrared absorption spectrum (KBr),~cm 1780, 1700.
Thin layer chromatography (silica gel):
(a~ Developing ~olvent (n-butanol/acetic acid/
.
water, 5: 4 :1 by volume~:
Rf value O. 53.
' .
(b) Developing solvent (methanollchloroform, 1:1 by volume):
Rf value - 0~44.
Preparation 2 3 -Carbamoyloxymethyl- 7~3- chloroacetamido- 7a-methox~3-., , ~
ce,phem-4-carboxylic acid ~ .
- ~S~Si3~
The proeedure described in Preparation 1 was repeated except that chloroacetyl ehloride was employed instead of the bromoacetyl bromideO Separation and puriiication took place as described in Preparation 1, giving the desired eompound .
in the form of a crude amorphous produet.
Nuelear magnetie resonanee speetrum ~CD3CN + D2O), ~ ppm:
5.1 (smglet, H at 6-position) 3.48 (singlet, OCH3 at 7-position) .
-~ 4.11 (singlet, ClCH2CO).
Ultraviolet absorption speetrurn (phosphorie aeid buffer, pH 6.86), max, m~
~6D~.
i. Infrared absorption speetrum (KBr), ~cm 1 ~ 1780, 1700, :: 15 Thin layer chromatography (silica gel):
..
, : Developing solvent ~methanol/ehloroiorm, 1 :1 by ~ . .
- volume):
Rf value = 0 . 35 .
~ ~:
PreE~aration 3 `
3-~Aeetoxymethyl-7,l3-ehloroacetamido-7~-methoxy-3-eephem-: :
~38 . 5 mg oi benzhydryl 3-aeetoxymethyl-7~e-ehloroaeetamido-7a~-metho~y-3-eephem-4-earbox~rlate were . ' .
., ' , , .; , .. , .. . . . . . , . , . : . . :. :
~5~53~
dissolved in 0.4 ml of anisole, and 0.8 ml of trifluoroacetic acid was added to the resulting solution. The mixture was agitated at room temperature for 5 minutes. The reaction mi~ture was then prompMy evaporated to dryness and the residue was washed with n-hexane and dissolved in 5 ml of 0. 25M phosphoric acid buffer (pH 7. 5). The resulting solution was neutralized with a 5% aqueous solution of sodium bicarbonate and washed with ethyl acetate. The pH of the aqueous phase was adjusted to 2. 0 with 60% phosphoric acid and the oily substance which precipitated was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate, after which the solvent was disti~led off, giving 276 mg of the desired compound in the form of an - ~ , amorphous powder.
Nuclear mag,netic resonance spectrum (CD3(:N -~ D20), ~ ppm:
;~ 15 5.08 (singlet, H at 6-position) 4.08 (singlet, S:lCH2CO) 3.55 (singlet, OCE3 at 7-position).
Thin layer chromatography (silica gel):
Developing solvent (chloroform/methanol, 9 :1 by 20 ~ volume):
1 ~ -,~ ' -' 53:~
Preparation 4 ~,B-Chloroacetamido-7O~-methoxy-3-(1-methyl-1 -tetrazol-5 yl)thiomethyl-3-cephern-4-carboxylic acid 27.6 g of disodium 7,B-(D-5-amino-5-carboxyvaler-aimido) - 3 - carbamoyloxym ethyl- 7a -m ethoxy - 3 - c ephem - 4 - carboxylate were dissolved in 1090 ml of a 5% aqueous solution of dipotassium phosphate, and 715 ml of acetone were added to the resulting solution. 8.1 g OI 4-dimethylaminopyridine were then added to the solution, whose pH was adjusted to 9. 5 by addition of 2, 5N aqueous sodium hydroxide, following which 34. 5 ml of t-butoxycarbonyl azide were added and the mixture was agitated at room temperature for 4 hours while maintaiining the pH at 9. 0 to 9.5. The reaction mixture was allowed to stand at 4C. overnight, at the end of which time 1000 ml of ethyl acetate were added ;' 15 thereto, and the mixture was well shaken. The aqueous phase ' ~ was collected and another 1000 rnl of ethyl acetate were ~dded thereto, after which tbie PE of the aqueous phase was adjusted to 2, 5 by addition of concentrated hydrochloric acidJ while maintaining the temperature at 0 to 2 C, The organic phase . ~ .
was separated and the aqueous phase was further extracted twice with laO0 ml OI ethyl acetate The organic phases were combined and waished with a saturated aqueous solution of sodium chloride until the pH of the washings reached 4 - 5, when they were dried :
.
, ~ - 56 -, .
,:
' . .: . i . ..
. . . . .. ...
, , ., - . , : , . .. .
. . . ; .
~5~3~
with anhydrous sodium sulphatc. On distilling off the solvent from thc solution, there were obtained 22.1 g of 7~B-(D-5-t-butoxycarbonylamino - 5 - carboxyvaleramido) - 3 - carbamoyloxymethyl -7~Y- m ethoxy- 3 - c ephem -4 - carboxylic acid .
.
This compound was added to a phosphoric acid buffer of pH 7. 0 containing 10 g of 5-mercapto-1-methyl-lH-; ` tetrazole, and the mixture was agitated at 95C. for 30 minutes,:, . . .
after which the pH was adjusted to 2. 5 by addition of hydrochloric acid, with ice-cooling. The reaction mixture was then extracted with ethyl acetate, and the extracts were washed with a saturated - aqueous solution of sodium chloride until the pH of the washings reached 4 - 5, after ~vhich the extracts were dried over anhydrous sodium sulphate. A solution of 20 g of diphenyldiazomethane l in ether was added to the dried extracts and the mixture was ; ,~ 15 agitated for 2 hours, aiter which it was washed first with a 20%
, ~ :
a~ueous solution of sodium chloride and then with a S~ aqueous solution of sodium bicarbonate. The washed mixture was dried ; ~ over anhydrous sodium sulphate and the solvents were distilled off; the residue was then dissolved in chloroform, adsorbed on a column packed with silica gel and eluted with chloroform ~` containing 1% y/v of methanol. Distil~ing off the solvent from , the eluent gave dLben~hydryl 7~B-(D-5-t-butoxycarbonylamino-5-.
. . .
~5~i3:3L
:` .
carboxy~aleramido)-7~-methox~y-3-(1-methyl-l:EI-tetrazol-5-yl) thiomethyl - 3 - c ephem -4 - carboxylate .
5 mmole of this compound were dissolved in 50 ml of chloroform, and the solution was added to a mixture of 2. 26 g of chloroacetyl chloride and 2. 26 g OI bis-(trimethylsilyl)trifluoro-~ acetamide, which had previously been allowed to stand at room -' temperature for 30 minutes, and the resulting mixture was allowed to stand at 40C for 100 hours. The reaction mixture was then poured into a 5% aqueous solution of sodium bicarbonate and the mixture ; 10 was agitated for 30 minutes. The organic phase was collected and washed with a 20% aqueous solution of sodium chlox ide, "
~, and then dried over anhydrouæ sodium sulphate, The solvent was distilled off ~rom the vvashed solution and the residue was dissolved in 5 ml of anisole and 10 ml of trifluoroacetic acid.
I, 15 This solution was shaken at room temperature for 5 minutes and then evaporated to dryness under reduced pressure. The residue was dissolved in lM phosphoric acid buffer (pH 7. 5) and extracted with ethyl acetate. The aqueous phase was collected , ~ and its pH adjusted to 2. 5 by addition of lN hydrochloric acid;
: . :
it was then extracted wlth ethyl acetate. The extract was dried ; ,~ over anhydrous sodium sulphate, and the solvent was distilled , : ' ' ' . ;
' ~ ' :, , .:
" ~, . . . .
j3~
off, giving 7,B-chloroacetamido-7c~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid in the form of an amorphous powder.
' ~, , ,:
, :
( I .
;, :
'' :
''.
',' ~ ' . ~
.. . .
.~ ~
.~ - 59 -
~ :l0 tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid :
NMR spectrum ~ ppm:
`~ 7.03 (singlet, H at 4- and 5-position of imidazole~
: 4. 95 ~singlet, H at 6-position) 3 . 84 (singlet, CH3 at l-posltion of tetrazole ring) : 15 3. 36 (singlet, OCH3 at 7-positionj .
1 . :
UV spectrum, ~max : 265 (~= 7200).
- IR spectrum, ~J cm l .~ 1760.
TLC, Rf value:
(b) = 0 . 36 .
: :
~ ~ -43 , . . . .
,. .. . . . . .
~CI Sq~153~il 7,B=cyanomethylthioacetamido-7~methoxy-3-(l-methyl-lH
tetra zol - 5 - yl)thiom ethyl - 3 - c eph em - 4 - c arboxylic acid NMR spectrum, ~ ppm:
5.10 (singlet, EI at 6-position) 4.3 - 4.6 (quartet, CH2-S at 3-position) 3. 98 (singlet, CH3 at l-position of tetrazole ring) 3 . 70 (singlet, -NCCH2S or -SCH2CO) 3.5 - 3.7 (quartet, H2 at 2-position~
3.60 (singlet, -NCCH2S or -SCH2CO) 3 . 50 ¦sin~let, OCEI3 at 7 -position) .
` UV spectrum ~ mp:
274 ( = 9ooo), 7a-~$ethoxy- 3 - (l-methyl -lH-tetrazol- 5 -yl)thiomethyl- 7,~ -propargyl-thioacetamido-3-cephem-4-carboxylic acid NMR spectrum (DMSO-d6), ~ ppm:
. ~ ~.05 (singlet, EI at 6-position) 4 . 2 - 4 . 3 (quartet, CH2-S at 3 -position) 3. 90 (singlet, CH3 at l-position of tetrazole ring) about 3. 5 (multiplet, OCH3 at 7-position, H2, -CEI2-S-CH2CO at 2-position) 3,20 (triplet, HC_C-).
.
.
, , , . ~ . : .
1~5~53~
Example 7 7~-Methoxy-3-(1-methyl-lH-tetrazol-5-yl )thiomethyl-7,B-(1, 3,4-_ thiadiazol- 2-yl-thioacetamido)- 3-cephem-4 -carboxylic acid To a solution of 596 mg of 2-[ 7,B-bromoacetamido-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-:~ 4-carbonyl] -s-triazolo[ 4,3-a] pyrid-3-one in 30 ml of acetone was added a solution of 86 mg of 2-mercapto-1, 3,4-thiadiazole and 84 mg of sodium hydrogen carbonate in 8 ml of water; the resulting mixture was stirred at room temperature for 1 hour, -1 lû The solvent was then distilled off under reduced pressure and 50 ~ ml of ethyl acetate were added to the residue, which was then washed ~ with water and dried over anhydrous magnesium sulphate. The solvent was distilled o~, giving crude 2 [7a-metho~y-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl 7~3-(1, 3,4-thiadiazol-2-yl-thioacetamido)-3 - cephem-~ -carbonyl~ - s - triazolo[ 4, 3 - a] pyrid- 3 -one as a powder .
Nuclear magnetic resonance spectrum (CDC13), ~ ppm:
3.43 (singlet, O-CH3 at 7-position) 3. ~0 (singlet, N-CH3 at 3-position of tetrazole) 4, 25 (singletJ -S-CH2-CO at 7-position) . 5,24 (singlet, 6-position, ~
--N~ H
'~ 6,3 - 7~9 (multlplet, 4-position -CO-N~
O H
.' ' ' .
, :
.
. .
5~3~
9,08 (7-position, thiadiazole) Ultraviolet absorption spectrum (THF), max nm:
227, 261, 359.
Infrared absorption spectrum (Nujol-trade mark), L~cm l 1770, 1700, 1650, Thin layer chromatography ( silica gel):
(a) Developing solvent (chloroform containing 10%
. methanol~:
' R E value = O . 56 .
; 10 (b) Developing solv~ent (n-butanol/acetic acid/water, . 4: 1 :1 by volunne): ;
Rf value - 0 . 47 .
To a ~olution of the compound obta~ned above in a mi~ture of 15 ml of tetrahydrofuran and 7. 5 ml of water were .
- . 15 added 600 mg of copper acetate monohydrate. The resulting ~' ~ mixture was stirred at room "emperature for 5 hours, after , .
which 50 ml of ethyl acetate and 7. 5 ml OI a 0. 5M citric acid , .
solution were added thereto. Insolubles were filtered off .' and the organic phase was washed three times with 50 ml OI
an aqueous solution of sodium chloride and then dried over anhydrous magneslum sulphate, The solvent was distilled off~
under reduced pressure to give a crude amorphous product, :. . ' .
~' ,: ~
., .. ' ' 53~
which was purified by thin layer chromatography, using as solvent a mixture of n-butanol/acetic acid/water (4: 1 :1 by volume), to give the desired product.
Nuclear rnagnet;c resonance spectrum (CD3CN + D20), ~ ppm:
3.46 (singlet, O-CH3 at 7-position) 3.94 (singlet, 3-position, tetrazole N--CH3) 6.02 (singlet, 6-position, Hy . ~ . ~N~
.. ..
9,28 (singlet, 7-position, ~J~S3~ ) Infrared absorption spectrum (KBr) 1~ cm 1:
:, 176 0 .
~, Ultraviolet absorption spectrurn (in phosphoric acid buffer of : ! pH 6, 86)~max nm ; 2~6, ' : Thin layer chromatography (~ilica gel):
eveloping solvent (chloroform/methanol,l :1 by J ~ volume):
Rf value = 0, 38, ' ~8 i 7,B (2-Carbo~y4henylthioacetamido)-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid , ~ '.
. .
3~a To a solution of 596 mg of 2-[ 7,B-bromoacetamido-7~-methoxy- 3 - (1-methyl -lH -tetrazol- 5 -yl)thiomethyl- 3 -cephem -4 -carbonyl] -s-triazolo[ 4, 3-a] pyrid-3-one in 30 ml of acetone was added a solution OI 152 mg of thiosalicylic acid and 173 mg of ' 5 sodium bicarbonate in 8 ml of water. The resulting mixture was stirred at room temperature for 30 minutes, The solvent was ` then distilled off under reduced pressure and 50 ml of ethyl ' acetate were added to the residue. The resulting solution was then washed with water and dried over anhydrous magnesium æulphate. The solvent was then distilled off under reduced pressure, giving crude 2-[ 7,B-(2-carboxyphenylthioacetamidoj-7,x-methoxy-, :
3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl] -s-tria~olo-1 4, 3-a] pyrid-3-one as a powdery residue, . . .
, This product was dissolved in a mixture of 15 ml oi tetrahydrofuran and 7. 5 ml of water and then 500 mg of copper ,, '~ ~ acetate monohydrate were added thereto. The resulting mixture ~ : . :
',, was stirred at room temperature for 5 hours, after which 50 ml ,~ .
of ethyl acetate and 7~ 5 ml of a 0. 5M citric acid solution were !~- added thereto. I~isolubles were filtered off and the organic phase 2~ was was,hed three times with an aqueous solution of sodium .
~` ~ chloride and then dried over anhydrous magnesium sulphate.
:
:, ' ' ,, - 48 -:;
.
. .
~5~3~
~; After the solvent had been distilled off under reduced pressure, the residue was purified by thin layer chromatography on silica gel, using as solvent a mixture OI n-butanol/acetic acid/water (4: 1: 1 by volume), to give the desired product.
Nuclear magnetic resonance spectrum (CD3CN ~ D20), ô ppm:
- 7. 2 - 7.6 (multiplet, proton in phenyl moiety) 5.13 (singlet, 6-position, ~~ ) ~N~
.:. ~ ' i 4.07 (singlet, 3-position tetrazole ,,N-CH3) 3.47 (singlet, 7-position, -O-C~H3), rared absorption spectrum (KBr) ~Jcm 1 1775.
.
Ultraviolet absorption spectrum (phosphoric acid buffer, pH
6. 86)J A nm:
: 15 253 ~'' .
~` Thin layer chromatography (silica gel):
.
- (a) Developing solvent (n-butanol/acetic acid/
water , 4 :1 :1 by volume) :
;: : Rf value = 0. 36.
(~) Developing solvent (chlorolorm/methanol/
water, 6: 4: 1 by volume):
'- Rf value = 0. 20.
, . 49 . , .
... . .
Example 9 7,,~ - ( 2 - H~droxyethylthioac etamido) - 7~- m ethoxy- 3 - (1- m ethyl -lH -tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 434 mg of 7,~-chloroacetamido-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid were ~igsolved in 20 ml of water containing 84 mg of sodium ` bicarbonate and 156 mg of thioglycol were added thereto. The - ~ resulting mixture was then stirred at room temperature for 3 hours, while maintaining the pH at 8. 0-3. 5 by addition of a lN sodium hydroxide solution, The pH was then adjuslted to 2. 0 - 2, 5 by addition of lN
hydrochloric acid and the mi~ture was freeze-dried. The residue 1: was extracted with methanol and the olvent was distilled off. The resulting residue was then purified by preparative silica gel chromatography u~ing as developing solvent a mixture of n-butanolJ
15 ~ acetic acid/water (4 :1: 1 by volume)9 to give 360 mg of the desired product as a powder.
: i I` Nuclear magnetic resonance spectrum (CD3CN + D2)J ~ ppm:
5.2G (singlet, 6-position, .i ,N~
4,15 - 4.25 (quartet, 3-position, \1CH2-S-) '' ' .
3.90 (~inglet, 3-position, tetr~zole , ~ ) , ' .
.
533~
3.44 (singlet, 7-position, -O-CH3) 3. 30 (singlet, 7-position, -S-CH2-C-) 3.68 and 2.74 (triplet, 7-position, HO-CH2CH2-S-).
Infrared absorption spectrum (KBr), lJcm 1 1740, 1675.
. .
Ultra~iolet absorption spectrum (phosphoric acid buffer, pH
6. ~6)~ ~max m~:
270 ( = 9450) Preparation 1 7,B-Bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-~'~ 10 cephem-4-carboxylic acid Into a beaker were charged 808 mg of bromoacetyl bromide and 1.030 g of bis-(trimethylsil~)triElworoacet~ id~
~-~ and the resulting m~xture was allowed to stand at room , :
temperature for 20 minutes. 5 ml of methylene chloride were then added to the mixture, followed by a solution of 879 mg of dibenzhydryl 7,B-(D-5-t-butoxycarbonylarnino-5-carboxyvaler-amido) - 3 -carbamoyloxymethyl- 7~-methoxy- 3-cephem-4 -carboxylate in 5 ml of methylene chloride. Thebeaker was washed with 10 ml of methylene chloride and the washings were combined , with the mixture. The mixture was aLlowed to stand at . .i room temperature under moist conditions for 2 hours. 1 g of sodium bicarbonate was then added to the reaction mixture, :~ .
whilst cooling with ice/sodium chloride, and then 20 ml of a 5% aqueous solution of sodium bicarbonate was added to the reaction mixture, which was agitated for 30 minutes.
The methylene chloride phase was combined with the washings obtained by washing the water phase wlth 10 ml of methylene chloride, and the mixture was washed twice with 20 ml of a 20% aqueous solution of sodium chloride. The organic phase was dried over sodium sulphate and the solvent was distilled off under reduced pressure, giving 1.194 g of crude diben~hydryl 7,B-[ (D- 5-t -butoxycarbonylamino- 5-carboxyvaleryl)-bromo-ac etylamino~ - 3 - carbamoyloxym ethyl - 7a - m ethoxy- 3 - c ephem -~, 4-carboxylate in the form of a yellow amorphous product.
, .
This ye:Uow pr~duct was dissolved in 1 rnl ~; of anisole and 2 ml of trifluoroacetic acid, and the resulting ' .
~ solution was allowed to stand at room temperature for 5 minutes, ;
after which the solvent was distilled off under reduced pressure.
, .
The r esulting yellow viscous paste was dissolved in 20 ml .,j ' of ethyl acetate and 20 ml of a 0. 2M phosphoric acid buffer ~pH 7~ 5), and the solutlon was then transferred into a separating funnel and well shaken. After phase separation, the pH of the aqueous phase was adjusted to 2. 5 with lN hydrochloric . ' , .
~. -52 -,. .
~ .
~ L~5~3~3~
acid and the aqueous phase was extracted 5 times with 20 ml of ethyl acetate, The extracts were dried over sodium sulphate, after which the solvent was distilled off under reduced ~`
pressure. 300 mg of the desired compound were obtained S ~n the`form of a crude amorphous product.
Nuclear magnetic resonance spectrum (CD3CN ~ D20), ~ ppmL
5.12 (singlet, H at 6-position) 3.95 (singlet, BrCH2CO) ~, . . .
3. 53 (singlet, OCH3 at 7-posltion), IJltraviolet absorptlon spectrum (CH30H), lmaX, mJl:
263.
Infrared absorption spectrum (KBr),~cm 1780, 1700.
Thin layer chromatography (silica gel):
(a~ Developing ~olvent (n-butanol/acetic acid/
.
water, 5: 4 :1 by volume~:
Rf value O. 53.
' .
(b) Developing solvent (methanollchloroform, 1:1 by volume):
Rf value - 0~44.
Preparation 2 3 -Carbamoyloxymethyl- 7~3- chloroacetamido- 7a-methox~3-., , ~
ce,phem-4-carboxylic acid ~ .
- ~S~Si3~
The proeedure described in Preparation 1 was repeated except that chloroacetyl ehloride was employed instead of the bromoacetyl bromideO Separation and puriiication took place as described in Preparation 1, giving the desired eompound .
in the form of a crude amorphous produet.
Nuelear magnetie resonanee speetrum ~CD3CN + D2O), ~ ppm:
5.1 (smglet, H at 6-position) 3.48 (singlet, OCH3 at 7-position) .
-~ 4.11 (singlet, ClCH2CO).
Ultraviolet absorption speetrurn (phosphorie aeid buffer, pH 6.86), max, m~
~6D~.
i. Infrared absorption speetrum (KBr), ~cm 1 ~ 1780, 1700, :: 15 Thin layer chromatography (silica gel):
..
, : Developing solvent ~methanol/ehloroiorm, 1 :1 by ~ . .
- volume):
Rf value = 0 . 35 .
~ ~:
PreE~aration 3 `
3-~Aeetoxymethyl-7,l3-ehloroacetamido-7~-methoxy-3-eephem-: :
~38 . 5 mg oi benzhydryl 3-aeetoxymethyl-7~e-ehloroaeetamido-7a~-metho~y-3-eephem-4-earbox~rlate were . ' .
., ' , , .; , .. , .. . . . . . , . , . : . . :. :
~5~53~
dissolved in 0.4 ml of anisole, and 0.8 ml of trifluoroacetic acid was added to the resulting solution. The mixture was agitated at room temperature for 5 minutes. The reaction mi~ture was then prompMy evaporated to dryness and the residue was washed with n-hexane and dissolved in 5 ml of 0. 25M phosphoric acid buffer (pH 7. 5). The resulting solution was neutralized with a 5% aqueous solution of sodium bicarbonate and washed with ethyl acetate. The pH of the aqueous phase was adjusted to 2. 0 with 60% phosphoric acid and the oily substance which precipitated was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate, after which the solvent was disti~led off, giving 276 mg of the desired compound in the form of an - ~ , amorphous powder.
Nuclear mag,netic resonance spectrum (CD3(:N -~ D20), ~ ppm:
;~ 15 5.08 (singlet, H at 6-position) 4.08 (singlet, S:lCH2CO) 3.55 (singlet, OCE3 at 7-position).
Thin layer chromatography (silica gel):
Developing solvent (chloroform/methanol, 9 :1 by 20 ~ volume):
1 ~ -,~ ' -' 53:~
Preparation 4 ~,B-Chloroacetamido-7O~-methoxy-3-(1-methyl-1 -tetrazol-5 yl)thiomethyl-3-cephern-4-carboxylic acid 27.6 g of disodium 7,B-(D-5-amino-5-carboxyvaler-aimido) - 3 - carbamoyloxym ethyl- 7a -m ethoxy - 3 - c ephem - 4 - carboxylate were dissolved in 1090 ml of a 5% aqueous solution of dipotassium phosphate, and 715 ml of acetone were added to the resulting solution. 8.1 g OI 4-dimethylaminopyridine were then added to the solution, whose pH was adjusted to 9. 5 by addition of 2, 5N aqueous sodium hydroxide, following which 34. 5 ml of t-butoxycarbonyl azide were added and the mixture was agitated at room temperature for 4 hours while maintaiining the pH at 9. 0 to 9.5. The reaction mixture was allowed to stand at 4C. overnight, at the end of which time 1000 ml of ethyl acetate were added ;' 15 thereto, and the mixture was well shaken. The aqueous phase ' ~ was collected and another 1000 rnl of ethyl acetate were ~dded thereto, after which tbie PE of the aqueous phase was adjusted to 2, 5 by addition of concentrated hydrochloric acidJ while maintaining the temperature at 0 to 2 C, The organic phase . ~ .
was separated and the aqueous phase was further extracted twice with laO0 ml OI ethyl acetate The organic phases were combined and waished with a saturated aqueous solution of sodium chloride until the pH of the washings reached 4 - 5, when they were dried :
.
, ~ - 56 -, .
,:
' . .: . i . ..
. . . . .. ...
, , ., - . , : , . .. .
. . . ; .
~5~3~
with anhydrous sodium sulphatc. On distilling off the solvent from thc solution, there were obtained 22.1 g of 7~B-(D-5-t-butoxycarbonylamino - 5 - carboxyvaleramido) - 3 - carbamoyloxymethyl -7~Y- m ethoxy- 3 - c ephem -4 - carboxylic acid .
.
This compound was added to a phosphoric acid buffer of pH 7. 0 containing 10 g of 5-mercapto-1-methyl-lH-; ` tetrazole, and the mixture was agitated at 95C. for 30 minutes,:, . . .
after which the pH was adjusted to 2. 5 by addition of hydrochloric acid, with ice-cooling. The reaction mixture was then extracted with ethyl acetate, and the extracts were washed with a saturated - aqueous solution of sodium chloride until the pH of the washings reached 4 - 5, after ~vhich the extracts were dried over anhydrous sodium sulphate. A solution of 20 g of diphenyldiazomethane l in ether was added to the dried extracts and the mixture was ; ,~ 15 agitated for 2 hours, aiter which it was washed first with a 20%
, ~ :
a~ueous solution of sodium chloride and then with a S~ aqueous solution of sodium bicarbonate. The washed mixture was dried ; ~ over anhydrous sodium sulphate and the solvents were distilled off; the residue was then dissolved in chloroform, adsorbed on a column packed with silica gel and eluted with chloroform ~` containing 1% y/v of methanol. Distil~ing off the solvent from , the eluent gave dLben~hydryl 7~B-(D-5-t-butoxycarbonylamino-5-.
. . .
~5~i3:3L
:` .
carboxy~aleramido)-7~-methox~y-3-(1-methyl-l:EI-tetrazol-5-yl) thiomethyl - 3 - c ephem -4 - carboxylate .
5 mmole of this compound were dissolved in 50 ml of chloroform, and the solution was added to a mixture of 2. 26 g of chloroacetyl chloride and 2. 26 g OI bis-(trimethylsilyl)trifluoro-~ acetamide, which had previously been allowed to stand at room -' temperature for 30 minutes, and the resulting mixture was allowed to stand at 40C for 100 hours. The reaction mixture was then poured into a 5% aqueous solution of sodium bicarbonate and the mixture ; 10 was agitated for 30 minutes. The organic phase was collected and washed with a 20% aqueous solution of sodium chlox ide, "
~, and then dried over anhydrouæ sodium sulphate, The solvent was distilled off ~rom the vvashed solution and the residue was dissolved in 5 ml of anisole and 10 ml of trifluoroacetic acid.
I, 15 This solution was shaken at room temperature for 5 minutes and then evaporated to dryness under reduced pressure. The residue was dissolved in lM phosphoric acid buffer (pH 7. 5) and extracted with ethyl acetate. The aqueous phase was collected , ~ and its pH adjusted to 2. 5 by addition of lN hydrochloric acid;
: . :
it was then extracted wlth ethyl acetate. The extract was dried ; ,~ over anhydrous sodium sulphate, and the solvent was distilled , : ' ' ' . ;
' ~ ' :, , .:
" ~, . . . .
j3~
off, giving 7,B-chloroacetamido-7c~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid in the form of an amorphous powder.
' ~, , ,:
, :
( I .
;, :
'' :
''.
',' ~ ' . ~
.. . .
.~ ~
.~ - 59 -
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 7.alpha.-methoxy-cephalosporin derivative of formula (II) where R1 is a hydrogen atom; a straight or branched- chain hydro-carbon group having from 1 to 6 carbon atoms which is unsubstituted or which has one or more hydroxy, azido, cyano, nitro, acylamino, alkoxycarbonylamino, alkoxy, phenyl, cyclohexadienyl, cyclohexyl or alkoxycarbonyl substituents; a phenyl or naphthyl group which is unsubstituted or which has one or more halogen, alkyl, alkoxy, cyano, nitro, acylamino or alkoxycarbonylamino substituents; a saturated or unsaturated monocyclic hydrocarbon group having a 5- or 6- mem-bered ring; an alkanoyl group having from 2 to 18 carbon atoms, which is unsubstituted or which has one or more cyano, nitro, acyl-amino, alkoxycarbonylamino or alkoxycarbonyl substituents; a benzoyl group which is unsubstituted or which has one or more halogen, alkyl, alkoxy, cyano, nitro, acylamino or alkoxycarbonylamino substituents;
a 2-imidazolyl group; a 1,2,4-triazol-3-yl group; a 1,3,4-thiadiazol-2-yl group; a 2-pyridyl group; a 2-pyrimidyl group; a purin-6-yl group; a 2-benzothiazolyl group; a 2-benzoxazolyl group; an s-tria-zolo [4,3-a] pyridin-3-yl group; or a 2-thiazolyl group, R2 is an acyloxymethyl group, a carbamoyloxymethyl group or a thiomethyl group which is S- substituted by an aromatic monocyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom; R3 is a carboxyl group or an esterified carboxyl group and A is methe-lene wherein 7.alpha.-methoxycephalosporin of formula (III):
(III) in which R2, R3 and A are as defined above and X is a halogen atom reacted with a thiol compound of formula (I):
R1 - SH (I) or with a metal salt thereof wherein R1 is as above.
a 2-imidazolyl group; a 1,2,4-triazol-3-yl group; a 1,3,4-thiadiazol-2-yl group; a 2-pyridyl group; a 2-pyrimidyl group; a purin-6-yl group; a 2-benzothiazolyl group; a 2-benzoxazolyl group; an s-tria-zolo [4,3-a] pyridin-3-yl group; or a 2-thiazolyl group, R2 is an acyloxymethyl group, a carbamoyloxymethyl group or a thiomethyl group which is S- substituted by an aromatic monocyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom; R3 is a carboxyl group or an esterified carboxyl group and A is methe-lene wherein 7.alpha.-methoxycephalosporin of formula (III):
(III) in which R2, R3 and A are as defined above and X is a halogen atom reacted with a thiol compound of formula (I):
R1 - SH (I) or with a metal salt thereof wherein R1 is as above.
2. A process as claimed in Claim 1, wherein an alkali metal or alkaline earth metal salt of said thiol compound (I) is employed.
3. A process as claimed in Claim 1, wherein a sodium potassium or lithium salt of said thiol compound (I) is employed.
4. A process as claimed in Claim 1, wherein when R3 is a carboxyl group the reaction is effected in the presence of a mixture of water and a water-miscible organic solvent.
5. A process as claimed in Claim 1, wherein when R3 is a carboxyl group the reaction is effected in a mixture of water and methanol or ethanol.
6. A process as claimed in Claim 1, wherein said thiol compound (I) itself is employed and the reaction is effected in the presence of an alkali.
7. A process as claimed in Claim 6, wherein said alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
8. A 7.alpha.-methoxycephalosporin derivative of formula (II):
(II) in which R1 is a hydrogen atom; a straight or branched- chain hydrocarbon group having from 1 to 6 carbon atoms which is unsubstituted or which has one or more hydroxy, azido, cyano, nitro, acylamino, alkoxycarbonylamino, alkoxy, phenyl, cyclo-hexadienyl, cyclohexyl or alkoxycarbonyl substituents: a phenyl or naphthyl group which is unsubstituted or which has one or more halogen, alkyl, alkoxy, cyano, nitro, acylamino or alkoxycarbonyl-amino substituents; a saturated or unsaturated monocyclic hydro-carbon group having a 5- or 6- membered ring; an alkanoyl group having from 2 to 18 carbon atoms, which is unsubstituted or which has one or more cyano, nitro, acylamino, alkoxycarbonyl amino or alkoxycarbonyl substituents; a benzoyl group which is unsubsti-tuted or which has one or more halogen, alkyl, alkoxy, cyano, nitro, acylamino or alkoxycarbonylamino substituents; a 2-imidazolyl group; a 1,2,4-triazol-3-yl group;, a 1,3,4-thiadiazol-2-yl group; a 2-pyridyl group; a 2-pyrimidyl group; a purin-6-yl group; a 2-benzothiazolyl group; a 2-benzoxazolyl group an s-triazolo [4,3,-a] pyridin-3-yl group; or a 2-thiazolyl group, R2 is an acyloxymethyl group, a carbamoyloxymethyl group or a thiomethyl group which is S-substituted by an aromatic monocyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom, R3 is a carboxyl group or esterified carboxyl group; and A is a methylene group whenever prepared or produced by the process as claimed in Claim 1, 2 or 3 or an obvious chemical equivalent thereof.
(II) in which R1 is a hydrogen atom; a straight or branched- chain hydrocarbon group having from 1 to 6 carbon atoms which is unsubstituted or which has one or more hydroxy, azido, cyano, nitro, acylamino, alkoxycarbonylamino, alkoxy, phenyl, cyclo-hexadienyl, cyclohexyl or alkoxycarbonyl substituents: a phenyl or naphthyl group which is unsubstituted or which has one or more halogen, alkyl, alkoxy, cyano, nitro, acylamino or alkoxycarbonyl-amino substituents; a saturated or unsaturated monocyclic hydro-carbon group having a 5- or 6- membered ring; an alkanoyl group having from 2 to 18 carbon atoms, which is unsubstituted or which has one or more cyano, nitro, acylamino, alkoxycarbonyl amino or alkoxycarbonyl substituents; a benzoyl group which is unsubsti-tuted or which has one or more halogen, alkyl, alkoxy, cyano, nitro, acylamino or alkoxycarbonylamino substituents; a 2-imidazolyl group; a 1,2,4-triazol-3-yl group;, a 1,3,4-thiadiazol-2-yl group; a 2-pyridyl group; a 2-pyrimidyl group; a purin-6-yl group; a 2-benzothiazolyl group; a 2-benzoxazolyl group an s-triazolo [4,3,-a] pyridin-3-yl group; or a 2-thiazolyl group, R2 is an acyloxymethyl group, a carbamoyloxymethyl group or a thiomethyl group which is S-substituted by an aromatic monocyclic heterocyclic group having at least one ring nitrogen, oxygen or sulphur atom, R3 is a carboxyl group or esterified carboxyl group; and A is a methylene group whenever prepared or produced by the process as claimed in Claim 1, 2 or 3 or an obvious chemical equivalent thereof.
9. A process as claimed in Claim 1, wherein the reactants R2 is a (1-methyl-1H-tetrazol-5-yl)-thiomethyl, car-bamoyloxymethyl or acetoxymethyl group.
10. A derivative of formula II given in Claim 1, in which R1, R3 and A are as in Claim 1 and R2 is as in Claim 9, whenever prepared or produced by the process as claimed in Claim 9, or an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 wherein in the reac-tants R1 is a cyanomethyl, 1-cyanoethyl, 2-hydroxyethyl, propargyl, azidomethyl or 3-isoxazolyl group.
12. A derivative of formula II given in claim 1 in which R2, R3 and A are as in claim 1 and R1 is as in claim 11 whenever prepared or produced by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 wherein in the reac-tants R1 is a cyanomethyl, 1-cyanoethyl, 2-hydroxyethyl, propargyl, azidomethyl or 3-isoxazolyl group and R2 is a (1-methyl-1H-tetrazol-5-yl) thiomethyl group, a carbamoyloxymethyl group or an acetoxy-methyl group.
14. A derivative of formula II given in claim 1 in which A and R3 are as in claim 1 and R1 and R are as in claim 13 whenever prepared or produced by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in claim 13 in which in the reactants R3 is a carboxyl group or a lower alkyl silyl ester; lower alkyl ester; a benzyl ester; a p-methoxy-benzyl ester; a benzyl-hydryl ester; a phenacyl ester; a p-bromo-phenacyl ester or a 2,2,2-trichloroethyI ester group.
16. A derivative of formula II given in claim 1 in which R1 and R2 are as in claim 13, A is methylene and R3 is as in claim 15 whenever prepared or produced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in claim 13 in which in the reactants R3 is a carboxyl group.
18. A derivative of formula II given in claim 1 in which R1 and R2 are as in claim 13 and A is methylene and R3 is as in claim 17 whenever prepared or produced by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 in which in the reac-tants R3 is a carboxyl, R1 is cyanomethyl, 1-cyanoethyl, 2-hydroxy-ethyl, propargyl, azidomethyl, or 3-isoxazolyl, and R2 is a (1-methyl-1H-tetrazol-5-yl)-thiomethyl, a carbamoyloxymethyl or an acetoxy methyl group.
20. A derivative of formula II given in claim 1 in which R1, R2 and R3 are as in claim 19 and A is methylene whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13244073A JPS5641637B2 (en) | 1973-11-26 | 1973-11-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050531A true CA1050531A (en) | 1979-03-13 |
Family
ID=15081403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA214,609A Expired CA1050531A (en) | 1973-11-26 | 1974-11-26 | Process for preparing cephalosporin derivatives |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5641637B2 (en) |
| CA (1) | CA1050531A (en) |
| CH (1) | CH609700A5 (en) |
| DK (1) | DK146539C (en) |
| NL (1) | NL187632C (en) |
| SE (1) | SE430065B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7435752B2 (en) | 2004-08-25 | 2008-10-14 | Ardea Biosciences, Inc. | N[S(4-aryl-triazol-3-yl)α-mercaptoacetyl]-p-amino benozioc acids as HIV reverse transcriptase inhibitors |
| US7947721B2 (en) | 2004-08-25 | 2011-05-24 | Ardes Biosciences Inc. | S-triazolyl α-mercaptoacetanilides as inhibitors of HIV reverse transcriptase |
| US8084483B2 (en) | 2007-11-27 | 2011-12-27 | Ardea Biosciences, Inc. | Compounds and compositions and methods of use |
| US8372807B2 (en) | 2009-05-20 | 2013-02-12 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4053605A (en) * | 1976-06-15 | 1977-10-11 | Merck & Co., Inc. | Esterified-2(3-lower-alkyl-amino-propoxy)-3-cyano-pyridines and derivatives |
| JPS5854156B2 (en) * | 1976-06-28 | 1983-12-02 | 山之内製薬株式会社 | New cephalosporin derivatives and their production method |
| JPS5887896U (en) * | 1981-12-09 | 1983-06-14 | 共和レザ−株式会社 | Sheet-like material with a blurred color pattern |
| JPH0295632U (en) * | 1989-01-11 | 1990-07-30 | ||
| JPH0463239U (en) * | 1990-10-03 | 1992-05-29 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL178971C (en) * | 1970-06-16 | 1986-06-16 | Merck & Co Inc | PROCESS FOR PREPARING ANTIBIOTICALLY ACTIVE PHARMACEUTICAL PREPARATIONS AND PROCESS FOR PREPARING CEPHALOSPORINE DERIVATIVES SUITABLE FOR USE |
| GB1449420A (en) * | 1973-11-26 | 1976-09-15 | Sankyo Co | 7alpha-methoxycephalosporing derivatives |
-
1973
- 1973-11-26 JP JP13244073A patent/JPS5641637B2/ja not_active Expired
-
1974
- 1974-11-22 SE SE7414705A patent/SE430065B/en not_active IP Right Cessation
- 1974-11-25 DK DK611474A patent/DK146539C/en not_active IP Right Cessation
- 1974-11-26 CH CH1568274A patent/CH609700A5/en not_active IP Right Cessation
- 1974-11-26 CA CA214,609A patent/CA1050531A/en not_active Expired
- 1974-11-26 NL NLAANVRAGE7415435,A patent/NL187632C/en not_active IP Right Cessation
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8252828B2 (en) | 2004-08-25 | 2012-08-28 | Ardea Biosciences, Inc. | S-triazolyl α-mercapto acetanilides as inhibitors of HIV reverse transcriptase |
| US8481581B2 (en) | 2004-08-25 | 2013-07-09 | Ardea Biosciences, Inc. | S-triazolyl α-mercaptoacetanilides as inhibitors of HIV reverse transcriptase |
| US7947721B2 (en) | 2004-08-25 | 2011-05-24 | Ardes Biosciences Inc. | S-triazolyl α-mercaptoacetanilides as inhibitors of HIV reverse transcriptase |
| US8003681B2 (en) | 2004-08-25 | 2011-08-23 | Ardea Biosciences, Inc. | 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid and methyl ester |
| US8946273B2 (en) | 2004-08-25 | 2015-02-03 | Ardea Biosciences, Inc. | S-Triazolyl alpha-mercapto acetanilides as inhibitors of HIV reverse transcriptase |
| US8106205B2 (en) | 2004-08-25 | 2012-01-31 | Ardea Biosciences, Inc. | N[S(4-aryl-triazol-3-yl)α-mercaptoacetyl]p-amino benzoic acids as HIV reverse transcriptase inhibitors |
| US7683087B2 (en) | 2004-08-25 | 2010-03-23 | Ardea Biosciences, Inc. | N[S(4-aryl-triazol-3-yl)α-mercaptoacetyl] -p-amino benzoic acids as HIV reverse transcriptase inhibitors |
| US8552043B2 (en) | 2004-08-25 | 2013-10-08 | Ardea Biosciences, Inc. | N[S(4-aryl-triazol-3-yl)α-mercaptoacetyl]-p-amino benzoic acids as HIV reverse transcriptase inhibitors |
| US7435752B2 (en) | 2004-08-25 | 2008-10-14 | Ardea Biosciences, Inc. | N[S(4-aryl-triazol-3-yl)α-mercaptoacetyl]-p-amino benozioc acids as HIV reverse transcriptase inhibitors |
| US8084483B2 (en) | 2007-11-27 | 2011-12-27 | Ardea Biosciences, Inc. | Compounds and compositions and methods of use |
| US8546437B2 (en) | 2007-11-27 | 2013-10-01 | Ardea Biosciences, Inc. | Compounds and compositions and methods of use |
| US8357713B2 (en) | 2007-11-27 | 2013-01-22 | Ardea Biosciences Inc. | Compounds and compositions and methods of use |
| US8283369B2 (en) | 2007-11-27 | 2012-10-09 | Ardea Biosciences. Inc. | Compounds and compositions and methods of use |
| US10183012B2 (en) | 2007-11-27 | 2019-01-22 | Ardea Biosciences, Inc. | Compounds and compositions and methods of use |
| US8372807B2 (en) | 2009-05-20 | 2013-02-12 | Ardea Biosciences, Inc. | Methods of modulating uric acid levels |
Also Published As
| Publication number | Publication date |
|---|---|
| DK146539B (en) | 1983-10-31 |
| NL187632B (en) | 1991-07-01 |
| JPS5083383A (en) | 1975-07-05 |
| DK611474A (en) | 1975-07-28 |
| SE430065B (en) | 1983-10-17 |
| JPS5641637B2 (en) | 1981-09-29 |
| CH609700A5 (en) | 1979-03-15 |
| NL7415435A (en) | 1975-05-28 |
| NL187632C (en) | 1991-12-02 |
| SE7414705L (en) | 1975-05-27 |
| DK146539C (en) | 1984-04-09 |
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