CA1069499A - Cephalosporin esters - Google Patents
Cephalosporin estersInfo
- Publication number
- CA1069499A CA1069499A CA220,470A CA220470A CA1069499A CA 1069499 A CA1069499 A CA 1069499A CA 220470 A CA220470 A CA 220470A CA 1069499 A CA1069499 A CA 1069499A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- alpha
- carboxylate
- phthalidyl
- ceph
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Phthalidyl and substituted phthalidyl esters of certain cephalosporins are absorbed by the oral route into the serum, where they are hydrolysed to the parent antibacterially active cephalosporin.
Phthalidyl and substituted phthalidyl esters of certain cephalosporins are absorbed by the oral route into the serum, where they are hydrolysed to the parent antibacterially active cephalosporin.
Description
This invention relates to phthalidyl and certain substituted phthalidyl esters of cephalosporins, and to a method for their preparation. Such esters are valuable in that they are absorbed by the oral route into the serum, where they are hydrolysed to release the parent antibacterially active cephalosporin.
According to the present invention there is provided a cephalosporin ester of formula (I) and pharmaceutically acceptable acid addition salts thereof:-H
R ~ CH - CO _ NH , ' / S j I C - C CH (I) NH2 .
~C N\ // CH2 COOCH ' ~ Rl R
wherein R is a phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, ~ 3-chloro-4-hydroxyphenyl, 2- or 3- thienyl or dihydrophenyl ; group; X is a carbomoyloxy or heterocyclic thio group;
and R2 are hydrogen or methoxy groups.
~ Suitable acid addition salts of the compounds of -~ formula (I) include, for example, inorganic salts such as the sulphate, nitrate, phosphate, borate and hydrohalides, ..
,~. .
.~3~ 9(~ ~
e.g. hydrochloride, hydrobromide and hydroiodide and organic salts such as the acetate, oxalate, tartrate, maleate, citrate, succinate, berlzoate, ascorbate and methanesulpho~ate.
The group X may be inter alia a heterocyclic thio group. Examples of particular X groups include the following:-CU3~ NIi/
N__N
s ( ~ s 4 ~> ; ~ ~
;S ~ ~ H2C02~l; ~ S ~ ~ -CH2c2H
O O S
: Preferably, the group X i5 (2-methyl-1,3,4-thiadiazol-5-yl)thio, (1-methyl-(lH)-1,2,3,4-tetrazol-S-yl) thio, ~2-methyl-1,3,4-oxadiazol-5-yl) thlo, or (lH-1,3,4-triazol-5-yl) thio.
The compounds of formula (I) may be prepared by reacting a compound Oe rormula (II):
~:3 ~ :
, i :
: ' ' ".
:
.. ..... . . . .. . - .~ , .. , ~- . . .. . . " ., . , ;
- . . : , . . , ., :
.. . : . . , : . . :, . . .: :
.: - , , .: . .... :, . : . ,, . : - . . - .,-: . . ,. -~ .: . , - . ~ . : , .. . ... . .. .. . . . . . . .
" ~69~
H H
R_ CH _CO ~
MH2 O)-- ~L CH2x (II) COOH
or a reactive esterifying derivative thereof, wherein R and X are as defined with respect to formula ~I), with a compound of formula (III): ..
H0---/CH ~ ~1 ~ ~ ~2 ~III) ' .
or a reactive esterifying derivative thereof, wherein Rl and R2 are as defined with respect to formu~a (I) and where-in any reactive groups such as amino and hydroxy may be blocked, and thereafter, if necessary;
(i) converting a ~ isomer into the desired A
isomer;
20:
(ii) removing any blocking group in the acyl side chain.
By "reactive esterifying derivative" in relation to compounds (II) and (III) above, we mean derivatives of (II) and (III) which when reacted together take part in a reaction with the consequent formation of an ester linkage of formula ~I). Many methods of esterification are known from the literature~ For example, the e~sterification reaction defined above may be achieved by reacting an N-protected cephalosporanic .
acid of formula (II) or a salt thereof with a 3-halophthalide ! - 4 ~ - - ' ' ' - ~., - . . ,. .. . ... . ~
~gi~
or 3-halo-5,6 dimethoxyphthalide. Examples of suitable salts include alkali me-tal salts such as sodium or potassium, or a trialkylammonium salt such as triethylammonium.
With this route i-t is preferable to protect the ~-amino group in the side chain o~ compound (I) prior to the esterification reaction. In such cases any of the amino pro-tecting groups known from the literature on the synthesis of ~-aminobenzyl penicillin or ~-aminobenzyl cephalosporanic acids are suitable.
Examples of protected amino groups include the proton-ated amino group (NH+3) which after the acylation reaction can be converted to a free amino group by simple neutralization;
the t-butyloxycarbonyl, benzyloxycarbonylami.no ~roup or sub-stituted benzyloxycarbonyl-amino groups which are subsequently converted to NH2 by catalytic hydrogenation; and various groups which after the acylation reaction reyenerate the amino group on mild acid hydrolysis. Alkaline hydrolysis is not generally useful since hydrolysis of the ester group takes place under alkaline conditions.
Examples of a protected amino sroup which may subse- :
; quently be converted to NH2 by mild acid hydrolysis include enamine groups of general formula (IV) or tautomeric modi-: fications thereof, and ~hydroxyarylidene groups of general formula ~V) or tautomeric modifications thereof:-¦ CH
R4--C~ \N -- ~C ~ _ 5 ~ H
R - C~ / H
(IV) ¦Y) ,, ~. , , . . : ,. . . .: ~
. .
. .
9~
In structures ~IV) and (V) the dotted lines repre~ent hydrogen bo~ds. In s~ructure (IV) ~3 is a lower a~kyl group, R4 is ei.ther a hydrogen atom or to~ether with R3 completes a carbocyclic ring, and R5 is a lower alkyl, aryl, or lower alkoxy group. In structure (~) ~ represents the residue of a substitu~ad or unsubstitutf~d ben~ene or naph~halene ringO
An exa~ple o~ a "protectecl amino" which can be con~
verted to NH2 after -the esteri~ication reaction is the azido group, In this case, the final conversion into NH2 may be brou~ht about by either cataly~ic hydrogenation or electrolytic reduction. Alternatively the amino ~roup ma~
b~ b~ocked as the nitro group whi.ch is later con~erted to the amino group by recluction.
In the above process, the esterification reaction may cause a clouble bond shift to pOSitiOll 2 of the cephem nucleus, thereby proclucing a mixture o~ 2-cephem and 3-cephem isomers~ If thiS happens, the 2-cephem/3~
cephem mixture can be converted to -the 3-cephem isomer by oxidation o~ the mixture to the sulphoxide followed by reduction. This is, of course~ a standard method for the preparation o~ 3-cephems ~rom 2-cep~ms, and is described for example in Brltish Patent No. 1,280,693. One such method;~is ~rea~ment with triphenylphosphine and acetyl
According to the present invention there is provided a cephalosporin ester of formula (I) and pharmaceutically acceptable acid addition salts thereof:-H
R ~ CH - CO _ NH , ' / S j I C - C CH (I) NH2 .
~C N\ // CH2 COOCH ' ~ Rl R
wherein R is a phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, ~ 3-chloro-4-hydroxyphenyl, 2- or 3- thienyl or dihydrophenyl ; group; X is a carbomoyloxy or heterocyclic thio group;
and R2 are hydrogen or methoxy groups.
~ Suitable acid addition salts of the compounds of -~ formula (I) include, for example, inorganic salts such as the sulphate, nitrate, phosphate, borate and hydrohalides, ..
,~. .
.~3~ 9(~ ~
e.g. hydrochloride, hydrobromide and hydroiodide and organic salts such as the acetate, oxalate, tartrate, maleate, citrate, succinate, berlzoate, ascorbate and methanesulpho~ate.
The group X may be inter alia a heterocyclic thio group. Examples of particular X groups include the following:-CU3~ NIi/
N__N
s ( ~ s 4 ~> ; ~ ~
;S ~ ~ H2C02~l; ~ S ~ ~ -CH2c2H
O O S
: Preferably, the group X i5 (2-methyl-1,3,4-thiadiazol-5-yl)thio, (1-methyl-(lH)-1,2,3,4-tetrazol-S-yl) thio, ~2-methyl-1,3,4-oxadiazol-5-yl) thlo, or (lH-1,3,4-triazol-5-yl) thio.
The compounds of formula (I) may be prepared by reacting a compound Oe rormula (II):
~:3 ~ :
, i :
: ' ' ".
:
.. ..... . . . .. . - .~ , .. , ~- . . .. . . " ., . , ;
- . . : , . . , ., :
.. . : . . , : . . :, . . .: :
.: - , , .: . .... :, . : . ,, . : - . . - .,-: . . ,. -~ .: . , - . ~ . : , .. . ... . .. .. . . . . . . .
" ~69~
H H
R_ CH _CO ~
MH2 O)-- ~L CH2x (II) COOH
or a reactive esterifying derivative thereof, wherein R and X are as defined with respect to formula ~I), with a compound of formula (III): ..
H0---/CH ~ ~1 ~ ~ ~2 ~III) ' .
or a reactive esterifying derivative thereof, wherein Rl and R2 are as defined with respect to formu~a (I) and where-in any reactive groups such as amino and hydroxy may be blocked, and thereafter, if necessary;
(i) converting a ~ isomer into the desired A
isomer;
20:
(ii) removing any blocking group in the acyl side chain.
By "reactive esterifying derivative" in relation to compounds (II) and (III) above, we mean derivatives of (II) and (III) which when reacted together take part in a reaction with the consequent formation of an ester linkage of formula ~I). Many methods of esterification are known from the literature~ For example, the e~sterification reaction defined above may be achieved by reacting an N-protected cephalosporanic .
acid of formula (II) or a salt thereof with a 3-halophthalide ! - 4 ~ - - ' ' ' - ~., - . . ,. .. . ... . ~
~gi~
or 3-halo-5,6 dimethoxyphthalide. Examples of suitable salts include alkali me-tal salts such as sodium or potassium, or a trialkylammonium salt such as triethylammonium.
With this route i-t is preferable to protect the ~-amino group in the side chain o~ compound (I) prior to the esterification reaction. In such cases any of the amino pro-tecting groups known from the literature on the synthesis of ~-aminobenzyl penicillin or ~-aminobenzyl cephalosporanic acids are suitable.
Examples of protected amino groups include the proton-ated amino group (NH+3) which after the acylation reaction can be converted to a free amino group by simple neutralization;
the t-butyloxycarbonyl, benzyloxycarbonylami.no ~roup or sub-stituted benzyloxycarbonyl-amino groups which are subsequently converted to NH2 by catalytic hydrogenation; and various groups which after the acylation reaction reyenerate the amino group on mild acid hydrolysis. Alkaline hydrolysis is not generally useful since hydrolysis of the ester group takes place under alkaline conditions.
Examples of a protected amino sroup which may subse- :
; quently be converted to NH2 by mild acid hydrolysis include enamine groups of general formula (IV) or tautomeric modi-: fications thereof, and ~hydroxyarylidene groups of general formula ~V) or tautomeric modifications thereof:-¦ CH
R4--C~ \N -- ~C ~ _ 5 ~ H
R - C~ / H
(IV) ¦Y) ,, ~. , , . . : ,. . . .: ~
. .
. .
9~
In structures ~IV) and (V) the dotted lines repre~ent hydrogen bo~ds. In s~ructure (IV) ~3 is a lower a~kyl group, R4 is ei.ther a hydrogen atom or to~ether with R3 completes a carbocyclic ring, and R5 is a lower alkyl, aryl, or lower alkoxy group. In structure (~) ~ represents the residue of a substitu~ad or unsubstitutf~d ben~ene or naph~halene ringO
An exa~ple o~ a "protectecl amino" which can be con~
verted to NH2 after -the esteri~ication reaction is the azido group, In this case, the final conversion into NH2 may be brou~ht about by either cataly~ic hydrogenation or electrolytic reduction. Alternatively the amino ~roup ma~
b~ b~ocked as the nitro group whi.ch is later con~erted to the amino group by recluction.
In the above process, the esterification reaction may cause a clouble bond shift to pOSitiOll 2 of the cephem nucleus, thereby proclucing a mixture o~ 2-cephem and 3-cephem isomers~ If thiS happens, the 2-cephem/3~
cephem mixture can be converted to -the 3-cephem isomer by oxidation o~ the mixture to the sulphoxide followed by reduction. This is, of course~ a standard method for the preparation o~ 3-cephems ~rom 2-cep~ms, and is described for example in Brltish Patent No. 1,280,693. One such method;~is ~rea~ment with triphenylphosphine and acetyl
2~ chloride~
The compounds o~ this inve~tion may also be prepared b~ reacting a compound o~ formula ~VI) . ~ .
- ~ . - , .
.
, .
.
~o~
2 \ ~ _ ~ ~ ~ fH2 CO N ~ C'~ C CH2X
CO.OCH ~/ ~ R
~\ R2 l (VI) wherein the dotted line represents ~ bond in the 2- or 3- position and n is O or 1 with a reactive N-acylating derivative of an acid of formula (VII):
R - CH - CO - OE~
NH2 (VII) wherein R, Rl, R2 and X are as defined in formula (I) and wherein any reactive groups, such as amino and hydroxy groups may be blocked, and thereafter, if necessary carrying out one or more o the following steps:
: (i) converting af~ isomer into the desired ~S3 isomer;
(ii) reduction o a sulphoxide compound to form the desired sulphide compound;
: (iii) removal of any blocking groups in the acyl side chain;
A reactive N-acylating derivative o the acid (VII) is em~
ployed in the above process. The choice of reactive derivative will o course be influenced by the chemical '~ :
':
:
~16~3~
270nm (c, 7750); CmCax3 3400, 1790, 1740, 1700 (b), 1495, 1165, 980cm 1~
Alternatively the crude product could be separated by silica gel chromatography into the 3-epimers.
(b) Phthalidyl 7-D-~-aminophenylacetamido-3-~1 -methyl-l -H-tetrazol-51-yl-thiomethyl)ceph-3-em-4-carboxylate .
The preceding t-butoxycarbonyl derivative (2~5g,
The compounds o~ this inve~tion may also be prepared b~ reacting a compound o~ formula ~VI) . ~ .
- ~ . - , .
.
, .
.
~o~
2 \ ~ _ ~ ~ ~ fH2 CO N ~ C'~ C CH2X
CO.OCH ~/ ~ R
~\ R2 l (VI) wherein the dotted line represents ~ bond in the 2- or 3- position and n is O or 1 with a reactive N-acylating derivative of an acid of formula (VII):
R - CH - CO - OE~
NH2 (VII) wherein R, Rl, R2 and X are as defined in formula (I) and wherein any reactive groups, such as amino and hydroxy groups may be blocked, and thereafter, if necessary carrying out one or more o the following steps:
: (i) converting af~ isomer into the desired ~S3 isomer;
(ii) reduction o a sulphoxide compound to form the desired sulphide compound;
: (iii) removal of any blocking groups in the acyl side chain;
A reactive N-acylating derivative o the acid (VII) is em~
ployed in the above process. The choice of reactive derivative will o course be influenced by the chemical '~ :
':
:
~16~3~
270nm (c, 7750); CmCax3 3400, 1790, 1740, 1700 (b), 1495, 1165, 980cm 1~
Alternatively the crude product could be separated by silica gel chromatography into the 3-epimers.
(b) Phthalidyl 7-D-~-aminophenylacetamido-3-~1 -methyl-l -H-tetrazol-51-yl-thiomethyl)ceph-3-em-4-carboxylate .
The preceding t-butoxycarbonyl derivative (2~5g,
3.6mmole) was stirred for 0.75 hour at 10 with trifluoracetic acid (25 mls). After e~aporation of the latter the residue was triturated with dry ether and the crude trifluoracetate of the title compound (2.48g, 97~) was collected and washed well with ether. The product showed one main zone on bioch-romatography, Rf = Q.85 in n-butanol-ethanol-water. ~ nUaxol 1785, 1680, 1200cn . ~ (DMSO) 3.4 - 4.1 (m, 2H, C2-H); 3.77 and 3.92 (2s, 3H, tetraxolyl-CH3)r4.1 0 4.6 (m, 2H, CH2S),
4.8 6.1 (m, 3H, C6, C7 and C~-H), 7.2 - 8.2 (m, 10H, Ar-H
+ OCHO). 8.9 (bs, 3H, NH3), 9.4 - 10.0 (m, NH); ~ max - 270nm (, 7410).
Example 4 (a) Phthalidyl 7-D-~-t-butoxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate Sodium 7-D ~-t-butoxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate (2.lg, 4mmole) is suspended in dry DMF (30 mls) and with ice cooling treated with bromophthalide (0.84g, 0.39mmole). After 1 hour at 20 ice-water (300 mls) is added and ~he solid collected. A solution of the latter in ethyl acetate is washed dilute sodium bicarbon-`~ ate, water, dried and evaporate`d. Precipitation of the residuefrom ethyl acetate - petrol ether provides the desired ester (1.9g) /
, ' ' '' ' ' ~ ' ' '~' ', ` ' ' ' ' '~ ' " ' ' ' 3~
~hich is used without further purification.
(b) Phthalidyl 7-D-~-aminophenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate _ The foregoing crude es-ter (1.6g) is treated with chilled trifluoroacetic acid (15 mls) over 40 mins. Evaporation and trituration with ether gives the title compound as its trifl-uoracetate (l.Sg). This shows one major zone on biochromato-graphy Rf = 0.75 in n-Butanol-water.
' '1 ,Z
.
.
. ~ . . . .. . . . .... ~ ..... . . . .. --- - ` - ` ` ` ` : :
.. . . . - . . ., . . . . . . . ~ .
-. ~ . . . .. ` ~ . ` -. . ..... . . . ... - .
. - - - - . ` . . -` .-. " . . :. ; . . . :
+ OCHO). 8.9 (bs, 3H, NH3), 9.4 - 10.0 (m, NH); ~ max - 270nm (, 7410).
Example 4 (a) Phthalidyl 7-D-~-t-butoxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate Sodium 7-D ~-t-butoxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate (2.lg, 4mmole) is suspended in dry DMF (30 mls) and with ice cooling treated with bromophthalide (0.84g, 0.39mmole). After 1 hour at 20 ice-water (300 mls) is added and ~he solid collected. A solution of the latter in ethyl acetate is washed dilute sodium bicarbon-`~ ate, water, dried and evaporate`d. Precipitation of the residuefrom ethyl acetate - petrol ether provides the desired ester (1.9g) /
, ' ' '' ' ' ~ ' ' '~' ', ` ' ' ' ' '~ ' " ' ' ' 3~
~hich is used without further purification.
(b) Phthalidyl 7-D-~-aminophenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate _ The foregoing crude es-ter (1.6g) is treated with chilled trifluoroacetic acid (15 mls) over 40 mins. Evaporation and trituration with ether gives the title compound as its trifl-uoracetate (l.Sg). This shows one major zone on biochromato-graphy Rf = 0.75 in n-Butanol-water.
' '1 ,Z
.
.
. ~ . . . .. . . . .... ~ ..... . . . .. --- - ` - ` ` ` ` : :
.. . . . - . . ., . . . . . . . ~ .
-. ~ . . . .. ` ~ . ` -. . ..... . . . ... - .
. - - - - . ` . . -` .-. " . . :. ; . . . :
Claims (14)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a cephalosporin ester of formula (I) or a pharmaceutically acceptable salt thereof:
(I) wherein R is a phenyl, 4-hydroxyphenyl, or a 2- or 3-thienyl group;
X is a carbamoyloxy, 1-methyl-1H-tetrazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio group; and R1 and R2 are hydrogen which process comprises:
(a) reacting a compound of formula (II):
(II) or a reactive esterifying derivative thereof, wherein R and X are as defined with respect to formula (I), with a compound of formula (III):
(III) or a reactive esterifying derivative thereof, R1 and R2 are hydrogen, and wherein any reactive amino and hydroxy groups may be blocked; or (b) reacting a compound of formula (VI):
(VI) wherein the dotted line represents a bond in the 2- or 3-position and n is 0 or 1 with a reactive N-acylating derivative of an acid of formula (VII):
(VII) wherein R, R1, R2 and X are as defined above and wherein any reactive amino and hydroxy groups may be blocked, or (c) in the case of compounds of formula (I) wherein x is carbamoyloxy; reacting a compound of formula (VIII):
(VIII) wherein the dotted line represents a bond in the 2- or 3-position, n is O or 1, R, R1, R2 are as defined above and wherein any reactive groups may be blocked, with an isocyanate of formula R6NCO where R6 is a group which is removable from the reaction product with compound (VIII) under mild conditions to give compound (I); and after reaction (a), (b) and (c), carrying out one or more of the following steps, if necessary:
(i) converting a .DELTA.2 isomer into the desired .DELTA.3isomer;
(ii) reduction of sulphoxide compound to form the desired sulphide compound;
(iii) removal of any blocking groups in the acyl side chain.
(I) wherein R is a phenyl, 4-hydroxyphenyl, or a 2- or 3-thienyl group;
X is a carbamoyloxy, 1-methyl-1H-tetrazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio group; and R1 and R2 are hydrogen which process comprises:
(a) reacting a compound of formula (II):
(II) or a reactive esterifying derivative thereof, wherein R and X are as defined with respect to formula (I), with a compound of formula (III):
(III) or a reactive esterifying derivative thereof, R1 and R2 are hydrogen, and wherein any reactive amino and hydroxy groups may be blocked; or (b) reacting a compound of formula (VI):
(VI) wherein the dotted line represents a bond in the 2- or 3-position and n is 0 or 1 with a reactive N-acylating derivative of an acid of formula (VII):
(VII) wherein R, R1, R2 and X are as defined above and wherein any reactive amino and hydroxy groups may be blocked, or (c) in the case of compounds of formula (I) wherein x is carbamoyloxy; reacting a compound of formula (VIII):
(VIII) wherein the dotted line represents a bond in the 2- or 3-position, n is O or 1, R, R1, R2 are as defined above and wherein any reactive groups may be blocked, with an isocyanate of formula R6NCO where R6 is a group which is removable from the reaction product with compound (VIII) under mild conditions to give compound (I); and after reaction (a), (b) and (c), carrying out one or more of the following steps, if necessary:
(i) converting a .DELTA.2 isomer into the desired .DELTA.3isomer;
(ii) reduction of sulphoxide compound to form the desired sulphide compound;
(iii) removal of any blocking groups in the acyl side chain.
2. A process for the preparation of phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-(2'-methyl-1',3',4'-thiadiazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate and its isomers which comprises reacting 7-D-.alpha.-t-butoxycarbonylphenylacetamido-3-(2'-methyl-1',3',4'-thiadiazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylic acid with triethylamine and then with bromophthalide to obtain the desired ester and when required isolating the isomers of the crude product.
3. A process for the preparation of phthalidyl 7[D-.alpha.-amino-phenyl-acetamido-3-(2'-methyl-1',3',4'-thiadiazol-5'-yl)thiomethyl] ceph-3-em-4-carboxylate trifluoroacetic acid salt which comprises reacting phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-(2'-methyl-1',3',4'-thiadiazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate with trifluoroacetic acid to obtain the corresponding salt.
4. A process for the preparation of phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-(1'-methyl-1'-H-tetrazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate and 3-epimers thereof which comprises reacting sodium 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-(1'-methyl-1'-H-tetrazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate with bromophthalide and when required separating the product into the 3-epimers.
5. A process for the preparation of phthalidyl 7-D-.alpha.-aminophenylacetamido-3-(1'-methyl-1'-H-tetrazol-5'-yl-thiomethyl) ceph-3-em-4-carboxylate trifluoroacetic acid salt which comprises treating phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-(1'-methyl-1'-H-tetrazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate with trifluoroacetic acid.
6. A process for the preparation of phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate which comprises reacting sodium 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-carbamoyl-oxy-methyl-3-cephem-4-carboxylate with bromophthalide.
7. A process for the preparation of phthalidyl 7-D-.alpha.-aminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate trifluoroacetic acid salt which comprises treating phthalidyl 7-D-.alpha.-t-butoxy-carbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate with trifluoroacetic acid.
8. A cephalosporin ester of formula (I) or a pharmaceuti-cally acceptable salt thereof as set forth and defined in Claim 1 whenever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
9. Phthalidyl 7-D-.alpha.-t-butoxycarbonyl-aminophenylacetamido -3-(2'-methyl-1',3',4'-thiadiazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate and its isomers whenever prepared by the process of Claim 2 or an obvious chemical equivalent thereof.
10. Phthalidyl 7[D-.alpha.-amino-phenylacetamido-3-(2'-methyl-1',3',4'-thiadiazol-5'-yl)thiomethyl]ceph-3-em-4-carboxylate trifluoroacetic acid salt whenever prepared by the process of Claim 3 or an obvious chemical equivalent thereof.
11. Phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenyl-acetamido-3-(1'-methyl-1'-H-tetrazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate and 3-epimers thereof whenever prepared by the process of Claim 4 or an obvious chemical equivalent thereof.
12. Phthalidyl 7-D-.alpha.-aminophenylacetamido-3-(1'-methyl-1'-H-tetrazol-5'-yl-thiomethyl)ceph-3-em-4-carboxylate trifluoro-acetic acid salt whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.
13. Phthalidyl 7-D-.alpha.-t-butoxycarbonylaminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate whenever prepared by the process of Claim 6 or an obvious chemical equivalent thereof.
14. Phthalidyl 7-D-.alpha.-aminophenylacetamido-3-carbamoyloxy-methyl-3-cephem-4-carboxylate trifluoroacetic acid salt whenever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7860/74A GB1492393A (en) | 1974-02-21 | 1974-02-21 | Cephalosporin esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1069499A true CA1069499A (en) | 1980-01-08 |
Family
ID=9841189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA220,470A Expired CA1069499A (en) | 1974-02-21 | 1975-02-20 | Cephalosporin esters |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS50121294A (en) |
| AU (1) | AU501950B2 (en) |
| BE (1) | BE825717A (en) |
| CA (1) | CA1069499A (en) |
| CH (3) | CH623589A5 (en) |
| DE (1) | DE2507374A1 (en) |
| DK (1) | DK57575A (en) |
| ES (1) | ES434923A1 (en) |
| FR (1) | FR2261773B1 (en) |
| GB (1) | GB1492393A (en) |
| IL (1) | IL46635A (en) |
| NL (1) | NL7501998A (en) |
| PH (1) | PH11815A (en) |
| SE (1) | SE7501878L (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1130969B (en) * | 1980-03-14 | 1986-06-18 | Dob Far Spa | CEFAPIRINE ESTERS, THEIR SALTS AND PROCEDURE FOR THEIR OBTAINMENT |
| IT1141286B (en) * | 1980-04-17 | 1986-10-01 | Dob Far Spa | ESTERS OF DESACETOXY Cephalosporins THEIR SALTS AND PROCEDURES FOR THEIR OBTAINING |
| WO1984001949A1 (en) * | 1982-11-10 | 1984-05-24 | Kyoto Pharma Ind | Cephalosporin derivatives, process and their preparation, and prophylactic and treating agent against bacterial infection |
-
1974
- 1974-02-21 GB GB7860/74A patent/GB1492393A/en not_active Expired
-
1975
- 1975-02-14 IL IL46635A patent/IL46635A/en unknown
- 1975-02-17 DK DK57575*#A patent/DK57575A/da not_active Application Discontinuation
- 1975-02-19 SE SE7501878A patent/SE7501878L/ not_active Application Discontinuation
- 1975-02-19 AU AU78374/75A patent/AU501950B2/en not_active Expired
- 1975-02-19 FR FR7505108A patent/FR2261773B1/fr not_active Expired
- 1975-02-19 BE BE153508A patent/BE825717A/en unknown
- 1975-02-20 PH PH18824A patent/PH11815A/en unknown
- 1975-02-20 CA CA220,470A patent/CA1069499A/en not_active Expired
- 1975-02-20 DE DE19752507374 patent/DE2507374A1/en not_active Withdrawn
- 1975-02-20 NL NL7501998A patent/NL7501998A/en not_active Application Discontinuation
- 1975-02-20 ES ES434923A patent/ES434923A1/en not_active Expired
- 1975-02-21 CH CH220575A patent/CH623589A5/en not_active IP Right Cessation
- 1975-02-21 JP JP50021047A patent/JPS50121294A/ja active Pending
-
1979
- 1979-03-09 CH CH228379A patent/CH622801A5/en not_active IP Right Cessation
-
1980
- 1980-06-12 CH CH454280A patent/CH623329A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU7837475A (en) | 1976-08-19 |
| ES434923A1 (en) | 1976-12-16 |
| BE825717A (en) | 1975-08-19 |
| SE7501878L (en) | 1975-08-22 |
| JPS50121294A (en) | 1975-09-23 |
| IL46635A0 (en) | 1975-04-25 |
| CH623589A5 (en) | 1981-06-15 |
| IL46635A (en) | 1978-07-31 |
| GB1492393A (en) | 1977-11-16 |
| DK57575A (en) | 1975-10-20 |
| FR2261773A1 (en) | 1975-09-19 |
| CH623329A5 (en) | 1981-05-29 |
| DE2507374A1 (en) | 1975-08-28 |
| FR2261773B1 (en) | 1978-08-04 |
| PH11815A (en) | 1978-07-14 |
| AU501950B2 (en) | 1979-07-05 |
| NL7501998A (en) | 1975-08-25 |
| CH622801A5 (en) | 1981-04-30 |
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| MKEX | Expiry |