CA1097653A - Process for the preparation of clavulanic acid esters - Google Patents
Process for the preparation of clavulanic acid estersInfo
- Publication number
- CA1097653A CA1097653A CA292,807A CA292807A CA1097653A CA 1097653 A CA1097653 A CA 1097653A CA 292807 A CA292807 A CA 292807A CA 1097653 A CA1097653 A CA 1097653A
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- CA
- Canada
- Prior art keywords
- salt
- ester
- acid
- base
- methyl
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Abstract
Abstract of the Disclosure A process for the preparation of a compound of the formula (1):
(I) or a salt or ester thereof wherein R is a methyl or ethyl group which process comprises the reaction of clavulanic acid or a salt or ester thereof with an oxonium salt of the formula (II):
R3O? X.THETA. (II) wherein R is a methyl or ethyl group and X.THETA. is an anion and thereafter if desired performing one or both of the following reactions: (a) con-verting the thus formed ester into the acid or salt and (b) converting the thus formed acid or salt into an alternative ester or alternative salt. The compounds of formula (I) have utility as additives to enhance the effectiveness of penicillins and cephalosporius. The novel process is generally convenient, safer and often higher yielding than known processes.
(I) or a salt or ester thereof wherein R is a methyl or ethyl group which process comprises the reaction of clavulanic acid or a salt or ester thereof with an oxonium salt of the formula (II):
R3O? X.THETA. (II) wherein R is a methyl or ethyl group and X.THETA. is an anion and thereafter if desired performing one or both of the following reactions: (a) con-verting the thus formed ester into the acid or salt and (b) converting the thus formed acid or salt into an alternative ester or alternative salt. The compounds of formula (I) have utility as additives to enhance the effectiveness of penicillins and cephalosporius. The novel process is generally convenient, safer and often higher yielding than known processes.
Description
~1997~3 The present invention relates to a process for the preparation of clavulanic acid ethers.
Belgian Patent No. 847045 (and also Canadian Patent Application No. 263,105) disclose that ethers of clavu]anic acid and their salts and esters may be used to enhance the effectiveness of penicillins and cephalosporins. The process illustrated for the preparation of such compounds involved the reaction of a diazocompound on an ester of clavulanic acid. A generally more convenient, safer and often higher yieldin~ process has now discovered.
Accordingly the present inven-tion provides a process for ~i .
the preparation of a compound of the formula (I):
.
H
~ O . f~H20 0'~ --or a salt or ester thereof wherein R is a methyl or ethyl group which process comprises the reaction of clavulanic ' `
~ 2 -~,~ .
! a . ~ . , .
` " ,'`` `~,' " ` ' ~ , :
", acid or a salt or ester thereof with a compound of the formula (II):
R30~ X~ (II) ` wherei~ R is a methyl or ethyl group and X~ is an anion and thereafter if desired performing one or more of the following reactions:. (a) convertingthe initially formed ester into an acid or sait and (b) converting the ,~ thus formed acid or salt into an alternative ester or alternatlve salt.
When the etherification is performed on an ester of clavulanic acid then usually at least 1 equivalent ~for example 1 - 5 equivalents) o~ a compound of ~he formula.
is employed per equivalent of ester of clavulanic acid. When the etheri~ication lS per-formed on:a salt of clavulanic acid (or on the aoid)~then usually at least
Belgian Patent No. 847045 (and also Canadian Patent Application No. 263,105) disclose that ethers of clavu]anic acid and their salts and esters may be used to enhance the effectiveness of penicillins and cephalosporins. The process illustrated for the preparation of such compounds involved the reaction of a diazocompound on an ester of clavulanic acid. A generally more convenient, safer and often higher yieldin~ process has now discovered.
Accordingly the present inven-tion provides a process for ~i .
the preparation of a compound of the formula (I):
.
H
~ O . f~H20 0'~ --or a salt or ester thereof wherein R is a methyl or ethyl group which process comprises the reaction of clavulanic ' `
~ 2 -~,~ .
! a . ~ . , .
` " ,'`` `~,' " ` ' ~ , :
", acid or a salt or ester thereof with a compound of the formula (II):
R30~ X~ (II) ` wherei~ R is a methyl or ethyl group and X~ is an anion and thereafter if desired performing one or more of the following reactions:. (a) convertingthe initially formed ester into an acid or sait and (b) converting the ,~ thus formed acid or salt into an alternative ester or alternatlve salt.
When the etherification is performed on an ester of clavulanic acid then usually at least 1 equivalent ~for example 1 - 5 equivalents) o~ a compound of ~he formula.
is employed per equivalent of ester of clavulanic acid. When the etheri~ication lS per-formed on:a salt of clavulanic acid (or on the aoid)~then usually at least
2 equivalents (for example 2 - 5 equi~valents) of a compound - of the formula (II) is employed per equivalent of clavulanlc acid salt.
. , .
-Most suitably ~ is BF4 or its equivalent such as PF6~ or 2,4,6-trinltrobenzenesulphonate.
. , .
-Most suitably ~ is BF4 or its equivalent such as PF6~ or 2,4,6-trinltrobenzenesulphonate.
3 -~ ' ~,"~,......
, . .
. ' - ' , ' , , .
.. . .
, ':,' ' ,' " ' ' ' , ~ ' ~
~7f~53 The preceding reaction generally employs a salt or ester of clavulanic acid which is the compound of the formula (III):
H CH20~
_~0~/
N ~ (III) When clavulanic acid or its salt is employed etherification and esterification take place so that methyl 9-O~methyl-clavulanate or ethyl 9-0-ethylclavulanate are produced. This reaction gener-ally proceeds via the methyl or ethyl ester intermediate formed in-situ.
~ost suitably the compound of the formula (II) is either trimethyl-oxonium tetrafluoroborate or tr:Lethyloxonium tetrafluoroborate.
Thus in one particularly suitable aspect this invention provides a process for the preparation of a compound of the formula (I) or a salt or ester thereof which process comprises the reaction of an ; ester Oe clavulanic acid with trimethyloxonium tetrafluoroborate or ~riethyloxonium tetrafluoroborate and thereafter if desired forming the free acid or~ salt thereof~from an ester.
:
, . .
. ' - ' , ' , , .
.. . .
, ':,' ' ,' " ' ' ' , ~ ' ~
~7f~53 The preceding reaction generally employs a salt or ester of clavulanic acid which is the compound of the formula (III):
H CH20~
_~0~/
N ~ (III) When clavulanic acid or its salt is employed etherification and esterification take place so that methyl 9-O~methyl-clavulanate or ethyl 9-0-ethylclavulanate are produced. This reaction gener-ally proceeds via the methyl or ethyl ester intermediate formed in-situ.
~ost suitably the compound of the formula (II) is either trimethyl-oxonium tetrafluoroborate or tr:Lethyloxonium tetrafluoroborate.
Thus in one particularly suitable aspect this invention provides a process for the preparation of a compound of the formula (I) or a salt or ester thereof which process comprises the reaction of an ; ester Oe clavulanic acid with trimethyloxonium tetrafluoroborate or ~riethyloxonium tetrafluoroborate and thereafter if desired forming the free acid or~ salt thereof~from an ester.
:
- 4 -~ ' .
-. .: - . : ' : . . . ~
.. . ~ .
: ' . ~' ' ' ~:: `
: : . . ' ' ' . ' : . .
':
. .
, ' - ~0~653 The ester of clavulanic acid is preferably one ~7hich is hydroly-sable or hydrogenolysable to the parent acid or its salt.
Suitable esters of clavulanic acid for use in the process of this invention include those of the formula (IV) and also those of the formula (V):
H H
r `1~ ~ C~l~O}I ` U~O}I
O
(IV) (V) where A is an alkyl group of 1 - 8 carbon atoms optionally sub-stituted by haogen or a group of the formula OA , OCOA , SA , . ~ 10~ 502A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms; A ls a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl gro~up optionally substituted by halogen or by~a~ grou~p A5 or oA5 ~here A5 is an alkyl ~group of~ up to 6 carbon atoms;~ and A ~is a phenyl group~optlonally substituted~by halogen, o~r a group A~ or OA where~A is an alkyl group. Othe:r sultable values~fo~r~A lnclud~e~a:lkenyl or~alkynyl:~groups; of~ up~:to 4 carbon ~ .
: ~ ~ ' :, ', '. : ' :- ~ ' ' ' ' ' ' ' ` ~ : -76~
Other suitable values for A include nitrophenyl.
Most suitably Al is an alkyl group of up to 4 carbon atoms, for example the methyl, ethyl, n-propyl or n-butyl groups or such a group substituted by a group of the :Eormula oA4 or oCOA4 where A4 is an alkyl group of up to ~ carbon atoms.
Preferably Al is either a me-thyl group or an ethyl group.
Particularly suitable values for CEIA A3 lnclude benzyl and mono-substituted benzyl such as bromobenzyl, nitro-benzyl, methoxybenzyl and the like in which thesubstituent is preferably in the para-position.
Other esters which may be employed include in-vivo hydrolysable esters such as those described in ~elgian Patent No. 827926 as~being in-vivo hydrolysable when attached to clavulanic acid. Such esters include acetoxymethyl, ~-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl, ~-ethoxycarbonyloxyethyl or the like.
When the process of this invention employs a salt of :
clavulanic acid~as starting material the process offers the advantages of good overall yields of pure products and an advantageously low number of reaction steps.
.
' - :. . . . .. . . .
- ~ : ; ... . .. : : -:: :
', ' . . ~
,. -: . ,, .:
, . . , ~q~976~3 Suitable salts of clavulanic acid used in the process of this invention may be any convenient salt of clavulanic acid such as an alkali metal or alkaline earth metal salt or a salt of a nitro-genous base. Thus suitable salts of clavulanic acid for use in this process include the lithium, sodium~ po~assium, calcium, magnesium, barium, tetramethylguandinium or the like salt.
The reaction of the~compound of the formula (II) with a salt or ester of clavulanic acid will take place in an inert dry organic solvent such as dichloromethane or chloroform, or other haloalkane or other non-hydroxylic solvent such as nitromethane. Most suitably the solvent system is strictly non-hydroxylic.
Preferably the etherification takes place in the presence of a base. Most suitably the base is one which is insoluble in the reaction medium such as an alkali metal carbonate or bicarbonate or an alkaline earth metal oxide or hydroxide or the like. Thus suitable bases include sodium carbonate, sodium bicarbonate, lithium carbonste, calcium carbonate, magnesium carbonate or the llke. The base used should be snhydrous. ~
Such insolublÆ bases are preferably presÆnt in excess, for example ~20 from 1 - 5 equivalents of ba~se per equivalent of oxonium salt may be used~
: ~ ~
~' :
-- 7 --:
~sr .
. . .
- ', . . ' ' , - : .
It has been found that the presence of a crown-ether in the reaction medium can increase the yield of the desired compound from the clavulanate salt. Thus crown-ethers such as "18 crown 6", "15 crown 5", "dicyclohexo 18 crown 6", or their equivalents may be used.
A preferred aspect this invention provides a process for the preparation of methyl 9-0-methylclavulanate which comprises the reaction of a salt of clavulanic acid with trimethyloxonium fluoroborate. ~ further preferred aspect of this invention provides 'a process for the preparat:ion ofethyl 9-0-ethylclavulanate which comprises the reaction of a salt of clavulanic acid with triethyl-oxonium tetrafluoroborate.
Once the etherification reaction is substantially complete (for --example as shown by thin layer chromatorgraphy-identification by permanganate spray) the desired compound may be obtained from thP
mixture by washing the organic phase with water to remove ionic materials, drying the organic phase and evaporating the solvent and thereafter if desired further purlfylng the ester/ether chromatographically. Suitable chromatographic systems employ stationary~phases such as silica gel, cellulose or the like and solvents such~as ester hydrocarbon mixtures such as ethyl acetate/
cyclohexane mixtures.
:
, :
: ~ :
.
~ - 8 -, .
Esters of the compounds of the formula (I) may be converted -to the :~ree acid or its sal-ts by the methods described in Belgian Patent No. 8470~5. Such methods include the hydrogJc-!na~i.on of hydrogenolysable esters such as the ben~.yl or p-methoxybenzyl. or ecluivalent esters (such as the p-nitroben~yl or p-bromobenzyl esters) optionally in the presence of a base such as Li2C03, Na2C03, ~2CO3, NaH C03, KHCO3, or the like and in the presence of a transition metal catalyst such as 10~ palladium on charcoal. Such methods also include mild base hydrolysis, for example hydrolysis of the methyl ester by the controlled addition of LiOH, NaOH
or the like aclded a-t a rate to maintain the pH (as recorded on a pII meter) of the solution in the region 7.5 - 10 for example malntamed between such ranges as 7.5 - 9, 8 - 10 or preferably 9 - 9.5. This may be conveniently affected using a plI-stat so that the base is normally used in an aqueous medium. Bases which may be employed inc].ude LlOH, NaOH, KOH, Li2C03, NaCO3, 20 ~ ~ICO3, ~K2CO3, Mg(II)2~ Ca(H)2~ or the like-;
In a particularly Lavourecl aspect thls invention provides a process adapted to the preparation of a salt of a compound of~ the formula (I) which process comprises :
.
~ 9 ~
"~
. . .
.
, forming the methyl ester of the mc-thyl ether of c:Lavulanic acid or the ethyl ester of the ethyl ether of clavulanic acid as hereinbeEore described and therea-Eter hydrolyslng the ester group to yield a salt oI the methyl ether of clavulanic acid or a salt of the ethyl ethex of clavulanic acid.
Generally the hydrolysis is e-ffected in an aqu~ous solvent system such as aqueous tetrahydrofuran or the like using a base such as one of those described above.
A preferred salt of clavulanic acid for use in the process of tllis invention is the sodium salt. A
further preferred salt of clavulanic acid for use in the process of this invention is the potassium salt. Yet another preferred salt for use in the process of this invention is the lithium salt.
It appears that the use of a finely divided form of the salt leads to improved yields. Such finely divided forms include those prepared by freeze drying a solution or by dehydratlng a hydrated salt such as sodium clavulanate tetrahydrate.
~: :
- .
-: .
'~ ' ~' ' ''' '~
.
~7653 The etherification reaction is normally carried out at a temperature of -80 (or more ~tsually -60) to +60 (or up to boiling point ol the solvent although temperatures of not more than +40 are more conventional) and more usually at from -40 t.o 30C. Often it is convenient to start -the reaction at a low temperature such as -30 to 0 and to allow the reaction mixture to gradually increase in temperature until an ambient or slightly depressed temperature is reached such as about 10 to 20C.
The hydrolysis is conveniently effected at roughly ambient temperature, for example at from about 10 to about 30C, for example at 15 to 25C.
; When the reaction is complete (for example no further base is taken up without degradation or as judged by : tlc) the pH of the medium may be adjusted to pH 7 by, for example, the addition of a small quantity of an acid such as acetic acid.
, ~ - In order to obtain the desired salt the solvent may , ~ :
: 20 be~removed for example by evaporation, and the dried :~ : salt obtained in crystalline form by the addition of . ;~. ; ~ an;approprlate solvent such as acetone,~acetonltrile, '` ; '`
' '' ' `~ ' . " ``
' , '- ` . , ` ' , ~ ~ ~ ,;
7~53 tetrahydrofuran or the like. It can be favourable if such solvents contain moisture but large proportions O:e water should be avoided owing to the solubility of the e~tllers.
A particularly suitable form of this part of the invention comprises hydrolysis of the ester to yield the lithium salt as this salt can be produced in highly pure form in good yield.
If other salts of the methyl or ethyl ether are required these may conveniently be prepared from the lithium salt, for example by dissolving the lithium salt in water, applying thissolution to a polymeric ca-tion exchange resin in the form of alternative salt (for example in the sodium, potassium, calcium, magnesium or like form) and eluting the alternative salt therefrom.
Suitable cation exchange resins lnclude cross-lined polystyrene-divinylbenzene co-polymers substituted - by sulphonic acid moieties; for example Amberlite 2~0 IR-120, IR-118 or IR-122, Dowex 50X8, Zerolit 225, : . *
;~ BioRad AG 50W-X8, Ionac C250, C255 or C258.
Normally the elution solvent is water or water in .2 -* All of whlch are Trade Marks , .
. .
,: . , , ' ' ' . . ' ' ': --, . :-: .
. . . .
. : , .. . , . - .
- - . . :. : : . . .. .
~ 7~3 admixture with an organic solvent such as methanol, ethanol, acetone or the like. Most suitably the elution solvent is water. The cation exchange resin is preferably present in large excess, -for example at least a 3-fold excess, most suitably at least an 8-~old excess and preferably at least a 10 fold excess. In the simplest and most convenient form of the process a solution of the lithium salt is simply percolated through a bed of resin from which it emerges in the form of the alternative salt. The desired salt may then be obtained from solution by conventional methods such as freeze-drying, evaporation, precipitation using an organic solvent or the like.
The acids o~ the formula (I~ may be prepared from the lithium or other salt by acidification, for example by using an acid such as a miueral acid or a strong acid cation exchange resin (which acts as a convenient insoluble acid~.
~ne follo~ Examples~illustrate the invention:
' :
~............................ .
iS3 Ethyl 9-0-ethylclavulate To a vigorously stirred suspension o~ potassium clav-ulanate (l.52g) and anhydrous sodium carbonate (4g) in dry dichloromethane (70 ml) cooled to -20C, was added dropwise a solution of triethyloxonium tetrafluoroborate (4.86g) in dry dichloromethane (40 ml). The reaction was stirred for 3 hours at circa -20C (very slow reaction) and then for l hour at circa 5C (ice-bath). At this time tlc showed a moderately strong ester zone and a strong ester-ether zone. Water (90 ml) was added, the phases separated and the organic phase dried over sodium sulphate.
The drying agent was filtered off and the filtrate evaorated to an orange oil. :
This was subjected to gradient elution chromatography on silica gel using ethyl acetate and cyclohexane, graded from l:l ratio to pure ethyl acetate. The ether-ester eluted before the éster. Fractions con-taining these (by tlc) were respectively combined and evaporated, to yield 44 mg of crude ethyl clavulanate and 520 mg of ester-e~ These were ; re-chromatographed separàtely. (The ester was~ ~ ~hromatographed 20~ using the~orlginal solvent system to yield-l5~g pure ester).
The ester-ether was re-chromatographed using ethyl acetate and cyc1Ohex~ane graded from 3:2 to 2:3 ratio,~to y~ield 375 mg of~pure ethy~l~9-0-ethylclavulanate as a~pale yellow~oil.
.R.~fmax (fi1m) 1802,~1744 and 1699 cm~l;
~ (CDCl3?: 1.14 (3H,~t,J 7Hz, ether C~I3)~, 1.26 ~3H, t, J
. . . ...
: . , ~ .
-. . - .
: . : : , ..
, . . ,, . . .
, . - . , : . :: .
:, :, : . - , . . .
"~ . . :: , , .. : . , : :
~L~Ca76~3 7 Hz, ester CH3), 2.97 (lH, d, J 17Hz, 6-~-CH), 3.46 (lH, dd, J 17 ancl 3Hz, 6-a-CH), 3.39 (2H, q, J 7Hz, 9-0-C_2), 4.01 (2H, d, J 7Hz, 9-CH2), 4.17 (2H, cl, J 7Hz, C02 CH2), 4.78 (lH, t, J 7Hz, 8-CH), 4.99 (lH, s, 3-CH), 5.63 (lH, d, J 3Hz,
-. .: - . : ' : . . . ~
.. . ~ .
: ' . ~' ' ' ~:: `
: : . . ' ' ' . ' : . .
':
. .
, ' - ~0~653 The ester of clavulanic acid is preferably one ~7hich is hydroly-sable or hydrogenolysable to the parent acid or its salt.
Suitable esters of clavulanic acid for use in the process of this invention include those of the formula (IV) and also those of the formula (V):
H H
r `1~ ~ C~l~O}I ` U~O}I
O
(IV) (V) where A is an alkyl group of 1 - 8 carbon atoms optionally sub-stituted by haogen or a group of the formula OA , OCOA , SA , . ~ 10~ 502A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms; A ls a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl gro~up optionally substituted by halogen or by~a~ grou~p A5 or oA5 ~here A5 is an alkyl ~group of~ up to 6 carbon atoms;~ and A ~is a phenyl group~optlonally substituted~by halogen, o~r a group A~ or OA where~A is an alkyl group. Othe:r sultable values~fo~r~A lnclud~e~a:lkenyl or~alkynyl:~groups; of~ up~:to 4 carbon ~ .
: ~ ~ ' :, ', '. : ' :- ~ ' ' ' ' ' ' ' ` ~ : -76~
Other suitable values for A include nitrophenyl.
Most suitably Al is an alkyl group of up to 4 carbon atoms, for example the methyl, ethyl, n-propyl or n-butyl groups or such a group substituted by a group of the :Eormula oA4 or oCOA4 where A4 is an alkyl group of up to ~ carbon atoms.
Preferably Al is either a me-thyl group or an ethyl group.
Particularly suitable values for CEIA A3 lnclude benzyl and mono-substituted benzyl such as bromobenzyl, nitro-benzyl, methoxybenzyl and the like in which thesubstituent is preferably in the para-position.
Other esters which may be employed include in-vivo hydrolysable esters such as those described in ~elgian Patent No. 827926 as~being in-vivo hydrolysable when attached to clavulanic acid. Such esters include acetoxymethyl, ~-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl, ~-ethoxycarbonyloxyethyl or the like.
When the process of this invention employs a salt of :
clavulanic acid~as starting material the process offers the advantages of good overall yields of pure products and an advantageously low number of reaction steps.
.
' - :. . . . .. . . .
- ~ : ; ... . .. : : -:: :
', ' . . ~
,. -: . ,, .:
, . . , ~q~976~3 Suitable salts of clavulanic acid used in the process of this invention may be any convenient salt of clavulanic acid such as an alkali metal or alkaline earth metal salt or a salt of a nitro-genous base. Thus suitable salts of clavulanic acid for use in this process include the lithium, sodium~ po~assium, calcium, magnesium, barium, tetramethylguandinium or the like salt.
The reaction of the~compound of the formula (II) with a salt or ester of clavulanic acid will take place in an inert dry organic solvent such as dichloromethane or chloroform, or other haloalkane or other non-hydroxylic solvent such as nitromethane. Most suitably the solvent system is strictly non-hydroxylic.
Preferably the etherification takes place in the presence of a base. Most suitably the base is one which is insoluble in the reaction medium such as an alkali metal carbonate or bicarbonate or an alkaline earth metal oxide or hydroxide or the like. Thus suitable bases include sodium carbonate, sodium bicarbonate, lithium carbonste, calcium carbonate, magnesium carbonate or the llke. The base used should be snhydrous. ~
Such insolublÆ bases are preferably presÆnt in excess, for example ~20 from 1 - 5 equivalents of ba~se per equivalent of oxonium salt may be used~
: ~ ~
~' :
-- 7 --:
~sr .
. . .
- ', . . ' ' , - : .
It has been found that the presence of a crown-ether in the reaction medium can increase the yield of the desired compound from the clavulanate salt. Thus crown-ethers such as "18 crown 6", "15 crown 5", "dicyclohexo 18 crown 6", or their equivalents may be used.
A preferred aspect this invention provides a process for the preparation of methyl 9-0-methylclavulanate which comprises the reaction of a salt of clavulanic acid with trimethyloxonium fluoroborate. ~ further preferred aspect of this invention provides 'a process for the preparat:ion ofethyl 9-0-ethylclavulanate which comprises the reaction of a salt of clavulanic acid with triethyl-oxonium tetrafluoroborate.
Once the etherification reaction is substantially complete (for --example as shown by thin layer chromatorgraphy-identification by permanganate spray) the desired compound may be obtained from thP
mixture by washing the organic phase with water to remove ionic materials, drying the organic phase and evaporating the solvent and thereafter if desired further purlfylng the ester/ether chromatographically. Suitable chromatographic systems employ stationary~phases such as silica gel, cellulose or the like and solvents such~as ester hydrocarbon mixtures such as ethyl acetate/
cyclohexane mixtures.
:
, :
: ~ :
.
~ - 8 -, .
Esters of the compounds of the formula (I) may be converted -to the :~ree acid or its sal-ts by the methods described in Belgian Patent No. 8470~5. Such methods include the hydrogJc-!na~i.on of hydrogenolysable esters such as the ben~.yl or p-methoxybenzyl. or ecluivalent esters (such as the p-nitroben~yl or p-bromobenzyl esters) optionally in the presence of a base such as Li2C03, Na2C03, ~2CO3, NaH C03, KHCO3, or the like and in the presence of a transition metal catalyst such as 10~ palladium on charcoal. Such methods also include mild base hydrolysis, for example hydrolysis of the methyl ester by the controlled addition of LiOH, NaOH
or the like aclded a-t a rate to maintain the pH (as recorded on a pII meter) of the solution in the region 7.5 - 10 for example malntamed between such ranges as 7.5 - 9, 8 - 10 or preferably 9 - 9.5. This may be conveniently affected using a plI-stat so that the base is normally used in an aqueous medium. Bases which may be employed inc].ude LlOH, NaOH, KOH, Li2C03, NaCO3, 20 ~ ~ICO3, ~K2CO3, Mg(II)2~ Ca(H)2~ or the like-;
In a particularly Lavourecl aspect thls invention provides a process adapted to the preparation of a salt of a compound of~ the formula (I) which process comprises :
.
~ 9 ~
"~
. . .
.
, forming the methyl ester of the mc-thyl ether of c:Lavulanic acid or the ethyl ester of the ethyl ether of clavulanic acid as hereinbeEore described and therea-Eter hydrolyslng the ester group to yield a salt oI the methyl ether of clavulanic acid or a salt of the ethyl ethex of clavulanic acid.
Generally the hydrolysis is e-ffected in an aqu~ous solvent system such as aqueous tetrahydrofuran or the like using a base such as one of those described above.
A preferred salt of clavulanic acid for use in the process of tllis invention is the sodium salt. A
further preferred salt of clavulanic acid for use in the process of this invention is the potassium salt. Yet another preferred salt for use in the process of this invention is the lithium salt.
It appears that the use of a finely divided form of the salt leads to improved yields. Such finely divided forms include those prepared by freeze drying a solution or by dehydratlng a hydrated salt such as sodium clavulanate tetrahydrate.
~: :
- .
-: .
'~ ' ~' ' ''' '~
.
~7653 The etherification reaction is normally carried out at a temperature of -80 (or more ~tsually -60) to +60 (or up to boiling point ol the solvent although temperatures of not more than +40 are more conventional) and more usually at from -40 t.o 30C. Often it is convenient to start -the reaction at a low temperature such as -30 to 0 and to allow the reaction mixture to gradually increase in temperature until an ambient or slightly depressed temperature is reached such as about 10 to 20C.
The hydrolysis is conveniently effected at roughly ambient temperature, for example at from about 10 to about 30C, for example at 15 to 25C.
; When the reaction is complete (for example no further base is taken up without degradation or as judged by : tlc) the pH of the medium may be adjusted to pH 7 by, for example, the addition of a small quantity of an acid such as acetic acid.
, ~ - In order to obtain the desired salt the solvent may , ~ :
: 20 be~removed for example by evaporation, and the dried :~ : salt obtained in crystalline form by the addition of . ;~. ; ~ an;approprlate solvent such as acetone,~acetonltrile, '` ; '`
' '' ' `~ ' . " ``
' , '- ` . , ` ' , ~ ~ ~ ,;
7~53 tetrahydrofuran or the like. It can be favourable if such solvents contain moisture but large proportions O:e water should be avoided owing to the solubility of the e~tllers.
A particularly suitable form of this part of the invention comprises hydrolysis of the ester to yield the lithium salt as this salt can be produced in highly pure form in good yield.
If other salts of the methyl or ethyl ether are required these may conveniently be prepared from the lithium salt, for example by dissolving the lithium salt in water, applying thissolution to a polymeric ca-tion exchange resin in the form of alternative salt (for example in the sodium, potassium, calcium, magnesium or like form) and eluting the alternative salt therefrom.
Suitable cation exchange resins lnclude cross-lined polystyrene-divinylbenzene co-polymers substituted - by sulphonic acid moieties; for example Amberlite 2~0 IR-120, IR-118 or IR-122, Dowex 50X8, Zerolit 225, : . *
;~ BioRad AG 50W-X8, Ionac C250, C255 or C258.
Normally the elution solvent is water or water in .2 -* All of whlch are Trade Marks , .
. .
,: . , , ' ' ' . . ' ' ': --, . :-: .
. . . .
. : , .. . , . - .
- - . . :. : : . . .. .
~ 7~3 admixture with an organic solvent such as methanol, ethanol, acetone or the like. Most suitably the elution solvent is water. The cation exchange resin is preferably present in large excess, -for example at least a 3-fold excess, most suitably at least an 8-~old excess and preferably at least a 10 fold excess. In the simplest and most convenient form of the process a solution of the lithium salt is simply percolated through a bed of resin from which it emerges in the form of the alternative salt. The desired salt may then be obtained from solution by conventional methods such as freeze-drying, evaporation, precipitation using an organic solvent or the like.
The acids o~ the formula (I~ may be prepared from the lithium or other salt by acidification, for example by using an acid such as a miueral acid or a strong acid cation exchange resin (which acts as a convenient insoluble acid~.
~ne follo~ Examples~illustrate the invention:
' :
~............................ .
iS3 Ethyl 9-0-ethylclavulate To a vigorously stirred suspension o~ potassium clav-ulanate (l.52g) and anhydrous sodium carbonate (4g) in dry dichloromethane (70 ml) cooled to -20C, was added dropwise a solution of triethyloxonium tetrafluoroborate (4.86g) in dry dichloromethane (40 ml). The reaction was stirred for 3 hours at circa -20C (very slow reaction) and then for l hour at circa 5C (ice-bath). At this time tlc showed a moderately strong ester zone and a strong ester-ether zone. Water (90 ml) was added, the phases separated and the organic phase dried over sodium sulphate.
The drying agent was filtered off and the filtrate evaorated to an orange oil. :
This was subjected to gradient elution chromatography on silica gel using ethyl acetate and cyclohexane, graded from l:l ratio to pure ethyl acetate. The ether-ester eluted before the éster. Fractions con-taining these (by tlc) were respectively combined and evaporated, to yield 44 mg of crude ethyl clavulanate and 520 mg of ester-e~ These were ; re-chromatographed separàtely. (The ester was~ ~ ~hromatographed 20~ using the~orlginal solvent system to yield-l5~g pure ester).
The ester-ether was re-chromatographed using ethyl acetate and cyc1Ohex~ane graded from 3:2 to 2:3 ratio,~to y~ield 375 mg of~pure ethy~l~9-0-ethylclavulanate as a~pale yellow~oil.
.R.~fmax (fi1m) 1802,~1744 and 1699 cm~l;
~ (CDCl3?: 1.14 (3H,~t,J 7Hz, ether C~I3)~, 1.26 ~3H, t, J
. . . ...
: . , ~ .
-. . - .
: . : : , ..
, . . ,, . . .
, . - . , : . :: .
:, :, : . - , . . .
"~ . . :: , , .. : . , : :
~L~Ca76~3 7 Hz, ester CH3), 2.97 (lH, d, J 17Hz, 6-~-CH), 3.46 (lH, dd, J 17 ancl 3Hz, 6-a-CH), 3.39 (2H, q, J 7Hz, 9-0-C_2), 4.01 (2H, d, J 7Hz, 9-CH2), 4.17 (2H, cl, J 7Hz, C02 CH2), 4.78 (lH, t, J 7Hz, 8-CH), 4.99 (lH, s, 3-CH), 5.63 (lH, d, J 3Hz,
5-CH).
Tetramethylguanidinium clavulanate can replace potassium clavulanate in this reaction, but without advantage, in spite of the solubility of the salt in dichloromethane.
, ~ . ' : , , . . :
.
. , . ~
7~53 -Ethyl 9-0-e-thylclavulanate The process of Example 1 can be improved by the addition oi a cata]ytic amount (0.17 g in this case) of crown ether ('18 crown 6') to the dichloromethane solution o the reagents before adding the oxonium salt. In this case 1.1 g (75%) of substantially pure ethyl O-ethylclavulanate was obtained after the first column (based on 89% pure potassium salt starting material).
, :
, '~
, . ~ , . .
, , ,, ' .' ~ .' ' :
' ' ~ ,,:- ', ', ', ' ' ' " .
-:
- : ' 7~i~i3 EXA~LE 3 Lithlum 9-0-ethylclavulanate A solution of ethyl 9-0-ethylclavulanate (1.1 g) in tetrahydrofuran/water (1:2, 60 ml) was maintained at pH
9.4(p~I-Stat) by the addition of lM Li OH solution until 4.0 ml had been used (about 90 min) at 22C with stirring.
One small drop of acetic acid was added to bring the pH
down to 7.0, and the solution then evaporated to an orange gum on the rotary evaporator at ambient temperature. The gum was dissolved in acetone (about 20 ml) and chilled at 2-3C for 1 hour, when the lithium salt crystallized.
It was filtered off, washed with acetone (20 ml) and with ether (20 ml) and dried in vacuo, to yield highly pure lithium 0-ethylclavulanate as a pale yellow crystalline solid (0.73 g).
(Overall yield from potassium clavulanate via Exa~ple 2 - 55%) (20 using Cu K ~ radiation = 12.6, 13.3, 14.7, 17.2, 17.8, 18.7, 19.9,20.8, 21.6, 22.8, 24.6, 26.8, 27.4, 28.2 and 28.7).
, --:
, 7~53 ~XAMPLE 4 -Sodium 9-0-ethylclavulanate A part of the product o:f Example 3 (0.25g) in water (2 ml) was passed through a bed o~` Amerlite IR-120 (Na form, 8 ml standard grade wet resin). The eluate was collected and evaporated under reduced pressure at ambient temperature. The residue was triturated under acetone-ether, filtered off, washed with ether and dried to : yield sodium 9~0-~thylclavulanate (0.2 g).
::
-:::
,:, ~
- . , .. : .. ... ,, ,: : ,. - - '-.
:,: ~ , , ,- -: ". - : . , - --~,:
~ AIPL~ 5 7~53 _ ~-thyl 9-0- e-thylcl~vulara-te Crystalline hydrated sodium clavulanate was dehydrated under vacuum over pho~phorus pentoxide to con.~tant weigllt. A suspension of the dry salt (1.11 g) and anhydrous sodiunl carbonate (2.65 g) in dry (treated with 3A molecular sieves), methanol-free methylene chloricle (50 ml) was treated with a crown e1;her (20 mg ol` 18 crown 6) and stirred and cooled to -20, protected from atmospheric moisture.
A solution of triethyloxonium tetrafluoroborate (3.8 g) in dry methylene chloride (50 ml) was added over 20 minutes and the mixture stirred vigorously at -20 for 3 hours.
~amples were taken at intervals and examined by tlc to ; follow the reaction. The stirred reaction was then kept at about 5 (ice/water bath) until the quantity o~ the desired product was at a maximum (as judged by tlc against a standard sample). Water (50 ml) was then added and the phases stirred and then separated. The methylene chloride solution was washed with more water (50 ml), dried over anhydrous sodium sulphate and the drying agent removed by ~iltration. The solvent was distilled at reduced pressure at <20 to give crude title product as a light orange oil (1.10 g). The crude etherlester was dissolved in a 1:1 mixture of cyclohexane: ethylacetate (25 ml) and run onto a column of silica gel (30 g) prepared in the same solvent mixture.
The colunm was eluted wlth 1.1 cyclohexane/ethyl acetate and the eluent examined by tlc at 10 ml intervals. Those ~ractions which contained the title compound were combined and the .
7~53 solven-t distilled at reduced pressure and <20. This gave ethyl 9-0-ethylclavulanate as a colourless oil (640 mg, 50%). It showed -the same spectrographic characteristlcs as the product ~rom E.Yample 1. Those ractions which were shown by t:l.c (.-gainst a standard sample) to contain e-thyl clavulanate were combined and the solvent removed. The ester was obtained as a colourless oil 350 mg, (31~o).
' ' -,, , ; -~,:, '~ :
' :. ,.
.
' ' ''.' ' ~g7~53 EXAM~L~ ~
Ethyl 9-0-ethylclavulanate Potassium clavulanate (1.19 g), anhydrous sodium carbonate (2.Gs g) and a trace of 'crown ether' (1 drop of 15-crown-5) were suspended in nitromethane (50 ml) and the mixture stirred and cooled to -20 and Pro~ected from atmospheric moisture. A solution of triethyloxonium t~tra~]uoroborate (3.8 g) in nitromethane (50 ml) was added over 20 minutes and the mixture stirred vigorously at -20 for 3 hours.
The stirred reaction was then kept at about 5 : (ice/water bath) for 5 hours, after which an analysis of the reaction mixture by tlc showed the presence of a large zone typical of ethyl 9-0-ethylclavulanate (as compared with a standard sample).
, : ~ :
: ~ :
, `: :
~ - 21 -- . ~ . ~ : .
-:
-: :
, 7~53 E~ample 7 Ethyl 9-0-_thylclavulanate Lithium clavulanate (1.03g), anhydrous sodium carbonate (2.65g) and a trace of crown ether~ (1 drop of 15-crown-5) wer0 suspended in dry methylene chloride (50ml) and the mixture stirred and cooled ~o -20 and ~rotected from atmospheric moisture. A solution of triekhyloxonium tetrafluoroborate (3.8g) in dry methylene chloride (50 ml) was added over 20 minutes and the mixture stirred vigorously at -20 for 1 hour.
The stirred reaction was then kept at about 5(ice/water bath) for 5 ho~rs, after which it was treated with water (50 ml) and the crude ester/ether (250mg) isolated as described in Example 5. This product was purified on a silica gel column to give the pure title compound (130mg, 10%)~ and ethyl clavu-~ lanate (50mg, 5%).
., ,:
-.
, : . : - .
. .'.' :' . ' ~- " . ;- .
.
. . : .
- . .: . . . .
~7653 ~XAM~LE 8 Ethyl 9-0-ethylclavulanate MaLrnesium clavulanate (0.60 g), anhydrous sodium cabonate (1.5 g) and a trace of 'crown ether' (10 mg of 1~-crown-6) were suspended in dry methylene chloride (30 ml) and the mixture stirred and cooled to -20 and protec-ted from atmospheric moisture. A solution of triethyloxonium tetrafluoroborate (2.15 g) in dry methylene chloride ( 30 ml) was added over 15 minutes and the mixture stirred vigorously at -20 for 1 hour.
The stirred reaction was then kept at 5 (icetwater bath) for 2 hours, after which an analysis of the reaction mixture by tlc showed the presence of a larger zone typical of ethy] 9-0-ethylclavulanate and only a small zone for ethyl clavulanate.
, ~, , --. ' ' ~
. . ., ~ ,:, , ..
' ' ~ ' :
,: . , . - , ~7~3 9-0-m~thvl clavulanate Potassium clavulanate (95,~ pure, 1.52 g) and anhydrous sodium carbonate (4.0 g) were suspended in dry methylene chloride (70 ml) in a vessel protected from moisture by a calcium chloride drying tube. 18-Crown-~ (0.17 g) was dissolved in the methylene chloride. The suspension was stirred and cooled to about -20 and a suspension of trimethyl-oxonium tetrafluoroborate (4.22 g) in dry methylene chloride (90 ml) added slowly. The reaction mixture was stirred at -20 for three hours and at about 0 for 1 hour.
Water (90 ml) was then added and the organic phase separated and dried (w:ith anhydrous sodium sulphate).
The solvent was removed under vacuum and the product purified by column chromatography on silica gel, eluting with cyclohexane/ethyl acetate (1:1).
Evaporation of appropriate eluent fract1ons yielded 0.54 g methyl 9-0-methylclavulanate (41%) and a further 0.37 g) methy] clavulanate (29%).
The sample of methyl 9-0-methylclavulanate was hydrolysed~ln aqueous tetrahydr~uran solution with molar lithium hydroxide on a pH-stat at pH 9.5.
Crystalline lithium 9-0-methylclavulanate (.43 g) was isolated by evaporation and addition o-F acetone.
:
.
:
: .......... . : .
: :
: . : . .. : .
' .: .... ' '. , :
' ' ~ ' , '76S3 X-ray powder diffractogram - reflections at following an~rles 2H,(~opper Ka radi~tion) 11.5, 12.9, 14.2, 15.3, 17.9, 19.1, 21.0, 21.3, 22.1, 23.5, 24.1, 24.6, 25.~, 28.6, 29,~.
~` :
- ZS -,. . , , ~ , .
.. . . . .
,:, "' , ' . ~ ' ' ' ,, ' . . .
7~i3 Methyl 9-0-methylclavul~a e Potassium clavulanate (95% pure, 4.56 g) anhydrous sodium carbonate (12 g), crown ether (18-crown-6, 0.5 g), trimethyloxonium tetra:Eluoroborate (12.7 g) were cooled at -70 and stirred while dried methylene chloride (200 ml) was added slowly. After addition of solvent the temperature was allowed to rise slowly to 20 . Aiter three hours stirring at room temperature tlc examination showed two zones (rf 0.35 and 0.12) with an area ratio of approximately 10:1.
Water (250 ml) was added to the stirring re`ac-tion mixture and the organic phase separated, dried (anhydrous - .
sodium sulphate), evaporated, and purified by column chromatography as in Example 9. The eluent fractions containing the desired product were evaporated to give 2.6 g (62%) methyl 9-0-methylclavulanate (pure:by~tlc).
; 1.13 g`of~ the~above product was dissolved in aqueous tetrahydrofuran and hydroIysed on a pH-stat at pE g.5 to give potassium 9-0-methylclavulanate.
.
. .
~: :
_ 26 -'~ .' :
.
-~., ` " ' ' ' ' ` ' ~ ' ~. ' ' ` , ' ' , .
. . . - . : , .
, : ' -: , . .
,
Tetramethylguanidinium clavulanate can replace potassium clavulanate in this reaction, but without advantage, in spite of the solubility of the salt in dichloromethane.
, ~ . ' : , , . . :
.
. , . ~
7~53 -Ethyl 9-0-e-thylclavulanate The process of Example 1 can be improved by the addition oi a cata]ytic amount (0.17 g in this case) of crown ether ('18 crown 6') to the dichloromethane solution o the reagents before adding the oxonium salt. In this case 1.1 g (75%) of substantially pure ethyl O-ethylclavulanate was obtained after the first column (based on 89% pure potassium salt starting material).
, :
, '~
, . ~ , . .
, , ,, ' .' ~ .' ' :
' ' ~ ,,:- ', ', ', ' ' ' " .
-:
- : ' 7~i~i3 EXA~LE 3 Lithlum 9-0-ethylclavulanate A solution of ethyl 9-0-ethylclavulanate (1.1 g) in tetrahydrofuran/water (1:2, 60 ml) was maintained at pH
9.4(p~I-Stat) by the addition of lM Li OH solution until 4.0 ml had been used (about 90 min) at 22C with stirring.
One small drop of acetic acid was added to bring the pH
down to 7.0, and the solution then evaporated to an orange gum on the rotary evaporator at ambient temperature. The gum was dissolved in acetone (about 20 ml) and chilled at 2-3C for 1 hour, when the lithium salt crystallized.
It was filtered off, washed with acetone (20 ml) and with ether (20 ml) and dried in vacuo, to yield highly pure lithium 0-ethylclavulanate as a pale yellow crystalline solid (0.73 g).
(Overall yield from potassium clavulanate via Exa~ple 2 - 55%) (20 using Cu K ~ radiation = 12.6, 13.3, 14.7, 17.2, 17.8, 18.7, 19.9,20.8, 21.6, 22.8, 24.6, 26.8, 27.4, 28.2 and 28.7).
, --:
, 7~53 ~XAMPLE 4 -Sodium 9-0-ethylclavulanate A part of the product o:f Example 3 (0.25g) in water (2 ml) was passed through a bed o~` Amerlite IR-120 (Na form, 8 ml standard grade wet resin). The eluate was collected and evaporated under reduced pressure at ambient temperature. The residue was triturated under acetone-ether, filtered off, washed with ether and dried to : yield sodium 9~0-~thylclavulanate (0.2 g).
::
-:::
,:, ~
- . , .. : .. ... ,, ,: : ,. - - '-.
:,: ~ , , ,- -: ". - : . , - --~,:
~ AIPL~ 5 7~53 _ ~-thyl 9-0- e-thylcl~vulara-te Crystalline hydrated sodium clavulanate was dehydrated under vacuum over pho~phorus pentoxide to con.~tant weigllt. A suspension of the dry salt (1.11 g) and anhydrous sodiunl carbonate (2.65 g) in dry (treated with 3A molecular sieves), methanol-free methylene chloricle (50 ml) was treated with a crown e1;her (20 mg ol` 18 crown 6) and stirred and cooled to -20, protected from atmospheric moisture.
A solution of triethyloxonium tetrafluoroborate (3.8 g) in dry methylene chloride (50 ml) was added over 20 minutes and the mixture stirred vigorously at -20 for 3 hours.
~amples were taken at intervals and examined by tlc to ; follow the reaction. The stirred reaction was then kept at about 5 (ice/water bath) until the quantity o~ the desired product was at a maximum (as judged by tlc against a standard sample). Water (50 ml) was then added and the phases stirred and then separated. The methylene chloride solution was washed with more water (50 ml), dried over anhydrous sodium sulphate and the drying agent removed by ~iltration. The solvent was distilled at reduced pressure at <20 to give crude title product as a light orange oil (1.10 g). The crude etherlester was dissolved in a 1:1 mixture of cyclohexane: ethylacetate (25 ml) and run onto a column of silica gel (30 g) prepared in the same solvent mixture.
The colunm was eluted wlth 1.1 cyclohexane/ethyl acetate and the eluent examined by tlc at 10 ml intervals. Those ~ractions which contained the title compound were combined and the .
7~53 solven-t distilled at reduced pressure and <20. This gave ethyl 9-0-ethylclavulanate as a colourless oil (640 mg, 50%). It showed -the same spectrographic characteristlcs as the product ~rom E.Yample 1. Those ractions which were shown by t:l.c (.-gainst a standard sample) to contain e-thyl clavulanate were combined and the solvent removed. The ester was obtained as a colourless oil 350 mg, (31~o).
' ' -,, , ; -~,:, '~ :
' :. ,.
.
' ' ''.' ' ~g7~53 EXAM~L~ ~
Ethyl 9-0-ethylclavulanate Potassium clavulanate (1.19 g), anhydrous sodium carbonate (2.Gs g) and a trace of 'crown ether' (1 drop of 15-crown-5) were suspended in nitromethane (50 ml) and the mixture stirred and cooled to -20 and Pro~ected from atmospheric moisture. A solution of triethyloxonium t~tra~]uoroborate (3.8 g) in nitromethane (50 ml) was added over 20 minutes and the mixture stirred vigorously at -20 for 3 hours.
The stirred reaction was then kept at about 5 : (ice/water bath) for 5 hours, after which an analysis of the reaction mixture by tlc showed the presence of a large zone typical of ethyl 9-0-ethylclavulanate (as compared with a standard sample).
, : ~ :
: ~ :
, `: :
~ - 21 -- . ~ . ~ : .
-:
-: :
, 7~53 E~ample 7 Ethyl 9-0-_thylclavulanate Lithium clavulanate (1.03g), anhydrous sodium carbonate (2.65g) and a trace of crown ether~ (1 drop of 15-crown-5) wer0 suspended in dry methylene chloride (50ml) and the mixture stirred and cooled ~o -20 and ~rotected from atmospheric moisture. A solution of triekhyloxonium tetrafluoroborate (3.8g) in dry methylene chloride (50 ml) was added over 20 minutes and the mixture stirred vigorously at -20 for 1 hour.
The stirred reaction was then kept at about 5(ice/water bath) for 5 ho~rs, after which it was treated with water (50 ml) and the crude ester/ether (250mg) isolated as described in Example 5. This product was purified on a silica gel column to give the pure title compound (130mg, 10%)~ and ethyl clavu-~ lanate (50mg, 5%).
., ,:
-.
, : . : - .
. .'.' :' . ' ~- " . ;- .
.
. . : .
- . .: . . . .
~7653 ~XAM~LE 8 Ethyl 9-0-ethylclavulanate MaLrnesium clavulanate (0.60 g), anhydrous sodium cabonate (1.5 g) and a trace of 'crown ether' (10 mg of 1~-crown-6) were suspended in dry methylene chloride (30 ml) and the mixture stirred and cooled to -20 and protec-ted from atmospheric moisture. A solution of triethyloxonium tetrafluoroborate (2.15 g) in dry methylene chloride ( 30 ml) was added over 15 minutes and the mixture stirred vigorously at -20 for 1 hour.
The stirred reaction was then kept at 5 (icetwater bath) for 2 hours, after which an analysis of the reaction mixture by tlc showed the presence of a larger zone typical of ethy] 9-0-ethylclavulanate and only a small zone for ethyl clavulanate.
, ~, , --. ' ' ~
. . ., ~ ,:, , ..
' ' ~ ' :
,: . , . - , ~7~3 9-0-m~thvl clavulanate Potassium clavulanate (95,~ pure, 1.52 g) and anhydrous sodium carbonate (4.0 g) were suspended in dry methylene chloride (70 ml) in a vessel protected from moisture by a calcium chloride drying tube. 18-Crown-~ (0.17 g) was dissolved in the methylene chloride. The suspension was stirred and cooled to about -20 and a suspension of trimethyl-oxonium tetrafluoroborate (4.22 g) in dry methylene chloride (90 ml) added slowly. The reaction mixture was stirred at -20 for three hours and at about 0 for 1 hour.
Water (90 ml) was then added and the organic phase separated and dried (w:ith anhydrous sodium sulphate).
The solvent was removed under vacuum and the product purified by column chromatography on silica gel, eluting with cyclohexane/ethyl acetate (1:1).
Evaporation of appropriate eluent fract1ons yielded 0.54 g methyl 9-0-methylclavulanate (41%) and a further 0.37 g) methy] clavulanate (29%).
The sample of methyl 9-0-methylclavulanate was hydrolysed~ln aqueous tetrahydr~uran solution with molar lithium hydroxide on a pH-stat at pH 9.5.
Crystalline lithium 9-0-methylclavulanate (.43 g) was isolated by evaporation and addition o-F acetone.
:
.
:
: .......... . : .
: :
: . : . .. : .
' .: .... ' '. , :
' ' ~ ' , '76S3 X-ray powder diffractogram - reflections at following an~rles 2H,(~opper Ka radi~tion) 11.5, 12.9, 14.2, 15.3, 17.9, 19.1, 21.0, 21.3, 22.1, 23.5, 24.1, 24.6, 25.~, 28.6, 29,~.
~` :
- ZS -,. . , , ~ , .
.. . . . .
,:, "' , ' . ~ ' ' ' ,, ' . . .
7~i3 Methyl 9-0-methylclavul~a e Potassium clavulanate (95% pure, 4.56 g) anhydrous sodium carbonate (12 g), crown ether (18-crown-6, 0.5 g), trimethyloxonium tetra:Eluoroborate (12.7 g) were cooled at -70 and stirred while dried methylene chloride (200 ml) was added slowly. After addition of solvent the temperature was allowed to rise slowly to 20 . Aiter three hours stirring at room temperature tlc examination showed two zones (rf 0.35 and 0.12) with an area ratio of approximately 10:1.
Water (250 ml) was added to the stirring re`ac-tion mixture and the organic phase separated, dried (anhydrous - .
sodium sulphate), evaporated, and purified by column chromatography as in Example 9. The eluent fractions containing the desired product were evaporated to give 2.6 g (62%) methyl 9-0-methylclavulanate (pure:by~tlc).
; 1.13 g`of~ the~above product was dissolved in aqueous tetrahydrofuran and hydroIysed on a pH-stat at pE g.5 to give potassium 9-0-methylclavulanate.
.
. .
~: :
_ 26 -'~ .' :
.
-~., ` " ' ' ' ' ` ' ~ ' ~. ' ' ` , ' ' , .
. . . - . : , .
, : ' -: , . .
,
6~3 E~A~LL 11 Methyl 9-0-me~ylclavul(~te Sodium clavulanate (1.6 g, vacuum dehydrated tetra-r) hydraC~? - 92% pure), ~nhydrous sodi-lm carbonate (4.~ g) and trimethyl-oxonium tetrafluoroborate (4.9 g) were cooled to -70 and stirred while dried methyle~ne chloride (100 ml) containing crown ether (about 50 mg 15-crown-5) was added gradually. Stirring was continued while the temperature was allowed to increase to room temperature. Progress of the reaction was monitored by thin layer chromatography and after three hours at room temperature the reaction mixture was worked up as in Example 10. The yield of methyl 9-0-methylclavulanate was 1.03 g (70%).
~ethyl clavulanate (0.22 g) was also isolated.
~(CDC13)2.99 l(H,d, J=16Hz, 6-~CH), 3.24 (3}I,s,e-ther CH3) 3.44 (lE, dd, J=16Hz and 3 ~z, 6-aCH), 3.72 (3H, a, ester, C 3) 3.96 (2H, d, J=7Hz, 9-CH20)~, 4.7~9 (lH,t,J=7Hz, 8-CH) 5.00 (lH, bs, 3-CH), 5.63 (}H,d,J=3 Hz,~ 5-CH) .: .
~: :
`: :
:::
, .. : , . ~ . . .. : .. . : : . . -- , -- ., . :' ... : :'. . ..
. - ,, - . . , . - .
: : . : ~
.
.
. . ' :
~37653 Me~yl 9-0-methylclavulanate Dry methylene chloride (110 ml) containing crown e-ther (about 50 mg. 15--crown-5) was added slowly to a stirred cold (-70) mixture of crystalline lithium clavulanate (1.0 g), anhydrous sodium carbonate (4.0 g) and trimethyloxonium tetrafluoroborate (4.4 g). The mixture was allowed to reach room temperature and then stirred for a further 4 hours. After work-up and chromatography as in Example 10 pure methyl 9-0-methylclavulanate was isolated (0.65 g, 57% yield). NMR identical to Example 11 product.
.
. . .
'' : ' ,.
' ~ - 28 -, . , ~. .
~ethyl clavulanate (0.22 g) was also isolated.
~(CDC13)2.99 l(H,d, J=16Hz, 6-~CH), 3.24 (3}I,s,e-ther CH3) 3.44 (lE, dd, J=16Hz and 3 ~z, 6-aCH), 3.72 (3H, a, ester, C 3) 3.96 (2H, d, J=7Hz, 9-CH20)~, 4.7~9 (lH,t,J=7Hz, 8-CH) 5.00 (lH, bs, 3-CH), 5.63 (}H,d,J=3 Hz,~ 5-CH) .: .
~: :
`: :
:::
, .. : , . ~ . . .. : .. . : : . . -- , -- ., . :' ... : :'. . ..
. - ,, - . . , . - .
: : . : ~
.
.
. . ' :
~37653 Me~yl 9-0-methylclavulanate Dry methylene chloride (110 ml) containing crown e-ther (about 50 mg. 15--crown-5) was added slowly to a stirred cold (-70) mixture of crystalline lithium clavulanate (1.0 g), anhydrous sodium carbonate (4.0 g) and trimethyloxonium tetrafluoroborate (4.4 g). The mixture was allowed to reach room temperature and then stirred for a further 4 hours. After work-up and chromatography as in Example 10 pure methyl 9-0-methylclavulanate was isolated (0.65 g, 57% yield). NMR identical to Example 11 product.
.
. . .
'' : ' ,.
' ~ - 28 -, . , ~. .
7~i3 EXAMPLE _ Methyl 9~0-methylclavulanate Dry methylene chloride (80 ml) containing crown ether (50 mg 18-crown-6) was added slowly to a stirred cold (-70) mixture of magnesium clavulanate (0.6 g), magnesium oxide (3.0 g) and trimethyloxonium tetra-fluoroboræte. The r~action mixture was allowed to reach room temperature and the progress of the reaction was followed by tlc. After several hours at room temperature zones corresponding to methyl clavulanate and methyl 9-0-methylclavulanate could be seen on the developed tlc plates.
: - 29 - . .
... . . .. . :
: . . . :
-.
.
i`k~h~l 9-0-meth~lclavulanate Dry nitromethane (110 ml) containing cro~vn ether (about 20 mg 15-crown-5) was added slowly to a cooled, stirred mixture of potassium clavulanate (1.52 g), anhydrous sodium carbonate(4.0 g) and trimethyloxonium tetrafluoroborate (4,5 g). The reaction mixture was allowed to warm to room temperature and was stirred at this temperature for three hours. Work-up and purification as in Example 10 gave methyl 9-0-methylclavulanate (0.72 g, 51% yield) (NMR
ide~tical t7 E~ample 11 product).
:
-: .
;
. .
~ ~ - 30 -' ~:
~@~6~ii3 Benzyl 9-0-Methylclavulanate Trimethyloxonium tetrafluoro~orate (100 g) in dry di.chloromethane (2 l) was slurried at -30 whilst anhydrous sodium carbonate (110 g) was added in one portion.
Benzyl clavulanate (70 g) in dry dichloromethane (11~
was added fairly rapidly keeping the temperature at -30.
The reaction then was carried out and worked up in tha same way as described in Example 10 to yield benzyl 9-0-methylclavulanate (39.2 g).
' .
~X~MPLE ~6 _ _ p-Methoxybenzyl 9-0-ethylclavulanate To a solution of p-methoxybenzyl clavulanate (9.6 g), ln dicllloromethane ~500 ml) stirred at -30C, was aclded successlve]y anhydrous sodium carbonate (15 g, excess and ~ solution o~ tr:iethyloxonium tetrafluoroborate 17.6 g) in dlchloromethane (100 ml).
The mixture was stirred at abou-t -10C Ior 6 hr, then allowed to warm to ambient temperature during ~ hr.
Water (100 ml) was added cautiously with stirring, the organic phase separated, dried over anhydrous sodium sulphate, and evaporated to a syrup. This was subjected to column chromatography on silica gel, eluting initially with 1:1, then with 2:1, ethylacetate-cyclohexane mixtures. The fir~t eluted product was the ethyl ether (4.9 g after evaporation of solvents) followed by recovered p-methoxybenzyl clavulanate (4 g). me-title c~ound was a pale yellow oil wlth the following properties.
I.r. (liquid film) 1805 (~-lactam C=O) 1750 (ester C=0) 1700cm l(C=C); nmr (CDC13) 1.17 (3H, t, J 7Hz, CH3CH~) 2.96 (lH, d, J 17Hz, 6-~-CH) 3.41 (2H, q, J
7Hz, CH3CH~-) 3.~7 (lH, dd, J 17 and 3Hz~ 6-~-CH) 3.79 (3H, s, OCH3) 4.03 (2H, d,~J 7Hz, -C~20) ~4.82 (lH, t, J 7Hz, CH-) 5.04 (lH, s,~3-CH) 5.11 (2~, s, PhCH2~, 5.65 (lH, d, J 3H3, 5 - CH~ 6.9, 7.3 (4H, A2B2q, J 10~ , ).
, ' : . . : ' ~37~3 Example 17 Lithium and sodium 9-0-ethyl.clavulanate p-Methoxybenzyl 9-0-ethylclavulanate (2.5 g) in tetrahydrofuran (25 ml) containing water (0.1 ml) was hydrogenated over 10% palladised charcoal (0.8 g).
After 2 hr, the absence of starting material was demonstrated by tlc. The catalyst was removed by filtration through a bed of finely divided silica, the filtrate diluted with an equal volume of water to yield a solution of 9-0-ethylclavulanic acid. This solution was titrated to pH 7.0 with lM lithium hydroxide solution. Evaporation of the solvents and trituration with acetone yielded the lithium salt as a pale cream crystalline solid (1.05 g).
The sodium salt was prepared in an identical manner using 1~ NaOH solution; yield 0.85 g .
I.r. (nujol mull) 1785 (~-lactam C=0) 1685 ~C-C) 1615 cm (-C02-). (Both salts).
(The s~ting material for this Example is produced as des~ i in E~1A 16).
. - 33 _ .
:. ' , ~: ' . , EXAMPI,E l8 Ethyl 9-0-ethylclavulanate Dehydrated sodi.um clavulanate (1.1 g), anhydrous sodlum carbonate (Z..65 g) and a trace of 'crown ether' (10 mg of 18-crown-6) were suspended in dry, methano:L -:Eree methylene chloride (50 ml) and the mixture stirred and cooled to -20~ A solution of tri-cthyloxonium hexafluorophosphate ( 5.0g ) in dry methylene chloride (50 ml) was added over 20 ~ninutes and the mixture stirred vlgorously at -20 for 3 hours.
The stirred reaction mixture was then kept at about 5 for 7 hours, a:Eter which it was treated with water (50 ml) and the ester/ether ( 250mg) isolated as described in Example 5. This product was : 15 purified on a silica ~el column to give the desircd ethyl 9-0-ethylclavulanate.
.
.~
, ' . .
. ' , ~ ~' ' , i53 9-0-Methylclavulanic acid A solution of Lithium 0-methyl clavulanate (0.9 g) in water (40 ml) was covered with a layer of ethyl acetate (150 ml) and stirred vigorously at room temperature. Strong acid ion exchange resin (Amberlite IR 120 (H )) (10 ml wet resin) was added. After 5 mins;
the resin was removed by decantation) and the layers separated. The aqueous layer was extracted with a further lO0 ml of ethyl acetate; the solvent layers were combined, washed with water (5 ml) dried over anhydrous calcium sulphate and iiltered~ The solution was evaporated to crystallization under reduced pressure then the remainder of the solvent removed in vacuo) to leave the free 0-methylclavulanic ._ acid as a colourless crystalline solid (0.85 g).
' ~ ~
_ 35 -:'' ~
:
- . , ., .-- , :
.
.
- - , -:
.
.
:' . : , ~7~53 Exa~pleZ0 P-~itrobenzyl 9-0-meth~lclavulanate P-Nitrobenzylclavulanate (3.51 g), trimethyloxonium tetrafluoroborate (3.15 g) and anhydrous sodiu~ carbonate (4.0 g) were stirred and cooled to -70. To the stirred mixture was slowly added methylene chloride (150 ml) co~taining --approximately 100 mg of 18 "crcwn" 6 crown ether.
After the addition the reaction mixture was allcwed to wanm up to rocm temperature and then stirred for a further three hours. The product was isolated as descriked in Example 10 to yield p-nitrobenzyl 9-0-methylclavulanate (2.91 g) as a white crystalline solid.
., .
~,.......... , ,, ., , , ., :: . . . .
: ' ' : .
, - ....
: - 29 - . .
... . . .. . :
: . . . :
-.
.
i`k~h~l 9-0-meth~lclavulanate Dry nitromethane (110 ml) containing cro~vn ether (about 20 mg 15-crown-5) was added slowly to a cooled, stirred mixture of potassium clavulanate (1.52 g), anhydrous sodium carbonate(4.0 g) and trimethyloxonium tetrafluoroborate (4,5 g). The reaction mixture was allowed to warm to room temperature and was stirred at this temperature for three hours. Work-up and purification as in Example 10 gave methyl 9-0-methylclavulanate (0.72 g, 51% yield) (NMR
ide~tical t7 E~ample 11 product).
:
-: .
;
. .
~ ~ - 30 -' ~:
~@~6~ii3 Benzyl 9-0-Methylclavulanate Trimethyloxonium tetrafluoro~orate (100 g) in dry di.chloromethane (2 l) was slurried at -30 whilst anhydrous sodium carbonate (110 g) was added in one portion.
Benzyl clavulanate (70 g) in dry dichloromethane (11~
was added fairly rapidly keeping the temperature at -30.
The reaction then was carried out and worked up in tha same way as described in Example 10 to yield benzyl 9-0-methylclavulanate (39.2 g).
' .
~X~MPLE ~6 _ _ p-Methoxybenzyl 9-0-ethylclavulanate To a solution of p-methoxybenzyl clavulanate (9.6 g), ln dicllloromethane ~500 ml) stirred at -30C, was aclded successlve]y anhydrous sodium carbonate (15 g, excess and ~ solution o~ tr:iethyloxonium tetrafluoroborate 17.6 g) in dlchloromethane (100 ml).
The mixture was stirred at abou-t -10C Ior 6 hr, then allowed to warm to ambient temperature during ~ hr.
Water (100 ml) was added cautiously with stirring, the organic phase separated, dried over anhydrous sodium sulphate, and evaporated to a syrup. This was subjected to column chromatography on silica gel, eluting initially with 1:1, then with 2:1, ethylacetate-cyclohexane mixtures. The fir~t eluted product was the ethyl ether (4.9 g after evaporation of solvents) followed by recovered p-methoxybenzyl clavulanate (4 g). me-title c~ound was a pale yellow oil wlth the following properties.
I.r. (liquid film) 1805 (~-lactam C=O) 1750 (ester C=0) 1700cm l(C=C); nmr (CDC13) 1.17 (3H, t, J 7Hz, CH3CH~) 2.96 (lH, d, J 17Hz, 6-~-CH) 3.41 (2H, q, J
7Hz, CH3CH~-) 3.~7 (lH, dd, J 17 and 3Hz~ 6-~-CH) 3.79 (3H, s, OCH3) 4.03 (2H, d,~J 7Hz, -C~20) ~4.82 (lH, t, J 7Hz, CH-) 5.04 (lH, s,~3-CH) 5.11 (2~, s, PhCH2~, 5.65 (lH, d, J 3H3, 5 - CH~ 6.9, 7.3 (4H, A2B2q, J 10~ , ).
, ' : . . : ' ~37~3 Example 17 Lithium and sodium 9-0-ethyl.clavulanate p-Methoxybenzyl 9-0-ethylclavulanate (2.5 g) in tetrahydrofuran (25 ml) containing water (0.1 ml) was hydrogenated over 10% palladised charcoal (0.8 g).
After 2 hr, the absence of starting material was demonstrated by tlc. The catalyst was removed by filtration through a bed of finely divided silica, the filtrate diluted with an equal volume of water to yield a solution of 9-0-ethylclavulanic acid. This solution was titrated to pH 7.0 with lM lithium hydroxide solution. Evaporation of the solvents and trituration with acetone yielded the lithium salt as a pale cream crystalline solid (1.05 g).
The sodium salt was prepared in an identical manner using 1~ NaOH solution; yield 0.85 g .
I.r. (nujol mull) 1785 (~-lactam C=0) 1685 ~C-C) 1615 cm (-C02-). (Both salts).
(The s~ting material for this Example is produced as des~ i in E~1A 16).
. - 33 _ .
:. ' , ~: ' . , EXAMPI,E l8 Ethyl 9-0-ethylclavulanate Dehydrated sodi.um clavulanate (1.1 g), anhydrous sodlum carbonate (Z..65 g) and a trace of 'crown ether' (10 mg of 18-crown-6) were suspended in dry, methano:L -:Eree methylene chloride (50 ml) and the mixture stirred and cooled to -20~ A solution of tri-cthyloxonium hexafluorophosphate ( 5.0g ) in dry methylene chloride (50 ml) was added over 20 ~ninutes and the mixture stirred vlgorously at -20 for 3 hours.
The stirred reaction mixture was then kept at about 5 for 7 hours, a:Eter which it was treated with water (50 ml) and the ester/ether ( 250mg) isolated as described in Example 5. This product was : 15 purified on a silica ~el column to give the desircd ethyl 9-0-ethylclavulanate.
.
.~
, ' . .
. ' , ~ ~' ' , i53 9-0-Methylclavulanic acid A solution of Lithium 0-methyl clavulanate (0.9 g) in water (40 ml) was covered with a layer of ethyl acetate (150 ml) and stirred vigorously at room temperature. Strong acid ion exchange resin (Amberlite IR 120 (H )) (10 ml wet resin) was added. After 5 mins;
the resin was removed by decantation) and the layers separated. The aqueous layer was extracted with a further lO0 ml of ethyl acetate; the solvent layers were combined, washed with water (5 ml) dried over anhydrous calcium sulphate and iiltered~ The solution was evaporated to crystallization under reduced pressure then the remainder of the solvent removed in vacuo) to leave the free 0-methylclavulanic ._ acid as a colourless crystalline solid (0.85 g).
' ~ ~
_ 35 -:'' ~
:
- . , ., .-- , :
.
.
- - , -:
.
.
:' . : , ~7~53 Exa~pleZ0 P-~itrobenzyl 9-0-meth~lclavulanate P-Nitrobenzylclavulanate (3.51 g), trimethyloxonium tetrafluoroborate (3.15 g) and anhydrous sodiu~ carbonate (4.0 g) were stirred and cooled to -70. To the stirred mixture was slowly added methylene chloride (150 ml) co~taining --approximately 100 mg of 18 "crcwn" 6 crown ether.
After the addition the reaction mixture was allcwed to wanm up to rocm temperature and then stirred for a further three hours. The product was isolated as descriked in Example 10 to yield p-nitrobenzyl 9-0-methylclavulanate (2.91 g) as a white crystalline solid.
., .
~,.......... , ,, ., , , ., :: . . . .
: ' ' : .
, - ....
Claims (148)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula (I):
(I) or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof wherein R is a methyl or ethyl group which process comprises the reaction of clavulanic acid or a salt or ester thereof with an oxonium salt of the formula (II):
R3O.THETA. X.THETA. (II) wherein R is a methyl or ethyl group and X.THETA. is an anion and thereafter if desired performing one or both of the following reactions: (a) converting the thus formed ester into the acid or pharmaceutically acceptable salt and (b) converting the thus formed acid or pharmaceutically acceptable salt into an alternative pharmaceutically acceptable ester or alternative pharmaceutically acceptable salt.
(I) or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof wherein R is a methyl or ethyl group which process comprises the reaction of clavulanic acid or a salt or ester thereof with an oxonium salt of the formula (II):
R3O.THETA. X.THETA. (II) wherein R is a methyl or ethyl group and X.THETA. is an anion and thereafter if desired performing one or both of the following reactions: (a) converting the thus formed ester into the acid or pharmaceutically acceptable salt and (b) converting the thus formed acid or pharmaceutically acceptable salt into an alternative pharmaceutically acceptable ester or alternative pharmaceutically acceptable salt.
2. A process is claimed in Claim 1 wherein X.THETA.
is BF4.THETA..
is BF4.THETA..
3. A process as claimed in Claim 1 wherein X.THETA.
is PF6.THETA..
is PF6.THETA..
4. A process as claimed in Claim 1 wherein X.THETA.
is 2,4,6-trinitrobenzenesulphonate.
is 2,4,6-trinitrobenzenesulphonate.
5. A process as claimed in Claim 1 wherein the oxonium salt of the formula (II) is trimethyloxonium tetrafluoroborate.
6. A process as claimed in Claim 1 wherein the oxonium salt of the formula (II) is triethyloxonium tetrafluoroborate.
7. A process as claimed in Claim 1 which employs a hydrolysable ester of clavulanic acid.
8. A process as claimed in Claim 1:
which employs a hydrogenolysable ester of clavulanic acid.
which employs a hydrogenolysable ester of clavulanic acid.
9. A process as claimed in Claim 1 which employs an ester of clavulanic acid of the formula (III):
(III) wherein A1 is an alkyl group of 1-8 carbon atoms optionally substituted by halogen or a group of the formula OA4, OCOA4, SA4 or SO2A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms.
(III) wherein A1 is an alkyl group of 1-8 carbon atoms optionally substituted by halogen or a group of the formula OA4, OCOA4, SA4 or SO2A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms.
10. A process as claimed in Claim 1 which employs an ester of clavulanic acid of the formula (III) as shown in claim 7 wherein A1 is an alkenyl or alkynyl group of up to 4 carbon atoms.
11. A process as claimed in Claim 1 which employs an ester of clavulanic of the formula (III) as shown in claim 9 wherein A1 is a group such that the compound is an acetoxymethyl, .alpha.-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl or .alpha.-ethoxycarbonyloxyethyl ester.
12. A process as claimed in Claim 1 which employs an ester of clavulanic acid of the formula (V):
(V) A2 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A5 or OA5 above A5 is an alkyl group of up to 6 carbon atoms; and A3 is a phenyl group optionally substituted by halogen or by a group A5 or OA5 where A5 is an alkyl group of up to 6 carbon atoms.
(V) A2 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A5 or OA5 above A5 is an alkyl group of up to 6 carbon atoms; and A3 is a phenyl group optionally substituted by halogen or by a group A5 or OA5 where A5 is an alkyl group of up to 6 carbon atoms.
13. A process as claimed in claim 9 wherein A1 is an alkyl group of up to 4 carbon atoms optionally substituted by a group of the formula OA4 or OCOA4 where A4 is an alkyl group of up to 4 carbon atoms.
14. A process as claimed in claim 9 wherein A1 is a methyl group.
15. A process as claimed in claim 9 wherein A1 is an ethyl group.
16. A process as claimed in Claim 1l which employs an ester of the formula (V) as shown in claim 12 wherein A2 is as defined in claim 12 and A3 is a nitrophenyl group.
17. A process as claimed in claim 12 wherein A2 is hydrogen.
18. A process as claimed in claim 12 wherein CHA2A3 is benzyl.
19. A process as claimed in claim 12 wherein CHA2A3 is p-methoxybenzyl.
20. A process as claimed in claim 12 wherein CHA2A3 is p-bromobenzyl.
21. A process as claimed in claim 12 wherein CHA2A3 is p-nitrobenzyl.
22. A process as claimed in Claim 1 which employs a salt of clavulanic acid.
23. A process as claimed in claim 22 wherein the salt is an alkali metal salt.
24. A process as claimed in claim 22 wherein the salt is an alkaline earth metal salt.
25. A process as claimed in claim 22 wherein the salt is of a nitrogenous base.
26. A process as claimed in claim 23 wherein the salt is the lithium salt.
27. A process as claimed in claim 23 wherein the salt is the sodium salt.
28. A process as claimed in claim 23 wherein the salt is the potassium salt.
29. A process as claimed in claim 25 wherein the base is tetramethylguanidine.
30. A process as claimed in Claim 22 wherein the salt is employed in finely divided form.
31. A process as claimed in Claim 22 wherein the salt employed has been prepared by freeze-drying.
32. A process as claimed in claim 27 wherein the sodium salt employed has been prepared by dehydrating sodium clavulanate tetrahydrate.
33. A process as claimed in Claim 1 carried out at a temperature of from -60° to 60°C.
34. A process as claimed in claim 33 wherein the temperature is from -40° to 30°C.
35. A process as claimed in claim 33 wherein the temperature is from -30° to 20°C.
36. A process as claimed in claim 33 wherein the initial temperature is from -30° to 0°C.
37. A process as claimed in claim 33 wherein the final temperature is 10 to 20°C.
38. A process as claimed in Claim 1 wherein the solvent is a haloalkane.
39. A process as in Claim 38 wherein the haloalkane is dichloromethane.
40. A process as claimed in Claim 38 wherein the solvent is chloroform.
41. A process as claimed in Claim 1 wherein the solvent is nitromethane.
42. A process as claimed in Claim 1 wherein the reaction is performed in the presence of a base.
43. A process as claimed in Claim 42 wherein the base is an insoluble base present to a large excess.
44. A process as claimed in Claims 42 or 43 wherein the base is an alkali metal carbonate or bicarbonate.
45. A process as claimed in Claims 41 or 42 wherein the base is an alkaline earth metal carbonate or bicarbonate.
46. A process as claimed in Claims 41 or 42 wherein the base is an alkaline earth metal oxide or hydroxide.
47. A process as claimed in Claim 42 wherein the base is sodium carbonate.
48. A process as claimed in Claim 43 wherein the base is sodium bicarbonate.
49. A process as claimed in Claim 42 or 43 wherein the base is lithium carbonate.
50. A process as claimed in Claim 42 wherein the base is potassium carbonate.
51. A process as claimed in Claim 43 wherein the base is potassium bicarbonate.
52. A process as claimed in Claim 42 wherein the base is calcium carbonate.
53. A process as claimed in Claim 43 wherein the base is calcium bicarbonate.
54. A process as claimed in Claim 42 or 43 wherein the base is magnesium carbonate or magnesium bicarbonate.
55. A process as claimed in Claim 1 wherein an ester of the ether is obtained from the reaction mixture by washing with water to remove ionic materials and thereafter evaporating the organic phase.
56. A process as claimed in Claim 1 wherein the initially produced ester of the compound of formula (1) is converted to a salt by hydrolysis.
57. A process as claimed in Claim 56 wherein the hydrolysis is effected by the addition of an alkali metal base.
58. A process as claimed in Claims 56 or 57 wherein the base is an hydroxide.
59. A process as claimed in any of Claims 56 or 57 wherein the base is a lithium base.
60. A process as claimed in any of Claims 56 or 57 wherein the base is a sodium base.
61. A process as claimed in any of Claims 56 or 57 wherein the base is a potassium base.
62. A process as claimed in Claims 56 or 57 wherein the base is lithium hydroxide.
63. A process as claimed in Claims 56 or 57 wherein the base is sodium hydroxide.
64. A process as claimed in Claims 56 or 57 wherein the base is potassium hydroxide.
65. A process as claimed in Claim 56 wherein the hydrolysis is effected by the addition of an alkaline earth metal base.
66. A process as claimed in Claims 56 or 57 wherein the initially produced base is a lithium salt and is converted into a sodium, potassium, calcium or magnesium salt.
67. A process as claimed in Claim 1 wherein the initially produced ester of the compound of the formula (I) is con-verted to the free acid by hydrogenolysis of a hydrogenoly-sable ester.
68. A process as claimed in Claim 1 wherein the initially produced hydrogenolysable ester is converted to the salt by hydrogenolysis in the presence of a base.
69. A process as in Claim 67 wherein the acid is converted to a salt by reaction with a base.
70. A process as claimed in Claims 68 or 69 wherein the base is a lithium, sodium, potassium calcium or magnesium carbonate, bicarbonate or hydroxide.
71. A process as claimed in Claims 68 or 69 wherein the base is lithium, sodium or potassium carbonate or sodium bicarbonate.
72. A process as claimed in Claims 68 or 69 wherein the base is lithium hydroxide.
73. A process as claimed in Claim 1 wherein the ester of clavulanic acid is prepared in-situ.
74. A process as claimed in Claim 9 wherein A' is a methyl or ethyl group and wherein the ester of clavulanic acid is produced by the reaction of a salt of clavulanic acid and an oxonium salt of the formula (II).
75. A process as claimed in claim 74 wherein the compound of the formula (II) is trimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate and the ester of clavulanic acid is produced by the reaction of a salt of clavulanic acid and an oxonium salt of the formula (II).
76. A process as claimed in Claim 74 or 75 wherein the salt of clavulanic is the lithium salt.
77. A process as claimed in Claims 74 or 75 wherein the salt of clavulanic acid is the sodium salt.
78. A process as claimed in Claims 74 or 75 wherein the salt of clavulanic acid is the potassium salt.
79. A process for the preparation of methyl 9-0-methylclavulanate which process comprises the reaction of a salt of clavulanic acid with a trimethyloxonium salt.
80. A process for the preparation of ethyl 9-0-ethylclavulanate which process comprises the reaction of a salt of clavulanic acid with a triethyloxonium salt.
81. A process as claimed in Claims 79 or 80 wherein the oxonium salt is the tetrafluoroborate.
82. A process as claimed in Claims 79 or 80 carried out at a temperature selected from -60° to 60°C, -40° to 30°C
-30° to 20°C, -30° to 0° C and 10 to 20°C.
-30° to 20°C, -30° to 0° C and 10 to 20°C.
83. A process as claimed in Claims 79 or 80 carried out at a temperature of from -50° to 20°C.
84. A process as claimed in Claims 79 or 80 wherein the solvent is selected from dichloromethane, chloroform and nitromethane.
85. A process for the preparation of a pharmaceutically acceptable salt of 9-0-methylclavulanate which comprises the base hydrolysis of methyl 9-0-methylclavulanate pre-pared by a process as claimed in Claim 79.
86. A process for the preparation of a pharmaceutically acceptable salt of 9-0-ethylclavulanate which comprises the base hydrolysis of ethyl 9-0-ethylclavulanate prepared by a process as claimed in Claim 80.
87. A process as claimed in Claims 85 or 86 wherein the hydrolysis employs an alkali base metal or an alkaline earth metal base.
88. A process as claimed in Claims 85 or 86 wherein the hydrolysis is effected by lithium hydroxide.
89. A process as claimed in Claims 85 or 86 wherein the initially produced lithium salt is converted into a sodium, potassium calcium or magnesium salt.
90. A process as claimed in Claims 85 or 86 wherein the convertion effected by contacting a solution of the lithium salt with a cation exchange resin in the form of the sodium, potassium, calcium or magnesium salt and thereafter eluting the desired salt from the resin.
91. A process as claimed in Claim 1 for the preparation of the sodium, potassium, calcium or magnesium salt of 9-0-methylclavulanic acid which process comprises contacting a solution of the lithium salt of 9-0-methylclavulanic acid with a cation exchange resin in the form of a sodium, pot-assium, calcium or magnesium salt and thereafter eluting the desired salt from the resin.
92. A process as claimed in Claim 1 for the preparation of the sodium, potassium, calcium or magnesium salt of 9-0-ethylclavulanic acid which process comprises contacting a solution of the lithium salt of 9-0-ethylclavulanic acid with a cation exchange resin in the form of a sodium, pot-assium, calcium or magnesium salt and thereafter eluting the desired salt from the resin.
93. A process as claimed in Claims 91 or 92 wherein the elution solvent is water or water in admixture with amiscible organic solvent.
94. A process as claimed in Claims 91 or 92 wherein the elution solvent is water.
95. A process as claimed in claim 1 for the preparation of 9-0-methylclavulanic acid or 9-0-ethylclavulanic acid which comprises the acidification of a salt of 9-0-methyl-clavulanic acid or of 9-0-ethylclavulanic acid prepared as claimed in Claim 1.
96. Compounds of the formula (I) as set forth and defined in Claim 1 and their pharmaceutically acceptable salts and esters whenever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
97. Methyl 9-0-methylclavulanate whenever prepared by the process of Claim 79 or an obvious chemical equivalent thereof.
98. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 80 or an obvious chemical equivalent thereof.
99. Pharmaceutically acceptable salts of 9-0-methylclavulanic acid whenever prepared by the process of Claim 85 or an obvious chemical equivalent thereof.
100. Pharmaceutically acceptable salts of 9-0-ethylclavulanic acid whenever prepared by the process of Claim 86 or an obvious chemical equivalent thereof.
101. The sodium, potassium, calcium or magnesium salts of 9-0-methylclavulanic acid whenever prepared by the process of Claim 91 or an obvious chemical equivalent thereof.
102. The sodium, potassium, calcium or magnesium salts of 9-0-ethylclavulanic acid whenever prepared by the process of Claim 92 or an obvious chemical equivalent thereof.
103. 9-0-methylclavulanic acid and 9-0-ethylclavulanic acid whenever prepared by the process of Claim 95 or an obvious chemical equivalent thereof.
104. A process for the preparation of ethyl 9-0-ethylclavul-anate which comprises reacting anhydrous sodium carbonate, potassium clavulanate with triethyloxonium tetrafluoroborate in dry dichloromethane and isolating the desired ester.
105. A process as claimed in Claim 104 wherein the ester is converted into the acid or a pharmaceutically acceptable salt and when required the thus formed acid or pharmaceutically acceptable salt is converted into an alternative pharmaceut-ically acceptable ester or alternative pharmaceutically accept-able salt.
106. A process as claimed in Claim 104 wherein tetramethyl-guanidinuim clavulanate is reacted with triethyloxonium tetra-fluoroborate.
107. A process as claimed in Claim 105 wherein tetramethyl-guanidinuim clavulanate is reacted with triethyloxonium tetra-fluroborate.
108. A process as claimed in Claim 104 wherein a catalytic amount of crown ether is added to the dry dichloromethane solution of reactants before the oxonium salt is added.
109. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 104 or an obvious chemical equivalent thereof.
110. Pharmaceutically acceptable salts, pharmaceutically acceptable esters and the acid form of ethyl 9-0-ethylclav-ulanate whenever prepared by the process of Claim 105 or an obvious chemical equivalent thereof.
111. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 106 or 107 or an obvious chemical equivalent thereof.
112. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 108 or an-obvious chemical equivalent thereof.
113. A process for the preparation of lithium 9-0-ethyl-clavulanate which comprises treating ethyl 9-0-ethylclavulanate with lithium hydroxide solution and isolating the desired salt.
114. Lithium 9-0-ethylclavulanate whenever prepared by the process of Claim 113 or an obvious chemical equivalent thereof.
115. A process for the preparation of sodium 9-0-ethyl-clavulanate which comprises treating lithium 9-0-ethyl-clavulanate with a cation exchange resin to obtain the de-sired sodium salt and isolating said salt.
116. Sodium 9-0-ethylclavulanate whenever prepared by the process of Claim 115 or an obvious chemical equivalent thereof.
117. A process for the preparation of ethyl 9-0-ethylclavu-lanate which comprises reacting anhydrous sodium carbonate, dehydated sodium clavulanate and triethyloxonium tetrafluoro-borate in dry methanol-free methylene chloride and in the presence of a catalytic amount of crown ether and isolating the desired ester.
118. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 117 or an obvious chemical equivalent thereof.
119. A process for the preparation of ethyl 9-0-ethylclav-ulanate which comprises reacting a solution of lithium clavulanate and anhydrous sodium carbonate in dry methylene chloride and a trace of crown ether with a solution of tri-ethyloxonium tetrafluoroborate in dry methylene chloride and isolating the desired ester.
120. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 119 or an obvious chemical equivalent thereof.
121. A process for the preparation of ethyl 9-0-ethyl-ethylclavulanate which comprises reacting a solution of magnesium clavulanate and anhydrous sodium carbonate in dry methylene chloride and a trace of crown ether with a solution of triethyloxonium tetrafluoroborate in dry methylene chloride and isolating the desired ester.
122. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 121 or an obvious chemical equivalent thereof.
123. A process for the preparation of methyl 9-0-methyl clavulanate and its lithium salt which comprises reacting a suspension of potassium clavulanate and anhydrous sodium carbonate in dry methylene chloride and 18-crown-6 with a suspension of trimethyl-oxonium tetrafluoroborate in dry methylene chloride and isolating the desired ester and when required hydrolyzing the ester with lithium hydroxide to obtain the lithium salt.
124. Methyl 9-0-methylclavulanate and its lithium salt when-ever prepared by the process of Claim 123 or an obvious chemical equivalent thereof.
125. A process for the preparation of methyl 9-0-methyl-clavulanate and its potassium salt which comprises reacting potassium clavulanate and anhydrous sodium carbonate in the presence of crown ether and dried methylene chloride with trimethyloxonium tetrafluoroborate to obtain an isolation of the desired ester and when required hydrolyzing the ester to obtain the potassium salt.
126. Methyl 9-0-methylclavulanate and its potassium salt whenever prepared by the process of Claim 125 or an obvious chemical equivalent thereof.
127. A process for the preparation of methyl 9-0-methyl-clavulanate which comprises reacting dehydrated sodium clavu-lanate and anhydrous sodium carbonate with trimethyloxonium tetrafluoroborate in the presence of dried methylene chloride containing crown ether to obtain the ester and isolating said ester.
128. Methyl 9-0-methylclavulanate whenever prepared by the process of Claim 127 or an obvious chemical equivalent thereof.
129. A process for the preparation of methyl 9-0-methyl-clavulanate which comprises adding dry methylene chloride containing crown ether to lithium clavulanate, anhydrous sodium carbonate and trimethyloxonium tetrafluoroborate and isolating the desired ester.
130. Methyl 9-0-methylclavulanate whenever prepared by the process of Claim 129 or an obvious chemical equivalent thereof.
131. A process for the preparation of methyl 9-0-methyl-clavulanate which comprises adding dry methylene chloride containing crown ether to magnesium clavulanate, magesium oxide and trimethyloxonium tetrafluoroborate and isolating the desired ester.
132. Methyl 9-0-methylclavulanate whenever prepared by the process of Claim 131 or an obvious chemical equivalent thereof.
133. A process for the preparation of methyl 9-0-methyl-clavulanate which comprises adding dry nitromethane contain-ing crown ether to potassium clavulanate, anhydrous sodium carbonate and trimethyloxonium tetrafluoroborate and isolating the desired ester.
134. Methyl 9-0-methylclavulanate whenever prepared by the process of Claim 133 or an obvious chemical equivalent thereof.
135. A process for the preparation of benzyl 9-0-methyl-clavulanate which comprises reacting trimethyloxonium tetra-fluoroborate in dry dichloromethane and anhydrous sodium car-bonate with benzyl clavulanate and isolating the desired ester.
136. Benzyl 9-0-methylclavulanate whenever prepared by the process of Claim 135 or an obvious chemical equivalent thereof.
137. A process for the preparation of p-methoxybenzyl 9-0-ethylclavulanate which comprises reacting a solution of p-methoxybenzyl clavulanate in dichloromethane with anhydrous sodium carbonate and a solution of triethyloxonium tetra-fluoroborate in dichloromethane and isolating the desired ester.
138. A process as claimed in Claim 137 wherein the ester is hydrogenated to obtain 9-0-ethylclavulanic acid which is then treated with lithium hydroxide or sodium hydroxide to obtain the lithium and sodium salts, respectively.
139. p-Methoxybenzyl 9-0-ethylclavulanate whenever prepared by the process of Claim 137 or an obvious chemical equivalent thereof.
140. Lithium and sodium 9-0-ethylclavulanate whenever pre-pared by the process of Claim 138 or an obvious chemical equivalent thereof.
141. A process for the preparation of ethyl 9-0-ethylclavu-lanate which comprises reacting dehydrated sodium clavulanate anydrous sodium carbonate and a trace of crown ether in dry, methanol-free methylene chloride with triethyloxonium hexa-fluorophosphate in dry methylene chloride and isolating the desired ether.
142. Ethyl 9-0-ethylclavulanate whenever prepared by the process of Claim 141 or an obvious chemical equivalent thereof.
143. A process for the preparation of 9-0-methylclavulanic acid which comprises treating lithium o-methylclavulanate with a cation exchange resin and isolating the desired acid.
144. 9-0-Methylclavulanic acid whenever prepared by the process of Claim 143 or an obvious chemical equivalent thereof.
145. A process for the preparation of p-nitrobenzyl 9-0-methylclavulanate which comprises reacting p-nitrobenzyl clavulanate, trimethyloxonium tetrafluoroborate and anhydrous sodium carbonate in the presence of methylene chloride and crown ether and isolating the desired ester.
146. p-Nitrobenzyl 9-0-methylclavulanate whenever prepared by the process of Claim 145 or an obvious chemical equivalent thereof.
147. A process as claimed in Claim 123 wherein the ester is converted into the acid or a pharmaceutically acceptable salt and when required the thus formed acid or pharmaceutically acceptable salt is converted into an alternative pharmaceut-ically acceptable ester or alternative pharmaceutically acceptable salt.
148. Pharmaceutically acceptable salts and esters of 9-0-methylclavulanic acid whenever prepared by the process of Claim 147 or an obvious chemical equivalent thereof.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB51808/76A GB1589367A (en) | 1976-12-11 | 1976-12-11 | Clavulanic acid ethers |
| GB51808/76 | 1976-12-12 | ||
| GB11116/77 | 1977-03-16 | ||
| GB1111677 | 1977-03-16 | ||
| GB38753/77 | 1977-09-16 | ||
| GB3875377 | 1977-09-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097653A true CA1097653A (en) | 1981-03-17 |
Family
ID=27256638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA292,807A Expired CA1097653A (en) | 1976-12-11 | 1977-12-09 | Process for the preparation of clavulanic acid esters |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5377090A (en) |
| AR (1) | AR216117A1 (en) |
| AT (1) | AT356269B (en) |
| CA (1) | CA1097653A (en) |
| CH (1) | CH636880A5 (en) |
| DE (1) | DE2754763A1 (en) |
| ES (1) | ES464941A1 (en) |
| FR (1) | FR2373545A1 (en) |
| GR (1) | GR64001B (en) |
| IE (1) | IE46436B1 (en) |
| IL (1) | IL53465A (en) |
| MX (1) | MX4846E (en) |
| NL (1) | NL7713644A (en) |
| NZ (1) | NZ185849A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2862254D1 (en) * | 1977-12-02 | 1983-06-16 | Beecham Group Plc | A process for the preparation of ether derivatives of clavulanic acid |
| DE3062347D1 (en) * | 1979-08-11 | 1983-04-21 | Beecham Group Plc | Process for the preparation of derivatives of clavulanic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1573503A (en) * | 1975-12-17 | 1980-08-28 | Glaxo Lab Ltd | Clavulanic acid derivatives |
-
1977
- 1977-11-25 IL IL53465A patent/IL53465A/en unknown
- 1977-12-05 NZ NZ185849A patent/NZ185849A/en unknown
- 1977-12-07 FR FR7736817A patent/FR2373545A1/en active Granted
- 1977-12-08 DE DE19772754763 patent/DE2754763A1/en not_active Withdrawn
- 1977-12-09 NL NL7713644A patent/NL7713644A/en not_active Application Discontinuation
- 1977-12-09 GR GR54946A patent/GR64001B/en unknown
- 1977-12-09 MX MX776680U patent/MX4846E/en unknown
- 1977-12-09 AR AR270306A patent/AR216117A1/en active
- 1977-12-09 CA CA292,807A patent/CA1097653A/en not_active Expired
- 1977-12-09 AT AT881677A patent/AT356269B/en not_active IP Right Cessation
- 1977-12-09 ES ES464941A patent/ES464941A1/en not_active Expired
- 1977-12-09 IE IE2501/77A patent/IE46436B1/en unknown
- 1977-12-09 JP JP14865677A patent/JPS5377090A/en active Pending
- 1977-12-12 CH CH1523577A patent/CH636880A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES464941A1 (en) | 1979-12-16 |
| IE772501L (en) | 1978-06-11 |
| NZ185849A (en) | 1980-11-28 |
| ATA881677A (en) | 1979-09-15 |
| AR216117A1 (en) | 1979-11-30 |
| MX4846E (en) | 1982-10-28 |
| IL53465A0 (en) | 1978-01-31 |
| DE2754763A1 (en) | 1978-06-15 |
| GR64001B (en) | 1980-01-18 |
| FR2373545A1 (en) | 1978-07-07 |
| IL53465A (en) | 1980-11-30 |
| IE46436B1 (en) | 1983-06-15 |
| NL7713644A (en) | 1978-06-13 |
| CH636880A5 (en) | 1983-06-30 |
| JPS5377090A (en) | 1978-07-08 |
| FR2373545B1 (en) | 1982-04-16 |
| AT356269B (en) | 1980-04-25 |
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