SI9500072A - Process for the preparation and/or purification of clavulanic acid or its pharmaceutically acceptable salts or esters - Google Patents
Process for the preparation and/or purification of clavulanic acid or its pharmaceutically acceptable salts or esters Download PDFInfo
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Abstract
Postopek obsega: i) kontaktiranje nečiste klavulanske kisline ali njenega labilnega derivata, v raztopini v organskem topilu, s terciarnim oktilaminom, ii) izolacijo soli klavulanske kisline, tvorjene s terciarnim oktilaminom, iii) pretvorbo tako tvorjene soli klavulanske kisline s terciarnim oktilaminom v klavulansko kislino ali njeno farmacevtsko sprejemljivo sol ali ester. Klavulanska kislina in njene soli in estri, pripravljeni po postopku v smislu izuma, so uporabni za izdelavo zdravil.The process comprises: i) contacting impure clavulanic acid or its labile derivative, v solution in an organic solvent, with tertiary octylamine, ii) isolation of the clavulanic acid salt formed by tertiary octylamine; iii) conversion of the salt thus formed clavulanic acids with tertiary octylamine to clavulanic an acid or a pharmaceutically acceptable salt thereof or ester. Clavulanic acid and its salts and esters, prepared by the process of the invention are useful for the manufacture of medicines.
Description
Postopek za pripravo in/ali čiščenje klavulanske kisline ali njene farmacevtsko sprejemljive soli ali estraProcess for the preparation and / or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof
Predloženi izum se nanaša na klavulanske kisline (I):The present invention relates to clavulanic acids (I):
nov postopek za pripravo in/ali čiščenjea new process for preparation and / or cleaning
in njenih farmacevtsko sprejemljivih soli in estrov.and its pharmaceutically acceptable salts and esters.
Klavulansko kislino normalno pripravijo s fermentacijo mikroorganizma, ki proizvaja klavulansko kislino, kot so razni mikroorganizmi, ki pripadajo raznim sojem (sevom) Streptomyces, kot so S. clavuligerus NRRL 3585, S. jumoninensis NRRL 5741,Clavulanic acid is normally prepared by fermentation of a microorganism producing clavulanic acid, such as various microorganisms belonging to different strains (strains) of Streptomyces, such as S. clavuligerus NRRL 3585, S. jumoninensis NRRL 5741,
S. katsurahamanus IFO 13716 in Streptomyces sp. P 6621 FERM P 2804, kot je opisano npr. v JP Kokai 80-162993. Nastalo vodno gojilno juho lahko očistijo in koncentrirajo po običajnih postopkih, ki obsegajo npr. filtracijo in kromatografsko čiščenje, kot je prikazano v GB 1508977 in JP Kokai 80-62993, pred ekstrakcijo vodne raztopine z organskim topilom, da dobijo raztopino surove klavulanske kisline v organskem topilu.S. katsurahamanus IFO 13716 and Streptomyces sp. P 6621 FERM P 2804 as described e.g. in JP Kokai 80-162993. The resulting aqueous culture broth can be cleaned and concentrated by conventional methods comprising e.g. filtration and chromatographic purification, as shown in GB 1508977 and JP Kokai 80-62993, before extracting the aqueous solution with an organic solvent to obtain a solution of crude clavulanic acid in an organic solvent.
GB 1508977 prikazuje med drugim, da soli klavulanske kisline lahko dobe z absorpcijo klavulanatnega aniona v filtrirani juhi na anionski izmenjalni smoli, pri čemer z nje eluirajo z elektrolitom, razsolijo nastalo raztopino, nanesejo razsoljeno raztopino na nadaljnjo anionsko izmenjalno smolo, z nje kromatografsko eluirajo z elektrolitom, razsolijo nastalo raztopino in zatem odstranijo topilo. Ta postopek lahko uporabijo, da dobijo sprejemljive dobitke čistega materiala, vendar terja uporaba smolnih kolon znatne investicije in le-te lahko omejujejo proizvodno obratovanje v velikem merilu. Zato bi bilo zaželeno imeti na voljo alternativen postopek, ki bi obsegal malo stopenj z uporabo smole.GB 1508977 illustrates, inter alia, that salts of clavulanic acid can be obtained by absorbing clavulanate anion in filtered soup on an anion exchange resin, eluting with it with an electrolyte, desalting the resulting solution, applying the desalinated solution to a further anion exchange resin, chromatographically using it electrolytes, desalinate the resulting solution and then remove the solvent. They can use this process to obtain acceptable yields of pure material, but the use of resin columns requires considerable investment and can limit production operations on a large scale. Therefore, it would be desirable to have an alternative process involving few steps using resin.
GB 1543563 prikazuje postopek za pripravo soli klavulanske kisline preko obarjanja litijevega klavulanata. GB 1578739 opisuje razne aminske soli klavulanske : : - - 2 -· . · ' kisline kot farmacevtske spojine. EP 0026044 prikazuje uporabo terc.butilaminske soli klavulanske kisline kot koristnega intermediata pri pripravi klavulanske kisline. Sol je prikazana v BE 862211, vendar samo kot prikladna sestavina za farmacevtske formulacije. PT.94.908 opisuje uporabo tri-(nižji alkil) aminskih soli in dimetilanilinskih soli klavulanske kisline pri čistilnem postopku za klavulansko kislino, kjer tvorijo trietilaminsko sol klavulanske kisline in jo nato pretvorijo v silil diester klavulanske kisline. EP 0887178A prikazuje postopek za čiščenje klavulanske kisline, pri katerem lahko uporabijo organske amine za tvorbo intermediame aminske soli s klavulansko kislino v nečisti raztopini. Tudi SI patent št. 9300296 opisuje postopek za pripravo klavulanske kisline ali njenih farmacevtsko sprejemljivih soli in estrov. Predloženi izum nudi postopek za pripravo in/ali Čiščenje klavulanske kisline ali njenih farmacevtsko sprejemljivih soli in estrov.GB 1543563 illustrates a process for the preparation of clavulanic acid salts via lithium clavulanate precipitation. GB 1578739 describes various amine salts of clavulanic :: - - 2 - ·. · 'Acids as pharmaceutical compounds. EP 0026044 illustrates the use of the tert.butylamine salt of clavulanic acid as a useful intermediate in the preparation of clavulanic acid. The salt is shown in BE 862211, but only as a suitable ingredient for pharmaceutical formulations. PT.94.908 describes the use of tri- (lower alkyl) amine salts and dimethylaniline salts of clavulanic acid in a clavulanic acid purification process, where they form the triethylamine salt of clavulanic acid and subsequently convert it to silyl diester of clavulanic acid. EP 0887178A discloses a process for the purification of clavulanic acid, in which organic amines can be used to form an intermediate amine salt with clavulanic acid in an impure solution. Also SI patent no. 9300296 describes a process for the preparation of clavulanic acid or its pharmaceutically acceptable salts and esters. The present invention provides a process for the preparation and / or purification of clavulanic acid or its pharmaceutically acceptable salts and esters.
Izhajamo iz amina s formulo (II):From the amine of formula (II):
kot intermediata pri postopku za pripravo klavulanske kisline ali njenih farmacevtsko sprejemljivih soli in estrov, kjer so Rl, R^ in R^ izbrani po naslednjih opcijah:as an intermediate in the process for the preparation of clavulanic acid or its pharmaceutically acceptable salts and esters, wherein R1, R4 and R4 are selected from the following options:
(1) Rl je v danem primeru substituirana ciklična skupina s splošno formulo :(1) R1 is, optionally, a substituted cyclic group of the general formula:
R- (CHR<)m kjer je m 0 ali celo Število 1 do 5, R je v danem primeru substituiran alifatski ogljikovodični obročni sistem, ki vsebuje 3 do 8 obročnih atomov ogljika, R^ je vodik ali alkil, amino- ali hidroksi- substituiran alkil, ali substituiran amino- substituiran alkil, ali skupina z enako splošno formulo, ali Rl zgoraj; R^ ali R^ sta lahko izbrana iz istih skupin, iz katerih je izbran R1, ali izmed vodika, alkila, alkenila, amino- ali hidroksisubstituiranega alkila ali alkenila, ali substituiranega amino- substituiranega alkila ali alkenila; le z izjemo cikloheksilamina; ali (2) vsak izmed Rl, R^ in R^ je lahko enak ali različen in neodvisno izbran izmed vodika, alkila, alkenila, amino- ali hidroksi- ali alkoksi- substituiranega alkila ali alkenila, ali substituiranega amino- substituiranega alkila ali alkenila, le z izjemo tbutilamina, s-butilamina, Ν,Ν-dimetiletilamina, 1,2-dimetilpropilamina, neopentilamina in 2-amino-3,3-dimetilbutana; in s pridržkom, da če je amin (II) trimetilamin ali trietilamin, je sol klavulanske kisline z aminom (II) tvorjena z reakcijo klavulanske kisline ali njenega labilnega derivata v raztopini z organskim topilom z aminom (II) aliR- (CHR <) m where m is 0 or even Number 1 to 5, R is optionally substituted by an aliphatic hydrocarbon ring system containing 3 to 8 ring carbon atoms, R ^ is hydrogen or alkyl, amino or hydroxy- substituted alkyl, or substituted amino-substituted alkyl, or a group of the same general formula, or R1 above; R ^ or R ^ may be selected from the same groups from which R 1 is selected, or from hydrogen, alkyl, alkenyl, amino- or hydroxy-substituted alkyl or alkenyl, or substituted amino-substituted alkyl or alkenyl; only with the exception of cyclohexylamine; or (2) each of R1, R4 and R4 may be the same or different and independently selected from hydrogen, alkyl, alkenyl, amino or hydroxy or alkoxy-substituted alkyl or alkenyl, or substituted amino-substituted alkyl or alkenyl, with the exception of tbutylamine, s-butylamine, Ν, Ν-dimethylethylamine, 1,2-dimethylpropylamine, neopentylamine and 2-amino-3,3-dimethylbutane; and with the proviso that if amine (II) is trimethylamine or triethylamine, the salt of clavulanic acid with amine (II) is formed by the reaction of clavulanic acid or its labile derivative in solution with an organic solvent with amine (II) or
- --3....- - 3 .....
njegovim labilnim derivatom, in da sol nato 'izoliramo kot ali v posebni fazi iz organskega topila; ali (3) Rl je v danem primeru substituirana arilna skupina s splošno formulo:its labile derivatives, and the salt is then isolated as or in a special phase from an organic solvent; or (3) R1 is optionally substituted aryl group of the general formula:
tkjer je R4 vodik ali eden ali več substituentov in je m nič ali celo število 1 do 5, R2 in R3 sta neodvisno izbrana izmed vodika, alkila, amino- ali hidroksi- substituiranega alkila ali substituiranega -amino- substituiranega alkila ali skupin z isto splošno formulo kot R1, s pridržkom, da če je R4 vodik in m nič, tedaj R2 in R3 nista oba metil; vendar z izjemo benzil terc.butilamina; ali (4) Rl in R2 ter v danem primeru R3 skupaj s prikazanim atomom dušika, ki je ostanek v danem primeru substituiranega heterocikličnega obročnega sistema, ki vključuje atom dušika kot obročni člen in v danem primeru vključuje enega ali več dodatnih obročnih heteroatomov in če R3 ni del obročnega sistema, je neodvisno izbran izmed vodika, alkila, amino- ali hidroksi- substituiranega alkila ali substituiranega amino- substituiranega alkila; le z izjemo piperidina; ali (5) Rl je skupina s splošno formulo:where R 4 is hydrogen or one or more substituents and m is zero or an integer 1 to 5, R 2 and R 3 are independently selected from hydrogen, alkyl, amino or hydroxy-substituted alkyl or substituted-amino-substituted alkyl or groups by the same general formula as R 1 , with the proviso that if R 4 is hydrogen and m is zero, then R 2 and R 3 are not both methyl; but with the exception of benzyl tert.butylamine; or (4) R, and R 2 and optionally R 3 together with the indicated nitrogen atom is the residue of an optionally substituted heterocyclic ring system which includes the nitrogen atom as a ring member, and optionally including one or more additional ring hetero atoms, and if R 3 is not part of a ring system, it is independently selected from hydrogen, alkyl, amino or hydroxy substituted alkyl or substituted amino substituted alkyl; only with the exception of piperidine; or (5) R1 is a group of the general formula:
5’ R χ 5 ' R χ
N ^ΟΗ^ΝηΤ-ΟΗ^i/ mN ^ ΟΗ ^ ΝηΤ-ΟΗ ^ i / m
R kjer sta R4 in R5 neodvisno vodik, alkil, amino- substituiran alkil ali substituiran amino-substituiran alkil in sta R2 in R3 neodvisno izbrana izmed vodika, alkila, aminoali hidroksi-substituiranega alkila, ali substituiranega amino-substituiranega alkila ter je m nič ali celo število 1 do 5; ali (6) eden ali oba izmed Rl in R2 sta vodik in R3 predstavlja ostanek amino kisline, v kateri je karboksilatna skupina amino kisline lahko zaestrena ali v obliki amida.R wherein R 4 and R 5 are independently hydrogen, alkyl, amino-substituted alkyl or substituted amino-substituted alkyl and R 2 and R 3 are independently selected from hydrogen, alkyl, amino or hydroxy-substituted alkyl, or substituted amino-substituted alkyl, and m is zero or an integer from 1 to 5; or (6) one or both of R 1 and R 2 are hydrogen and R 3 represents an amino acid residue in which the carboxylate group of the amino acid may be esterified or in the form of an amide.
Če tukaj omenjamo alkilne ali substituirane alkilne skupine - razen če ni definirano drugače - lahko le-te prikladno vsebujejo 1 do 6 atomov ogljika v alkilnera sistemu. Prikladni substituenti na amino skupinah vključujejo alkil.Unless otherwise defined herein, alkyl or substituted alkyl groups may conveniently contain 1 to 6 carbon atoms in an alkylner system. Suitable amino group substituents include alkyl.
-- 4_- 4_
Pri opciji (1) zgoraj je amin (II) prikladno različen od amina, v katerem je RA cikloalkilna skupina, in je m nič ter sta R^ in R^ oba izbrana izmed cikloalkila ali vodika ali CnH2n+i, kjer je n 1 do 7.In option (1) above, the amine (II) is suitably different from the amine in which RA is a cycloalkyl group, and m is zero and R ^ and R ^ are both selected from cycloalkyl or hydrogen or C n H2 n + i, where n 1 to 7.
Pri opciji (1) zgoraj je ciklična skupina R lahko prikladno nasičena, pri čemer je m prikladno nič. Skupina R je lahko monociklična ali policiklična in vsak obroč lahko prikladno vsebuje 5, 6 ali 7 obročnih atomov ogljika, vključno atome, ki si jih delijo obroči v sklenjenih ali premoščenih obročnih sistemih. Prikladno je ciklična skupina R lahko nesubstituirana.In Option (1) above, the cyclic group R may be suitably saturated, with m being suitably zero. Group R may be monocyclic or polycyclic, and each ring may conveniently contain 5, 6 or 7 ring carbon atoms, including ring-shared atoms in closed or bridged ring systems. Suitably, the cyclic group R may be unsubstituted.
Prikladno lahko amin (II) vključuje dva ali več cikličnih skupin Rl ali sklenjen obročni sistem R^ ali substituiran obročni sistem R, npr. z enim ali več alkilnih substituentov kot je alkil. Prikladno sta R7 in R^ lahko različna od vodika, tako npr. je eden ali oba lahko alkil ali substituiran alkil.Suitably, the amine (II) may include two or more cyclic groups R1 or a contracted ring system R1 or a substituted ring system R1, e.g. with one or more alkyl substituents such as alkyl. Suitably, R 7 and R 6 may be different from hydrogen, e.g. one or both may be alkyl or substituted alkyl.
Primeri za take amine vključujejo ciklopentilamin, cikloheptilamin, N,Ndimetilcikloheksilamin, dicikloheksilamin, adamantilamin, N,N-dietilcikloheksilamin, N-izopropilcikloheksilamin, N-metilcikloheksilamin, ciklopropilamin, ciklobutilamin, norbornilamin in dehidroabietilamin.Examples of such amines include cyclopentylamine, cycloheptylamine, N, N-dimethylcyclohexylamine, dicyclohexylamine, adamantylamine, N, N-diethylcyclohexylamine, N-isopropylcyclohexylamine, N-methylcyclohexylamine, cyclopropylamine, cyclobutylamine, norblobutylamine, cyclobutylamine, cyclobutylamine, cyclobutylamine.
Pri opciji (2) zgoraj je amin (II) prikladno drugačen od amina, v katerem je Rl vodik ali CnH2n+i, kjer je n 1 do 7 in sta R7 in R^ oba izbrana izmed vodika ali cnH2n+l· kJer je n ] do7·In option (2) above, the amine (II) is suitably different from the amine in which R1 is hydrogen or C n H2 n + i, where n is 1 to 7 and R 7 and R 4 are both selected from hydrogen or c nH 2 n + l · k J er j en] to7 ·
Prikladno je pri opciji (2) zgoraj Rl lahko alkilna ali substituirana alkilna skupina s splošno formulo:Suitably in Option (2) above, R1 may be an alkyl or substituted alkyl group of the general formula:
R4 R 4
R6 - Č R5.R 6 - R5.
kjer R4, R5 in R6 neodvisno predstavljajo C].]p alkil, ali amino- ali hidroksisubstituiran alkil ali substituiran amino- substituiran alkil.wherein R 4 , R 5 and R 6 independently represent C 1-3 alkyl, or amino or hydroxysubstituted alkyl or substituted amino substituted alkyl.
R4, R5 in R^ so lahko prikladno vsi alkil, pri čemer sta prikladno dva izmed R4, R^ ali R^ metil. Primeri za take amine vključujejo t-oktilamin (2-amino-2,4,4-trimetilpentan) in t-amilamin. Alternativno sta dva izmed R4, R$ ali R6 lahko alkil in je eden lahko hidroksi - substituiran alkil. Primeri za take amine vključujejo l-hidroksi-2-metil2-propilamin.R 4 , R 5 and R 4 may suitably be all alkyl, with two of R 4 , R 4 or R 4 methyl being suitably present. Examples of such amines include t-octylamine (2-amino-2,4,4-trimethylpentane) and t-amylamine. Alternatively, two of R 4, R $ or R6 may be alkyl and one may be hydroxy - substituted alkyl. Examples of such amines include 1-hydroxy-2-methyl2-propylamine.
Pri opciji (2) zgoraj je RJ lahko alternativno prikladno Cj.20 alkil, npr. Cg-20 alkil, Ci_20 alkenil, C]_2() hidroksialkil ali C]_20 amino alkil.In Option (2) above, R J may alternatively be suitably C 1-20 alkyl, e.g. C 20-20 alkyl, C 1-2 alkenyl, C 1-2 () hydroxyalkyl or C 1-20 amino alkyl.
Primeri takšnih aminov vključujejo tri-n-propilamin, tri-n-oktilamin, tri-nbutilamin, dimetilamin, i-propilamin, di-n-heksilamin, di-n-butilamin, dietilamin, 2aminoetanol, NN-dietiletanolamin, NN-dimetiletanolamin, etanolamin, n-butilamin, nheksilamin, n-oktadecilamin, N-etiletanolamin, 1-hidroksietilamin, dietanolamin, NNdimetiletanolamin, N-etildietanolamin, 1,6-diamino heksan, trietanolamin, diizobutilamin, diizopropilamin, 2-metoksietilamin, hidroksilamin, amoniak, metilamin, etilamin, N-propilamin, n-butilamin, n-pentilamin, n-heksilamin, n-heptilamin, noktilamin, n-nonilamin, n-decilamin, n-undecilamin, n-dodecilamin, n-prop-2-ilamin, nbut-2-ilamin, n-pent-2-ilamin, n-heks-2-ilamin, n-hept-2-ilamin, n-okt-2-ilamin, n-non2- ilamin, n-dek-2-ilamin, n-undek-2-ilamin, n-dodek-2-ilamin, n-heks-3-ilamin, n-hept3- ilamin, n-okt-3-ilamin, n-non-3-ilamin, n-dek-3-ilamin, n-undek-3-ilamin, n-dodek-3ilamin, n-okt-4-ilamin, n-non-4-ilamin, n-dek-4-ilamin, n-undek-4-ilamin, n-dodek-4ilamin, n-non-5-ilamin, n-undek-5-ilamin, n-dodek-5-ilamin in n-oktadecilamin.Examples of such amines include tri-n-propylamine, tri-n-octylamine, tri-n-butylamine, dimethylamine, i-propylamine, di-n-hexylamine, di-n-butylamine, diethylamine, 2aminoethanol, NN-diethylethanolamine, NN-dimethylethanolamine, ethanolamine, n-butylamine, nhexylamine, n-octadecylamine, N-ethylethanolamine, 1-hydroxyethylamine, diethanolamine, N-dimethylethanolamine, N-ethyldiethanolamine, 1,6-diamino hexane, triethanolamine, diisobutylamine, diisopropylamine, 2-methoxyethylamine, hydroxylamine, hydroxylamine, hydroxylamine, hydroxyethylamine , ethylamine, N-propylamine, n-butylamine, n-pentylamine, n-hexylamine, n-heptylamine, noctylamine, n-nonylamine, n-decylamine, n-undecylamine, n-dodecylamine, n-prop-2-ylamine, nbut -2-ylamine, n-pent-2-ylamine, n-hex-2-ylamine, n-hept-2-ylamine, n-oct-2-ylamine, n-non2-ylamine, n-dec-2-ylamine , n-undec-2-ylamine, n-dodec-2-ylamine, n-hex-3-ylamine, n-hept3-ylamine, n-oct-3-ylamine, n-non-3-ylamine, n-dec -3-ylamine, n-undec-3-ylamine, n-dodec-3ylamine, n-oct-4-ylamine, n-non-4-ylamine, n-dec-4-ylamine, n-undec-4-ylamine , n-dodec-4ylamine, n-non-5-ylamine, n-undec-5-ylamine, n-dodec-5-ylamine and n-octadecylamine.
Pri opciji (3) zgoraj amin (II) prikladno ni amin, v katerem sta in R3 izbrana izmed vodika ali CnH2n + j kjer je n 1 do 7 ali benzil ali substituiran benzil.For option (3) above, amine (II) is suitably not an amine in which and R 3 is selected from hydrogen or C n H2 n + j wherein n is 1 to 7 or benzyl or substituted benzyl.
Pri opciji (3) zgoraj zgornje prikladne substituirne skupine R^ vključujejo Cj.g alkil kot metil, fenil ali v danem primeru substituiran fenil, skupine karboksilne ali sulfonske kisline in derivate takih kislinskih skupin kot estre (npr. Cj.g alkil estre) in amide; nitro, in halogene kot brom. Prikladen m je lahko nič, 1 ali 2, R3 pa je lahko vodik ali metil. Prikladno sta R^ in R3 lahko vodik, ali pa je eden izmed R3 in R3 lahko vodik, drugi pa je lahko aromatska skupina z enako splošno formulo kot RA.In Option (3), the above suitable suitable substituent groups R 1 include C 1-8 alkyl as methyl, phenyl or optionally substituted phenyl, carboxylic or sulfonic acid groups and derivatives of such acid groups as esters (e.g. C 1-8 alkyl esters) and amides; nitro, and halogens as bromine. Suitable m may be zero, 1 or 2, and R 3 may be hydrogen or methyl. Suitably, R and R 3 can be hydrogen, or one of R 3 and R 3 can be hydrogen, and the other may be an aromatic group of the same general formula as RA.
Primeri za take amine vključujejo 1-feniletilamin, p-toluidin, p-aminobenzojsko kislino, p-bromoanilin, etil-4-aminobenzoat (benzokain), benzilamin, difenilamin, pmetilaminobenzen sulfonamid, m-nitroanilin, Ν,Ν’-dibenziletilendiamin (benzatin), difenilmetilamin, 4-metilbenzilamin in 4-fenilbutilamin.Examples of such amines include 1-phenylethylamine, p-toluidine, p-aminobenzoic acid, p-bromoaniline, ethyl-4-aminobenzoate (benzocaine), benzylamine, diphenylamine, pmethylaminobenzene sulfonamide, m-nitroaniline, Ν, Ν'-benzylethine (dibenzylethine). ), diphenylmethylamine, 4-methylbenzylamine and 4-phenylbutylamine.
Pri opciji (4) zgoraj je obročni sistem lahko aromatski ali alifatski in je lahko monocikličen ali policikličen. Prikladno lahko vsebuje vsak obroč v sistemu 5 ali 6 obročnih atomov, vključno obročne dušikove atome in vključno atome, ki si jih delijo obroči. Primerni opcijski substituenti v obročnem sistemu vključujejo alkil, amino, substituiran amino, okso in halogen. Če obročni sistem vključuje dodatne obročne hetero atome poleg prikazanega atoma dušika, so taki hetero atomi lahko prikladno izbrani izmed dušika in kisika.In Option (4) above, the ring system may be aromatic or aliphatic and may be monocyclic or polycyclic. Suitably, each ring in the system may have 5 or 6 ring atoms, including ring nitrogen atoms and including ring-shared atoms. Suitable optional substituents in the ring system include alkyl, amino, substituted amino, oxo and halogen. If the ring system includes additional ring hetero atoms in addition to the nitrogen atom shown, such hetero atoms may be conveniently selected from nitrogen and oxygen.
Primeri za razrede takih aminov vključujejo substituirane piperidine in opcijsko substituirane piperidine, npr. take, kjer so substituenti izbrani izrned alkila, hidroksialkila, halogena, amino, substituiranega amino in amino-substituiranega alkila. Specifični primeri za take amine vključujejo N-etil piperidin, 2,6-dimetil piperidin, 2metil-N-hidroksipropil piperidin (ciklo-metikan), 4-metil piperazin, l-metil-4-fenil piperazin, N-etil morfolamin, heksametilenimin, piridin, 2-propilpiridin, 3-kloro-2:6 -.aminopiridin, morfolamin, l,5-diazabiciklo[4,3,0]non-5-en, l,4-diazabiciklo[2,2,2joktan, pirolidon, kinuklidin in ksantinol.Examples of classes of such amines include substituted piperidines and optionally substituted piperidines, e.g. such wherein the substituents are selected from alkyl, hydroxyalkyl, halogen, amino, substituted amino and amino-substituted alkyl. Specific examples of such amines include N-ethyl piperidine, 2,6-dimethyl piperidine, 2methyl-N-hydroxypropyl piperidine (cyclo-methicane), 4-methyl piperazine, 1-methyl-4-phenyl piperazine, N-ethyl morpholine, hexamethylenimine , pyridine, 2-propylpyridine, 3-chloro-2: 6-aminopyridine, morpholine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, pyrrolidone, quinuclidine and xanthinol.
Pri opciji (5) zgoraj sta in lahko prikladno oba vodik, ali pa je eden lahko vodik in drugi alkil. in sta lahko prikladno vodik ali alkil.In Option (5) above, both may be hydrogen, or one may be hydrogen and the other alkyl. and may be conveniently hydrogen or alkyl.
Primeri za take amine vključujejo etilen diamin, Ν,Ν-dietiletilen diamin, N,N’diizopropiletilen diamin in trietilen tetramin.Examples of such amines include ethylene diamine, Ν, diet-diethylethylene diamine, N, N'diisopropylethylene diamine and triethylene tetramine.
Pri opciji (6) zgoraj je amino kislina lahko v naravi nastopajoča amino kislina. Estri amino kislin so lahko alkilne skupine ali substituirane alkilne skupine kot benzil.In option (6) above, the amino acid may be a naturally occurring amino acid. The amino acid esters may be alkyl groups or substituted alkyl groups such as benzyl.
Primeri za take amine vključujejo arginin, ornitin, histidin, lizin, benzilglicin, 3amino-3-metilbutanojsko kislino, L-etil lizinat, L-metil histidinat, metil N-karbobenziloksi-L-lizinat, metil L-fenilalanat, etil glicil glicinat, etil p-hidroksi fenil glicinat, etil p-hidroksi fenil glicinat, etil glicinat, etil L-tirozinat, p-metoksibenzil aaminofenilacetat, n-butil α-aminofenilacetat, metil arginat, benzilglicin, benzil fenilglicin, 1-nitrobenzil fenil glicin, n-butil fenilglicin, p-metoksibenzil fenilglicin, etil fenil glicin, p-nitrobenzil p-hidroksifenil-glicin, p-nitrobenzil serin, n-butil serin, metil arginin, dimetil glutamat, p-nitrobenzil tirozinat, p-nitrobenzil glicinat, benzil glicinat, p-nitrobenzil α-amino-p-hidroksi-fenil acetat, p-nitrobenzil α-aminofenilacetat, etil aamino-p-hidroksi fenil acetat, etil L-tirozinat.Examples of such amines include arginine, ornithine, histidine, lysine, benzylglycine, 3 amino-3-methylbutanoic acid, L-ethyl lysinate, L-methyl histidinate, methyl N-carbobenzyloxy-L-lysinate, methyl L-phenylalanine, ethyl glycyl glycine, ethyl glycyl glycine ethyl p-hydroxy phenyl glycinate, ethyl p-hydroxy phenyl glycinate, ethyl glycinate, ethyl L-tyrosinate, p-methoxybenzyl aminophenyl acetate, n-butyl α-aminophenyl acetate, methyl arginate, benzylglycine, benzyl phenylglycine, 1-nitrobenzyl, 1-nitrobenzyl butyl phenylglycine, p-methoxybenzyl phenylglycine, ethyl phenyl glycine, p-nitrobenzyl p-hydroxyphenyl-glycine, p-nitrobenzyl serine, n-butyl serine, methyl arginine, dimethyl glutamate, p-nitrobenzyl tyrosinate, p-nitrobenzyl glycinate, p-nitrobenzyl glycinate, p-nitrobenzyl α-amino-p-hydroxy-phenyl acetate, p-nitrobenzyl α-aminophenyl acetate, ethyl amino-p-hydroxy phenyl acetate, ethyl L-tyrosinate.
Kadar amin (II) vsebuje več kot en atom dušika, lahko tvori klavulanska kislina sol z enim ali več atomov dušika, npr. kot v ΝΝ’-diizopropiletilendiamin diklavulanatu.When amine (II) contains more than one nitrogen atom, clavulanic acid may form a salt with one or more nitrogen atoms, e.g. as in ΝΝ′-diisopropylethylenediamine diclavulanate.
Izmed zgoraj omenjenih aminov so prednostni amini: feniletilamin, t-amilamin, t-oktilamin, l-hidroksi-2-metil-2-propilamin, ciklopentilamin, cikloheptilamin, 1adamantanamin, N-etilpiperidin, Ν’Ν’-diizopropiletilendiamin in NN-dimetilcikloheksilamin.Among the aforementioned amines, the preferred amines are phenylethylamine, t-amylamine, t-octylamine, 1-hydroxy-2-methyl-2-propylamine, cyclopentylamine, cycloheptylamine, 1adamantanamine, N-ethylpiperidine, N'-diisopropylethylenediamine and NN-dimethylethylamine .
Postopek v smislu izuma obsega:The process of the invention comprises:
i) kontaktiranje nečiste klavulanske kisline ali njenega labilnega derivata, v raztopini v organskem topilu, s terciarim oktilaminom, ii) izolacijo soli klavulanske kisline, tvorjene s terciarnim oktilaminom, iii) pretvorbo tako tvorjene soli klavulanske kisline s terciarnim oktilaminomv klavulansko kislino ali njeno farmacevtsko sprejemljivo sol ali ester.i) contacting the impure clavulanic acid or its labile derivative, in solution in an organic solvent, with tertiary octylamine, ii) isolating the clavulanic acid salt formed with tertiary octylamine, iii) converting the clavulanic acid salt thus formed with tertiary octylamine into a clavulanic acid or acceptable clavulanic acid salt or ester.
Pri postopku predloženega izuma lahko uporabimo sol klavulanske kisline z aminom (II) za čiščenje nečiste klavulanske kisline med njeno pripravo. Zato se lahko tvori sol v raztopini klavulanske kisline ali njenega labilnega derivata, ki vsebuje nečistoče, z izolacijo soli kot posebne faze, npr. kot trdno oborino, iz raztopine, ki vsebuje preostale nečistoče, nakar ponovno tvorimo klavulansko kislino ali pa tvorimo njeno farmacevtsko sprejemljivo sol ali ester.In the process of the present invention, a clavulanic acid salt with an amine (II) may be used to purify impure clavulanic acid during its preparation. Therefore, salt may be formed in a solution of clavulanic acid or a labile impurity-containing derivative thereof, by isolating the salt as a special phase, e.g. as a solid precipitate, from a solution containing residual impurities, then re-formulate clavulanic acid or form a pharmaceutically acceptable salt or ester thereof.
Prikladni labilni derivati klavulanske kisline vključujejo soli, npr. sol z alkalijsko kovino kot litijev ali natrijev klavulanat, ali estre kot silil estre. Primerni labilni derivati amina (II) vključujejo soli kot fosfat, borat, klorid, klorat, perklorat, bromid, toluensulfonat, ali alkanoate, kot acetat ali etilheksonoat. Prikladno kontaktiramo sam amin (II) s samo nečisto klavulansko kislino v raztopini v organskem topilu.Suitable labile clavulanic acid derivatives include salts, e.g. an alkali metal salt such as lithium or sodium clavulanate, or esters such as silyl esters. Suitable labile derivatives of amine (II) include salts such as phosphate, borate, chloride, chlorate, perchlorate, bromide, toluenesulfonate, or alkanoates, such as acetate or ethylhexonoate. It is convenient to contact the amine (II) itself with only impure clavulanic acid in solution in an organic solvent.
Zgornji postopek prikladno izvedemo v organskem topilu, ki kljub temu, da je prednostno pretežno suho in vsebuje npr. pod 6 g/L, npr. 0.25-0.6 g/L vode, lahko vsebuje nekoliko vode kot topila za klavulansko kislino in amin (11). Primerno stopnjo sušenja lahko dosežemo z običajnimi postopki odstranjevanja vode kot centrifugiranjem. V topilu prisotna voda je lahko raztopljena ali v obliki kapljic ločene faze.The above process is conveniently carried out in an organic solvent which, although preferably substantially dry and containing e.g. below 6 g / L, e.g. 0.25-0.6 g / L of water may contain some water as solvents for clavulanic acid and amine (11). Suitable drying rates can be achieved by conventional water removal processes such as centrifugation. Water present in the solvent may be dissolved or in the form of separate phase droplets.
Raztopino klavulanske kisline v organskem topilu lahko dobimo z ekstrakcijo nakisane vodne raztopine klavulanske kisline, kot je zgoraj omenjena fermentacijska tekočina. Če je izhodni vir klavulanske kisline gojilna juha, nastala pri fermentaciji mikroorganizma, ki proizvaja klavulansko kislino, kot so npr. zgoraj navedeni, je za doseganje ekstrakta v topilu s prikladno koncentracijo klavulanske kisline za uporabo pri predloženem postopku lahko zaželeno, da ne ekstrahiramo same gojilne juhe, ampak da odstranimo vsaj del v juhi suspendiranih trdnih snovi, npr. s filtracijo pred ekstrakcijo. Lahko je tudi zaželeno, da dodatno predhodno koncentriramo vodno raztopino klavulanske kisline, dobljene pri fermentacji, tako, da je npr. vodna raztopina klavulanske kisline nekajkrat bolj koncentrirana s klavulansko kislino kot izhodna gojilna juha, npr. predhodno koncentrirana na koncentracijo okoli 10 - 100 mg/ml, npr. 10 - 40 mg/ml, kot 10 - 25 g/L klavulanske kisline.A solution of clavulanic acid in an organic solvent can be obtained by extracting an acidified aqueous solution of clavulanic acid, such as the fermentation liquid mentioned above. If the source of clavulanic acid is a culture broth resulting from the fermentation of a clavulanic acid-producing organism, such as e.g. above, to obtain an extract in a solvent with a suitable concentration of clavulanic acid for use in the present process, it may be desirable not to extract the culture broth itself, but to remove at least a portion of the suspended solids, e.g. by filtration before extraction. It may also be desirable to further pre-concentrate the aqueous clavulanic acid solution obtained from the fermentation such that e.g. aqueous clavulanic acid solution several times more concentrated with clavulanic acid than the starting culture broth, e.g. previously concentrated to a concentration of about 10-100 mg / ml, e.g. 10 - 40 mg / ml as 10 - 25 g / L of clavulanic acid.
Prikladni postopki za predhodno koncentracijo vključujejo absorpcijo klavulanske kisline na anionsko izmenjalno smolo, čemur sledi elucija klavulanske kisline z nje z vodno raztopino elektrolita kot natrijevega klorida, ter v danem primeru odstranitev soli. Prednostno je tudi nakisanje vodne raztopine, npr. gojilne juhe ali predhodno koncentrirane vodne raztopine pred ekstrakcijo s topilom, npr. na pH 1-3, npr. pH okoli 1.5 - 2.5. Prednostno je tudi sušenje ali odstranitev vode iz ekstrakta v organskem topilu pred tvorbo soli z aminom (11), npr. pod 6 g/L vode. Prednostno izvedemo ekstrakcijo pri temperaturi od 5 do 15 °C.Suitable methods for pre-concentration include absorption of clavulanic acid onto the anion exchange resin, followed by elution of clavulanic acid with it with an aqueous solution of electrolyte as sodium chloride, and optionally removing the salt. Acidification of the aqueous solution is also preferred, e.g. cultivation soups or pre-concentrated aqueous solutions prior to solvent extraction, e.g. at pH 1-3, e.g. pH about 1.5 - 2.5. It is also preferable to dry or remove the water from the extract in an organic solvent before forming a salt with an amine (11), e.g. under 6 g / L of water. The extraction is preferably carried out at a temperature of from 5 to 15 ° C.
Prikladna organska topila, v katerih lahko nečisto klavulansko kislino spravimo v stik z aminom (II), vključujejo ogljikovodična topila kot toluen in hehsan, etre kotSuitable organic solvents in which impure clavulanic acid can be contacted with an amine (II) include hydrocarbon solvents such as toluene and hexane, ethers as
-- &--- ......- & --- ......
tetrahidrofuran, dioksan, dietil eter, halogenirana topila kot diklorometan in kloroform, ketone kot aceton in metil izobutil keton ter estre kot etil acetat. Topila, ki vključujejo karbonilno skupino, npr. tista s formulo (III):tetrahydrofuran, dioxane, diethyl ether, halogenated solvents such as dichloromethane and chloroform, ketones as acetone and methyl isobutyl ketone, and esters as ethyl acetate. Solvents that include a carbonyl group, e.g. the one of formula (III):
IIII
R8 - C - R9 (III) kjer pomeni C]_6 alkilno skupino ali Cj_6 alkoksi skupino ter je R^ alkilna skupina, so primeri za podrazred primernih topil, npr. organskih ketonov ali organskih alkanoatnih estrov. Predloženi izum obsega tudi uporabo zmesi takih topil.R 8 - C - R 9 (III) wherein C 1-6 is an alkyl group or a C 1-6 alkoxy group and R 16 is an alkyl group are examples of subclasses of suitable solvents, e.g. organic ketones or organic alkanoate esters. The present invention also encompasses the use of mixtures of such solvents.
Prikladneje pa je organsko topilo tako, ki ga lahko uporabimo direktno za ekstrakcijo nakisane vodne raztopine; to so npr. organski alkil alkanoatni estri, ketoni in določeni alifatski alkoholi, ali njihove zmesi, kot etil acetat, metil acetat, propil acetat, n-butil acetat, metil etil keton, metil izobutil keton, tetrahidrofuran, butanol in zmesi takih topil. Izmed teh se zdijo najprikladnejši metil izobutil keton, metil etil keton in etil acetat. Prikladne zmesi topil vključujejo metil etil keton/metil izobutil keton in tetrahidrofuran/metil izobutil keton. Prednostno topilo je etil acetat.More preferably, the organic solvent is one that can be used directly to extract the acidic aqueous solution; these are e.g. organic alkyl alkanoate esters, ketones and certain aliphatic alcohols, or mixtures thereof, such as ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, butanol and mixtures of such solvents. Of these, methyl isobutyl ketone, methyl ethyl ketone and ethyl acetate are most suitable. Suitable solvent mixtures include methyl ethyl ketone / methyl isobutyl ketone and tetrahydrofuran / methyl isobutyl ketone. The preferred solvent is ethyl acetate.
Prikladna topila za amin (II) vključujejo tista izmed zgoraj navedenih, v katerih se da klavulansko kislino raztopiti ali ekstrahirati; to so npr. aceton, etil acetat, metil izobutil keton in metil etil keton.Suitable solvents for amine (II) include those mentioned above in which clavulanic acid can be dissolved or extracted; these are e.g. acetone, ethyl acetate, methyl isobutyl ketone and methyl ethyl ketone.
Zdi se posebno zaželeno vključiti ketone kot aceton v sistem topil, ker je videti, da inhibirajo tvorbo soli klavulanske kisline z aminom (II) kot olja.It seems particularly desirable to include ketones as acetone in the solvent system because they appear to inhibit the formation of clavulanic acid salts with amine (II) as oils.
Na splošno uporabimo en ekvivalent amina (II) ali njegov majhen prebitek na en mol klavulanske kisline, da pripravimo sol klavulanske kisline. Raztopine klavulanske kisline in amina (II) lahko npr. počasi pomešamo in zmes mešamo nekaj časa po končanem dodajanju. Reakcijo med klavulansko kislino ali njenim labilnim derivatom prikladno izvedemo pri temperaturi pod sobno temperaturo, npr. pri 0 do 15 °C, npr. 0 do 10 °C, npr. 0 do 5 °C. Prikladna koncentracija klavulanske kisline ali njenega labilnega derivata v raztopini je vsaj 1.0 g/L, npr. v območju 1.0 do 4.0 g /L, klavulanske kisline. Lahko je prikladno, da nadalje koncentriramo ekstrakt v topilu do koncentracije nad to vrednostjo, npr. nad 20 g /L.In general, one equivalent of amine (II) or a small excess of one mole of clavulanic acid is used to prepare the clavulanic acid salt. Solutions of clavulanic acid and amine (II) may e.g. mix slowly and mix for a while after adding. The reaction between clavulanic acid or its labile derivative is conveniently carried out at a temperature below room temperature, e.g. at 0 to 15 ° C, e.g. 0 to 10 ° C, e.g. 0 to 5 ° C. A suitable concentration of clavulanic acid or its labile derivative in the solution is at least 1.0 g / L, e.g. in the range 1.0 to 4.0 g / L, clavulanic acid. It may be convenient to further concentrate the extract in the solvent to a concentration above this value, e.g. above 20 g / L.
Pri nadaljnjem postopku pa lahko amin (II) uvedemo z umešanjem v tok raztopine klavulanske kisline v topilu, tako, da se v toku tvori sol, bodisi v raztopini ali kot delci, ali kot suspendirane kapljice raztopljene soli v suspenziji. Na ta način uvedeni amin (II) lahko uvedemo čistega brez dodatkov ali pa ga uvedemo kotIn a further process, amine (II) can be introduced by mixing in a stream of a solution of clavulanic acid in a solvent so that salt is formed in the stream, either in solution or as particles, or as suspended droplets of dissolved salt in suspension. The amine (II) thus introduced can be introduced pure without additives or introduced as
--9---raztopino v topilu, npr. v istem organskem topilu, v katerem je raztopljena klavulanska kislina.--9 --- Solution in solvent, e.g. in the same organic solvent in which clavulanic acid is dissolved.
Nato lahko izoliramo želeno sol klavulanske kisline z aminom (II). Na ta način lahko ločimo sol klavulanske kisline z aminom (II) iz večine ali vseh nečistoč. Izolacijo lahko izvedemo na običajen način, npr. s centrifugiranjem ali filtracijo.The desired salt of clavulanic acid can then be isolated with amine (II). In this way, the clavulanic acid salt with amine (II) can be separated from most or all impurities. The insulation can be carried out in the usual way, e.g. by centrifugation or filtration.
Pri alternativnem izolacijskem postpoku lahko izoliramo sol klavulanske kisline z aminom (II) iz organskega topila, če se topilo v celoti ali delno ne meša z vodo, s kontaktiranjem topila z vodo, da ekstrahiramo sol, ki je lahko v raztopini ali suspenziji, iz organskega topila in tvorimo vodno raztopino soli. Ker so soli klavulanske kisline z aminom (II) precej dobro topne v vodi, je tovrstna vodna raztopina lahko zelo koncentrirana, npr. okoli 20 do 30% mas./mas.In an alternative isolation procedure, the clavulanic acid salt with amine (II) can be isolated from the organic solvent if the solvent is not completely or partially miscible with water by contacting the solvent with water to extract the salt, which may be in solution or suspension, from the organic solvent. solvents and form an aqueous solution of salt. Since the salts of clavulanic acid with amine (II) are quite soluble in water, this aqueous solution can be very concentrated, e.g. about 20 to 30% w / w
Na ta način večina organskih nečistoč, ki so se nahajale v raztopini klavulanske kisline v organskem topilu, ostane v organskem topilu, medtem ko dobimo klavulansko kislino v obliki njene soli z aminom (11) v sorazmerno čistem stanju v vodni raztopini. Tako tvorjeno vodno raztopino soli klavulanske kisline lahko nadalje obdelamo na običajen način, npr. očistimo ali pretvorimo v klavulansko kislino ali v njeno farmacevtsko sprejemljivo sol ali ester, kot je spodaj opisano.In this way, most of the organic impurities present in the clavulanic acid solution in the organic solvent remain in the organic solvent, while clavulanic acid is obtained in the form of its salt with an amine (11) in a relatively pure state in aqueous solution. The aqueous solution of clavulanic acid salt thus formed can be further treated in the usual way, e.g. is purified or converted to clavulanic acid or a pharmaceutically acceptable salt or ester thereof, as described below.
Pri nadaljnji alternativi ali dodatnem postopku lahko klavulansko kislino in amin pomešamo v raztopini v prvem organskem topilu, nato pa izvedemo izločanje soli iz raztopine z dodatkom drugega organskega topila. Prikladno je prvo organsko topilo lahko organski ester kot etil acetat, drugo topilo pa je lahko halogenirano topilo kot kloroform, eter kot dietil eter, ogljikovodik kot toluen, alkohol kot etanol, ali topilo s formulo (III) zgoraj, kot npr. aceton ali metil izobutil keton.In a further alternative or additional process, clavulanic acid and an amine may be mixed in solution in a first organic solvent and then the salts extracted from the solution by the addition of a second organic solvent. Suitably, the first organic solvent may be an organic ester such as ethyl acetate, and the second solvent may be a halogenated solvent such as chloroform, an ether such as diethyl ether, a hydrocarbon such as toluene, an alcohol as ethanol, or a solvent of formula (III) above, such as e.g. acetone or methyl isobutyl ketone.
Nekatere izmed zgoraj omenjenih soli klavulanske kisline smatramo za nove spojine in so kot take nadaljnji vidik predloženega izuma: npr. soli klavulanske kisline s feniletilaminom, t-amilaminom, l-hidroksi-2-metil-2-propilaminom, ciklopentilaminom, cikloheksilaminom, 1-adamantanaminom, N-etilpiperidinom, NN-dimetilcikloheksilaminom in NN’-diizopropiletilendiaminom.Some of the above mentioned salts of clavulanic acid are considered novel compounds and are, as such, a further aspect of the present invention: e.g. salts of clavulanic acid with phenylethylamine, t-amylamine, 1-hydroxy-2-methyl-2-propylamine, cyclopentylamine, cyclohexylamine, 1-adamantanamine, N-ethylpiperidine, NN-dimethylcyclohexylamine and NN'-diisopropylethylenediamine.
Pri eni izmed izvedb predloženega izuma lahko uporabimo sol klavulanske kisline z aminom (II) kot solvat v acetonu. Solvati v acetonu imajo v nekaterih primerih prikladne karakteristike glede stabilnosti in čistoče v primeri s solmi klavulanske kisline s samimi amini. Taki solvati so posebno koristni pri predloženem izumu, saj se jih da pogosto izolirati kot zelo čiste in stabilne kristalne spojine.In one embodiment of the present invention, a clavulanic acid salt with an amine (II) may be used as a solvate in acetone. Acetone solvates in some cases have suitable stability and purity characteristics compared to the amine salts of clavulanic acid. Such solvates are particularly useful in the present invention as they can often be isolated as very pure and stable crystalline compounds.
V skladu s predloženim izumom nudimo tudi sol klavulanske kisline z aminom (II) v obliki solvata v acetonu. Med izolacijo in/ali sušenjem se lahko izgubi nekolikoThe present invention also provides a salt of clavulanic acid with an amine (II) solvate in acetone. There may be some loss of insulation and / or drying
14-,-acetona, ker solvacijska moč morda ni velika, vendar množina acetona v produktu ni kritična.14 -, - acetone, because the solvation power may not be large, but the amount of acetone in the product is not critical.
Solvat v acetonu lahko tvorimo s kontaktiranjem klavulanske kisline z aminom (II) v prisotnosti acetona. Na splošno lahko pomešamo raztopino, ki vsebuje klavulansko kislino, z vsaj enakim volumnom acetona skupaj z aminom (II), če obarjamo sol.The solvate in acetone can be formed by contacting clavulanic acid with amine (II) in the presence of acetone. Generally, a solution containing clavulanic acid can be mixed with at least the same volume of acetone together with amine (II) if the salt is precipitated.
Amin (II) lahko raztopimo v acetonu in pomešamo z raztopino klavulanske kisline v organskem topilu. Priljubljena organska topila vključujejo etil acetat, tetrahidrofuran, metil etil keton, metil izobutil keton in zmesi tovrstnih topil; izmed teh je prednosten etil acetat. Alternativno lahko pomešamo vodno raztopino soli klavulanske kisline z aminom (II), dobljeno z ekstrakcijo z vodo, kot je zgoraj prikazano, z acetonom za tvorbo solvata. Prikladno lahko pomešamo koncentrirano vodno raztopino soli s prebitnim acetonom, da tvorimo solvat.Amin (II) can be dissolved in acetone and mixed with a solution of clavulanic acid in an organic solvent. Popular organic solvents include ethyl acetate, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, and mixtures of such solvents; ethyl acetate is preferred. Alternatively, the aqueous solution of the clavulanic acid salt with the amine (II) obtained by extraction with water as shown above may be mixed with acetone to form a solvate. Concentrated aqueous salt solution with excess acetone may conveniently be mixed to form a solvate.
Prekristalizacija soli klavulanske kisline ali solvata v acetonu je lahko nadalje primerna, da nadalje zmanjšamo množino nečistoč. Primerno topilo za prekristalizacijo je vodni aceton. Tako prekristalizacijo izvedemo na običajen način, da npr. v vodi raztopljeno sol ali solvat obdelamo z majhno množino acetona, filtriramo in nato obdelamo z večjimi volumni acetona v danem primeru ob mešanju in/ali hlajenju, da dobimo prekristalizirani produkt.Recrystallization of the clavulanic acid salt or solvate in acetone may be further suitable to further reduce the amount of impurities. A suitable recrystallization solvent is aqueous acetone. Such recrystallization is carried out in the usual way that e.g. The dissolved salt or solvate in water is treated with a small amount of acetone, filtered and then treated with larger volumes of acetone, optionally with stirring and / or cooling, to give a recrystallized product.
Nadaljni vidik predloženega izuma nudi postopek za pripravo klavulanske kisline ali njene farmacevtsko sprejemljive soli ali estra, pri čemer postopek obsega pretvorbo soli klavulanske kisline z aminom s formulo (II) v klavulansko kislino ali v njeno farmacevtsko sprejemljivo sol ali ester.A further aspect of the present invention provides a process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof, the method comprising converting a clavulanic acid salt of an amine of formula (II) into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.
Farmacevtsko sprejemljive soli in estri klavulanske kisline, pripravljeni po postopkih v smislu predloženega izuma, vključujejo tiste, ki so opisani v GB 1508977 in 1508978, kijih tukaj vključujemo z referenco.Pharmaceutically acceptable salts and clavulanic acid esters prepared according to the methods of the present invention include those described in GB 1508977 and 1508978, which are incorporated herein by reference.
Posebno prikladne farmacevtsko sprejemljive soli vključujejo farmacevtsko sprejemljive soli alkalijskih in zemljoalkalijskih kovin, npr. natrijeve, kalijeve, kalcijeve in magnezijeve soli. Izmed teh soli sta najprimernejši natrijeva in kalijeva, prednostna pa je kalijeva.Particularly suitable pharmaceutically acceptable salts include pharmaceutically acceptable salts of alkali and alkaline earth metals, e.g. sodium, potassium, calcium and magnesium salts. Of these salts, sodium and potassium are preferred, and potassium is preferred.
Primerni estri vključujejo tiste, ki se dajo cepiti, da dobimo klavulansko kislino ali njeno sol s kemičnimi metodami kot hidrogenolizo, ali z biološkimi metodami.Suitable esters include those which can be vaccinated to obtain clavulanic acid or a salt thereof by chemical methods such as hydrogenolysis, or by biological methods.
Sol klavulanske kisline z aminom (II), v danem primeru v obliki njenega solvata v acetonu, se da pretvoriti v klavulansko kislino ali njeno farmacevtsko sprejemljivo sol ali ester, npr. z zamenjavo iona v primeru proste kisline ali soli, ali z zaestrenjem.A clavulanic acid salt with an amine (II), optionally in the form of a solvate thereof in acetone, can be converted to clavulanic acid or a pharmaceutically acceptable salt or ester thereof, e.g. by ion exchange in the case of free acid or salt, or by esterification.
Zamenjavo iona lahko izvedemo z uporabo ionsko izmenjalnih smol, npr. z vodenjem raztopine soli skozi veso kationske izmenjalne smole v natrijevi, kalijevi ali kalcijevi obliki. Primerne kationske izmenjalne smole vključujejo Amberlite IR 120 in ekvivalentne smole.The ion exchange can be performed using ion exchange resins, e.g. by guiding the salt solution through the weight of the cation exchange resin in sodium, potassium or calcium form. Suitable cation exchange resins include Amberlite IR 120 and equivalent resins.
Alternativno pa lahko izvedemo zamenjavo ionov z reakcijo protoniranega aminskega kationa s spojino, ki je prekurzor za sol, ki je lahko npr. baza kot karbonat, hidrogen karbonat ali hidroksid, farmacevtsko sprejemljive alkalijske ali zemljoalkalijske kovine, ali sol organske karboksilne kisline s farmacevtsko sprejemljivim kationom, kot alkalijsko ali zemljoalkalijsko kovino, npr. sol alkanojske kisline s formulo (IV):Alternatively, ion exchange can be performed by reacting the protonated amine cation with a compound that is a precursor to a salt that may be e.g. a base such as carbonate, hydrogen carbonate or hydroxide, a pharmaceutically acceptable alkali or alkaline earth metal, or a salt of an organic carboxylic acid with a pharmaceutically acceptable cation, such as an alkali or alkaline earth metal, e.g. alkanoic acid salt of formula (IV):
R10-CO2H (IV) v kateri je R^ alkilna skupina, ki vsebuje npr. 1 do 20 atomov ogljika, prednostno 1 do 8 atomov ogljika. Primeri za prikladne soli vključujejo acetatno, propionatno ali etilheksanoatno sol, pri čemer sta prednostna kalijev 2-etilheksanoat in natrijev 2etilheksanoat. Značilno lahko reagira sol klavulanske kisline z aminom (II) v raztopini s soljo alkalijske kovine s kislino (IV) v raztopini ali suspenziji v primernem topilu, kije lahko organsko topilo, voda ali zmes vode in organskega topila, kot izopropanola. Prikladno lahko pomešamo raztopine soli klavulanske kisline z aminom (II) in spojino, ki je prekurzor za sol, ter pustimo kristalizirati farmacevtsko sprejemljivo sol. Prikladno lahko izvedemo reakcijo pri temperaturi pod sobno temperaturo, npr. pri 0 do 15 °C, npr. pri 0 do 10 °C, prikladno pri 0 do 5 °C. Če tvorimo sol klavulanske kisline z aminom (11) v vodni raztopini, jo prikladno lahko oborimo s primešanjem prebitnega acetona k vodni raztopini.R 10 -CO 2 H (IV) in which R 6 is an alkyl group containing e.g. 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. Examples of suitable salts include the acetate, propionate or ethylhexanoate salt, potassium 2-ethylhexanoate and sodium 2-ethylhexanoate being preferred. Typically, a clavulanic acid salt may be reacted with an amine (II) in solution with an alkali metal salt with an acid (IV) in solution or suspension in a suitable solvent, which may be an organic solvent, water or a mixture of water and an organic solvent such as isopropanol. Conveniently, solutions of the clavulanic acid salt can be mixed with the amine (II) and the salt precursor compound and the pharmaceutically acceptable salt is allowed to crystallize. Conveniently, the reaction can be carried out at a temperature below room temperature, e.g. at 0 to 15 ° C, e.g. at 0 to 10 ° C, preferably at 0 to 5 ° C. If a clavulanic acid salt is formed with an amine (11) in an aqueous solution, it can conveniently be precipitated by mixing excess acetone with the aqueous solution.
Primerne metode za zaestrenje vključujejo:Suitable methods for esterification include:
a) reakcijo soli klavulanske kisline z aminom (II) s spojino s formulo Q-R^, kjer je Q zlahka premestljiva skupina in je R^ organska skupina;a) reacting a clavulanic acid salt with an amine (II) with a compound of formula Q-R 4, wherein Q is an easily displaced group and R 4 is an organic group;
b) reakcijo soli klavulanske kisline z aminom (II) z alkoholom ali tiolom v prisotnosti sredstva za pospešitev kondenzacije kot karbodiimida; inb) reacting the clavulanic acid salt with an amine (II) with an alcohol or thiol in the presence of a condensation promoter such as carbodiimide; and
c) reakcijo soli klavulanske kisline z aminom (TI) z diazo spojino.c) reaction of a clavulanic acid salt with an amine (TI) with a diazo compound.
Zgornji postopki naj obsegajo tudi tiste izvedbe, kjer je sol klavulanske kisline z aminom (II) najprej pretvorjena v klavulansko kislino ali neko njeno drugo sol in zatem pretvorjena v želeni ester. Nadaljnje podrobnosti za metode zaestrenja soThe above procedures should also cover those embodiments where the clavulanic acid salt with an amine (II) is first converted to clavulanic acid or another salt thereof and subsequently converted to the desired ester. Further details for esterification methods are
- 13-.-prikazane v GB 1508977 in 1508978. Uporaba predloženega izuma omogoča, da soli in estre klavulanske kisline laže dobimo v čisti obliki, kot pa pri izvedbi po postopkih GB 1508977 in 1543563.13 -.- shown in GB 1508977 and 1508978. The use of the present invention makes it easier to obtain clavulanic acid salts and esters in pure form than in the GB 1508977 and 1543563 processes.
Izum bomo sedaj prikazali z naslednjimi Primeri, ki pa naj ga nikakor ne omejujejo. V Primerih stoji THF za tetrahidrofuran in RV za relativno vlago.The invention will now be illustrated by the following Examples, but by no means limited thereto. In the Examples, THF stands for tetrahydrofuran and RV for relative humidity.
13'-Primer 113'-Example 1
Pri vseh naslednjih Primerih je bil postopek enak; amin smo pomešali z raztopino klavulanske kisline v raztopini THF in opazili smo hitro kristalizacijo, da se je tvorila trdna sol.In all the following Examples, the procedure was the same; the amine was mixed with a clavulanic acid solution in THF solution and rapid crystallization was observed to form a solid salt.
- 14--.- 14--.
sobna temp. oranžno poroom temp. orange after
16h50%RV sobna temperatura16h50% RV room temperature
Primer 2Example 2
V tem primeru pa smo tvorili sol klavulanske kisline z aminom v raztopini v prvem organskem topilu in nato povzročili, da se je izločila iz raztopine kot trdna oborina s pomešanjem z drugim organskim topilom.In this case, however, a clavulanic acid salt was formed with the amine in solution in the first organic solvent and then caused to be separated from the solution as a solid precipitate by mixing with the second organic solvent.
2a. t-Oktilamin - Pripravili smo izhodno raztopino klavulanske kisline v etil acetatu, ki je vsebovala okoli 28 g /L klavulanske kisline v nečisti obliki, z ekstrakcijo nečiste fermentacijske juhe S. clavuligerus z etil acetatom. K 46 ml le-tega smo dodali toktilamin (0.84 g). Po 10 minutah se je zmes zmotnila in izkristalizirali so se fini kristali soli. K alikvotu raztopine smo dodali kloroform, kar je izzvalo tvorbo večjih iglic. K nadaljnjemu alikvotu smo dodali aceton, kar je ponovno izzvalo tvorbo igličastih kristalov, vendar manjših in to počasneje kot s kloroformom. Preostanku raztopine smo dodali okoli 20 ml kloroforma, nato pa volumen toluena, približno enak začetni masi raztopine, kar je izzvalo obarjanje znatne množine igličastih kristalov.2a. t-Octylamine - A stock solution of clavulanic acid in ethyl acetate containing about 28 g / L of clavulanic acid in impure form was prepared by extracting the impure fermentation broth of S. clavuligerus with ethyl acetate. Toxylamine (0.84 g) was added to 46 ml of this. After 10 minutes, the mixture was disturbed and fine crystals of salt were crystallized. Chloroform was added to an aliquot of the solution, which caused the formation of larger needles. Acetone was added to the further aliquot, again causing the formation of needle crystals, but smaller and slower than with chloroform. About 20 ml of chloroform was added to the remainder of the solution, followed by a volume of toluene approximately equal to the initial weight of the solution, which caused a significant amount of needle crystals to precipitate.
2b. Dicikloheksilamin - K 46 ml izhodne raztopine, pripravljene kot za 2a zgoraj, smo dodali dicikloheksilamin (1.18 g). Nastala je bistra raztopina. Aceton smo dodali k enemu alikvotu, pri čemer seje tvorila fina amorfna usedlina.2b. Dicyclohexylamine - Dicyclohexylamine (1.18 g) was added to 46 ml of stock solution prepared as for 2a above. A clear solution was formed. Acetone was added to one aliquot, forming a fine amorphous precipitate.
2c. Amoniak - K 500 ml izhodne raztopine, pripravljene kot za 2a zgoraj, smo dodali amoniak (21.1 ml 2.5M amonijevega 2-etilheksanoata v etil acetatu, t.j. okoli 1 ekvivalent). Dodatek 50 ml industrijskega metiliranega špirita (IMS) je zlahka izzval tvorbo oborine finih iglic. Opazili pa smo, da pri uporabi nečiste raztopine klavulanske kisline, kar se odraža na barvi raztopine, preostane v raztopini znatna množina obarvanih nečistoč. Dobitek - 75 %.2c. Ammonia - To 500 ml of stock solution prepared as for 2a above was added ammonia (21.1 ml of 2.5M ammonium 2-ethylhexanoate in ethyl acetate, i.e. about 1 equivalent). The addition of 50 ml of industrial methylated spirit (IMS) easily elicited the formation of a fine needle precipitate. However, it was observed that when using an impure clavulanic acid solution, as reflected by the color of the solution, a significant amount of colored impurities remained in the solution. Yield - 75%.
-- 15...- 15 ...
2d. Ν,Ν-dimetilcikloheksilamin - K 500 ml izhodne raztopine, pripravljene kot za 2a zgoraj, smo dodali Ν,Ν-dimetilcikloheksilamin (6.7 ml). Na začetku dodajanja seje tvorilo olje. Postopoma smo dodajali aceton (150 ml), pri čemer je nastala motna raztopina. Vzeli smo alikvotni del te motne raztopine in mu dodali dietileter, kar je povzročilo kristalizacijo. Dietileter (100 ml) smo dodali h glavnini raztopine, kar je povzročilo takojšnjo kristalizacijo. Kristale (13.4 g) smo filtrirali in izprali z acetonom. 2e. t-Oktilamin - K 500 ml izhodne raztopine, pripravljene kot za 2a zgoraj, smo dodali t-oktilamin (6.7 g). Raztopina se je lahno zmotnila. Dodali smo aceton (20 ml), kar je zbistrilo raztopino. K alikvotu raztopine smo dodali dietileter, kar je povzročilo takojšnjo kristalizacijo. Dietileter (55 ml) smo dodali h glavnini raztopine, kar je izzvalo kristalizacijo. Kristale smo filtrirali in izprali z acetonom. Dobitek (12.9 g) je predstavljal 77 % rekuperacijo klavulanske kisline iz raztopine.2d. N, N-dimethylcyclohexylamine - To 500 ml of stock solution prepared as in 2a above was added N, N-dimethylcyclohexylamine (6.7 ml). It formed an oil at the beginning of the session. Acetone (150 ml) was added gradually to give a cloudy solution. An aliquot part of this cloudy solution was taken and diethyl ether was added to it, causing crystallization. Diethyl ether (100 ml) was added to the bulk of the solution, resulting in immediate crystallization. The crystals (13.4 g) were filtered and washed with acetone. 2e. t-Octylamine - To 500 ml of stock solution prepared as for 2a above was added t-octylamine (6.7 g). The solution was slightly mistaken. Acetone (20 ml) was added, which clarified the solution. Diethyl ether was added to an aliquot of the solution, resulting in immediate crystallization. Diethyl ether (55 ml) was added to the bulk of the solution, causing crystallization. The crystals were filtered and washed with acetone. Yield (12.9 g) represented 77% recovery of clavulanic acid from solution.
2f. Benzatin - Benzatin diacetat (9.16 g) smo mešali z vodnim natrijevim hidroksidom (5N, 10.15 ml). Vodno raztopino smo ekstrahirali z etil acetatom (55 ml) in ekstrakt dodali k izhodni raztopini klavulanske kisline, pripravljene kot za 2a zgoraj (1.0 L). Na začetku se je tvorilo olje. Dodali smo aceton (600 ml) in tvorili so se kristali (dodali smo okoli 10 ml dietil etra), kar je ostanek iz poskusa z epruvetko. Nato smo dodali metil izobutil keton (200 ml) in dopolnili zmes na 2 L z acetonom. Tvorjene kristale smo filtrirali in izprali z acetonom. Dobitek je znašal 11.5 g, kar predstavlja 59.1 % rekuperirane klavulanske kisline.2f. Benzatin - Benzatin diacetate (9.16 g) was stirred with aqueous sodium hydroxide (5N, 10.15 ml). The aqueous solution was extracted with ethyl acetate (55 ml) and the extract added to the clavulanic acid stock solution prepared as for 2a above (1.0 L). Initially, oil was formed. Acetone (600 ml) was added and crystals formed (about 10 ml of diethyl ether were added), which is the residue from the test tube. Methyl isobutyl ketone (200 ml) was then added and the mixture was added to 2 L with acetone. The crystals formed were filtered and washed with acetone. The yield was 11.5 g, representing 59.1% of the recovered clavulanic acid.
Primer 3Example 3
Raztopino klavulanske kisline v etil acetatu (okoli 20 /tg/ml) smo razredčili z enakim volumnom acetona. Nato smo dokapavali acetonsko raztopino t-oktilamina (1.25 mol ekvivalentov) v teku pol ure pri 10 °C. Po nadaljnjem mešanju v teku 1 ure smo oborjene kristale zbrali, izprali z acetonom in sušili v vakuumu. Zlahka se je tvorila oborina, kije bila bele barve. Dobitek (korigiran za čistočo) = 76 %.A solution of clavulanic acid in ethyl acetate (about 20 / tg / ml) was diluted with an equal volume of acetone. Then, an acetone solution of t-octylamine (1.25 mol equivalents) was added dropwise over 10 hours at 10 ° C. After further stirring for 1 hour, the precipitated crystals were collected, washed with acetone and dried in vacuo. A precipitate formed, which was white in color. Yield (adjusted for purity) = 76%.
Primer 4Example 4
0.012M raztopino benzil klavulanata v THF smo katalitsko hidrogenirali, da smo tvorili raztopino klavulanske kisline v THF. K tej raztopini (100 ml) smo dodali 1aminoadamantan (25 ml 0.012M v THF) pri sobni temperaturi. Prišlo je do hitre kristalizacije. Raztopino smo mešali 30 minut pri sobni temperaturi, nato pa 2 uri pri 5 °C. Raztopino smo nato filtrirali in kristale izprali in sušili.A 0.012M solution of benzyl clavulanate in THF was catalytically hydrogenated to form a solution of clavulanic acid in THF. To this solution (100 ml) was added 1aminoadamantane (25 ml 0.012M in THF) at room temperature. Rapid crystallization occurred. The solution was stirred for 30 minutes at room temperature and then at 5 ° C for 2 hours. The solution was then filtered and the crystals were washed and dried.
-- 16.,.- 16.,.
Dobitek = 83 %. Tališče soli je znašalo 190 - 192 °C (razpad).Yield = 83%. The salt melting point was 190 - 192 ° C (decomposition).
Primer 5Example 5
Benzil klavulanat očiščen s Sephadex kromatografijo (20 g, 0.07 molov) smo raztopili v tetrahidrofuranu (destiliranem s kalcijevega hidrida, 400 ml) in dodali 10 % katalizatorja paladija-na-oglju (5.7 g). Zmes smo hidrogenirali z mešanjem pri sobni temperaturi in pri okoli 1.2 bar 20 do 30 minut. Stanje reakcije smo ocenili s tankoslojno kromatografijo ob uporabi kremeničnih plošč, razvitih z etil acetatom in vizualiziranih z uporabo trifeniltetrazolijevega klorida kot razpršilnega reagenta. Klavulanska kislina Rf 0.0, benzil ester 0.4.Benzyl clavulanate purified by Sephadex chromatography (20 g, 0.07 mol) was dissolved in tetrahydrofuran (distilled from calcium hydride, 400 ml) and 10% palladium-on-charcoal catalyst (5.7 g) was added. The mixture was hydrogenated by stirring at room temperature and at about 1.2 bar for 20 to 30 minutes. The state of the reaction was evaluated by thin layer chromatography using silica plates developed with ethyl acetate and visualized using triphenyltetrazolium chloride as a spray reagent. Clavulanic acid Rf 0.0, benzyl ester 0.4.
Reakcijsko zmes smo filtrirali in filtrni vložek dobro izprali. Združene filtrate (približno 500 ml), ki so vsebovali klavulansko kislino, smo obdelali z mešanjem z 2amino-2,4,4-trimetilpentanom (9.0 g, 0.07 molov) v suhem THF (50 ml). Kristalizacijo smo opazili v teku 1 minute. Zmes smo mešali 0.5 ur pri sobni temperaturi in nato 2 uri pri 5 °C. Produkt smo odfiltrirali, ga izprali s suhimTHF (100 ml) in sušili v vakuumu 12 ur, da smo dobili 23.0 g, 100 % naslovne soli s tal. 160 - 170 °C (razpad).The reaction mixture was filtered and the filter cartridge was well washed. The combined filtrates (approximately 500 ml) containing clavulanic acid were treated by mixing with 2 amino-2,4,4-trimethylpentane (9.0 g, 0.07 mol) in dry THF (50 ml). Crystallization was observed within 1 minute. The mixture was stirred for 0.5 hours at room temperature and then at 5 ° C for 2 hours. The product was filtered off, washed with dry THF (100 ml) and dried under vacuum for 12 hours to give 23.0 g, 100% of the title salt from the ground. 160 - 170 ° C (decomposition).
Primer 6Example 6
Pripravo smo izvedli kot pri Primeru 5 ob uporabi benzil klavulanata (0.9 g, 0.003 moli) in obdelali nastalo raztopino klavulanske kisline z 2-amino-2-metilpropanom (0.22 g, 0.003 moli) v suhem THF (10 ml).The preparation was carried out as in Example 5 using benzyl clavulanate (0.9 g, 0.003 mol) and treated the resulting clavulanic acid solution with 2-amino-2-methylpropane (0.22 g, 0.003 mol) in dry THF (10 ml).
Naslovna sol (0.6 g, 73% dobitek) je imela tal. 150 - 152 °C (razpad).The title salt (0.6 g, 73% yield) had a melt. 150 - 152 ° C (decomposition).
Primer 7Example 7
Pripravo smo izvedli kot pri Primeru 5 ob uporabi benzil klavulanata (0.9 g, 0.003 moli) in obdelali nastalo raztopino klavulanske kisline z D( + ) 1-metilbenzilamina v suhem THF (10 ml). Zmes smo shranili pri 5 °C dva dni, medtem pa je prišlo do počasne kristalizacije. Filtracija je dala naslovno sol (0.6 g, 62% dobitek) s tal. 125 °C (razpad).The preparation was carried out as in Example 5 using benzyl clavulanate (0.9 g, 0.003 mol) and treated the resulting clavulanic acid solution with D (+) 1-methylbenzylamine in dry THF (10 ml). The mixture was stored at 5 ° C for two days while slow crystallization occurred. Filtration gave the title salt (0.6 g, 62% yield) from the ground. 125 ° C (decomposition).
Primer 8Example 8
Vodno raztopino litijevega klavulanata srno pomešali z vodno raztopino alkilamonijevega fosfata. Oborjeni litijev fosfat smo odfiltrirali in sol amin klavulanatThe aqueous solution of lithium clavulanate was mixed with the aqueous solution of alkylammonium phosphate. The precipitated lithium phosphate was filtered off and the salt amine clavulanate
- - I /-oborili z dodatkom acetona. Ugotovili smo, da se da uporabiti tudi natrijev klavulanat, vendar je tedaj potrebno dodati etanol, da izzovemo ločbo natrijevega fosfata. Uporabiti se da tudi amin hidrokloride.- - I / -colorants with the addition of acetone. We have found that sodium clavulanate can also be used, but then ethanol must be added to induce sodium phosphate separation. Amine hydrochlorides are also used.
Na ta način smo uporabili litijev klavulanat za pripravo N-etilpiperidin klavulanata in uporabili natrijev klavulanat za pripravo N-etilpiperidin klavulanata.In this way, lithium clavulanate was used to prepare N-ethylpiperidine clavulanate and sodium clavulanate was used to prepare N-ethylpiperidine clavulanate.
Primer 9Example 9
Nečisto raztopino klavulanske kisline, kije surov ekstrakt izfermentacijskejuhe S. clavuligerus, smo po delnem predhodnem očiščenju z ionsko izmenjavo (500 ml, /zg/ml v etil acetatu) pomešali z acetonom (150 ml) in postopoma obdelali z raztopino Ν,Ν-dimetilcikloheksil amina (6.7 ml) v acetonu (25 ml). Alikvotni del smo odstranili in obdelali z dietiletrom in prišlo je do neposredne kristalizacije, s cepljenjem glavne mase je prišlo do hitre kristalizacije belih ploščic, ki je bilo dokončano z dodatkom etra (110 ml). Aminsko sol smo odfiltrirali in izprali z acetonom (3 x 100 ml) ter sušili na zraku. Dobitek = 13.4 g, 82 % rekuperacija, 64.9 % ugot. (teoretsko 61.0 %).An impure solution of clavulanic acid, which is a crude extract of S. clavuligerus fermentation broth, was mixed with acetone (150 ml) after partial pre-purification by ion exchange (500 ml / wg / ml in ethyl acetate) and gradually treated with Ν, Ν-dimethylcyclohexyl solution. of amine (6.7 ml) in acetone (25 ml). An aliquot was removed and treated with diethyl ether and direct crystallization took place, grafting of the bulk resulted in rapid crystallization of the white plates, which was completed with the addition of ether (110 ml). The amine salt was filtered off and washed with acetone (3 x 100 ml) and air-dried. Yield = 13.4 g, 82% recovery, 64.9% found. (theoretically 61.0%).
Primer 10Example 10
K nečisti raztopini klavulanske kisline, uporabljene v Primeru 9 (500 ml, 21 Mg/ml), ki je dodatno vsebovala aceton, (20 ml), smo dodali t-oktilamin (7.6 g, 1.0 ekv.), kar je povzročilo lahno zmotnitev. Dodatek dietil etra (55 ml) je povzročil izločanje aminske soli kot fine bele iglice, ki smo jih odfiltrirali in izprali z acetonom.To the impure solution of clavulanic acid used in Example 9 (500 ml, 21 Mg / ml), which further contained acetone (20 ml), was added t-octylamine (7.6 g, 1.0 eq), which caused a slight disruption . The addition of diethyl ether (55 ml) resulted in the elimination of the amine salt as fine white needles, which were filtered off and washed with acetone.
Dobitek = 12.9 g, 77.2 % rekuperacija, 62.8 % ugot. (teoretsko 60.6 %).Yield = 12.9 g, 77.2% recovery, 62.8% found. (theoretically 60.6%).
Primer 11Example 11
Nečisto raztopino klavulanske kisline v etil acetatu (IL, 10.14 /ig/ml), dobljeno z ekstrakcijo iz fermentacijske juhe 5. clavuligerus z etil acetatom in delnem predhodnem očiščenju z ionsko izmenjavo, smo pomešali z acetonom (600 ml) in nato obdelali z raztopino benzatina (6.15 g) v etil acetatu (55 ml). Zmes je pričela kristalizirati, ko se je dodajanje benzatina približevalo zaključku. Nato smo dodali metilizobutil keton (200 ml), da je postalo obarjanje bolj popolno. Kristale smo odfiltrirali in izprali z acetonom (3 x 100 ml). Dobitek = 11.5 g, 67.0 % rekuperacija.An impure solution of clavulanic acid in ethyl acetate (IL, 10.14 / ig / ml) obtained by extraction from fermentation broth 5. clavuligerus with ethyl acetate and partial pre-purification by ion exchange was mixed with acetone (600 ml) and then treated with a solution of benzatin (6.15 g) in ethyl acetate (55 ml). The mixture began to crystallize as the addition of benzatin was nearing completion. Methylisobutyl ketone (200 ml) was then added to make the precipitation more complete. The crystals were filtered off and washed with acetone (3 x 100 ml). Yield = 11.5 g, 67.0% recovery.
- IH.- IH.
Primer 12Example 12
Ponovili smo postopek iz Primera 11 ob uporabi nečiste, vlažne (okoli 1% vode) raztopine klavuJanske kisline v etil acetatu. Za ločitev IL šarž te raztopine smo dodali ob mešanju prebitek samega etilen diamina, ΝΝ’-dietiletilen diamina in NN’diizopropiletilen diamina, pri čemer je množina vsakega amina v prebitku z ozirom na množino, potrebno za tvorbo diamonijeve soli s klavulansko kislino. Po kontinuirnem mešanju se je tvorila oborina soli. Dobili smo nadaljnjo porcijo kristalov z dodatkom prebitnega acetona. Oborjeno diamonijevo sol smo odfiltrirali in izprali z acetonom.The procedure of Example 11 was repeated using an impure, moist (about 1% water) solution of clavian acid in ethyl acetate. To separate the IL batches of this solution, an excess of ethylene diamine alone, ΝΝ′-diethylethylene diamine and NN′diisopropylethylene diamine was added with stirring, the amount of each amine being in excess of the amount needed to form the diammonium salt with clavulanic acid. After continuous stirring, a precipitate of salt formed. A further portion of the crystals was obtained by the addition of excess acetone. The precipitated diammonium salt was filtered off and washed with acetone.
Tako tvorjene kristale vsake izmed teh diamonijevih soli smo pretvorili v kalijev klavulanat z raztapljanjem soli v minimalni množini vode, čemur sledi dodatek raztopine prebitka kalijevega 2-etilheksanoata v izopropil alkoholu. Po kontinuirnem mešanju smo tvorili oborino kalijevega klavulanata in smo jo filtrirali, izprali z izopropil alkoholom in sušili.The thus formed crystals of each of these diammonium salts were converted to potassium clavulanate by dissolving the salt in a minimal amount of water, followed by the addition of a solution of excess potassium 2-ethylhexanoate in isopropyl alcohol. After continuous stirring, a precipitate of potassium clavulanate was formed and filtered, washed with isopropyl alcohol and dried.
Primer 13Example 13
Raztopino klavulanske kisline (0.0046 molov) v tetrahidrofuranil (30 ml) smo obdelali z raztopino trimetilamina v metanolu (1.0 ml 25% mas./vol. raztopine, okoli 0.0042 molov), pri čemer smo dobili bledorumeno raztopino. Kristalizacijo smo sprožili s cepljenjem in stanjem pri sobni temperaturi. Kristalizacija je bila hitra, dala je fine iglice in je bila zaključena s stanjem čez noč pri + 4°C. Produkt smo odfiltrirali, izprali z majhnim volumnom svežega topila (okoli 5 ml) in sušili v vakuumu. Dobitek je znašal 0.9 g (75 %); tal. nad 310 °C, počasno porjavenje pri temperaturi nad okoli 130 °C.A solution of clavulanic acid (0.0046 moles) in tetrahydrofuranyl (30 ml) was treated with a solution of trimethylamine in methanol (1.0 ml of a 25% w / v solution, about 0.0042 moles) to give a pale yellow solution. Crystallization was initiated by vaccination and condition at room temperature. Crystallization was rapid, gave fine needles and was terminated overnight at + 4 ° C. The product was filtered off, washed with a small volume of fresh solvent (about 5 ml) and dried in vacuo. The yield was 0.9 g (75%); m.p. above 310 ° C, slow tanning at temperatures above about 130 ° C.
Poskus B 24641: Ugot. C, 51.32; H, 7.15; N, 10.68% C11H18N2°5 terja C 51.16; H, 7.02; N, 10.84%Experiment B 24641: Det. C, 51.32; H, 7.15; N, 10.68% C 11 H 18 N 2 ° 5 requires C 51.16; H, 7.02; N, 10.84%
Poskus A 15230: Imidazol 77.2; 76.4% (izrač. 77.1% okoli 99.5% čistoča)Experiment A 15230: Imidazole 77.2; 76.4% (calc. 77.1% about 99.5% purity)
Voda 1.18; 1.34%Water 1.18; 1.34%
Spojina (kot krem obarvane fine iglice) se pokvari pri stanju na zraku v nekaj dneh, navzema vodo in počasi porumeni.The compound (like a cream colored fine needle) breaks down in air for several days, absorbs water and slowly turns yellow.
- 19 . Primer 14- 19. Example 14
Vključili smo dve pripravi zgornje spojine, ker je vsaka dala nekoliko drugačen rezultat. Prva je dala skromen dobitek vodo vsebujočega produkta, v taki meri, da ustreza hemihidratu, medtem ko je druga dala pretežno brezvoden material, čeprav v majhnem dobitku.We included two preparations of the above compound because each gave a slightly different result. The former yielded a modest yield of water-containing product to the extent that it corresponded to the hemihydrate, while the latter yielded predominantly anhydrous material, albeit in small yield.
14A. Klavulansko kislino (0.00346 molov) v tetrahidrofuranu (25 ml) smo obdelali s trietilaminom (0.4 g, 0.00346 molov) in mešali, da smo dobili homogeno bistro raztopino. Kristalizacijo smo sprožili s cepljenjem in dokončali s stanjem čez noč pri +4° C. Produkt smo odfiltrirali in sušili v vakuumu. Dobitek 0.7 g (63%) kot velike umazano bele iglice.14A. Clavulanic acid (0.00346 moles) in tetrahydrofuran (25 ml) was treated with triethylamine (0.4 g, 0.00346 moles) and stirred to give a homogeneous clear solution. Crystallization was initiated by grafting and terminated overnight at + 4 ° C. The product was filtered off and dried in vacuo. Yield 0.7 g (63%) as large dirty white needles.
Poskus B 24639: Ugot. C, 54.74; H, 7.95; N, 8.94%Experiment B 24639: Found. C, 54.74; H, 7.95; N, 8.94%
C14H24N2O5 terja C, 56.05; H, 8.00; N, 9.33% C14H24N2°5/2H2° terja C, 54.36; H, 8.14; N, 9.05%C14H24N2O5 requires C, 56.05; H, 8.00; N, 9.33% C 14 H 24 N 2 ° 5/2 H 2 ° requires C, 54.36; H, 8.14; N, 9.05%
Poskus A 15220: Imidazol 61.0; 61.1% (izrač. 64.4%, okoli 95.0% čistoča)Experiment A 15220: Imidazole 61.0; 61.1% (calculated 64.4%, about 95.0% purity)
Voda 2.64% (hemihidrat terja 12.91%)Water 2.64% (hemihydrate requires 12.91%)
14.B Klavulansko kislino (0.021 molov) v tetrahidrofuranu (60 ml) smo obdelali s trietil aminom (2.1 g, 0.021 molov) in mešano nastalo bistro raztopino cepili z avtentično soljo. Produkt je pričel kristalizirati v obliki dolgih iglic pri sobni temperaturi, pri čemer je bil postopek zaključen pri + 4 °C čez noč. Produkt smo zbrali s filtracijo, izprali na filtru s svežim topilom (okoli 10 ml) in dietil etrom (okoli 20 ml) in končno sušili v vakuumu, da smo dobili umazano bel kristalen produkt.14.B Clavulanic acid (0.021 mol) in tetrahydrofuran (60 ml) was treated with triethyl amine (2.1 g, 0.021 mol) and the resulting clear solution was cleaved with an authentic salt. The product began to crystallize in the form of long needles at room temperature, ending the process at + 4 ° C overnight. The product was collected by filtration, washed on the filter with fresh solvent (about 10 ml) and diethyl ether (about 20 ml) and finally dried in vacuo to give a dirty white crystalline product.
Dobitek 1.7 g (27%).Yield 1.7 g (27%).
Poskus B 24676: Ugot. C, 56.07; H, 7.83; N, 9.32%Experiment B 24676: Det. C, 56.07; H, 7.83; N, 9.32%
C14H24N2O5 terja C, 56.05; H, 8.00; N, 9.33%C14H24N2O5 requires C, 56.05; H, 8.00; N, 9.33%
C14H24N2O5/2H2O terja C, 54.36; H, 8.14; N, 9.05%C14H24N2O5 / 2H2O requires C, 54.36; H, 8.14; N, 9.05%
Poskus A 15268: Imidazol 65.1; 65.1% (Izrač. 66.3%, okoli 98.2% čistoča)Experiment A 15268: Imidazole 65.1; 65.1% (Calc. 66.3%, about 98.2% purity)
Voda 0.9% [ο;]024 + 47.00 c (c=0.2% v vodi)Water 0.9% [ο;] 0 24 + 47.00 c (c = 0.2% in water)
- ζΡ- ζΡ
Kot trimetil aminska sol se tudi produkt pokvari pri stanju na zraku v teku nekaj dni. Ta dva primera pojasnjujeta tvorbo zelo čistih soli klavulanske kisline iz raztopin klavulanske kisline v organskih topilih.Like trimethyl amine salt, the product also breaks down in the air for several days. These two examples explain the formation of very pure salts of clavulanic acid from solutions of clavulanic acid in organic solvents.
Primer 15Example 15
Ločene vzorce trimetilamin klavulanata in trietilamin klavulanata iz Primerov 13 in 14 smo raztopili v minimalni množini mrzle vode. Tem raztopinam smo dodali ob mešanju močno raztopino kalijevega 2-etilheksanoata v izopropanolu. Po kontinuirnem mešanju so se izločili kristali kalijevega klavulanata in smo jih lahko odfiltrirali, izprali s hladnim izopropanolom in sušili.Separate trimethylamine clavulanate and triethylamine clavulanate samples from Examples 13 and 14 were dissolved in a minimum amount of cold water. To these solutions, a strong solution of potassium 2-ethylhexanoate in isopropanol was added with stirring. After continuous stirring, the potassium clavulanate crystals were separated and could be filtered off, washed with cold isopropanol and dried.
Primer 16Example 16
Nečisto vodno raztopino klavulanske kisline, dobljene iz fermentacijske juhe S. clavuligerus s predhodnim čiščenjem, ki obsega ionsko izmenjalno kromatografijo ali tako, kot je na splošno nakazano zgoraj, ki vsebuje okoli 17.1 g/L, smo nakisali na pH 2.0 s 25 % vol./vol. žveplove kisline in nato kontinuirno ekstrahirali v etil acetat. Etil acetatni ekstrakt smo ohladili na 2 °C, odstranili vodo s centrifugiranjem, zatem sušili z MgSC>4, nato pa vodili skozi CPG ogljeno kolono. Pri tej stopnji je etil acetatni ekstrakt vseboval 6.02 g/L klavulanske kisline in smo ga nato koncentrirali z uparjenjem na koncentracijo 25.7 g/L klavulanske kisline in uporabili pri tej koncentraciji. Nivo vlažnosti koncentrata je znašal okoli 0.26 vol./vol. %.An impure aqueous solution of clavulanic acid obtained from S. clavuligerus fermentation broth by preliminary purification comprising ion exchange chromatography or as generally indicated above containing about 17.1 g / L was acidified to pH 2.0 with 25% vol. / vol. sulfuric acid and then continuously extracted into ethyl acetate. The ethyl acetate extract was cooled to 2 ° C, the water was removed by centrifugation, then dried with MgSC> 4, and then run through a CPG carbon column. At this stage, the ethyl acetate extract contained 6.02 g / L of clavulanic acid and was then concentrated by evaporation to a concentration of 25.7 g / L of clavulanic acid and used at this concentration. The humidity level of the concentrate was about 0.26 vol./vol. %.
7.8 ml t-oktilamina smo pomešali s 25 ml svežega etil acetata. To zmes smo počasi dodali k 2 L na klavulanatu bogatega etil acetatnega ekstrakta, razredčenega ponovno do titra 23.0 g/L s svežim etil acetatom, ob hitrem mešanju. Goščo smo mešali nadaljnjo uro pri 5 °C. t-Oktilamin klavulnat smo zatem izolirali s filtracijo in izprali z etil acetatom. Končno sušenje smo izvedli čez noč v vakumski peči pri 20 °C ob oddajanju dušika. Masa produkta = 6.13 g.7.8 ml of t-octylamine was mixed with 25 ml of fresh ethyl acetate. This mixture was slowly added to 2 L on clavulanate-rich ethyl acetate extract, diluted again to a titer of 23.0 g / L with fresh ethyl acetate, with rapid stirring. The slurry was stirred for a further hour at 5 ° C. The t-octylamine clavulnate was then isolated by filtration and washed with ethyl acetate. The final drying was carried out overnight in a vacuum oven at 20 ° C with nitrogen emission. Product weight = 6.13 g.
Primer 17 g aminske soli, pripravljene v Primeru 16, smo raztopili v 97 ml izopropanola. Produkt se ni zlahka raztopil in ugotovili smo, da je potrebno previdno ogrevanje na 24 °C, da dosežemo popolno raztapljanje. V teku 10 minut smo dodali 14 ml 1.5N kalijevega 2-etilheksanoata v izopropanolu. Goščo smo zatem mešali 1.5 ur pri 5 °C.Example 17 g of the amine salt prepared in Example 16 was dissolved in 97 ml of isopropanol. The product did not dissolve easily and we found that careful heating to 24 ° C was required to achieve complete dissolution. Within 10 minutes, 14 ml of 1.5N potassium 2-ethylhexanoate in isopropanol was added. The slurry was then stirred for 1.5 hours at 5 ° C.
Produkt kalijev klavulanat smo nato odfiltrirali, izprali z majhnimi množinami izopropanola, nato pa acetona in sušili Čez noč v vakuumu ob oddajanju dušika pri 20 °C. Masa produkta = 3.16 g.The potassium clavulanate product was then filtered off, washed with small amounts of isopropanol, then acetone and dried overnight in vacuo with nitrogen at 20 ° C. Product weight = 3.16 g.
Primer .18Example .18
Filtrirano (RVF) fermentacijsko juho S. clavuligerus, ki vsebuje 2 g/L klavulanske kisline, smo nakisali na pH 1.6 s 25 % vol./vol. žveplove kisline in nato kontinuirno ekstrahirali v etil acetat. Estrakt v topilu smo ohladili na 3 °C, odstranili vodo s centrifugiranjem, zatem sušili z MgSC>4, nato pa vodili skozi CPG ogljeno kolono. Z ogljem obdelani ekstrakt smo nato koncentrirali z uparjenjem na koncentracijo okoli 20 g/L klavulanske kisline z vsebnostjo vlage okoli 0.06 vol./vol. %.The filtered (RVF) fermentation broth of S. clavuligerus containing 2 g / L of clavulanic acid was acidified to pH 1.6 with 25% vol./vol. sulfuric acid and then continuously extracted into ethyl acetate. The extract in the solvent was cooled to 3 ° C, the water was removed by centrifugation, then dried with MgSC> 4, and then run through a CPG carbon column. The charcoal-treated extract was then concentrated by evaporation to a concentration of about 20 g / L of clavulanic acid with a moisture content of about 0.06 vol./vol. %.
13.5 ml t-oktilamina smo pomešali s 43 ml svežega etil acetata. To zmes smo počasi dodali k 400 ml na klavulanatu bogatega etil acetatnega ekstrakta, s titrom 20 g/L klavulanske kisline, ob hitrem mešanju. Goščo smo mešali nadaljnjo uro pri 5 °C. t-Oktilamin klavulnat smo zatem izolirali s filtracijo in izprali z etil acetatom. Končno sušenje smo izvedli čez noč v vakumski peči pri 20 °C ob oddajanju dušika. Masa produkta = 12.44 g.13.5 ml of t-octylamine were mixed with 43 ml of fresh ethyl acetate. This mixture was slowly added to 400 ml on clavulanate-rich ethyl acetate extract, with a titer of 20 g / L of clavulanic acid, with rapid stirring. The slurry was stirred for a further hour at 5 ° C. The t-octylamine clavulnate was then isolated by filtration and washed with ethyl acetate. The final drying was carried out overnight in a vacuum oven at 20 ° C with nitrogen emission. Product weight = 12.44 g.
Primer 19 lig aminske soli, pripravljene v Primeru 18, smo raztopili v 213 ml izopropanola. Produkt se ni zlahka raztopil celo po previdnem ogrevanju na 24 °C. Dodali smo vodo (3.75 ml), da smo omogočili raztapljanje. Ko smo dobili raztopino, smo še dodali izopropanol (100 ml), da smo zmanjšali vsebnost vode pred kristalizacijo. 30 ml 1.5N kalijevega 2-etilheksanoata v izopropanolu smo dodali v teku 15 minut. Goščo smo zatem mešali 1.5 ur pri 5 °C. Produkt kalijev klavulanat smo nato odfiltrirali, izprali z majhnimi množinami izopropanola, nato pa acetona in sušili čez noč v vakuumu ob oddajanju dušika pri 20 °C. Masa produkta = 7.29 g.Example 19 of the amine salt prepared in Example 18 was dissolved in 213 ml of isopropanol. The product did not dissolve easily even after careful heating to 24 ° C. Water (3.75 ml) was added to allow dissolution. After the solution was obtained, isopropanol (100 ml) was added to reduce the water content before crystallization. 30 ml of 1.5N potassium 2-ethylhexanoate in isopropanol was added over 15 minutes. The slurry was then stirred for 1.5 hours at 5 ° C. The potassium clavulanate product was then filtered off, washed with small amounts of isopropanol, then acetone and dried overnight in vacuo, under nitrogen evolution at 20 ° C. Product weight = 7.29 g.
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