SI7913086A8 - Process for obtaining the 7-alpha-methoxy-cephalosporin derivate - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Description
Postopek za pripravo derivata 7-a-metoksicefalosporinaA process for the preparation of a 7-α-methoxycephalosporin derivative
Tehnično področje izumsTechnical field of inventions
C 07D 501/00C 07D 501/00
A 61K 31/545A 61K 31/545
Predloženi izum se nanaša na postopek za pripravo novega derivata 7-a-metoksi-cefalosporina z antibakterijsko aktivnostjo.The present invention relates to a process for the preparation of a novel 7-α-methoxy-cephalosporin derivative with antibacterial activity.
Tehnični problemA technical problem
Obstajala je potreba po tehnološko naprednem postopku za pripravo novih derivatov cefalosporina z izboljšanimi antibakterijskimi učinki, v dobrih dobitkih in v zadovoljivi čistoči.There was a need for a technologically advanced process for the preparation of novel cephalosporin derivatives with improved antibacterial effects, in good yields and in satisfactory purity.
- 1a Stanje tehnike- 1a State of the art
Spojine, definirane s formulo (I) v nadaljevanju opisa, so nove, zato postopek za njihovo pripravo še ni bil opisan.The compounds defined by the formula (I) below are novel, and the process for their preparation has not yet been described.
Opis rešitve tehničnega problema z izvedbenimi primeriDescription of solution to a technical problem with implementation examples
Predloženi izum se naneŠa na postopek za pripravo novega derivata 7-a-metoksicef8losporina s splošno formuloThe present invention relates to a process for the preparation of a novel derivative of 7-a-methoxyf8losporin of the general formula
OCHOCH
O coor4 About coor 4
- 2 kjer Ηη stoji za (1-metil-/lH-tetrazol-5-il)-tio, (1-karboksimetil-1H-tetrazol-5-il)-tio, (1-sulfonilmetil-1H-tetrazol5-il)-tio, (1-sulfoniletil-1H-tetrazol-5-il)-tio, (2-karboksimetil-1H-triazol->-il)-tio, (2-karboksi-l-metil1S-triazol-5-il)-tio, (4-metil-5-okso-6-hidroksi-4,5-dihidro-1,2,4-triazin-3-il)-tio, piridihij ali p-karbamoilpiridinij,- 2 where Ηη stands for (1-methyl- / 1H-tetrazol-5-yl) -thio, (1-carboxymethyl-1H-tetrazol-5-yl) -thio, (1-sulfonylmethyl-1H-tetrazol5-yl) -thio, (1-sulfonylethyl-1H-tetrazol-5-yl) -thio, (2-carboxymethyl-1H-triazol-1-yl) -thio, (2-carboxy-1-methyl-S-triazol-5-yl) -thio, (4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl) -thio, pyridichium or p-carbamoylpyridinium,
S2 stoji za vodik ali za skupino -COOR^, pri čemer R^ pomeni vodik, nižji alkil, dialkilamino-nižjialkil ali skupino -CH-Ο-Εθ, v kateri Εθ pomeni nižji alkil, nižji acil ali nižjiS 2 stands for hydrogen or for the -COOR 4 group, wherein R 4 represents hydrogen, lower alkyl, dialkylamino-lower alkyl or -CH-Ο-Εθ, in which Εθ means lower alkyl, lower acyl or lower
Y alkoksikarbonil in Ϊ vodik ali nižji alkil,Y is alkoxycarbonyl and Ϊ is hydrogen or lower alkyl,
R^ stoji za vodik, karbamoil, nižji acil, ki je v danem primeru lahko substituiran s halogenom ali aminom, ali za nižji alkoksikarbonil ,R4 stands for hydrogen, carbamoyl, lower acyl, optionally substituted by halogen or amine, or lower alkoxycarbonyl,
R^ vodik ali skupino -CH-0-Εθ , kjer imata Εθ in Y zgoraj naY vedeni pomen,R ^ is hydrogen or a group -CH-0-Εθ, where Εθ and Y have the meanings given above,
A in B sta enaka ali različna in predstavljata razvejen ali nerazvejen C^-C^-alkilen, kot tudi njihovih farmacevtsko sprejemljivih soli.A and B are the same or different and represent branched or unbranched C 1 -C 4 -alkylene as well as their pharmaceutically acceptable salts.
Kot rezultat številnih raziskav se je pokazalo, da se v smislu izuma pripravljene spojine odlikujejo v primeri z znanimi derivati 7-a-metoksicefalosporina po izredno izboljšanih antibakterijskih učinkih. V smislu izuma pripravljene spojine lahko dobimo kot notranje soli. Ce je R2 v danem primeru .- 3..- substituirana karboksilna skupina lahko spojina nastopa bodisi kot D-stereoizomer ali L-stereoizomer, pri čemer izum obsega obe obliki. D-oblika ima običajno boljši antibakterijski učinek kot L-oblika, razen če R^ pomeni acilno skupino, substituirano z aminsko skupino.As a result of numerous studies, it has been shown that, according to the invention, the compounds prepared are distinguished, in comparison with the known 7-a-methoxycephalosporin derivatives, by extremely improved antibacterial effects. According to the invention, the compounds prepared can be obtained as internal salts. If R 2 is, as the case may be, a 3-3- substituted carboxyl group, the compound may be present as either a D-stereoisomer or an L-stereoisomer, the invention comprising both forms. The D-form usually has a better antibacterial effect than the L-form, unless R1 represents an acyl group substituted with an amine group.
Nižja acilna skupina, ki stoji za R^, je lahko ravna ali razvejena alifatska acilna skupina z 1 do 6 atomi ogljika, ki je v danem primeru lahko substituirana z atomom halogena ali aminsko skupino.The lower acyl group, which stands for R4, may be a straight or branched aliphatic acyl group of 1 to 6 carbon atoms which may optionally be substituted by a halogen atom or an amine group.
Alkil- oz. alkoksikarbonilne skupine za R^ in Rg so lahko ravne ali razvejene z do 6, prednostno do 4 atomi ogljika.Alkyl- oz. alkoxycarbonyl groups for R1 and R8 may be straight or branched with up to 6, preferably up to 4, carbon atoms.
Y v pomenu nižji alkil je ravna ali razvejena alkLlna skupina z 1 do 4 atomi ogljika.Y in the meaning of lower alkyl is a straight or branched alkyl group of 1 to 4 carbon atoms.
Alkilenske skupine A in B so linearne ali razvejene z 1 do 5 atomi ogljika, prednostno 1 do 5 atomi ogljika.The alkylene groups A and B are linear or branched with 1 to 5 carbon atoms, preferably 1 to 5 carbon atoms.
Skupine, ki so v smislu definicije prikazane z Ηη, imajo naslednje formule:The groups represented by Ηη in the definition have the following formulas:
N-NN-N
-S-S
-S 'N č-ch2-cooh ch2-so3h-S 'N h-ch 2 -cooh ch 2 -so 3 h
CH2CH2-SO3HCH 2 CH 2 -SO 3 H
CH3 ch2-coohCH 3 ch 2 -cooh
V formuli I lahko, kot je navedeno, ostanek predstavlja tudi karboksilno skupino ali kislinski derivat. Spojine zato lahko tvorijo notranje soli ali jih pri zaostrenih karboksilnih skupinah pridobimo kot prosto bazo. Vendar pa je prikladno, kadar jih uporabljamo v obliki farmacevtsko sprejemljive kislinske adicijske soli, npr. s solno, žveplovo, fosforjevo, ocetno, vinsko, maleinovo, jantarno, glutaminsko ali asparaginsko kislino ali kot notranje soli. Te kislinske adicijske soli ali notranje soli pa niso le zelo stabilne, temveč tudi v vodi lahko topne in zato zelo primerne za dajanje. Razen tega je terapevtski efekt povišan zaradi njihove enotne sposobnosti raztapljanja.In formula I, as indicated, the residue may also represent a carboxyl group or an acid derivative. The compounds may therefore form internal salts or be obtained as the free base in sharpened carboxyl groups. However, it is convenient when used in the form of a pharmaceutically acceptable acid addition salt, e.g. with hydrochloric, sulfuric, phosphoric, acetic, tartaric, maleic, succinic, glutamic or aspartic acids, or as internal salts. These acid addition salts or internal salts, however, are not only very stable but also water soluble and therefore very suitable for administration. In addition, the therapeutic effect is enhanced by their unique dissolution ability.
Če nastopa karboksilna skupina v legi 4 obročnega sistema v zaestreni obliki, lahko ostanek R^ predstavlja nižji alkil (kot npr. metil, etil, propil ali terc.butil), dimetilaminoetil, metoksimetil, etoksimetil, 1-etoksietil , acetoksimetil, 1-acetoksietil, propioniloksimetil, 1-propioniloksietil, pivaloiloksimetil, 1-pivaloiloksietil, metoksikarboniloksimetil, 1-metoksikarboniloksietil, etoksikarboniloksimetil, 1-etoksikarboniloksietil.If the carboxyl group in position 4 of the ring system is in esterified form, the residue R1 may represent lower alkyl (such as methyl, ethyl, propyl or tert-butyl), dimethylaminoethyl, methoxymethyl, ethoxymethyl, 1-ethoxyethyl, acetoxymethyl, 1-acetoxyethyl , propionyloxymethyl, 1-propionyloxyethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl.
) 77'')'-'7 ) /77- 5 Ostanki amino kislin substituentov v legi 7 obročnega sistema so lahko D- ali L-stereoizomeri, katere se da pripraviti v okviru predloženega izuma. D-oblika kaže običajno višjo antibakterijsko učinkovitost in vivo kot L-oblika.) 77 '') '-' 7) / 77- 5 The amino acid residues of the substituents at position 7 of the ring system can be D- or L-stereoisomers which can be prepared in the context of the present invention. The D-form shows typically higher antibacterial efficacy in vivo than the L-form.
Postopek v smislu izuma poteka tako, da spojino, s splošno formuloThe process of the invention is carried out by the compound of the general formula
X-(A)-CONHX- (A) -CONH
ch2-Ri (II), kjer X stoji za halogen in imajo R^ kot tudi A zgoraj na· vedeni pomen, presnovimo s spojino s splošno formuloch 2 - Ri (II), where X stands for halogen and R 1 as well as A have the above meaning, are reacted with a compound of the general formula
NHR-,NHR-,
I 2 , CH-(B)-SH (III) .I 2, CH- (B) -SH (III).
I * kjer imajo Rg» in B zgornji pomen, v inertnem topilu v prisotnosti baze za vezanje halogenovodika pri sobni temperaturi ali manj v teku Ί do 5 ur, po želji v dobljeni spojini s formulo (I) karboksilno skupino, ki stoji za Rg» zaestrimo ob uvedbi skupine R^, pri čemer ima R^ z izjemo vodika zgornji pomen in/ali za primer, da R^ predstavlja vodik, uvedemo skupino -ΟΗ-Ο-βθ , kjer imata Ηθ in Y zgoraj definirani pomen, naΪ mesto vodika in/ali dobljeno spojino s formulo (I), v kateriI * where Rg »and B are of the above meaning, in an inert solvent in the presence of a hydrogen halide bonding base at room temperature or less for up to 5 hours, optionally in the compound obtained with formula (I), a carboxyl group which stands for Rg» esterate upon the introduction of the group R ^, where R ^ with the exception of hydrogen has the above meaning and / or in the case where R ^ represents hydrogen, introduce the group -ΟΗ-Ο-βθ, where Ηθ and Y have the meanings defined above, in the hydrogen position and / or the compound of formula (I) obtained wherein
- 6 R^ pomeni vodik, za uvedbo karbamoila obdelamo s cianatom alkalijske kovine in/ali dobljeno spojino s formulo (I) po želji prevedemo v farmacevtsko sprejemljivo sol, ali sprostimo iz soli·- R 6 represents hydrogen, treated with alkali metal cyanate to introduce the carbamoyl, and / or the resulting compound of formula (I) is optionally converted into a pharmaceutically acceptable salt, or released from the salt ·
Prednostno uporabimo spojino s formulo (III), kjer Rj pomeni formil, acetil, propionil, glicil, trifluoracetil ali alanil·Preferably, a compound of formula (III) is used wherein R1 is formyl, acetyl, propionyl, glycyl, trifluoroacetyl or alanyl
Prikladno uporabimo v smislu izuma spojine, kjer A in B vsakokrat predstavljata metilen.Conveniently used according to the invention are compounds wherein A and B each represent methylene.
Po nadaljnji prednostni izvedbeni obliki uporabljamo spojine, kjer Rg stoji za karboksil in R^ za vodik.In a further preferred embodiment, compounds are used wherein Rg stands for carboxyl and R4 stands for hydrogen.
Izhodno spojino s formulo II sintetiziramo po običajnih metodah, kot npr. v smislu US-PB 4 115 645·The starting compound of formula II is synthesized by conventional methods, such as e.g. in the sense of US-PB 4 115 645 ·
Halogen Σ v formuli (II) lahko pomeni klor, brom ali jod, pri čemer dajemo prednost kloru in bromu.Halogen Σ in formula (II) may mean chlorine, bromine or iodine, with chlorine and bromine being preferred.
Reakcijo za pripravo spojine (I) iz spojine (II) izvedemo na splošno tako, da spojino s formulo (III) pustimo učinkovati na spojino (II) v inertnem topilu v prisotnosti sredstva za vezanje kisline, t.j. baze za vezanje halogenovodika.The reaction for the preparation of compound (I) from compound (II) is generally carried out by allowing the compound of formula (III) to act on compound (II) in an inert solvent in the presence of an acid-binding agent, i.e. bases for hydrogen halide bonding.
Pri tej reakciji lahko uporabimo vsako poljubno topilo brez posebne omejitve, le da, ne.. . sodeluje pri reakcijiposebno primerna topila so voda, metanol in aceton. Primeri za sredstva za vezanje kisline so baze, kot hidrogenkarbonat alkalijske kovine, trialkilamini in piridin. Spojina (II) reagira s spojino (III)In this reaction, any solvent can be used without any particular restriction, yes, no ... reaction solvents are particularly suitable solvents are water, methanol and acetone. Examples of acid-binding agents are bases such as alkali metal hydrogen carbonate, trialkylamines and pyridine. Compound (II) reacts with compound (III)
- 7 v prisotnosti takega sredstva za vezanje kisline pri sobni temperaturi ali man j; pri bistveno nevtralnih pogojih (pH- 7 in the presence of such an acid-binding agent at room temperature or less ; under substantially neutral conditions (pH
6,5 do 7»5)» pri čemer se tvori spojina s formulo (1). Reakcijski čas je v glavnem odvisen od reaktivnosti halogena, kot tudi od vrste sredstva za vezanje kisline in topila in znaša na splošno med 50 minutami in 5 urami.6.5 to 7.5 to form a compound of formula (1). The reaction time is mainly dependent on the reactivity of the halogen as well as the type of acid and solvent binding agent and generally ranges between 50 minutes and 5 hours.
Reakcijski produkt lahko ločimo od reakcijske zmesi na običajen način. Reakcijsko zmes npr. nakisamo, tako da se tvori oborina reakcijskega produkta, katero odločimo. Nadalje lahko reakcijski produkt adsorbiramo na aktivnem oglju ali absorpcijski smoli, eluiramo s topilom, ki vsebuje vodo ter za čiščenje podvržemo kolonski kromatografiji.The reaction product can be separated from the reaction mixture in the usual way. The reaction mixture e.g. it is acidified to form a precipitate of the reaction product to be decided. Further, the reaction product can be adsorbed on activated carbon or absorbent resin, eluted with a solvent containing water and subjected to column chromatography for purification.
Spojino s formulo (1), kjer je R^ karbamoilna ali acilna skupina, lahko pripravimo tudi tako, da spojino s formulo (1), kjer Rj pomeni vodik, presnovimo z nekim drugim reagentom kot je cianat alkalijske kovine, npr. s karbamoilkloridom ali acilirnim reagentom kot npr. S-etiltrifluortioacetatom, anhidridom trifluorocetne kisline, anhidridom mravljinčne kisline ali anhidridom ocetne kisline. Reakcijo lahko izvedemo v topilu, ki ne sodeluje pri reakciji (npr. vodi, piridinu ali dimetilformamidu), je pa končana po nekaj urah (5 do 3θ ur) pri sobni temperaturi ali manj,pri nevtralnih do šibko alkalnih pogojih (pH 7,5 do 8). Po reakciji končno spojino s formulo (I), kjer R^ stoji za karbamoil ali nižji acil, s pridom izoliramo in očistimo z adsorpcijo na aktivnem oglju ali adsorpcijski smoli, elucijo in kolonsko kromatografijo.A compound of formula (1) wherein R1 is a carbamoyl or acyl group can also be prepared by reacting with a compound of formula (1) where R1 is hydrogen with another reagent such as an alkali metal cyanate, e.g. with carbamoyl chloride or an acylating reagent such as e.g. S-ethyltrifluorothioacetate, trifluoroacetic anhydride, formic anhydride or acetic anhydride. The reaction may be carried out in a non-reaction solvent (e.g. water, pyridine or dimethylformamide) but terminated after a few hours (5 to 3θ hours) at room temperature or less, under neutral to slightly alkaline conditions (pH 7.5 to 8). After the reaction, the final compound of formula (I) wherein R1 is carbamoyl or lower acyl is advantageously isolated and purified by adsorption on activated carbon or adsorption resin, elution and column chromatography.
- 8 (Ha)- 8 (Ha)
Priprava izhodnih spojin s formuloPreparation of starting compounds of formula
CH2r1 je opisana v US-PS 4 115 645. Obdelava poteka analogno zgoraj opisanemu načinu dela.CH 2 r 1 is described in US-PS 4 115 645. The treatment is carried out analogously to the method described above.
Nadaljnja možnost sinteze je opisana v US-PSA further synthesis option is described in US-PS
007 177·007 177 ·
Reakcija spojine (II) s ci s teinom, njegovimi homologi ali njihovimi alkilestri lahko poteka v topilu, pri čemer nastane spojina s formulo (I). Za to reakcijo lahko uporabimo vsako poljubno topilo, dokler ostane inertno proti udeležencem reakcije.Reaction of compound (II) with ci with tein, its homologs or their alkylesters can be carried out in a solvent to form a compound of formula (I). Any solvent can be used for this reaction as long as it remains inert to the participants in the reaction.
Primerna topila so: voda, metanol, etanol, aceton, dioksan, tetrahidrofuran in dimetilformamid, katere vsakokrat lahko uporabimo same ali v zmesi. Reakcija poteka prednostno pri v bistvu nevtralnih pogojih, pri čemer pa lahko primešamo kislino ali alkalno sredstvo, da vzdržujemo pH vrednost reakcijske zmesi med 6,5 in 7,5· Reakcija poteka v temperaturnem območju med -10 °C in sobno temperaturo. Reakcijski čas je odvisen od reaktivnosti halogena in vrste topila in leži na splošno med 50 minutami in 5 urami.Suitable solvents are: water, methanol, ethanol, acetone, dioxane, tetrahydrofuran and dimethylformamide, which can each be used alone or in a mixture. The reaction is preferably carried out under substantially neutral conditions, but the acid or alkaline agent may be admixed to maintain the pH of the reaction mixture between 6.5 and 7.5. The reaction takes place in a temperature range between -10 ° C and room temperature. The reaction time depends on the reactivity of the halogen and the type of solvent and generally lies between 50 minutes and 5 hours.
- 9 V smislu izuma pripravljene spojine s splošno formulo (I) imajo LD^-vrednost približno 6 do 8 g/kg pri intravenozni injekciji mišim ter »«bistvu niso toksične.According to the invention, the compounds of general formula (I) have an LDl value of about 6 to 8 g / kg by intravenous injection in mice and are substantially non-toxic.
Iz tega sklepamo, da bi se dalo v smislu izuma pripravljene spojine s formulo (I) s pridom uporabiti kot zdravila za zdravljenje bolezni, ki jih, povzročajo bakterije. V ta namen dajemo spojino s formulo (I) bodisi parenteralno v obliki intravenoznih ali intramuskularnih injekcij; v svečkah ali oralno kot tablete, praške, kapsule, sirup itd. Predloženi izum sedaj podrobneje opisujemo z ozirom na naslednje primere, katere pa podajamo samo za pojasnjevalne namene in obsega izuma nikakor ne omejujejo.From this, it is concluded that the compounds of formula (I) of the invention can advantageously be used as medicaments for the treatment of bacteria-induced diseases. To this end, the compound of formula (I) is administered either parenterally in the form of intravenous or intramuscular injections; in suppositories or orally as tablets, powders, capsules, syrup, etc. The present invention is now described in more detail with reference to the following examples, which, however, are given for illustrative purposes only, and in no way limit the scope of the invention.
- 10 I- 10 I
PRIMER 1 ; 73-bromacetamido-7a-metoksi-3-(1-nietil-1HI · tetrazol-5-il)tiometil-3-cefem~4-karboksilno kislino (9,2 g) iEXAMPLE 1; 73-Bromoacetamido-7a-methoxy-3- (1-niethyl-1H · tetrazol-5-yl) thiomethyl-3-cephem ~ 4-carboxylic acid (9.2 g) and
suspendiramo v 100 ml vode ter dodamo nasičeno vodno raztoi pino natrijevega bikarbonata k suspenziji ob hlajenju, da upavianamo pH na 7,2 in s tem tvorimo vodno raztopino kisline. Raztopini dodamo ob hlajenju 4,63 S D-cisteinhidroklorida, iis suspended in 100 ml of water and a saturated aqueous solution of sodium bicarbonate is added to the suspension upon cooling to reduce the pH to 7.2 to form an aqueous acid solution. To the solution, 4.63 S of D-cysteine hydrochloride, i, was cooled
I :I:
čemur sledi mešanje pri sobni temperaturi v teku 3θ do 40 minut, v tem času pa pH uravnamo na vrednost med 7,1 in 7,2.followed by stirring at room temperature for 3θ to 40 minutes, during which time the pH was adjusted to a value between 7.1 and 7.2.
Reakcijsko zmes vodimo skozi kolono (5 x 7θ cm), polnjeno zThe reaction mixture was led through a column (5 x 7θ cm) filled with
HH
800 ml Diaiona HP-20 in eluiramo z vodo. Iz z vodo eluiranih frakcij dobimo 5,25 g natrijeve soli 73-(2D-2-amino-2-karboI ksi)etiltioacetamido-7a-metoksi-3-('1-metil-1H-tetrazol-5-il)tiomctil-3-cefem-4-karboksilne kisline. Kolono Diaiona HP-20 izperemo s 5 %-nim vodnim acetonom, da pridobimo dodatnih 1,45 g končne spojine. Rf-vrednost proste 4-karboksilne kisline znaša 0,41 (DO na silikagelu; tekočinsko sredstvo: n-butanol:800 ml of Diaion HP-20 and eluted with water. From the water-eluted fractions, 5.25 g of the sodium salt of 73- (2D-2-amino-2-carboxy) ethylthioacetamido-7a-methoxy-3- ('1-methyl-1H-tetrazol-5-yl) thiomethyl- 3-Cephem-4-carboxylic acids. The Diaion HP-20 column was washed with 5% aqueous acetone to obtain an additional 1.45 g of the final compound. The Rf value of free 4-carboxylic acid is 0.41 (DO on silica gel; liquid: n-butanol:
ocetna kislina: voda =2:1:1). , !acetic acid: water = 2: 1: 1). ,!
PRIMER 2 '· \EXAMPLE 2 '· \
7P-bromoacetamido-7a-aietoksi-3-(1-metil-1Htetrazol-5-il)tiometil-3-cefem-4-karboksilno kislino (96θ mg)7P-Bromoacetamido-7a-aetoxy-3- (1-methyl-1Htetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (96θ mg)
- 11 suspendiramo v 20 ml vode, dodamo natrijev hidrogenkarbonat, da uravnamo pH suspenzije na 7,0 in tvorimo vodno raztopino kisline. Raztopini dodamo D_homocistein (300 mg) ter izvedemo reakcijo pri sobni temperaturi v teku 1,5 ur, pri čemer vzdržujemo pH med 7 in 7,5· Po reakciji uravnamo reakcijsko zmes na pH med 5,5 in 6,0, koncentriramo na majhen volumen, vodimo skozi kolono (2 x 68 cm), polnjeno s 150 ml Diaiona HP-20 ter eluiramo z vodo. Frakcije, ki vsebujejo končno spojino, združimo, koncentriramo in sušimo z zmrzovanjem, da dobimo 390 mg natrijevega 7P-(3H-3-amino-3-karboksi)propiltioacetamidc-7a-metoksi-3-(1-metil-1H-tetrazol-5-il)tiometil-3~cefem 4-kai*boksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,39 (n-butanol/ocetna kislina/voda = 2:1:1).- 11 is suspended in 20 ml of water, sodium hydrogen carbonate is added to adjust the pH of the suspension to 7.0 and form an aqueous acid solution. D_homocysteine (300 mg) was added to the solution and the reaction was carried out at room temperature for 1.5 hours, maintaining the pH between 7 and 7.5 · After adjusting the reaction mixture to pH between 5.5 and 6.0, concentrating on a small volume, run through a column (2 x 68 cm) filled with 150 ml of Diaion HP-20 and elute with water. The fractions containing the final compound were combined, concentrated and freeze-dried to give 390 mg of sodium 7P- (3H-3-amino-3-carboxy) propylthioacetamide-7a-methoxy-3- (1-methyl-1H-tetrazole- 5-yl) thiomethyl-3 ~ cephem 4-carboxylate. Rf on silica gel thin layer chromatography: 0.39 (n-butanol / acetic acid / water = 2: 1: 1).
PRIMER 3 7P-bromoacetamido-7a-metcksi-3-(p-karbamoilpiridinij)metil-3-cefem-4-karboksilno kislino (1,45 g) raztopimo v 3θ ml vode, dodamo 450 mg DL-homocisteina ter izvedemo i reakcijo pri sobni temperaturi v teku 2 ur, pri čemer vzdržujemo pH raztopine pri 7,θ· Po reakciji ponovimo način dela primera 11, da dobimo 600 mg 7p-(3DL-3-amino-karboksi)propiltioacetamido-7a-metoksi~3-(p-karbamoilpiridini j)metil3-cefem-4-karboksilne kisline. Rf pri tankoslojni kromatografiji na silikagelu: 0,25 (n-butanol/ocetna kislina/voda = 2:1:1).EXAMPLE 3 7P-Bromoacetamido-7a-methoxy-3- (p-carbamoylpyridinium) methyl-3-cephem-4-carboxylic acid (1.45 g) was dissolved in 3θ ml of water, 450 mg of DL-homocysteine was added and the reaction was carried out at room temperature for 2 hours while maintaining the pH of the solution at 7, θ · After reaction, repeat the method of working of Example 11 to give 600 mg of 7p- (3DL-3-amino-carboxy) propylthioacetamido-7a-methoxy ~ 3- (p -carbamoylpyridines (j) methyl 3-cephem-4-carboxylic acids. Rf on silica gel thin layer chromatography: 0.25 (n-butanol / acetic acid / water = 2: 1: 1).
-12 PRIMER 4-12 EXAMPLE 4
73-bromoacetamido-7a-metoksi-3-(1-nietil-1Htetrazol-5-il)'tiometil-3-cefem-4-karboksilno kislino (1,25 g) suspendiramo v 20 ral vode, dodamo natrijev hidrogenkarbonat, da tvorimo vodno raztopino kisline, zatem 550 mg D-penicilamin hidroklorida ter vršimo reakcijo pri 10 °C v teku 1,5 ur, pri čemer vzdržujemo pH reakcijske zmesi med 7,0 in 7,5»73-Bromoacetamido-7a-methoxy-3- (1-niethyl-1Htetrazol-5-yl) 'thiomethyl-3-cephem-4-carboxylic acid (1.25 g) was suspended in 20 acres of water, sodium hydrogen carbonate was added to form aqueous acid solution, followed by 550 mg of D-penicillamine hydrochloride and reacted at 10 ° C for 1.5 hours, maintaining the pH of the reaction mixture between 7.0 and 7.5 "
Po reakciji obdelamo reakcijsko zmes na enak način kot pri primeru 11, da dobimo 680 mg natrijevega 73-(2D-2-jamino-2~ karboksi-1,1-dimetil)etiltioacetamido-7a-metoksi-3-(1-nietil1H-tetrazol-5-il)tiometil-3-cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,45 (n-butanol/ ocetna kislina/voda = 2:1:1).After the reaction, the reaction mixture was treated in the same manner as in Example 11 to give 680 mg of sodium 73- (2D-2-ylamino-2 ~ carboxy-1,1-dimethyl) ethylthioacetamido-7a-methoxy-3- (1-methyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate. Rf on silica gel thin layer chromatography: 0.45 (n-butanol / acetic acid / water = 2: 1: 1).
PRIMER 5EXAMPLE 5
73-2-bromopropionamido-7a-metoksi-3-(1-®etil1H-tetrazol-5-il)tiometil-3-cefem-4-karboksilno kislino (5θθ mg) suspendiramo v 10 ml vode, dodamo natrijev hidrogenkarbonat, da uravnamo pH suspenzije na 7,0 in tvorimo vodno raztopino kisline, nato dodamo raztopini 210 mg D-cistein hidroklorida, zatem pa izvedemo reakcijo pri sobni temperaturi v teku 2 ur, pri čemer vzdržujemo pH reakcije med 7,0 in 7,5» Po reakciji uravnamo reakcijsko zmes na pH 6,0, koncentriramo na majhen volumen in obdelamo na enak način, kot pri primeru73-2-Bromopropionamido-7a-methoxy-3- (1-ethyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (5θθ mg) was suspended in 10 ml of water, sodium hydrogen carbonate was added to regulate The pH of the suspension is 7.0 and an aqueous acid solution is formed, then a solution of 210 mg of D-cysteine hydrochloride is added to the solution, then the reaction is carried out at room temperature for 2 hours while maintaining the pH of the reaction between 7.0 and 7.5. adjust the reaction mixture to pH 6.0, concentrate on small volume and treat in the same manner as in the example
- 13 11, da dobimo 230 mg natrijevega 73-[2-(2D_2-amino-2-karboksi)etiltiopropionamidoJ-7α“mθ'toksi-5-(1-metil-1H-tetrazol5-il) tiometil-3-cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,4 (n-butanol/ocetna kislina/ voda s 2:1:1).- 13 11 to give 230 mg of sodium 73- [2- (2D_2-amino-2-carboxy) ethylthiopropionamido] -7 α -nitroxy-5- (1-methyl-1H-tetrazol5-yl) thiomethyl-3-cephem -4-carboxylate. Rf on silica gel thin layer chromatography: 0.4 (n-butanol / acetic acid / water 2: 1: 1).
PRIMER,6EXAMPLE 6
73-bromopropionamido-7a-raetoksi-3-(1-nietil1H-tetrazol-5-il)tiometil-3-cefem-4-karboksilno kislino (980 mg) suspendiramo v 20 ml vode, dodamo natrijev hidrogen karbonat, da uravnamo pH na 7,0, pri čemer se tvori vodna raztopina kisline, Tej raztopini dodamo 325 mg D-cisteina ter vršimo reakcijo v teku 2 ur pri pH reakcijske zmesi med 7,0 in 7,5· Reakcijsko zmes obdelamo na enak način, kot pri primeru 11, da dobimo 410 mg natrijevega 73—C3D-3-amino-3karboksi)propiltiopropionamido-7a-metoksi-3-(1-metil-1Htetrazol-5-il)tionietil-3-cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,43 (n-butanol/ ocetna kislina/voda = 2:1:1). - 14 PRIMER 773-Bromopropionamido-7 ? -Raethoxy-3- (1-niethyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (980 mg) was suspended in 20 ml of water, sodium hydrogen carbonate was added to adjust the pH to 7.0 to form an aqueous acid solution, 325 mg of D-cysteine is added to this solution and the reaction is carried out for 2 hours at a pH of the reaction mixture between 7.0 and 7.5 · The reaction mixture is treated in the same way as for Example 11 to give 410 mg of sodium 73-C3D-3-amino-3-carboxy) propylthiopropionamido-7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thionethyl-3-cephem-4-carboxylate. Rf on silica gel thin layer chromatography: 0.43 (n-butanol / acetic acid / water = 2: 1: 1). - 14 EXAMPLE 7
73-bromoacetamido-7a-metoksi-5-(zl-me‘til-'1Htetrazol-5-il)tiometil-3-cefem-4-karboksilno kislino (480 mg) suspendiramo v 15 ml vode ter dodamo natrijev bikarbonat k suspenziji, da uravnamo njen pH na 7,0 in pri tem tvorimo vodno raztopino kisline. D-cistein-etilester-hidroklorid (17θ mg) dodamo k raztopini, katero vzdržujemo pri pH 7,0, medtem ko reakcijo nadaljujemo v teku 2 ur pri temperaturi 5 °C. Reakcijsko zmes uravnamo na pH 6,0, vodimo skozi kolono, napolnjeno s 7θ ml IAL-2, izperemo z vodo in eluiramo s 50 9&-nim vodnim acetonom. Frakcije, ki vsebujejo končno spojino,, koncentriramo in sušimo z zmrzovanjem, da dobimo 45O mg belega prahu 73-(2D-2-amino-2-etoksikarbonil)etiltioacetamido-7a-metoksi-3-(1-metil-1H-tetrazol~5-il)tiometil~ 3-cefem-4-karboksilne kisline. Prah nam da eno samo liso pri Rf 0,6 pri tankoslojni kromatografiji na silikagelu (aceton/metanol = 2:1).73-Bromoacetamido-7a-methoxy-5- ( with 1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (480 mg) was suspended in 15 ml of water and sodium bicarbonate added to the suspension to adjust its pH to 7.0 to form an aqueous acid solution. D-cysteine-ethyl ester hydrochloride (17θ mg) was added to a solution maintained at pH 7.0, while the reaction was continued for 2 hours at 5 ° C. The reaction mixture was adjusted to pH 6.0, passed through a column filled with 7θ ml of IAL-2, washed with water and eluted with 50 N aqueous acetone. The fractions containing the final compound were concentrated and freeze dried to give 45O mg of white powder 73- (2D-2-amino-2-ethoxycarbonyl) ethylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazole ~ 5-yl) thiomethyl ~ 3-cephem-4-carboxylic acid. The powder gave us a single spot at Rf 0.6 on thin layer chromatography on silica gel (acetone / methanol = 2: 1).
7P-(2D-2-amino-2-etoksikarbonil)etiltioacetamido-7<x-metoksi-3-(1-metil-1H-tetrazol-5-il)tiometil-3cefem-4-karboksilno kislino (310 mg) raztopimo v 5 ml vode, nato obdelamo raztopino z 1 n natrijevim lugom pri 0 °C, da uravnamo njen pH na 9,5 in takoj zatem sušimo z zmrzovanjem. Z zmrzovanjem sušeni proizvod suspendiramo v 6 ml Ν,Ν-dimetilformamida in dokapavamo suspenziji 3 ml raztopineN- (2D-2-Amino-2-ethoxycarbonyl) ethylthioacetamido-7H-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cepheme-4-carboxylic acid (310 mg) was dissolved in 5 ml of water is then treated with 1 n sodium hydroxide solution at 0 ° C to adjust its pH to 9.5 and then freeze-dried. The freeze-dried product was suspended in 6 ml of Ν, Ν-dimethylformamide, and a suspension of 3 ml of solution was added dropwise.
- 15 220 mg pivaloiloksimetiljodida v Ν,Ν-dimetilformamidu v teku 10 minut pri -20 °C, čemur sledi 1-urna reakcija pri 0 °C ob mešanju. Reakcijsko zmes razredčimo s 50 ml vode, izperemo s 30 ml etilacetata pri pH 3,0, obdelamo z natrijevim bikarbonatom, da spravimo pH na 8,0 in ekstrahiramo s 100 ml etilacetata. Ekstrakt dvakrat izperemo s 30 ml vode, sušimo z brezvodnim natrijevim sulfatom in filtriramo. Filtrat pomešamo z 0,3 ml trifluorocetne kisline in takoj zatem koncentriramo do suhega, da dobimo 340 mg belega prahu trifluoroacetata pivaloiloksimetil-73-(2D_2-amino-2-etoksikarbonil)etiltioacetamido-7a-metoksi-3-(1-metil-1H-tetrazol-5-il)tiometil-3-cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,75 (etilacetat/aceton = 5:1)·- 15 220 mg pivaloyloxymethyl iodide in Ν, dim-dimethylformamide for 10 minutes at -20 ° C, followed by a 1-hour reaction at 0 ° C with stirring. The reaction mixture was diluted with 50 ml of water, washed with 30 ml of ethyl acetate at pH 3.0, treated with sodium bicarbonate to bring the pH to 8.0 and extracted with 100 ml of ethyl acetate. The extract was washed twice with 30 ml of water, dried with anhydrous sodium sulfate and filtered. The filtrate was mixed with 0.3 ml of trifluoroacetic acid and concentrated immediately to dryness to give 340 mg of white powder of pivaloyloxymethyl-73- (2D_2-amino-2-ethoxycarbonyl) ethylthioacetamido-7a-methoxy-3- (1-methyl-1H trifluoroacetate). -tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate. Rf on silica gel thin layer chromatography: 0.75 (ethyl acetate / acetone = 5: 1) ·
PRIMER 8EXAMPLE 8
73-bromoacetamido-7a-metoksi-3-(1-nietil-1H~ tetrazol-5-il)tiometil-3-cefem-4~karboksilno kislino (960 mg) raztopimo v 10 ml Ν,Ν-dimetilformamida, dodamo 0,28 ml trietilamina k raztopini pri -20 °C ter dobljeni zmesi 5 ml raztopine 5θθ mg 1-acetoksietiljodida v N,N-dimetilformamidu po kapljicah v teku 15 minut, čemur sledi 1-urno mešanje pri 0 °C. Reakcijsko zmes razredčimo s 50 ml vode in ekstrahiramo s 100 ml etilacetata pri pH 6,0. Ekstrakt izperemo s 50 ml vode, sušimo z brezvodnim natrijevim sulfatom,73-Bromoacetamido-7a-methoxy-3- (1-niethyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 ~ carboxylic acid (960 mg) was dissolved in 10 ml of N, N-dimethylformamide, 0 was added. 28 ml of triethylamine to a solution at -20 ° C and the resulting mixture of 5 ml of a solution of 5θθ mg of 1-acetoxyethyliodide in N, N-dimethylformamide dropwise over 15 minutes, followed by stirring at 0 ° C for 1 hour. The reaction mixture was diluted with 50 ml water and extracted with 100 ml ethyl acetate at pH 6.0. The extract was washed with 50 ml of water, dried with anhydrous sodium sulfate,
- 16 filtriramo in koncentriramo do suhega. Preostanek izperemo s 30 ml petroletra in netopni preostanek sušimo nad fosforovim pentoksidom, da dobimo 1080 mg belega prahu 1-acetoksietil-7P--bromoacetamido-7oc-tnetoksi-3-(z1-nietil-.'1H-tetrazol5-il)tiometil-3-cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,85 (aceton/metanol = 2:1).- 16 filtered and concentrated to dryness. The residue was washed with 30 ml of petroleum ether and the insoluble residue was dried over phosphorus pentoxide to give 1080 mg of white powder 1-acetoxyethyl-7P-bromoacetamido-7oc-tnetoxy-3- ( with 1-methyl-1H-tetrazol5-yl) thiomethyl -3-Cephem-4-carboxylate. Rf on silica gel thin layer chromatography: 0.85 (acetone / methanol = 2: 1).
565 mg-ski delež prahu raztopimo v 8 ml dioksana, dodamo 15 ml vode v raztopini, katero nato obdelamo z natrijevim bikarbonatom, da uravnamo njen pH na 7,0, nakar dodamo raztopini 180 mg D-cisteinmetilester-hidroklorida, nato pa vršimo reakcijo pri 0 do 5 °C v teku 2,5 ur, pri čemer vzdržujemo pH med 6,5 in 6,8. Reakcijsko zmes razredčimo s 50 ml vode, ekstrahiramo s 100 ml etilacetata pri pH 8,0 in nato prenesemo v 50 ml razredčene klorovodikove kisline. Ekstrakt obdelamo z natrijevim bikarbonatom, da uravnamo njegov pH na 8,0, ponovno ekstrahiramo s 100 ml etilacetata in ekstrakt sušimo z brezvodnim natrijevim sulfatom ter koncentriramo do suhega, da dobimo 470 mg belega prahu 1-acetoksiet il-75-( 2D-2-amino-2-metoksikarbonil)etiltioacetamido-7ametoksi-3-(1-metil-1H-tetrazol-5-il)tiometil-3-cefem-4karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,70 (etilacetat/aceton = 5*·Ό·Dissolve 565 mg of the powder in 8 ml of dioxane, add 15 ml of water in solution, which is then treated with sodium bicarbonate to adjust its pH to 7.0, then add to the solution 180 mg of D-cysteine methyl ester hydrochloride and then react at 0 to 5 ° C for 2.5 hours, maintaining a pH between 6.5 and 6.8. The reaction mixture was diluted with 50 ml of water, extracted with 100 ml of ethyl acetate at pH 8.0 and then transferred to 50 ml of dilute hydrochloric acid. The extract was treated with sodium bicarbonate to adjust its pH to 8.0, re-extracted with 100 ml of ethyl acetate, and the extract was dried with anhydrous sodium sulfate and concentrated to dryness to give 470 mg of white powder 1-acetoxyethyl-75- (2D-2 -amino-2-methoxycarbonyl) ethylthioacetamido-7amethoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4carboxylate. Rf on silica gel thin layer chromatography: 0.70 (ethyl acetate / acetone = 5 * · Ό ·
- 17 PRIMER ,,9- 17 EXAMPLE, 9
1-pivaloiloksietilester (620 mg) 7P-bromoacetamido-7d-metoksi-3-(^-metil-1H-tetrazol-5-il)'tiouietil3-cefem-4-karboksilne kisline, dobljen po metodi primera 8, raztopimo v 10 ml tetrahidrofurana, dodamo 20 ml vode k raztopini, katero nato obdelamo z vodnim natrijevim bikarbonatom, da uravnamo njen pH na 7,θ, dodamo raztopini 19θ mg D-cistein-hidroklorida, reakcijo pa zatem izvršimo pri 0 do 5 °C v teku 2 ur, pri čemer vzdržujemo pH med 6,5 in 6,8. Reakcijsko zmes uravnamo na pH 5,5, neposredno zatem sušimo z zmrzovanjem in preostanek ekstrahiramo z 20 ml acetona.Dissolve 1-pivaloyloxyethyl ester (620 mg) of 7P-bromoacetamido-7d-methoxy-3- (N-methyl-1H-tetrazol-5-yl) -thioethyl-3-cephem-4-carboxylic acid in 10 ml. of tetrahydrofuran, 20 ml of water was added to the solution, which was then treated with aqueous sodium bicarbonate to adjust its pH to 7, θ, a solution of 19θ mg of D-cysteine hydrochloride was added, and the reaction was then carried out at 0 to 5 ° C for 2 hours , maintaining a pH between 6.5 and 6.8. The reaction mixture was adjusted to pH 5.5, then freeze-dried and the residue extracted with 20 ml of acetone.
Topilo uparimo do suhega in preostalo trdno snov raztopimo v 5θ ml vode in izperemo s 5θ ml etilacetata pri pH 2,0.The solvent was evaporated to dryness and the remaining solid dissolved in 5θ ml of water and washed with 5θ ml of ethyl acetate at pH 2.0.
Vodni sloj ponovno uravnamo na pH 5,5, nasitimo z natrijevim kloridom in trikrat ekstrahiramo s 100 ml etilacetata.The aqueous layer was again adjusted to pH 5.5, saturated with sodium chloride and extracted three times with 100 ml of ethyl acetate.
Ekstrakte združimo in sušimo z brezvodnim natrijevim sulfitom in koncentriramo do suhega, da dobimo 380 mg belega prahuThe extracts were combined and dried with anhydrous sodium sulfite and concentrated to dryness to give 380 mg of white powder
1-pivaloiloksietil-7P-(2D-2-amino-2-karboksi)etiltioacet~ amido-7a-metoksi-3-(1-metil-1H-tetrazol~5~il)tiometil~3cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,2 (aceton/metanol = 2:1).1-pivaloyloxyethyl-7P- (2D-2-amino-2-carboxy) ethylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cepheme-4-carboxylate. Rf on silica gel thin layer chromatography: 0.2 (acetone / methanol = 2: 1).
- 18 PRIMER 10 mg 73-aminoetiltioacetamido-7a-metoksi-3(1-metil-1H-tetrazol-5-il) tiometil-3-cefem-4-karboksilne kisline raztopimo v 3 ml vode, dodamo mg kalijevega cianata k raztopini, katero zatem uravnamo na pH med 7,5 in 8,0 in podvrženo reakciji pri sobni temperaturi v teku 6 ur. Po reakciji dodamo 7 ml vode k reakcijski zmesi, pH uravnamo na 6,5 in vodimo zmes skozi kolono Diaiona HP-20, eluiramo frakcije z vodo in frakcije, ki vsebujejo končno spojino, koncentriramo in sušimo z zmrzovanjem, da dobimo 20 mg 73-ureidoetiltioacetamido-7a-metoksi-3-(1-metil'H-tetrazol-5-il)tiometil-3-cefem-4-karboksilne kisline.- 18 EXAMPLE 10 mg of 73-aminoethylthioacetamido-7a-methoxy-3 (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was dissolved in 3 ml of water, mg of potassium cyanate was added to the solution, which was then adjusted to a pH between 7.5 and 8.0 and subjected to reaction at room temperature for 6 hours. After the reaction, 7 ml of water was added to the reaction mixture, the pH was adjusted to 6.5 and the mixture was passed through a Diaion HP-20 column, eluted with water and the fractions containing the final compound were concentrated and freeze dried to give 20 mg 73- ureidoethylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
Rf-vrednost pri tankoslojni kromatografiji na silikagelu: 0,73.Rf value for thin layer chromatography on silica gel: 0.73.
(n-butanol/ocetna kislina/voda = 2:1:1).(n-butanol / acetic acid / water = 2: 1: 1).
PRIMER 11EXAMPLE 11
Natrijevo sol (200 mg) 7P-(2D~2-amino-2~ karboksi)etiltioacetamido-7«·-metoksi-3-(1-metil-1H-tetrazol5-il)tiometil-5-cefem-4-karboksilne kisline, dobljeno pri primeru 1, raztopimo v 2 ml vode, raztopino obdelamo z 1 n klorovodikovo kislino, da uravnamo njen pH med 2,5 in 2,6, vodimo skozi kolono, napolnjeno s 100 ml Diaiona HP-20, izperemo z vodo, .eluiramo z 20 %—nim vodnim acetonom, da dobimo 184 mg proste kisline. 140 mg kisline raztopimo v 5 ml vode in tej raztopini dodamo raztopino 40 mg L_lizina v 0,8 ml vode, nastalo zmes (pH 7,05) pa sušimo z zmrzovanjem, da dobimo 180 mg L-lisinske soli 7£-(2D-2-amino-2karboksi)-etiltioacetamido-7«-metoksi-3-(^-nietil-1H-tetrazolSodium salt (200 mg) 7- (2D-2-amino-2-carboxy) ethylthioacetamido-7 '-methoxy-3- (1-methyl-1H-tetrazol5-yl) thiomethyl-5-cephem-4-carboxylic acid obtained in Example 1, dissolved in 2 ml of water, treated with 1 n hydrochloric acid to adjust its pH between 2.5 and 2.6, run through a column filled with 100 ml of Diaion HP-20, washed with water, is eluted with 20% aqueous acetone to give 184 mg of free acid. Dissolve 140 mg of acid in 5 ml of water and add a solution of 40 mg of L_lysine in 0.8 ml of water to this solution and freeze-dry the resulting mixture (pH 7.05) to give 180 mg of 7-L - lysine salts - (2D- 2-Amino-2carboxy) -ethylthioacetamido-7-methoxy-3- (N-ethyl-1H-tetrazole
5-il)tiometil-3-cefem-4-karboksilne kisline.5-yl) thiomethyl-3-cephem-4-carboxylic acid.
PRIMER 12EXAMPLE 12
7P-(2D-2-terc.butoksikarbonilamino-2-karboksi) etiltioacetamido-7a-tnetoksi-3-(1-metil-1H-tetrazol-5-il) tiometil-3-cefem-4-karboksilno kislino (1,25 g) raztopimo v 20 ml Ν,Ε-dimetilformamida, dodamo 0,66 ml trietilamina k raztopini ob hlajenju na -15 °C in zmesi dokapavamo raztopino 1,2 g pivaloiloksimetiljodida v Ν,Ν-dimetilformamidu po kapljicah v teku 20 minut, nakar pustimo reagirati 1 uro ob mešanju. Reakcijsko zmes izlijemo v 100 ml ledene vode, nakar ekstrahiramo dvakrat s 100 ml etilacetata. Ekstrakte združimo trikrat izperemo s 5θ ®1 vode, sušimo z brezvodnim natrijevim sulfatom in koncentriramo do suhega. Preostanek izperemo z 20 ml petroletra, da dobimo 1,02 g bledorumenega sirupa pivaloil oksimetil-73-(2D-2-terc.butoksikarbonilamino-2-pivaloiloksime toksikarbonil) etil tioacet amido-7oc-metoksi-3-(1-me til-1 lite trazol-5-il)tiometil-3-cefem-4-karboksilata.7P- (2D-2-tert-Butoxycarbonylamino-2-carboxy) ethylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (1,25 g) dissolved in 20 ml of Ε, Ε-dimethylformamide, 0.66 ml of triethylamine was added to the solution at -15 ° C and the solution was added dropwise with a solution of 1.2 g of pivaloyloxymethyl iodide in Ν, dim-dimethylformamide dropwise over 20 minutes; allowed to react for 1 hour with stirring. The reaction mixture was poured into 100 ml of ice water and then extracted twice with 100 ml of ethyl acetate. The extracts were combined three times washed with 5θ ® 1 water, dried with anhydrous sodium sulfate and concentrated to dryness. The residue was washed with 20 ml of light petroleum to give 1.02 g of pale yellow syrup of pivaloyl oxymethyl-73- (2D-2-tert.butoxycarbonylamino-2-pivaloyloxime toxicarbonyl) ethyl thioacet amido-7oc-methoxy-3- (1-methylo- 1 liter of trazol-5-yl) thiomethyl-3-cephem-4-carboxylate.
45O mg-ski delež sirupa raztopimo v 4 ml trifluorocetne kisline pri -10 °G in pustimo stati 20 minut. Trifluorocetno kislino odstranimo z uparevanjem, nakar vodimo reakcijsko zmes skozi kolono napolnjeno s 100 ml Sephadex LH-20 in eluiramo z acetonom. Frakcije, ki vsebujejo končno spojino, združimo in koncentriramo do suhega, da tako dobimo 260 mg belega prahu pivaloiloksimetil-7P-(2D-2-amino- 20 2-pivaloiloksimetoksikarbonil)etiltioacetamido-7a-metoksi-3(1-metil-1H-tetrazol-5-il)tiometil-3-cefem-4-karboksilata.The 45O mg portion of the syrup was dissolved in 4 ml of trifluoroacetic acid at -10 ° G and allowed to stand for 20 minutes. The trifluoroacetic acid was removed by evaporation and then the reaction mixture was passed through a column filled with 100 ml Sephadex LH-20 and eluted with acetone. The fractions containing the final compound were combined and concentrated to dryness to give 260 mg of white powder of pivaloyloxymethyl-7P- (2D-2-amino-20 2-pivaloyloxymethoxycarbonyl) ethylthioacetamido-7a-methoxy-3 (1-methyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.
Rf pri tankoslojni kromatografiji na silikagelu: 0,33 (etilacetat/aceton = 5:1).Rf on silica gel thin layer chromatography: 0.33 (ethyl acetate / acetone = 5: 1).
PRIMER 13EXAMPLE 13
73-(3D,L-3-amino-3-karboksi)propiltioacetamido-7a-metoksi-3-(1-metil-1H-tetrazol-5-il)tiometil-3cefem-4-karhoksilno kislino (250 mg) raztopimo v zmesi 4,0 ml Ν,Ν-dimetilformamida in 1,5 ml diklorometana ter nastali raztopini dodamo 0,135 ml trietilamina. Nato po kapljicah dodamo 3 ml diklorometanske raztopine, ki vsebuje 80 jul metoksimetilklorida, pri -35 °C v teku 30 minut, čemur sledi 3-urna reakcija pri -35 °0 ob mešanju. Reakcijsko zmes izlijemo v 50 ml ledene vode in trikrat ekstrahiramo s 50 ml etilacetata pri pH 8,0. Ekstrakte združimo, izperemo z vodo, dehidriramo z brezvodnim natrijevim sulfatom ter koncentriramo do suhega. Preostanek izperemo z 10 ml heksana, raztopimo v 3 ml dioksana in sušimo z zmrzovanjem, da dobimo 80 mg belega prahu metoksimetil 75-(3R,ij-3-amino-3-metoksime toksikarbonil) propil tioace tamido-7oc-metoksi-3-(1-met il-1Htetrazol-5-il)tiometil-3-cefem-4-karboksilata. Rf pri tankoslojni kromatografiji na silikagelu: 0,19 (etilacetat/ aceton = 5:1)21 Analogno zgornjim primerom pripravimo naslednje spojine s formulo (I):73- (3D, L-3-amino-3-carboxy) propylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cepheme-4-carboxylic acid (250 mg) was dissolved in to a mixture of 4.0 ml of Ν, Ν-dimethylformamide and 1.5 ml of dichloromethane and 0.135 ml of triethylamine are added to the resulting solution. Then, 3 ml of dichloromethane solution containing 80 µl of methoxymethyl chloride are added dropwise at -35 ° C for 30 minutes, followed by a 3-hour reaction at -35 ° 0 with stirring. The reaction mixture was poured into 50 ml of ice water and extracted three times with 50 ml of ethyl acetate at pH 8.0. The extracts were combined, washed with water, dehydrated with anhydrous sodium sulfate, and concentrated to dryness. The residue was washed with 10 ml of hexane, was dissolved in 3 ml of dioxane and dried by freezing to give 80 mg of a white powder methoxymethyl 75 (3R, and j-3-amino-3-methoxymethyl toksikarbonil) propyl thioacyl tamido-7oc-methoxy-3 - (1-Methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate. Rf for thin layer chromatography on silica gel: 0.19 (ethyl acetate / acetone = 5: 1) 21 The following compounds of formula (I) are prepared analogously to the above example:
7-P-aminoetil ti oace tamido-7o-me toksi-3- (1 -metil-1H-tetrazol5-il)-tiometil-3-cefem-4-karboksilno kislino; Rf (DC na silikagelu); 0,49 (n-butanol: ocetna kislina : voda = 2:1:1). EMR (DgO; vrednosti za kemični pomik v ppm proti TM3 kot zunanji standard)7-P-aminoethyl thiamine Tamido-7o-toxi-3- (1-methyl-1H-tetrazol5-yl) -thiomethyl-3-cepheme-4-carboxylic acid; Rf (DC on silica gel); 0.49 (n-butanol: acetic acid: water = 2: 1: 1). EMR (DgO; chemical shift values in ppm versus TM3 as an external standard)
5,16 (1H,s), 4,16 (2H, q), 4,05 ($H, s),5.16 (1H, s), 4.16 (2H, q), 4.05 ($ H, s),
3,6 (2H, q), 3,55 (5H, s), 3,5 (2H, q),3.6 (2H, q), 3.55 (5H, s), 3.5 (2H, q),
3,3 (2H, t), 3,0 (2H, t)3.3 (2H, t), 3.0 (2H, t)
7P-(2D-2-amino-2-karboksi-etiltioacetamido)-7a-iaetoksi-3piridinij-metil-3“cefem-4-karboksilna kislina, Rf (DC na silikagelu); 0,27 (tek. sredstvo: n-butanol : ocetna kislina : voda = 2:1:1).N- (2D-2-amino-2-carboxy-ethylthioacetamido) -7a-ethoxy-3-pyridinium-methyl-3 ' c epheme-4-carboxylic acid, Rf (DC on silica gel); 0.27 (liquid: n-butanol: acetic acid: water = 2: 1: 1).
ΙΑΙΑ
Navedbe ο najboljši, prijaviteljici znani izvedbi za gospodarsko izkoriščanje izuma ’ 7P-bromacetamido-7a-metoksi-3-(1-tnetil-1Htetrazol-5-il)tiometil-3-cefem-4-karboksilno kislino (9,2 g) suspendiramo v 100 ml vode ter dodamo nasičeno vodno raztopino natrijevega bikarbonata k suspenziji ob hlajenju, da uravnanamo pH na 7,2 in s tem tvorimo vodno raztopino kisline. Raztopini dodamo ob hlajenju 4,63 g D-cisteinhidroklorida, čemur sledi mešanje pri sobni temperaturi v teku 3θ do 40 minut, v tem času pa pH uravnamo na vrednost med 7,1 in 7,2. Reakcijsko zmes vodimo skozi kolono (5 χ 7θ cm), polnjeno z 800 ml Diaiona HP-20 in eluiramo z vodo. Iz z vodo eluiranih frakcij dobimo 5,25 g natrijeve soli 7P-(2D-2-amino-2-karboI ksi)etiltioacetamido-7a-metoksi-3-(1-iuetil-1H-tetrazol-5-il)tiometil-3-cefem-4-karboksilne kisline. Kolono Diaiona HP-20 izperemo s 5 %-nim vodnim acetonom, da pridobimo dodatnihSpecifications ο Best Applicant of the Known Commercial Use for the Invention of the invention 7β-Bromoacetamido-7α-methoxy-3- (1-tnetyl-1 Htetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (9.2 g) in 100 ml of water, and a saturated aqueous solution of sodium bicarbonate is added to the suspension upon cooling to adjust the pH to 7.2 to form an aqueous solution of acid. To the solution was added 4.63 g of D-cysteine hydrochloride while cooling, followed by stirring at room temperature for 3θ to 40 minutes, during which time the pH was adjusted to a value between 7.1 and 7.2. The reaction mixture was run through a column (5 χ 7θ cm) filled with 800 ml of Diaion HP-20 and eluted with water. From the water-eluted fractions, 5.25 g of the sodium salt of 7P- (2D-2-amino-2-carboxy) ethylthioacetamido-7a-methoxy-3- (1-ethyl-1H-tetrazol-5-yl) thiomethyl-3 is obtained -cephem-4-carboxylic acids. The Diaion HP-20 column was washed with 5% aqueous acetone to obtain additional
1,45 g končne spojine. Rf-vrednost proste 4-karboksilne kisline •znaša 0,41 (DC na silikagelu; tekočinsko sredstvo: n-butanol: ocetna kislina: voda = 2:1:1).1,45 g of the final compound. The free value of the free 4-carboxylic acid • is 0.41 (DC on silica gel; liquid: n-butanol: acetic acid: water = 2: 1: 1).
Claims (2)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15499778A JPS5583791A (en) | 1978-12-18 | 1978-12-18 | 7-methoxycephalosporin derivative and its preparation |
| JP12316079A JPS5646885A (en) | 1979-09-27 | 1979-09-27 | Novel cephamycin ester and its preparation |
| JP12315979A JPS5646884A (en) | 1979-09-27 | 1979-09-27 | Novel cephamycin derivative and its preparation |
| YU3086/79A YU41900B (en) | 1978-12-18 | 1979-12-17 | Process for obtaining the 7-alpha-methoxy - cephalosporin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI7913086A8 true SI7913086A8 (en) | 1997-04-30 |
Family
ID=27314644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI7913086A SI7913086A8 (en) | 1978-12-18 | 1979-12-17 | Process for obtaining the 7-alpha-methoxy-cephalosporin derivate |
Country Status (13)
| Country | Link |
|---|---|
| AU (1) | AU528886B2 (en) |
| CH (1) | CH643851A5 (en) |
| DE (1) | DE2950990C2 (en) |
| ES (1) | ES8101609A1 (en) |
| FR (1) | FR2444684A1 (en) |
| GB (1) | GB2040926B (en) |
| IL (1) | IL58939A (en) |
| IT (1) | IT1162424B (en) |
| NL (1) | NL186161C (en) |
| PT (1) | PT70602A (en) |
| SE (1) | SE446535B (en) |
| SI (1) | SI7913086A8 (en) |
| YU (1) | YU41900B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5630986A (en) * | 1979-08-23 | 1981-03-28 | Meiji Seika Kaisha Ltd | Preparation of 7-methoxycephalosporin derivative and drug composition |
| PL2121593T3 (en) | 2006-12-10 | 2015-11-30 | Chongxi Yu | Transdermal delivery systems of beta-lactam antibiotics |
| US9969751B2 (en) | 2009-06-10 | 2018-05-15 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4126745A (en) * | 1975-04-30 | 1978-11-21 | Sankyo Company Limited | 7-Methoxycephalosporin derivatives |
-
1979
- 1979-12-12 IL IL58939A patent/IL58939A/en unknown
- 1979-12-14 GB GB7943159A patent/GB2040926B/en not_active Expired
- 1979-12-14 AU AU53869/79A patent/AU528886B2/en not_active Expired
- 1979-12-17 YU YU3086/79A patent/YU41900B/en unknown
- 1979-12-17 IT IT51101/79A patent/IT1162424B/en active
- 1979-12-17 CH CH1114979A patent/CH643851A5/en not_active IP Right Cessation
- 1979-12-17 PT PT70602A patent/PT70602A/en unknown
- 1979-12-17 SE SE7910387A patent/SE446535B/en not_active IP Right Cessation
- 1979-12-17 FR FR7930864A patent/FR2444684A1/en active Granted
- 1979-12-17 SI SI7913086A patent/SI7913086A8/en unknown
- 1979-12-18 ES ES487040A patent/ES8101609A1/en not_active Expired
- 1979-12-18 DE DE2950990A patent/DE2950990C2/en not_active Expired
- 1979-12-18 NL NLAANVRAGE7909104,A patent/NL186161C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NL186161C (en) | 1990-10-01 |
| GB2040926B (en) | 1983-02-09 |
| IL58939A (en) | 1983-03-31 |
| SE7910387L (en) | 1980-06-19 |
| ES487040A0 (en) | 1980-12-16 |
| SE446535B (en) | 1986-09-22 |
| IT7951101A0 (en) | 1979-12-17 |
| YU308679A (en) | 1983-02-28 |
| CH643851A5 (en) | 1984-06-29 |
| FR2444684A1 (en) | 1980-07-18 |
| DE2950990C2 (en) | 1983-12-22 |
| NL186161B (en) | 1990-05-01 |
| DE2950990A1 (en) | 1980-06-19 |
| IT1162424B (en) | 1987-04-01 |
| NL7909104A (en) | 1980-06-20 |
| AU5386979A (en) | 1981-06-25 |
| ES8101609A1 (en) | 1980-12-16 |
| YU41900B (en) | 1988-02-29 |
| FR2444684B1 (en) | 1983-04-01 |
| PT70602A (en) | 1980-01-01 |
| AU528886B2 (en) | 1983-05-19 |
| GB2040926A (en) | 1980-09-03 |
| IL58939A0 (en) | 1980-03-31 |
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