NO127106B - - Google Patents
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- NO127106B NO127106B NO00139438A NO13943861A NO127106B NO 127106 B NO127106 B NO 127106B NO 00139438 A NO00139438 A NO 00139438A NO 13943861 A NO13943861 A NO 13943861A NO 127106 B NO127106 B NO 127106B
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- Prior art keywords
- acid
- salts
- penicillins
- penicillin
- general formula
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- 229930182555 Penicillin Natural products 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- 150000002960 penicillins Chemical class 0.000 claims description 14
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 13
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 8
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 229940049954 penicillin Drugs 0.000 description 6
- 108010087702 Penicillinase Proteins 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940056360 penicillin g Drugs 0.000 description 5
- 229950009506 penicillinase Drugs 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229930195708 Penicillin V Natural products 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940056367 penicillin v Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- -1 trialkylamines Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229960004894 pheneticillin Drugs 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229960003672 propicillin Drugs 0.000 description 1
- ULBKMFLWMIGVOJ-CFXUUZMDSA-M propicillin potassium Chemical compound [K+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C(CC)OC1=CC=CC=C1 ULBKMFLWMIGVOJ-CFXUUZMDSA-M 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte for fremstilling av penicilliner. Process for the production of penicillins.
Oppfinnelsen vedrører.en fremgangsmåte for fremstilling av en ny klasse av penicilliner, som utmerker seg overfor kjente penicilliner ved sin høye aktivitet overfor B-laktamase (penicillinase)-produserende stammer, spesielt av Staph.aureus såvelsom ved sin syreresistens. The invention relates to a process for the production of a new class of penicillins, which are distinguished from known penicillins by their high activity against B-lactamase (penicillinase)-producing strains, especially by Staph.aureus, as well as by their acid resistance.
Oppfinnelsen tilveiebringer således en fremgangsmåteThe invention thus provides a method
for fremstilling av nye penicilliner med gode antibakterielle egenskaper, særlig like overfor resistente stammer, og som-videre er syrestabile, av den generelle formel: for the production of new penicillins with good antibacterial properties, particularly similar to resistant strains, and which are also acid-stable, of the general formula:
hvor R betyr en fenylrest som eventuelt er substituert med étt eller to kloratomer; . og, ikke-tpksiske salter , derav. where R means a phenyl radical which is optionally substituted with one or two chlorine atoms; . and, non-tpxic salts, thereof.
Som salter kan nevnes ikké-toksiske metallsalter, f.eks. natrium-, kalium-, kalsium og aluminiumsalter, ammonium- og substituerte ammoniumsalter, f.eks. salter av ikke-toksiske aminer, f.eks. trialkylaminer, deriblant trietylamin, prokain, dibenzylamin, N-benzyl-B-féirétylamin, 1-N-métyl-l, 2-difényl"-2-hydroksyetylamin, N,N'-dibenzyletylendiamin, dehydroabietylamin, N,N'-bis-dehydroabiet-yletylendiamin og andre aminer som anvendes til dannelse av salter med benzylpenicillin. Non-toxic metal salts can be mentioned as salts, e.g. sodium, potassium, calcium and aluminum salts, ammonium and substituted ammonium salts, e.g. salts of non-toxic amines, e.g. trialkylamines, including triethylamine, procaine, dibenzylamine, N-benzyl-B-feyrethylamine, 1-N-methyl-1, 2-diphenyl"-2-hydroxyethylamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, N,N'-bis- dehydroabietylethylenediamine and other amines used to form salts with benzylpenicillin.
Penicillinene av den generelle formel I fremstilles i henhold til foreliggende fremgangsmåte ved at man på i og for seg kjent måte omsetter 6-aminopenicillansyre eller et av dennes nøy-trale salter eller en væske som inneholder 6-aminopenicillansyre eller et av dennes nøytrale salter, med et' syreklorid, -bromid, The penicillins of the general formula I are prepared according to the present method by reacting 6-aminopenicillanic acid or one of its neutral salts or a liquid containing 6-aminopenicillanic acid or one of its neutral salts in a manner known per se, with an' acid chloride, bromide,
-anhydrid eller et blandet anhydrid som er avledet fra en karboksylsyre med den generelle formel -anhydride or a mixed anhydride derived from a carboxylic acid of the general formula
og eventuelt overfører de fremstilte syrer til. sine salter ved be-handling med baser. and possibly transfer the produced acids to their salts by treatment with bases.
En måte å fremstille forbindelser av den generelle formel I på under.anvendelse av et blandet anhydrid av en klorkarbonsyre-alkylester består i at en syre av den generelle formel.II omsettes med klorkarbonsyrealkylesteren i nærvær av et tertiært, alif^— tisk amin, som f.eks. trietylamin, i et vannfritt, inert og fortrinnsvis med vann blandbart oppløsningsmiddel som f.eks. dioksan, og om ønskes en liten mengde av ren, tørr aceton. Til denne opp- løsning av det blandede anhydrid tilsettes derpå én oppvarmet opp-løsning av 6-aminopenicillansyre og tertiært alifatisk amin i et oppløsningsmiddel, f.eks. vann, slik at det dannes det substituerte ammoniumsalt av det ønskede produkt. Den videre opparbeidelse og rensning foregår over den frie syre, som etterpå omdannes til et ønsket metall- eller aminsalt. Disse salter er vanligvis uløselige i organiske oppløsningsmidler, f.eks. eter, og kan utvinnes i ren form ved enkel filtrering. One way of preparing compounds of the general formula I using a mixed anhydride of a chlorocarbonic acid alkyl ester consists in reacting an acid of the general formula II with the chlorocarbonic acid alkyl ester in the presence of a tertiary, aliphatic amine, which e.g. triethylamine, in an anhydrous, inert and preferably water-miscible solvent such as e.g. dioxane, and if desired a small amount of pure, dry acetone. To this solution of the mixed anhydride is then added one heated solution of 6-aminopenicillanic acid and tertiary aliphatic amine in a solvent, e.g. water, so that the substituted ammonium salt of the desired product is formed. Further processing and purification takes place over the free acid, which is then converted into a desired metal or amine salt. These salts are usually insoluble in organic solvents, e.g. ether, and can be recovered in pure form by simple filtration.
En annen fremgangsmåte vedrører omsetning av 6-aminopenicillansyre i en vandig løsning under tilsetning av natriumbikarbonat med syrekloridet, respektive det tilsvarende syrebromid eller syreanhydrid. Også her følger opparbeidelse og rensning over den frie syre. Another method concerns the reaction of 6-aminopenicillanic acid in an aqueous solution with the addition of sodium bicarbonate with the acid chloride, respectively the corresponding acid bromide or acid anhydride. Here, too, processing and purification of the free acid follows.
Hvis syrekloridet reagerer hurtigere med vann enn med 6-aminopenicillansyren, er det nødvendig å arbeide under utelukkelse av vann. Da blandes 6-aminopenicillansyre og trietylamin med et vannfritt oppløsningsmiddel, f.eks. aceton, kloroform eller metylen-diklorid, og syrekloridet tilsettes i det samme oppløsningsmiddel. If the acid chloride reacts more quickly with water than with the 6-aminopenicillanic acid, it is necessary to work under the exclusion of water. Then mix 6-aminopenicillanic acid and triethylamine with an anhydrous solvent, e.g. acetone, chloroform or methylene dichloride, and the acid chloride is added in the same solvent.
De valgte reaksjonsbetingelser avhenger i stor utstrek-ning av reaksjonsevnen til det anvendte acyleringsmiddel. Tempera-turen skal vanligvis ikke være mer enn 30°c. Fremgangsmåten ut-føres fortrinnsvis ved en pH-verdi på 6-9. The chosen reaction conditions depend to a large extent on the reactivity of the acylating agent used. The temperature should not normally be more than 30°c. The method is preferably carried out at a pH value of 6-9.
Når det foreligger mer enn én fase,, f.eks. faste og flytende eller to flytende faser, må det røres kraftig. When there is more than one phase, e.g. solid and liquid or two liquid phases, it must be stirred vigorously.
Det anvendes i det vesentlige tre forskjellige fremgangs-måter for acylering, og disse betegnes fremgangsmåte A, B og C. Essentially three different methods of acylation are used, and these are called methods A, B and C.
FREMGANGSMÅTE AMETHOD OF PROCEDURE A
Er<i>oppløsning av 0,04 mol av det angjeldende syrekloridIs<i>solution of 0.04 mol of the relevant acid chloride
i 60 ml tørr kloroform tilsettes under røring langsomt til ehmed is avkjølt blanding av 0,04 mol 6-aminopenicillansyre, 11 ml trietylamin og 60 ml vannfri kloroform, og blandingen røres så i tre timer ved romtemperatur. Etter inndampnirig i vakuum ved romtemperatur ristes blandingen med 120 ml vann, og sjiktene skilles. in 60 ml of dry chloroform is slowly added while stirring to an ice-cooled mixture of 0.04 mol of 6-aminopenicillanic acid, 11 ml of triethylamine and 60 ml of anhydrous chloroform, and the mixture is then stirred for three hours at room temperature. After evaporation in a vacuum at room temperature, the mixture is shaken with 120 ml of water, and the layers are separated.
Den vandige fase bririgés ved tilsetning av natriumbikarbonat til The aqueous phase is bririgés by adding sodium bicarbonate to
pH 7 og vaskes to ganger med 100 ml eter eig deretter to ganger med 30 ml butånol. Den dekkes sa med 30 ml butanol og surgjøres med saltsyre til pH 3. Sjiktene skilles, og den vandige fase ekstra*-<;>i; pH 7 and washed twice with 100 ml of ether, then twice with 30 ml of butanol. It is then covered with 30 ml of butanol and acidified with hydrochloric acid to pH 3. The layers are separated, and the aqueous phase extra*-<;>i;
heres med to. ytterligere porsjoner a 20 ml butanol. De forenede butanolekstrakter, som i dette trinn inneholder penicillinet som fri syre, vaskes med 25 ml vann og nøytraliseres så under tilsetning av 8%-ig natriumbikarbonatløsning under kraftig røring. Sjiktene skilles, og vannfasen avdampes ved lav temperatur og trykk, hvorved det urene natriumsalt blir tilbake, som til slutt tørkes i en vakuum-eksikator. here with two. further portions of 20 ml butanol. The combined butanol extracts, which in this step contain the penicillin as free acid, are washed with 25 ml of water and then neutralized with the addition of 8% sodium bicarbonate solution with vigorous stirring. The layers are separated, and the water phase is evaporated at low temperature and pressure, whereby the impure sodium salt remains, which is finally dried in a vacuum desiccator.
FREMGANGSMÅTE BPROCEDURE B
En løsning av 0,016 mol av det angjeldende syreklorid i 95 ml tørr aceton- tilsettes under røring i løpet av 15 minutter til A solution of 0.016 mol of the relevant acid chloride in 95 ml of dry acetone is added with stirring over the course of 15 minutes to
en løsning av 0,01 (P-mol 6-aminopenicillansyre i 135 ml 3%-ig vandig natriumbikarbonat og 40 ml aceton. Blandingen røres i fire timer, og filtreres så. Filtratet ekstraheres to ganger med 150 ml eter. Vannfasen dekkes så med 75 ml eter og bringes ved tilsetning av for-tynnet saltsyre til pH 2. Sjiktene skilles, og den vandige fase a solution of 0.01 (P-mol 6-aminopenicillanic acid in 135 ml of 3% aqueous sodium bicarbonate and 40 ml of acetone. The mixture is stirred for four hours, and then filtered. The filtrate is extracted twice with 150 ml of ether. The aqueous phase is then covered with 75 ml of ether and brought to pH 2 by the addition of dilute hydrochloric acid. The layers are separated, and the aqueous phase
ekstraheres med ytterligere to 50ml-porsjoner eter. De forenede eterekstrakter, som i dette trinn inneholder penicillinet som fri syre, vaskes tre ganger med 25 ml vann og ristes deretter med en tilstrekkelig mengde 8%-ig natriumbikarbonatløsning, hvorved man får en nøytral vannfase med pH 7. Det nøytrale vannsjikt skilles fra, vaskes med eter og inndampes ved lav temperatur og trykk. Resten extracted with two further 50ml portions of ether. The combined ether extracts, which in this step contain the penicillin as free acid, are washed three times with 25 ml of water and then shaken with a sufficient amount of 8% sodium bicarbonate solution, whereby a neutral aqueous phase with pH 7 is obtained. The neutral aqueous layer is separated, washed with ether and evaporated at low temperature and pressure. The rest
tørkes i vakuum over fosforpentoksyd, hvorved det rå natriumsalt blir tilbake. is dried in vacuum over phosphorus pentoxide, whereby the crude sodium salt remains.
FREMGANGSMÅTE CPROCEDURE C
5,8 ml trietylamin tilsettes under røring til en suspensjon av 0,02 mol av den angjeldende syre i 30 ml vannfri kloroform og gir en klar løsning. Denne avkjøles til -20°cog behandles i 5 minutter med en løsning av .1,64 ml tionylklorid i 6,5 ml vannfri kloroform. Blandingen røres 30 minutter ved -20°c. 5.8 ml of triethylamine is added with stirring to a suspension of 0.02 mol of the relevant acid in 30 ml of anhydrous chloroform and gives a clear solution. This is cooled to -20° and treated for 5 minutes with a solution of 1.64 ml of thionyl chloride in 6.5 ml of anhydrous chloroform. The mixture is stirred for 30 minutes at -20°c.
Den løsning som fremkommer, som inneholder det tilsvarende karboxylsyreklorid, tilsettes under røring i løpet av 10 minut-' ter til en suspensjon av 0,02 .mol 6-aminopenicillansyre i 100 ml vannfri kloroform, som inneholder 2,9 ml trietylamin.Blandingen røres i tre timer og filtreres så.. Løsningen inndampes ved lav temperatur og trykk og gir en rest som ristes med 40 ml vann og 150 ml eter. The resulting solution, which contains the corresponding carboxylic acid chloride, is added with stirring over 10 minutes to a suspension of 0.02 mol of 6-aminopenicillanic acid in 100 ml of anhydrous chloroform, which contains 2.9 ml of triethylamine. The mixture is stirred for three hours and then filtered. The solution is evaporated at low temperature and pressure to give a residue which is shaken with 40 ml of water and 150 ml of ether.
Eterekstrakten inndampes ved lav temperatur og trykk og etterlater en fast rest. The ether extract is evaporated at low temperature and pressure, leaving a solid residue.
UTFØRELSESEKSEMPLEREXECUTION EXAMPLES
I nedenstående tabell I er det angitt syreklorider somIn Table I below, acid chlorides are indicated which
1 hvert tilfelle er blitt omsatt med 6-aminopenicillansyre ved den angitte fremgangsmåte B. Den antibiotiske aktivitet overfor tre forskjellige stammer av Staphylococcus uttrykkes som "minimal in-, hibitorkonsentrasjon" (M.I.C.). Til sammenligning er det. gjengitt tilsvarende data for penicillin G. Av de tre stammér er bare 1 each case has been reacted with 6-aminopenicillanic acid by the specified method B. The antibiotic activity against three different strains of Staphylococcus is expressed as "minimal inhibitor concentration" (M.I.C.). In comparison, it is. reproduced similar data for penicillin G. Of the three strains, only
Staph.Oxford høyømfindtlig overfor Penicillin G. Staph. 1 og Staph. Staph.Oxford highly sensitive to Penicillin G. Staph. 1 and Staph.
2 er høyresistente stammer som produserer store mengder av penicillinase. Videre er det i denne tabell angitt syreresistens, uttrykt som halveringstid i timer ved en pH-verdi på 2 og en temperatur på 35°C. 2 are highly resistant strains that produce large amounts of penicillinase. Furthermore, acid resistance is indicated in this table, expressed as half-life in hours at a pH value of 2 and a temperature of 35°C.
Følgende penicilliner ble fremstilt.ved omsetning av de nevnte syrer i form av syrekloridet, -bromidet, -anhydridet eller et blandet anhydrid med 6-aminopenicillansyre i overensstemmelse med fremgangsmåtene A, B eller C: The following penicillins were prepared by reacting the aforementioned acids in the form of the acid chloride, bromide, anhydride or a mixed anhydride with 6-aminopenicillanic acid in accordance with methods A, B or C:
Aktiviteten av disse penicilliner overfor Staph. Oxford, såvelsom overfor to forskjellige resistente stammer fremgår av nedenstående tabell II. The activity of these penicillins against Staph. Oxford, as well as against two different resistant strains is shown in Table II below.
Dét i tabell li oppførte penicillin nr. 1 tilsvarer med hensyn til sin penicillinase-stabilitet det 3-fenyl-5-metyl-isoxazolyl-(4)-penicillin som kan fremstilles ved fremgangsmåten i henhold til oppfinnelsen, men er dog, med hensyn til' resorpsjon og aktivitet, enda noe gunstigere enn sistnevnte. The penicillin no. 1 listed in Table 1 corresponds with regard to its penicillinase stability to the 3-phenyl-5-methyl-isoxazolyl-(4)-penicillin which can be produced by the method according to the invention, but is, however, with regard to ' resorption and activity, even somewhat more favorable than the latter.
Syreresistensen hos de nye penicilliner i sammenligning med penicillin G og penicillin V fremgår av nedenstående tabell III. Som mål for denne resistens bestemmes halveringstiden av penicillinene, oppløst i 50%-ig vandig etanol ved en pH-verdi på 1,3 og 35°C. De undersøkte, nye penicilliner er i henhold til dette like stabile som penicillin V, og de egner seg.derfor meget godt for oralterapi. The acid resistance of the new penicillins in comparison with penicillin G and penicillin V is shown in table III below. As a measure of this resistance, the half-life of the penicillins, dissolved in 50% aqueous ethanol at a pH value of 1.3 and 35°C, is determined. According to this, the investigated new penicillins are as stable as penicillin V, and they are therefore very suitable for oral therapy.
Det er kjent at den i tiltagende, grad iakttatte opptreden av bakteriestammer som er resistente overfor de mest brukte penicilliner G og V i sykehus og i -privat legepraksis har ført til store vanskeligheter", spesielt ved akutte infeksjoner. Riktignok viser noen å<3 halvsyntetisk vei fremstilte penicilliner, spesielt a-fenoksyetyl - penicillin og a-fenoksypropylpenicillin en tydelig bedre virkning enn penicillin,G og V overfor svakt penicillinase-dannende stafylokokker, men allikevel finnes det et større antall resistente stammer med høy penicillinasedannelsesevne, overfor hvilke disse penicilliner ikke viser tilstrekkelig aktivitet, slik at det ikke i alle forekommende tilfeller -bys en sikker terapi. It is known that the increasingly observed appearance of bacterial strains that are resistant to the most commonly used penicillins G and V in hospitals and in private medical practice has led to major difficulties", especially in acute infections. Admittedly, some show <3 semi-synthetic Penicillins, especially a-phenoxyethyl penicillin and a-phenoxypropylpenicillin, have a clearly better effect than penicillin, G and V against weakly penicillinase-producing staphylococci, but there are still a large number of resistant strains with a high penicillinase-forming ability, against which these penicillins do not show sufficient activity, so that a safe therapy is not offered in all cases.
Overraskende nok er de produkter som fremstilles ved fremgangsmåten i henhold til oppfinnelsen, såvel penicillinasefaste og også oralt administrerbare. Surprisingly, the products produced by the method according to the invention are both penicillinase-resistant and also orally administrable.
Eksempelvis viste undersøkelsen av 448 stafylokokkstammer at ikke en eneste stamme er resistent overfor det i henhold til oppfinnelsen fremstilte 3-fenyl-5-metyl-isoxazolyl-(4)-penicillin 1 en konsentrasjon av 5 y - mens det for penicillin G (konsentrasjon 2 IE) ble funnet et resistenstall på 39,8% (447 stammer) og for det kjente a-fenoksypropylpenicillin (konsentrasjon 1^) et resistenstall på 31,2% (413 stammer). For example, the examination of 448 staphylococcal strains showed that not a single strain is resistant to the 3-phenyl-5-methyl-isoxazolyl-(4)-penicillin 1 produced according to the invention at a concentration of 5 y - while for penicillin G (concentration 2 IE) a resistance figure of 39.8% (447 strains) was found and for the known α-phenoxypropylpenicillin (concentration 1^) a resistance figure of 31.2% (413 strains).
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1141260A GB905778A (en) | 1960-03-31 | 1960-03-31 | Improvements in or relating to penicillins |
GB2504960 | 1960-07-18 |
Publications (1)
Publication Number | Publication Date |
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NO127106B true NO127106B (en) | 1973-05-07 |
Family
ID=26248261
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO00139438A NO127106B (en) | 1960-03-31 | 1961-03-10 |
Country Status (11)
Country | Link |
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BE (1) | BE601969A (en) |
BR (1) | BR6127716D0 (en) |
CH (1) | CH401976A (en) |
CY (1) | CY262A (en) |
DK (1) | DK137049B (en) |
ES (1) | ES265959A1 (en) |
FR (1) | FR1033M (en) |
MY (1) | MY6300087A (en) |
NO (1) | NO127106B (en) |
OA (1) | OA01036A (en) |
SE (1) | SE346003B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1212089B (en) * | 1961-05-03 | 1966-03-10 | Smith Kline French Lab | Process for the preparation of heterocyclic 6-acylaminopenicillanic acids |
-
1961
- 1961-03-10 NO NO00139438A patent/NO127106B/no unknown
- 1961-03-14 SE SE2737/61A patent/SE346003B/xx unknown
- 1961-03-17 BR BR127716/61A patent/BR6127716D0/en unknown
- 1961-03-22 ES ES0265959A patent/ES265959A1/en not_active Expired
- 1961-03-28 DK DK132661AA patent/DK137049B/en unknown
- 1961-03-29 CH CH371661A patent/CH401976A/en unknown
- 1961-03-29 BE BE601969A patent/BE601969A/en unknown
- 1961-03-30 FR FR857297A patent/FR1033M/en active Active
-
1963
- 1963-08-09 CY CY26263A patent/CY262A/en unknown
- 1963-12-30 MY MY87/63A patent/MY6300087A/en unknown
-
1964
- 1964-12-18 OA OA50917A patent/OA01036A/en unknown
Also Published As
Publication number | Publication date |
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DK137049C (en) | 1978-06-12 |
BE601969A (en) | 1961-09-29 |
CH401976A (en) | 1965-11-15 |
BR6127716D0 (en) | 1973-06-07 |
MY6300087A (en) | 1963-12-31 |
SE346003B (en) | 1972-06-19 |
CY262A (en) | 1963-08-09 |
ES265959A1 (en) | 1961-08-01 |
FR1033M (en) | 1962-01-02 |
OA01036A (en) | 1968-08-07 |
DK137049B (en) | 1978-01-09 |
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