NO124690B - - Google Patents
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- NO124690B NO124690B NO14502962A NO14502962A NO124690B NO 124690 B NO124690 B NO 124690B NO 14502962 A NO14502962 A NO 14502962A NO 14502962 A NO14502962 A NO 14502962A NO 124690 B NO124690 B NO 124690B
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- Norway
- Prior art keywords
- acid
- azidobenzylpenicillin
- aminobenzylpenicillin
- solution
- salt
- Prior art date
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- 150000003839 salts Chemical class 0.000 claims description 12
- 229960004328 azidocillin Drugs 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 231100000252 nontoxic Toxicity 0.000 claims description 7
- 230000003000 nontoxic effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 9
- 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 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 7
- 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 description 6
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940056360 penicillin g Drugs 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XUICXMXDTICQOZ-UHFFFAOYSA-N 2-azido-2-phenylacetic acid Chemical compound [N-]=[N+]=NC(C(=O)O)C1=CC=CC=C1 XUICXMXDTICQOZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 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 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 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
- 241001465754 Metazoa Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 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
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- -1 trialkylamines Chemical class 0.000 description 1
- 238000005406 washing Methods 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Fremgangsmåte for fremstilling av a-aminobenzylpenicillin og dets ikke giftige salter. Process for the production of α-aminobenzylpenicillin and its non-toxic salts.
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av a-aminobenzylpenicillin som er beskrevet i søke-rens norske patent 115 737. The present invention relates to a method for the production of α-aminobenzylpenicillin which is described in the applicant's Norwegian patent 115 737.
a-aminobenzylpenicillinet er av verdi som et antibakteri-elt middel, som middel for behandling av mastitis hos kveg og som et terapeutisk middel for fjærkre og dyr, innbefattet mennesker, ved behandling spesielt av infeksjonssykdommer som forårsakes av Gram-positive og Gram-negative bakterier. The α-aminobenzylpenicillin is of value as an antibacterial agent, as an agent for the treatment of mastitis in cattle and as a therapeutic agent for poultry and animals, including humans, in the treatment especially of infectious diseases caused by Gram-positive and Gram-negative bacteria .
Ved den kjente arbeidsmåte går man ut fra a-aminofenyl-eddiksyre, overfører først den frie aminogruppe til en amidgruppe og lar da syren reagere med 6-aminopenicillansyre, og fjerner til slutt beskyttelsesgruppen ved katalytisk hydrering. Da penicillinmolekylet som skal reduseres, inneholder såvel et svovelatom som også den i og for seg allerede ømfintlige struktur til /?-laktam-ringen, er reduksjonen ganske vanskelig å utføre og kan bare gjen-nomføres under anvendelse av edelmetallkatalysatorer i et passende tidsrom, hvorunder det imidlertid kreves relativt store kataly-satormengder og gjenvinningen av edelmetallet er bare mulig når man tar med på kjøpet tap av dette. In the known working method, one starts from α-aminophenyl-acetic acid, first transfers the free amino group to an amide group and then allows the acid to react with 6-aminopenicillanic acid, and finally removes the protective group by catalytic hydrogenation. As the penicillin molecule to be reduced contains both a sulfur atom and the already delicate structure of the /?-lactam ring, the reduction is rather difficult to carry out and can only be carried out using noble metal catalysts for a suitable period of time, during which however, relatively large amounts of catalyst are required and the recovery of the precious metal is only possible when loss of this is included in the purchase.
Overraskende nok ble det nu funnet at det verdifulle a-aminobenzylpenicillin også lar seg fremstille på en helt annen vei og under anvendelse av et annet utgangsmateriale. Surprisingly, it was now found that the valuable α-aminobenzylpenicillin can also be produced in a completely different way and using a different starting material.
I henhold til oppfinnelsen fremstilles a-aminobenzylpenicillinet eller et av dets ikke-giftige salter ved at a-azidobenzylpenicillin, resp. et av dettes ikke-giftige salter hydrogeneres ved romtemperatur med hydrogen i nærvær av Raney-nikkel i et oppløs-ningsmiddel. Det herunder som utgangsmateriale anvendte axazido-benzylpenicillin fremstilles ved behandling av a-bromfenyleddiksyre med et azid og omsetning av et derivat av den . dannede a-azidofenyleddiksyre med 6-aminopenicillansyre. Som derivat av den frie azidofenyleddiksyre omsettes det tilsvarende syreklorid, -bromid eller -anhydrid, resp. et blandet anhydrid, med 6-aminopenicillansyren eller et salt av denne. Denne omsetning kan gjennomføres under vann-frie betingelser i et inert organisk oppløsningsmiddel eller med en vandig gjæringsoppløsning resp. med oppløsninger som inneholder 6-aminopenicillansyre, hvilke er blitt dannet ved enzymatisk, inntil 6-aminopenicillansyre førende oppspaltning av f»eks. penicillin G. According to the invention, the α-aminobenzylpenicillin or one of its non-toxic salts is prepared by α-azidobenzylpenicillin, resp. one of its non-toxic salts is hydrogenated at room temperature with hydrogen in the presence of Raney nickel in a solvent. The axazido-benzylpenicillin used below as starting material is produced by treating a-bromophenylacetic acid with an azide and reacting a derivative of it. formed α-azidophenylacetic acid with 6-aminopenicillanic acid. As a derivative of the free azidophenylacetic acid, the corresponding acid chloride, bromide or anhydride reacts, resp. a mixed anhydride, with the 6-aminopenicillanic acid or a salt thereof. This reaction can be carried out under water-free conditions in an inert organic solvent or with an aqueous fermentation solution or with solutions containing 6-aminopenicillanic acid, which have been formed by enzymatic, up to 6-aminopenicillanic acid leading to splitting of e.g. penicillin G.
I det følgende skal beskrives fremstillingen av a-azido4-benzylpenicillin under anvendelse av et blandet anhydrid. For fremstillingen av denne forbindelse kreves det beskyttelse i søknad nr. In the following, the preparation of α-azido4-benzylpenicillin using a mixed anhydride will be described. For the production of this compound, protection is required in application no.
169.877. i 169,877. in
Fremstilling av g- azidobenzylpenicillinPreparation of g-azidobenzylpenicillin
En oppløsning av 8,9 g (0,05 mol) a-azidofenyleddiksyre og 5,1 g (0,05 mol) trietylamin i 50 ml vannfritt dimetylformamid ble omrørt og avkjølt til under -5°C. Ved denne temperatur ble tilsatt 4,7 ml klormaursyreetylester i andeler, slik at temperaturen ikke steg over -5°c. Etter at blandingen var blitt omrørt i 20 minutter, ble på én gang tilsatt 100 ml vannfritt aceton som var kjølt til -5°C, hvorpå med én gang ble tilsatt en iskold oppløsning av 10,8 g (0,05 mol) 6-aminopenicillansyre og 5,1 g (0,05 mol) trietylamin i 100 ml vann, og omrøringen ble fortsatt ennu i 1 1/2 time ved 0°C. A solution of 8.9 g (0.05 mol) of α-azidophenylacetic acid and 5.1 g (0.05 mol) of triethylamine in 50 ml of anhydrous dimethylformamide was stirred and cooled to below -5°C. At this temperature, 4.7 ml of ethyl chloroformate was added in portions, so that the temperature did not rise above -5°c. After the mixture had been stirred for 20 minutes, 100 ml of anhydrous acetone cooled to -5°C was added at once, after which an ice-cold solution of 10.8 g (0.05 mol) of 6- aminopenicillanic acid and 5.1 g (0.05 mol) of triethylamine in 100 ml of water, and stirring was continued for another 1 1/2 hours at 0°C.
Blandingens pH-verdi ble innstillet på 7,5 ved tilset- ning av en mettet natriumbikarbonatoppløsning. Etter to gangers vaskning med dietyleter ble reaksjonsoppløsningen ansyret med fortynnet saltsyre til pH 2 og ekstrahert med eter. Eteroppløsningen som inneholdt det frie penicillin, ble vasket to ganger med vann og derpå ekstrahert med 50 ml normal kaliumbikarbonatoppløsning. The pH value of the mixture was adjusted to 7.5 by adding a saturated sodium bicarbonate solution. After washing twice with diethyl ether, the reaction solution was acidified with dilute hydrochloric acid to pH 2 and extracted with ether. The ether solution containing the free penicillin was washed twice with water and then extracted with 50 ml of normal potassium bicarbonate solution.
Efter frysetørkning av den erholdte nøytrale oppløsning ble utvun-After freeze-drying the neutral solution obtained, the
net kaliumsaltet til a-azidobenzylpenicillinet som et svakt farvet pulver (11,2 g, 54% utbytte) med en renhet av 55%, bestemt etter hydroksylaminmetoden (hvorunder kaliumsaltet til penicillin G ble anvendt som standardforbindelse.) net the potassium salt of the α-azidobenzylpenicillin as a faintly colored powder (11.2 g, 54% yield) with a purity of 55%, determined by the hydroxylamine method (wherein the potassium salt of penicillin G was used as the standard compound.)
Det infrarøde spektrum av denne substans viste, tilstede-værelsen av en azidogruppe. og et fS-1 aktamsystem. The infrared spectrum of this substance showed the presence of an azido group. and an fS-1 actam system.
Det i henhold til oppfinnelsen som katalysator anvendte nikkel er så billig at det ikke er nødvendig å gjenvinne nikkelet. Særlig overraskende er det at det fra litteraturen som avsvovlings-middel i og for seg kjente nikkel (sml. f.eks. arbeidet av BOUGAULT The nickel used as a catalyst according to the invention is so cheap that it is not necessary to recover the nickel. It is particularly surprising that nickel is known from the literature as a desulphurisation agent in and of itself (cf. e.g. the work of BOUGAULT
og medarbeidere i "Bull. Soc. Chim. Fr." [5], 7, 1940, s. 781, samt BEHRINGER og medarbeidere i "Chemisene Berichte", bd. 91, 1958, s. 2773, resp. ALLAN og medarbeidere i "J. Chem. Soc", 1952, s. 5053, and associates in "Bull. Soc. Chim. Fr." [5], 7, 1940, p. 781, as well as BEHRINGER and colleagues in "Chemisene Berichte", vol. 91, 1958, p. 2773, resp. ALLAN et al. in "J. Chem. Soc", 1952, p. 5053,
og RYLANDER&COMPAIGNE, "J. Org. Chem.", bd. 15, 1950, s. 249)i foreliggende tilfelle hverken angriper svovelet og heller ikke strukturen til 0-1aktamringen i penicillinmolekylet. Hydrogene-ringen av a-azidobenzylpenicillinet forløper tvertimot uten noen som helst komplikasjoner. and RYLANDER&COMPAIGNE, "J. Org. Chem.", vol. 15, 1950, p. 249) in the present case attacks neither the sulfur nor the structure of the 0-1actam ring in the penicillin molecule. The hydrogenation of the α-azidobenzylpenicillin, on the contrary, proceeds without any complications whatsoever.
De ikke giftige salter av utgangsmaterialet omfatter me-tallsalter, som natrium-, kalium-, kalsium- og aluminiumsaltet, ammoniumsaltet og substituerte ammoniumsalter, f.eks. salter av ikke giftige aminer, som trialkylaminer, f.eks. trietylamin, p-aminobenzoesyre-/?-dietylaminoetylester , dibenzylamin, N-benzyl-Ø-fenetylamin, 1-N-metyl-1,2-difenyl-2-hydroksyetylamin, N,N'-diben-zyletylendiamin, dehydroabietylamin, N,N'-bis-dehydroabietyletylen-diamin samt andre aminer som-er blitt anvendt for fremstilling av salter med benzylpenicillin. The non-toxic salts of the starting material include metal salts, such as the sodium, potassium, calcium and aluminum salts, the ammonium salt and substituted ammonium salts, e.g. salts of non-toxic amines, such as trialkylamines, e.g. triethylamine, p-aminobenzoic acid-/?-diethylaminoethyl ester, dibenzylamine, N-benzyl-Ø-phenethylamine, 1-N-methyl-1,2-diphenyl-2-hydroxyethylamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, N, N'-bis-dehydroabiethylethylenediamine and other amines which have been used for the preparation of salts with benzylpenicillin.
Den katalytiske hydrogenering med Raney-nikkel gjennom-føres ved anvendelse av a-azidobenzylp(anicillin i et passende opp-løsningsmiddel eller ved anvendelse av et salt av or-azidobenzylpenicillinet i vann eller i et annet oppløsningsmiddel, hvorunder det for reaksjonen foretrekkes omtrent romtemperatur og i det mins- The catalytic hydrogenation with Raney nickel is carried out by using α-azidobenzylpenicillin in a suitable solvent or by using a salt of the α-azidobenzylpenicillin in water or in another solvent, under which approximately room temperature is preferred for the reaction and at least
te atmosfærisk trykk.te atmospheric pressure.
Fremgangsmåteproduktet inneholder i det minste et asymmetrisk karbonatom og foreligger i d- og l-formene„ Det skal bemerkes at oppfinnelsen omfatter fremstillingen av såvel d- og 1-formen som også dl-blandingen. Hydrogeneringsreaksjonen er stéreo-spesifikk, slik at det praktisk ikke opptrer noen racemisering. The process product contains at least one asymmetric carbon atom and exists in the d and l forms. It should be noted that the invention includes the production of both the d and 1 forms as well as the dl mixture. The hydrogenation reaction is stereo-specific, so that practically no racemization occurs.
De i henhold til oppfinnelsen fremstilte produkter anven-des, isoleres og renses efter de kjente fremgangsmåter som brukes ved andre amfotære penicilliner. The products produced according to the invention are used, isolated and purified according to the known methods used for other amphoteric penicillins.
Det følgende eksempel skal klargjøre oppfinnelsen: The following example shall clarify the invention:
EksempelExample
En suspensjon av 1 g Raney-nikkel i 30 ml vann ble ved romtemperatur og ved et trykk av 3,5 kg/cm<2>mettet med hydrogen. Til denne suspensjon ble tilsatt en oppløsning av 4,1 g a-azidobenzylpenicillin-kalium (renhetsgrad 83%, bestemt efter hydroksylaminmetoden) i 30 ml vann. Blandingen ble rystet i 30 minutter under en hydrogenatmosfære av 3,5 kg/cm 2. Katalysatoren ble filtrert fra og grundig vasket med vann. Filtratet ble innstillet på pH 2 med fortynnet saltsyre og to ganger ekstrahert med dietyleter. Oppløsningens pH-verdi ble derpå innstillet på 5 med fortynnet nat-riumhydroksyd. Ved konsentrering av oppløsningen i vakuum under 20°C fikk man 3 g a-aminobenzylpenicillin (86% utbytte) i form av et hvitt pulver (renhetsgrad 61%) . Det infrarøde spektrum av dette produkt var identisk med spekteret til a-aminobenzylpenicillin som var erholdt etter eksempel 7 i det norske patent 115 737 fra karbo-benzoksyaminobenzylpenicillin. Produktet forhindret veksten av Staph. aureus Oxford ved en konsentrasjon av 0,13 mcg/ml. A suspension of 1 g of Raney nickel in 30 ml of water was saturated with hydrogen at room temperature and at a pressure of 3.5 kg/cm<2>. To this suspension was added a solution of 4.1 g of α-azidobenzylpenicillin potassium (purity 83%, determined according to the hydroxylamine method) in 30 ml of water. The mixture was shaken for 30 minutes under a hydrogen atmosphere of 3.5 kg/cm 2 . The catalyst was filtered off and thoroughly washed with water. The filtrate was adjusted to pH 2 with dilute hydrochloric acid and extracted twice with diethyl ether. The pH value of the solution was then adjusted to 5 with dilute sodium hydroxide. By concentrating the solution in vacuum below 20°C, 3 g of α-aminobenzylpenicillin (86% yield) was obtained in the form of a white powder (purity 61%). The infrared spectrum of this product was identical to the spectrum of α-aminobenzylpenicillin which was obtained according to example 7 in the Norwegian patent 115 737 from carbo-benzoxyaminobenzylpenicillin. The product prevented the growth of Staph. aureus Oxford at a concentration of 0.13 mcg/ml.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO169877A NO129299B (en) | 1961-07-21 | 1967-09-26 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB26488/61A GB940488A (en) | 1961-07-21 | 1961-07-21 | Penicillins |
| GB26489/61A GB940489A (en) | 1961-07-21 | 1961-07-21 | Penicillins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO124690B true NO124690B (en) | 1972-05-23 |
Family
ID=26258263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO14502962A NO124690B (en) | 1961-07-21 | 1962-07-06 |
Country Status (6)
| Country | Link |
|---|---|
| BR (1) | BR6240282D0 (en) |
| CH (1) | CH430718A (en) |
| DK (1) | DK129939B (en) |
| ES (1) | ES279025A1 (en) |
| NO (1) | NO124690B (en) |
| SE (2) | SE315898B (en) |
-
1962
- 1962-06-25 BR BR14028262A patent/BR6240282D0/en unknown
- 1962-07-06 NO NO14502962A patent/NO124690B/no unknown
- 1962-07-07 ES ES0279025A patent/ES279025A1/en not_active Expired
- 1962-07-18 DK DK321862A patent/DK129939B/en unknown
- 1962-07-19 SE SE806562A patent/SE315898B/xx unknown
- 1962-07-20 CH CH879162A patent/CH430718A/en unknown
-
1967
- 1967-06-28 SE SE09551/67A patent/SE350052B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH430718A (en) | 1967-02-28 |
| DK129939B (en) | 1974-12-02 |
| ES279025A1 (en) | 1962-11-01 |
| BR6240282D0 (en) | 1973-07-19 |
| SE315898B (en) | 1969-10-13 |
| SE350052B (en) | 1972-10-16 |
| DK129939C (en) | 1975-07-21 |
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