NO119271B - - Google Patents
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- NO119271B NO119271B NO145720A NO14572062A NO119271B NO 119271 B NO119271 B NO 119271B NO 145720 A NO145720 A NO 145720A NO 14572062 A NO14572062 A NO 14572062A NO 119271 B NO119271 B NO 119271B
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- Prior art keywords
- amino
- acid
- water
- formula
- alkali metal
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- 229930182555 Penicillin Natural products 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 13
- 150000002960 penicillins Chemical class 0.000 claims description 13
- 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 claims description 10
- 229940049954 penicillin Drugs 0.000 claims description 10
- -1 alkali metal salt Chemical class 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 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 6
- 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 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- 229930007886 (R)-camphor Natural products 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 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
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NONJJLVGHLVQQM-JHXYUMNGSA-N phenethicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C)OC1=CC=CC=C1 NONJJLVGHLVQQM-JHXYUMNGSA-N 0.000 description 1
- 229960004894 pheneticillin Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 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
- 238000000746 purification Methods 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/44—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
-
- 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
Analogifremgangsmåte til fremstilling av farmakologisk aktive, syntetiske penicilliner. Analogy process for the production of pharmacologically active, synthetic penicillins.
Foreliggende oppfinnelse angår en analogifremgangsmåte til fremstilling av farmakologisk aktive, syntetiske penicilliner samt ikke-giftige salter av disse ut fra et alkalimetallsalt av 6-aminopenicillansyre som har formelen: The present invention relates to an analogous process for the production of pharmacologically active, synthetic penicillins as well as non-toxic salts thereof from an alkali metal salt of 6-aminopenicillanic acid which has the formula:
De ovennevnte penicilliner kån representeres ved den gene-relle formel: The above-mentioned penicillins can be represented by the general formula:
hvor X er oksygen eller (C^^ hvor n er et helt tall fra 1 til 3« where X is oxygen or (C^^ where n is an integer from 1 to 3«
Blant deres salter er ikke-giftige metallsalter, f.eks. natrium-, kalium-, aluminium-, ammonium- og substituerte ammoniumsal-ter, som kan fås ved reaksjon med aminer som vanlig anvendes i forbind-t Among their salts are non-toxic metal salts, e.g. sodium, potassium, aluminium, ammonium and substituted ammonium salts, which can be obtained by reaction with amines which are commonly used in compounds
else med penicilliner, f.eks. prokain, dibenzylamin og N,N -dibenzyl-etylendiamin. etc. with penicillins, e.g. procaine, dibenzylamine and N,N-dibenzyl-ethylenediamine.
Penicilliner som har en kjemisk struktur som er beslektet med de som fremstilles ifolge foreliggende oppfinnelse, er kjent fra britisk patent nr. 873 049, hvor imidlertid acylradikalet som er bun-det til 6-aminopenicillansyren ved hjelp av en peptidbinding, er et <x-aminosyreradikal. Penicillins having a chemical structure similar to those produced according to the present invention are known from British patent no. 873 049, where, however, the acyl radical which is bound to the 6-aminopenicillanic acid by means of a peptide bond is a <x- amino acid radical.
Analogifremgangsmåten ifolge foreliggende oppfinnelse er kjennetegnet ved at en aminosyre med formel: hvor X har den ovenfor angitte betydning, omsettes med fosgen i et inert organisk opplosningsmiddel og det erholdte indre anhydrid med formelen: The analogue method according to the present invention is characterized by the fact that an amino acid with the formula: where X has the meaning given above, is reacted with phosgene in an inert organic solvent and the obtained internal anhydride with the formula:
hvor X har den ovenfor angitte betydning, bringes i kontakt med en omtrent ekvivalent mengde av et alkalimetallsalt av 6-aminopenicillansyre i en blanding av vann og et i vann oppl5selig organisk opplosningsmiddel, ved en temperatur som ikke overstiger 2Q°Ci hvoretter det erholdte alkalimetallsalt av penicillin på kjent måte eventuelt omdannes til den frie syre eller andre ikke-giftige salter av denne. wherein X has the above meaning, is brought into contact with an approximately equivalent amount of an alkali metal salt of 6-aminopenicillanic acid in a mixture of water and a water-soluble organic solvent, at a temperature not exceeding 20°C, after which the resulting alkali metal salt of Penicillin is optionally converted in a known manner into the free acid or other non-toxic salts thereof.
Reaksjonen mellom aminosyrer og fosgen hvorved det oppnås et cyklisk anhydrid er beskrevet i Ree. Trav. Chim., 71, 387*, 1952. ;Videre er det kjent fra C.A. 53, B006 b, 1959, at ovennevnte anhydrid kan reagere med en aminogruppe slik at det dannes én peptidbinding. ;Folgelig må foreliggende fremgangsmåte betraktes som en analogifremgangsmåte som skaffer nye antibiotiske stoffer med forbed- ;rede egenskaper slik som de farmakologiske data, som angis i det folgende, vil vise. ;For utforelse av fremgangsmåten blir den valgte aminosyre suspendert i et vannfritt, inert organisk opplosningsmiddel, f.eks. dioksan, tetrahydrofuran eller toluen, og fosgen bobles inn inntil det er blitt oppnådd en fullstendig opplosning. Etter fordampning av opplosningsmidlet får man det indre anhydrid. Kn oppl5sning av dette anhydrid i et med vann blandbart inert opplosningsmiddel blir deretter bragt i beroring med en vandig opplosning av en omtrent ekvivalent mengde av et alkalimetallsalt av 6-aminopenicillansyre ved en tempera- ;tur på ikke over 20°C, hvoretter opplosningsmidlet fordampes, og det dannede penicillin utvinnes fra resten ved vanlige fremgangsmåter. Eksempelvis kan man etter surgjoring av reaksjonsblandingen med en mineralsyre og frafiltrering av eventuelt tilstedeværende små mengder uoppløselige biprodukter, samt inndampning til torrhet i vakuum, ;fjerne den uorganiske del ved filtrering etter å ha lost opp resten i et opplosningsmiddel i hvilket penicillinet er opploselig..<*>The reaction between amino acids and phosgene whereby a cyclic anhydride is obtained is described in Ree. Trot. Chim., 71, 387*, 1952. Furthermore, it is known from C.A. 53, B006 b, 1959, that the above-mentioned anhydride can react with an amino group so that one peptide bond is formed. Consequently, the present method must be regarded as an analogue method which provides new antibiotic substances with improved properties, as the pharmacological data, which is set out below, will show. To carry out the method, the selected amino acid is suspended in an anhydrous, inert organic solvent, e.g. dioxane, tetrahydrofuran or toluene, and phosgene is bubbled in until complete dissolution has been achieved. After evaporation of the solvent, the internal anhydride is obtained. A solution of this anhydride in a water-miscible inert solvent is then brought into contact with an aqueous solution of an approximately equivalent amount of an alkali metal salt of 6-aminopenicillanic acid at a temperature not exceeding 20°C, after which the solvent is evaporated, and the penicillin formed is recovered from the residue by usual methods. For example, after acidifying the reaction mixture with a mineral acid and filtering off any small amounts of insoluble by-products that may be present, as well as evaporating to dryness in a vacuum, the inorganic part can be removed by filtration after dissolving the remainder in a solvent in which the penicillin is soluble. <*>
Det er klart at når disse rensemetoder forer til en opplosning av penicillinet i et opplosningsmiddel, vil man ved å fjerne opplosningsmidlet ved destillasjon få penicillinet som rest. I andre tilfeller kan det være å foretrekke å isolere penicillinet !• form av dets alkalimetallsalt. Ved slutten av acyleringsreaksjonen blir det vannopploselige produkt, som utgjøres av penicillinets alkalimetall- It is clear that when these purification methods lead to a dissolution of the penicillin in a solvent, by removing the solvent by distillation, the penicillin will be obtained as a residue. In other cases it may be preferable to isolate the penicillin !• form of its alkali metal salt. At the end of the acylation reaction, the water-soluble product is formed, which is made up of penicillin's alkali metal
salt, skilt ved filtrering fra den uoppløselige andel, og fra oppløs-ningen isoleres produktet ved inndampning eller ved frysetørking. salt, separated by filtration from the insoluble portion, and the product is isolated from the solution by evaporation or freeze-drying.
De nye penicillinprodukter som er av særlig interesse er (3-amino-oc-f enyletylpenicillin og f-amino-cc-f enylpropylpenicillin. The new penicillin products that are of particular interest are (3-amino-oc-phenylethylpenicillin and f-amino-cc-phenylpropylpenicillin.
Disse stoffer har et asymmetrisk karbonatom og de tilsvarende diaste-reoisomere kan fremstilles ved vanlige arbeidsmåter. Eksempelvis kan optisk aktive former av P-amino-a-fenyletylpenicillin fremstilles ved å gå ut fra optisk aktive a-fenyl-P-karbobenzoksyaminopropionsyre, som er fremstilt av racematet gjennom dettes salt med optisk aktive baser, These substances have an asymmetric carbon atom and the corresponding diastereoisomers can be prepared by usual methods. For example, optically active forms of P-amino-a-phenylethylpenicillin can be prepared by starting from optically active a-phenyl-P-carbobenzoxyaminopropionic acid, which is prepared from the racemate through its salt with optically active bases,
som f.eks. kinin, stryknin, cinkonin eller morfin. like for example. quinine, strychnine, cinchonine or morphine.
Den folgende tabell angir den minste inhibitoriske kon-sentrasjon i Y/ml in vitro av noen av de nye penicilliner like over- The following table indicates the minimum inhibitory concentration in Y/ml in vitro of some of the new penicillins just above
for en del patogene mikroorganismer. for some pathogenic microorganisms.
Penicilliner som fremstilles ifolge foreliggende oppfinn-• else har en overlegen aktivitet i forhold til de som er sitert i det ovenfor angitte britiske patent slik som det vil fremgå av folgende tabell: Penicillins produced according to the present invention have a superior activity compared to those cited in the above-mentioned British patent, as will be seen from the following table:
Dessuten har de nye penicilliner en hoy motstandsevne både mot syrer og mot penase. Stabiliteten av noen av de nye penicilliner i saltsyre (pH = 1) sammenlignet med fenoksyetylpenicillin, som er kjent som et av de penicilliner som er minst folsomme for sure media, er vist i den folgende tabell. Prosentmengden av ikke-nedbygget penicillin til forskjellige tider er angitt i tabellen. In addition, the new penicillins have a high resistance to both acids and penase. The stability of some of the new penicillins in hydrochloric acid (pH = 1) compared to phenoxyethylpenicillin, which is known as one of the penicillins least sensitive to acidic media, is shown in the following table. The percentage amount of undegraded penicillin at different times is indicated in the table.
De folgende eksempler belyser oppfinnelsen nærmere. Eksempel 1 DL-( 3- amino- a- f enyletylpenicillin The following examples illustrate the invention in more detail. Example 1 DL-(3-amino-a-f phenylethylpenicillin
DL-5-fenyl-dihydro-1,3-oksazin-2,6-dion. DL-5-phenyl-dihydro-1,3-oxazin-2,6-dione.
I en suspensjon av 5 g DL-P-amino-a-fenyl-propionsyre i 100 ml vannfritt dioksan bobles det gjennom en fosgenstrom i 2 timer ved 40°-45°C. Deretter omrores blandingen i 2 timer, inntil produktet er fullstendig opplost. Opplosningsmidlet fjernes i vakuum, og resten tas opp med benzen og filtreres. Produktet krystalliseres fra aceton og man får 5-4g DL-5-fenyl-dihydro-1,3-oksazin-2,6-dion, smeltepunkt 120-4°C (spalting). A suspension of 5 g of DL-P-amino-α-phenyl-propionic acid in 100 ml of anhydrous dioxane is bubbled through a stream of phosgene for 2 hours at 40°-45°C. The mixture is then stirred for 2 hours, until the product is completely dissolved. The solvent is removed in vacuo, and the residue is taken up with benzene and filtered. The product is crystallized from acetone and 5-4 g of DL-5-phenyl-dihydro-1,3-oxazin-2,6-dione are obtained, melting point 120-4°C (decomposition).
nL- (3-amino-a-f enyletylpenicillin. nL-(3-amino-α-phenylethylpenicillin.
6-aminopenicillansurt natriumsalt (4.8 g) loses ved 0°C opp i 12 ml vann og settes til en på forhånd til 10°-15°C avkjolt opplosning av DL-5-fenyl-dihydro-1,3-oksazin-2,6-dion (3-7 g) i 25 ml aceton. Etter 0.5 timers omroring lar man temperaturen få stige til romtemperatur. Det iakttas da en utvikling av CO^. Etter 30 minut-ters forlop reguleres blandingens pH til 4'6 og den filtreres, fil-tratet inndampes til torrhet i vakuum, hvorved man får et rått produkt som tas opp i metylalkohol og filtreres, og den klare opplosning inndampes til torrhet, hvorved man får DL-(3-amino-a-fenyletylpenicillin, som smelter ved 220°-225°C. 6-aminopenicillanic acid sodium salt (4.8 g) is dissolved at 0°C in 12 ml of water and added to a previously cooled to 10°-15°C solution of DL-5-phenyl-dihydro-1,3-oxazin-2, 6-dione (3-7 g) in 25 ml of acetone. After stirring for 0.5 hours, the temperature is allowed to rise to room temperature. A development of CO^ is then observed. After a period of 30 minutes, the pH of the mixture is adjusted to 4.6 and it is filtered, the filtrate is evaporated to dryness in vacuum, whereby a crude product is obtained which is taken up in methyl alcohol and filtered, and the clear solution is evaporated to dryness, whereby gives DL-(3-amino-α-phenylethylpenicillin, which melts at 220°-225°C.
Eksempel 2 (+ )- [ 3- amino- a- f enyletylpenicillin Example 2 (+ )-[ 3-amino-α-f phenylethylpenicillin
a) (+) - (3-amino-a-f enylpropionsyre. a) (+)-(3-amino-α-phenylpropionic acid.
Til en suspensjon av DL-(3-amino-a-fenyl-propionsyre (16 g) To a suspension of DL-(3-amino-a-phenyl-propionic acid (16 g)
i etylalkohol (150 ml), settes en varm opplosning av D-kamfersulfon-syre (24.5 g) i etylalkohol f60 ml). in ethyl alcohol (150 ml), a warm solution of D-camphorsulfonic acid (24.5 g) in ethyl alcohol (60 ml) is placed.
Ved avkjoling får man 23 g D-kamf ersulf onat av ( + )-|3-amino- a-fenylpropionsyre, /a/^ = + 63° f0.5 % i vann), smeltepunkt I9O<0->192°C. Dette salt loses opp i vann og det tilsettes NaOH til pH = 5. Ved avkjoling dannes det.en utfelling som filtreres fra, vaskes og torkes, hvorved man får (+)-(3-amino-a-fenyl-propionsyre, /cc/^ 20 = +85o (0.5 % i vann), smeltepunkt 223°-226°C (spaltning). On cooling, 23 g of D-camphor sulfonate of ( + )-|3-amino-a-phenylpropionic acid is obtained, /a/^ = + 63° f0.5% in water), melting point I9O<0->192°C . This salt is dissolved in water and NaOH is added to pH = 5. Upon cooling, a precipitate is formed which is filtered off, washed and dried, thereby obtaining (+)-(3-amino-a-phenyl-propionic acid, /cc /^ 20 = +85o (0.5% in water), melting point 223°-226°C (decomposition).
b) (<+>)-5-fenyldihydro-l,3-oksazin-2,6-dion. Fremstilles som beskrevet i eksempel 1 for det racemiske b) (<+>)-5-phenyldihydro-1,3-oxazin-2,6-dione. Prepared as described in example 1 for the racemic
produkt. product.
c) ( + )- (3-amino-oc-f enyletylpenicillin. c) ( + )-(3-amino-oc-phenylethylpenicillin.
Fremstilles ved samme arbeidsmåte som beskrevet i eksempel 1. Produced using the same method as described in example 1.
Fysikalsk-kjemiske egenskaper: /a/p 20 = +203 o (0.5 % i vann), smeltepunkt 207°-210°C (spaltning). Physico-chemical properties: /a/p 20 = +203 o (0.5% in water), melting point 207°-210°C (decomposition).
Eksempel 3 (-) - ( 3- amino- oc- f enyletylpenicillin. Example 3 (-)-(3-amino-oc-f-phenylethylpenicillin.
Ble fremstilt av (-)-(3-amino-oc-fenylpropionsyre isolert fra moderluten erholdt etter fraskillelse av D-kamfersulfonatet av ( + )-(3-amino-oc-fenylpropionsyre (se eksempel 2) ved samme arbeidsmåte som beskrevet for de foran angitte penicilliner, smeltepunkt 225° - 230°C (spaltning), /a/^<0>= 203° (0.5 % i vann). Was prepared from (-)-(3-amino-oc-phenylpropionic acid isolated from the mother liquor obtained after separation of the D-camphor sulphonate from ( + )-(3-amino-oc-phenylpropionic acid) (see example 2) by the same procedure as described for the preceding penicillins, melting point 225° - 230°C (decomposition), /a/^<0>= 203° (0.5% in water).
Eksempel 4- 6 Example 4-6
Ved den samme arbeidsmåte som beskrevet i de foranstående eksempler ble det fremstilt folgende penicilliner: oc-aminoksybenzylpenicillin, smeltepunkt 78°-85°C a-fenyl-V-aminopropylpenicillin, smeltepunkt 193°-19^<>>C. a-fenyl-£-aminobutylpenicillin, smeltepunkt l80°-l85°C. The following penicillins were prepared using the same method as described in the preceding examples: α-aminooxybenzylpenicillin, melting point 78°-85°C α-phenyl-V-aminopropylpenicillin, melting point 193°-19°C. a-phenyl-£-aminobutylpenicillin, melting point 180°-185°C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB34459/61A GB960896A (en) | 1961-09-26 | 1961-09-26 | Production of penicillins |
| GB489262 | 1962-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO119271B true NO119271B (en) | 1970-04-27 |
Family
ID=26239453
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO145720A NO119271B (en) | 1961-09-26 | 1962-09-14 |
Country Status (6)
| Country | Link |
|---|---|
| CH (1) | CH398600A (en) |
| ES (1) | ES280753A1 (en) |
| FI (1) | FI42959B (en) |
| FR (2) | FR1575504A (en) |
| NO (1) | NO119271B (en) |
| SE (1) | SE308112B (en) |
-
1962
- 1962-09-08 FI FI1644/62A patent/FI42959B/fi active
- 1962-09-13 ES ES280753A patent/ES280753A1/en not_active Expired
- 1962-09-14 NO NO145720A patent/NO119271B/no unknown
- 1962-09-25 SE SE10275/62A patent/SE308112B/xx unknown
- 1962-09-25 CH CH1126962A patent/CH398600A/en unknown
- 1962-09-25 FR FR1575504D patent/FR1575504A/fr not_active Expired
- 1962-12-18 FR FR918935A patent/FR2651M/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| FR2651M (en) | 1964-07-15 |
| ES280753A1 (en) | 1963-02-01 |
| FI42959B (en) | 1970-09-02 |
| CH398600A (en) | 1966-03-15 |
| FR1575504A (en) | 1969-07-25 |
| SE308112B (en) | 1969-02-03 |
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