NO116085B - - Google Patents
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- Publication number
- NO116085B NO116085B NO15373664A NO15373664A NO116085B NO 116085 B NO116085 B NO 116085B NO 15373664 A NO15373664 A NO 15373664A NO 15373664 A NO15373664 A NO 15373664A NO 116085 B NO116085 B NO 116085B
- Authority
- NO
- Norway
- Prior art keywords
- penicillin
- infrared spectrum
- aminobenzylpenicillin
- hydrated
- temperature
- Prior art date
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- AVKUERGKIZMTKX-YXLKDIQASA-N (2s,5r)-6-[(2-amino-2-phenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)NC(=O)C(N)C1=CC=CC=C1 AVKUERGKIZMTKX-YXLKDIQASA-N 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 13
- 230000018044 dehydration Effects 0.000 claims description 10
- 238000006297 dehydration reaction Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000002329 infrared spectrum Methods 0.000 description 28
- 229930182555 Penicillin Natural products 0.000 description 24
- 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 23
- 229940049954 penicillin Drugs 0.000 description 23
- 239000000047 product Substances 0.000 description 19
- 238000001228 spectrum Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 150000002960 penicillins Chemical class 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 description 1
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- -1 aliphatic nitro compound Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/04—Oxygen-containing compounds
- C08K5/09—Carboxylic acids; Metal salts thereof; Anhydrides thereof
- C08K5/098—Metal salts of carboxylic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Fremgangsmåte til fremstilling av et dehydratisert stabilt krystallinsk D (-)-a-aminobenzylpenicillin. Process for the preparation of a dehydrated stable crystalline D (-)-α-aminobenzylpenicillin.
Det har vist seg at ustabiliteten ved oppbevaring av det _ kjente D(-)-a-aminobenzylpenicillin (6-D(-)-o-aminofenylacetamido-penicillansyre), aom er et verdifullt legemiddel mot infeksjonssyk-dommene fremkalt av Gram-positive og Gram-negative bakterier, skyldes forbindelsens innhold av krystallvann, og at denne ustabilitet kan unngåes ved dehydratisering av penicillinet. It has been shown that the instability during storage of the known D(-)-α-aminobenzylpenicillin (6-D(-)-o-aminophenylacetamido-penicillanic acid), aom is a valuable drug against the infectious diseases caused by Gram-positive and Gram-negative bacteria, due to the compound's water of crystal content, and that this instability can be avoided by dehydrating the penicillin.
Oppfinnelsen bygger på denne erkjennelse og angår en fremgangsmåte til fremstilling av et dehydratisert stabilt krystallinsk D(-)-a-aminobenzylpenicillin, som erkarakterisert vedat hydratisertD(-)-a-aminobenzylpenicillin dehydratiseres ved oppvarmning i et flytende medium tii en temperatur på over 60°C, hvoretter dehydratiseringsproduktet isoleres fra reaksjonsblandingen. The invention is based on this realization and relates to a method for the production of a dehydrated stable crystalline D(-)-α-aminobenzylpenicillin, which is characterized in that hydrated D(-)-α-aminobenzylpenicillin is dehydrated by heating in a liquid medium at a temperature of over 60° C, after which the dehydration product is isolated from the reaction mixture.
Ved denne fremgangsmåte kan det hydratiserte penicillins dehydratisering utføres på forskjellig måte. Således kan oppvarmnin-gen utføres med en suspensjon av det hydratiserte penicillin i vann eller et vannholdig organisk oppløsningsmiddel eller i nitrobenzen eller en alifatisk nitroforbindelse med høyst 6 karbonatomer, fortrinnsvis nitroetan, 1-nitropropan, 2-nitropropan eller især nitrometan. In this method, the hydrated penicillin's dehydration can be carried out in different ways. Thus, the heating can be carried out with a suspension of the hydrated penicillin in water or an aqueous organic solvent or in nitrobenzene or an aliphatic nitro compound with at most 6 carbon atoms, preferably nitroethane, 1-nitropropane, 2-nitropropane or especially nitromethane.
Ved en annen fordelaktig utførelsesform for fremgangsmåten kan opp-varmningen av det hydratiserte penicillin utføres med en oppløsning i en fortynnet uorganisk syre, fortrinnsvis fortynnet saltsyre, under utfelning av dehydratiseringsproduktet ved tilsetning av en base, som kan være en uorganisk base, især natrium- eller kaliumhydroksyd, eller en organisk base, især trietylamin, trietanolamin eller tri-n-butylamin. Når det anvendes en organisk base, kan utbyttet av det dehydratiserte penicillin økes ved å utføre dehydratiseringsproduktets utfelning og hensiktsmessig også penicillinoppløsningens oppvarmning i nærvær av et vannoppløselig organisk oppløsningsmiddel for det av den uorganiske syre og den organiske base dannede salt, og et sådant oppløsningsmiddel er f.eks. en alkohol, såsom 2-propanol eller tertiær butylalkohol. In another advantageous embodiment of the method, the heating of the hydrated penicillin can be carried out with a solution in a dilute inorganic acid, preferably dilute hydrochloric acid, during precipitation of the dehydration product by the addition of a base, which can be an inorganic base, especially sodium or potassium hydroxide, or an organic base, especially triethylamine, triethanolamine or tri-n-butylamine. When an organic base is used, the yield of the dehydrated penicillin can be increased by carrying out the precipitation of the dehydration product and suitably also the heating of the penicillin solution in the presence of a water-soluble organic solvent for the salt formed by the inorganic acid and the organic base, and such a solvent is f .ex. an alcohol such as 2-propanol or tertiary butyl alcohol.
Ved fremgangsmåten ifølge oppfinnelsen avhenger den til oppvarmning av det hydratiserte penicillin anvendte tid av den anvendte temperatur. Ved 70°C er en oppvarmningstid på i det høyeste 5 minutter som regel tilstrekkelig til oppnåelse av et så godt som vannfritt D(-)-aaminobenzylpenicillin, mens ved en høyere temperatur kan det anvendes en kortere oppvarmning. In the method according to the invention, the time used to heat the hydrated penicillin depends on the temperature used. At 70°C, a heating time of at most 5 minutes is usually sufficient to obtain an almost anhydrous D(-)-aaminobenzylpenicillin, while at a higher temperature, a shorter heating time can be used.
Den ved fremgangsmåten ifølge oppfinnelsen fremstilte,The one produced by the method according to the invention,
hittil ukjente stabile krystallform av så godt som vannfritt D(-)-a-aminobenzylpenicillin har et infrarødt spektrum som i følgende punkter avviker vesentlig fra det infrarøde spektrum av det hydratiserte penicillin. Det infrarøde spektrum av dehydratiseringsproduktet har i forhold til det infrarøde spektrum av de hydratiserte peni-cilliner i stedet for de ikke særlig utpregede bånd omkring 2,8 og 2,9 og 3,15^u, en meget skarp spiss ved 3, 0^ u, paret av ved siden av hverandre liggende bånd ved 6,25 og 6,37^u er erstattet med et par av sterkere bånd ved 6,35 og 6,6^u, hvorved det åpnes en kløft mellom disse bånd og det nærmeste bånd med en lavere bølgelengde ved 6,15^,u, og samtidig lukkes kløften mellom disse bånd og det nærmeste bånd med en høyere bølgelengde ved 6,7^u, og båndet med en moderat intensitet ved 7,52^u er forsvunnet og sannsynligvis forflyttet slik at det er gått sammen med båndet ved 7,7^u. hitherto unknown stable crystal form of virtually anhydrous D(-)-α-aminobenzylpenicillin has an infrared spectrum which in the following points deviates significantly from the infrared spectrum of the hydrated penicillin. The infrared spectrum of the dehydration product has, in relation to the infrared spectrum of the hydrated penicillins, instead of the not particularly pronounced bands around 2.8 and 2.9 and 3.15^u, a very sharp peak at 3.0^ u, the pair of adjacent bands at 6.25 and 6.37^u is replaced by a pair of stronger bands at 6.35 and 6.6^u, thereby opening a gap between these bands and the nearest band with a lower wavelength at 6.15^u, and at the same time the gap between these bands and the nearest band with a higher wavelength at 6.7^u closes, and the band with a moderate intensity at 7.52^u has disappeared and probably moved so that it has merged with the band at 7.7^u.
Fremgangsmåten ifølge oppfinnelsen skål forklares nærmereThe method according to the invention is explained in more detail
i de følgende eksempler under henvisning til tegningen, hvor:in the following examples with reference to the drawing, where:
fig. 1 viser det infrarøde spektrum av hydratisert D(-)-a-amino- benzylpenicillin med et vanninnhold på 14,3 %, fig. 1 shows the infrared spectrum of hydrated D(-)-α-amino- benzylpenicillin with a water content of 14.3%,
fig. 2 viser det infrarøde spektrum av det ved oppvarmning av det hydratiserte D(-)-a-aminobenzylpenicillin i et lukket glass-rør i 17 timer til 90°C erholdte-produkt, fig. 2 shows the infrared spectrum of the product obtained by heating the hydrated D(-)-α-aminobenzylpenicillin in a closed glass tube for 17 hours at 90°C,
fig. 3 viser det infrarøde spektrum av det ved oppvarmning av det hydratiserte D(-)-a-aminobenzylpenicillin i vann i 3 minutter til 80°C fremstilte dehydratiseringsprodukt med et vanninnhold på 2,7 %, og fig. 3 shows the infrared spectrum of the dehydration product produced by heating the hydrated D(-)-α-aminobenzylpenicillin in water for 3 minutes at 80°C with a water content of 2.7%, and
fig. 4 viser det infrarøde spektrum av det ved oppvarmning av dehydratiseringsproduktet i et lukket glassrør i 17 timer til 90°C fremstilte produkt. fig. 4 shows the infrared spectrum of the product produced by heating the dehydration product in a closed glass tube for 17 hours at 90°C.
Eksempel 1Example 1
En vandig oppslemming av hydratisert D(-)-a-aminobenzyl-penicillin med en renhet som svarer til 85,7 % vannfritt D(-)-aamino-benzylpenicillin, og hvis infrarøde spektrum er som vist i fig. 1, oppvarmes i 3 minutter til 80°C, hvorpå penicillinet filtreres fra og tørres ved ca. 60°C. Dehydratiseringsproduktet, hvis infrarøde spektrum er som vist i fig. 3, har en renhet på 97,3 % og utbyttet er stør-re enn 90 % av utgangsmaterialet. An aqueous slurry of hydrated D(-)-α-aminobenzylpenicillin with a purity corresponding to 85.7% anhydrous D(-)-αaminobenzylpenicillin, and whose infrared spectrum is as shown in fig. 1, is heated for 3 minutes to 80°C, after which the penicillin is filtered off and dried at approx. 60°C. The dehydration product, whose infrared spectrum is as shown in fig. 3, has a purity of 97.3% and the yield is greater than 90% of the starting material.
Dehydratiseringsproduktet oppvarmes i et lukket glassrør iThe dehydration product is heated in a closed glass tube i
17 timer, 66 timer og 142 timer til 90°C. Renheten av de oppvarmede produkter hvis farve alltid var uforandret, og som alltid var krystal-linske, var henholdsvis 93,9 %, 95,7 % og 94,0 %. Det infrarøde spektrum av det i 17 timer oppvarmede produkt var som vist i fig. 4. 17 hours, 66 hours and 142 hours at 90°C. The purity of the heated products whose color was always unchanged, and which were always crystalline, were respectively 93.9%, 95.7% and 94.0%. The infrared spectrum of the product heated for 17 hours was as shown in fig. 4.
Til sammenligning ble det som utgangsmateriale anvendte, hydratiserte penicillin oppvarmet i et lukket glassrør i 17 timer til 90°C. Renheten av det oppvarmede produkt, som var et oransje-gul-far-vet residuum, var 2,3 %, og produktets infrarøde spektrum var som vist i fig. 2. For comparison, the hydrated penicillin used as starting material was heated in a closed glass tube for 17 hours at 90°C. The purity of the heated product, which was an orange-yellow colored residue, was 2.3%, and the infrared spectrum of the product was as shown in fig. 2.
Eksempel 2Example 2
En suspensjon av 1 g D(-)-a-aminobenzylpenicillin-trihydrat, fremstilt ved omrøring, og hvis infrarøde spektrum ligner spektret ifølge fig. 1, i en blanding av 2,4 ml vann og 13,6 ml propanol-2 oppvarmes hurtig til kokepunktet og kokes deretter i 5 minutter, hvorpå den varme suspensjon filtreres, og det frafiltrerte penicillin tørres ved ca. 60°C. Utbyttet av det dehydratiserte penicillin er 0,8 g.Penicillinets infrarøde spektrum ligner spektret ifølge fig. 3. A suspension of 1 g of D(-)-α-aminobenzylpenicillin trihydrate, prepared by stirring, and whose infrared spectrum resembles the spectrum of fig. 1, in a mixture of 2.4 ml of water and 13.6 ml of propanol-2 is quickly heated to the boiling point and then boiled for 5 minutes, after which the hot suspension is filtered, and the filtered penicillin is dried at approx. 60°C. The yield of the dehydrated penicillin is 0.8 g. The penicillin's infrared spectrum is similar to the spectrum according to fig. 3.
Eksempel 3Example 3
A. Ved koking av en blanding av 60 ml nitrometan og 6 g hydratisert D(-)-aaminobenzylpenicillin med et vanninnhold på 11 % og en renhet på 86 %, bestemt som vannfritt penicillin, i 5 minutter, filt-rering av blandingen og tørking av filterresten ved ca. 60°C fremstil-les 4,94 g D(-)-a-aminobenzylpenicillin med et vanninnhold på 0,8 % og en renhet på 98 %. Etter oppvarmning av produktet i 45 timer til 90°C var renheten 91 %. A. By boiling a mixture of 60 ml of nitromethane and 6 g of hydrated D(-)-aminobenzylpenicillin with a water content of 11% and a purity of 86%, determined as anhydrous penicillin, for 5 minutes, filtering the mixture and drying of the filter residue at approx. 60°C, 4.94 g of D(-)-α-aminobenzylpenicillin are produced with a water content of 0.8% and a purity of 98%. After heating the product for 45 hours at 90°C, the purity was 91%.
Ved gjentagelse av forsøket ble det oppnådd 5,09 gD(-)-a-aminobenzylpenicillin med et vanninnhold på 1 % og en renhet på 92 %. Etter oppvarmning av produktet i 45 timer til 90°C var dets renhet 87 %. By repeating the experiment, 5.09 g of D(-)-α-aminobenzylpenicillin was obtained with a water content of 1% and a purity of 92%. After heating the product for 45 hours at 90°C, its purity was 87%.
Til sammenligning ble det som utgangsmateriale anvendte hydratiserte D(-)-a-aminobenzylpenicillin oppvarmet i 45 timer til90°C. Produktets renhet var 0 %. For comparison, the hydrated D(-)-α-aminobenzylpenicillin used as starting material was heated for 45 hours to 90°C. The purity of the product was 0%.
B. Forsøk A ble gjentatt med et hydratisert D(-)-a-aminobenzyl-penicillin med et vanninnhold på 13 % og en renhet på 77 %. Det ble oppnådd 4,84 g dehydratisert penicillin med et vanninnhold på 1,2 %, og en renhet på 92 %. Etter oppvarmning av produktet i 45 timer til 90°C var dets renhet 85 %. B. Experiment A was repeated with a hydrated D(-)-α-aminobenzyl penicillin with a water content of 13% and a purity of 77%. 4.84 g of dehydrated penicillin with a water content of 1.2% and a purity of 92% were obtained. After heating the product for 45 hours at 90°C, its purity was 85%.
Til sammenligning ble det som utgangsmateriale anvendte hydratiserte D(-)-a-aminobenzylpenicillin oppvarmet i 45 timer til 90°C. Produktets renhet var 0 %. For comparison, the hydrated D(-)-α-aminobenzylpenicillin used as starting material was heated for 45 hours to 90°C. The purity of the product was 0%.
Eksempel 4 Example 4
Oppløsninger av 4 g hydratisert D(-)-a-aminobenzylpenicil-lin, hvis infrarøde spektrum lignet spektret ifølge fig. 1, i 10 ml N-saltsyre ble oppvarmet til forskjellige temperaturer, hvoretter Solutions of 4 g of hydrated D(-)-α-aminobenzylpenicillin, whose infrared spectrum resembled the spectrum according to fig. 1, in 10 ml of N-hydrochloric acid was heated to various temperatures, after which
det ved den anvendte temperatur under omrøring ble tilsatt 5 ml 2 N vandig natriumhydroksydoppløsning, og den anvendte temperatur ble opprettholdt i noen minutter, inntil utfelningen av penicillinets krystaller var avsluttet, hvorpå krystallene ble filtrert fra og tørket i 2 timer ved 62-65°C. at the temperature used, with stirring, 5 ml of 2 N aqueous sodium hydroxide solution was added, and the temperature used was maintained for a few minutes, until the precipitation of the penicillin's crystals had ended, after which the crystals were filtered off and dried for 2 hours at 62-65°C .
Ved anvendelse av en temperatur på 30-35°C ble det erholdt 3,51 g penicillin, hvis infrarøde spektrum lignet utgangsmaterialets infrarøde spektrum. Using a temperature of 30-35°C, 3.51 g of penicillin was obtained, the infrared spectrum of which resembled the infrared spectrum of the starting material.
Ved anvendelse av en temperatur på 40-45°C ble det erholdt 3,25 g penicillin, hvis infrarøde spektrum lignet utgangsmaterialets infrarøde spektrum. Using a temperature of 40-45°C, 3.25 g of penicillin was obtained, the infrared spectrum of which resembled the infrared spectrum of the starting material.
Ved anvendelse av en temperatur på 50-55°C ble det erholdt 2,92 g penicillin, hvis infrarøde spektrum var en blanding av spektret ifølge fig. 1 og av spektret ifølge fig. 3. By using a temperature of 50-55°C, 2.92 g of penicillin were obtained, whose infrared spectrum was a mixture of the spectrum according to fig. 1 and of the spectrum according to fig. 3.
Ved anvendelse av en temperatur på 55-60°C ble det erholdt 2,66 g penicillin, hvis infrarøde spektrum var en blanding av spektret ifølge fig. 1 og av spektret ifølge fig. 3. By using a temperature of 55-60°C, 2.66 g of penicillin were obtained, whose infrared spectrum was a mixture of the spectrum according to fig. 1 and of the spectrum according to fig. 3.
Ved anvendelse av en temperatur på 60-65°C ble det erholdt 2,62 g penicillin, hvis infrarøde spektrum lignet spektret ifølge fig. 3. By using a temperature of 60-65°C, 2.62 g of penicillin were obtained, whose infrared spectrum resembled the spectrum according to fig. 3.
Ved anvendelse av en temperatur på 80°C ble det erholdtBy using a temperature of 80°C it was obtained
2,38 g penicillin, hvis infrarøde spektrum lignet spektret ifølge fig. 3. 2.38 g of penicillin, whose infrared spectrum resembled the spectrum according to fig. 3.
Ved anvendelse av en temperatur på 100°C ble det erholdt 1,46 g penicillin, hvis infrarøde spektrum lignet spektret ifølge fig. 3. By using a temperature of 100°C, 1.46 g of penicillin was obtained, whose infrared spectrum resembled the spectrum according to fig. 3.
Eksempel 5Example 5
En oppløsning av 4 g hydratisert D(-)-a-aminobenzylpenicil-lin i 5 ml 2 N saltsyre, som var fortynnet med 20 ml tertiær butylalkohol ble oppvarmet til 70°C, hvorpå det ved samme temperatur under omrøring ble tilsatt 1,38 ml trietylamin, hvorved penicillinet ble utfelt. Til blandingen ble tilsatt 25 ml kokende tertiær buta-nol, og blandingen ble omrørt inntil dens temperatur var falt til 65°C, hvorpå det utkrystalliserte penicillin ble frafiltrert og tør-ket ved 62°C. Man fikk 2,96 g dehydratisert D(-)-a-aminobenzylpeni-cillin, hvis infrarøde spektrum lignet spektret ifølge fig. 3. Utbyttet var 85 % av det teoretiske. A solution of 4 g of hydrated D(-)-α-aminobenzylpenicillin in 5 ml of 2 N hydrochloric acid, which had been diluted with 20 ml of tertiary butyl alcohol, was heated to 70°C, whereupon at the same temperature, with stirring, 1.38 ml of triethylamine, whereby the penicillin was precipitated. To the mixture was added 25 ml of boiling tertiary butanol, and the mixture was stirred until its temperature had fallen to 65°C, whereupon the crystallized penicillin was filtered off and dried at 62°C. 2.96 g of dehydrated D(-)-α-aminobenzylpenicillin was obtained, the infrared spectrum of which resembled the spectrum according to fig. 3. The yield was 85% of the theoretical.
Eksempel 6Example 6
En med 2,5 ml vann og 42,5 ml tertiær butylalkohol fortynnet oppløsning av 4 g hydratisert D(-)-a-aminobenzylpenicillin i 5 A with 2.5 ml of water and 42.5 ml of tertiary butyl alcohol diluted solution of 4 g of hydrated D(-)-α-aminobenzyl penicillin in 5
ml 2N saltsyre ble oppvarmet til 70°C, og ved denne temperatur ble det under omrøring tilsatt 1,38 ml trietylamin med en slik hastighet at det såvidt mulig ble unngått en geldannelse. Blandingen ble holdt ved 70°C inntil det var dannet en krystallinsk utfelning, som ble frafiltrert og tørket ved 62°C. Man fikk 2,95 g krystallinsk stabilt dehydratisert D(-)-a-aminobenzylpenicillin med et infrarødt spektrum som lignet spektret ifølge fig. 3. Utbytte: 86 % av det teoretiske. ml of 2N hydrochloric acid was heated to 70°C, and at this temperature 1.38 ml of triethylamine was added with stirring at such a rate that gel formation was avoided as far as possible. The mixture was kept at 70°C until a crystalline precipitate had formed, which was filtered off and dried at 62°C. 2.95 g of crystalline stable dehydrated D(-)-α-aminobenzylpenicillin with an infrared spectrum similar to the spectrum according to fig. 3. Yield: 86% of the theoretical.
Eksempel 7Example 7
En med 40 ml tertiær butylalkohol fortynnet oppløsning avA diluted solution of 40 ml of tertiary butyl alcohol
4 g hydratisert D(-)-a-aminobenzylpenicillin, hvis infrarøde spektrum ligner spektret ifølge fig. 1., i 10 ml 1 N saltsyre ble oppvarmet til 70°C, hvorpå det ved denne temperatur under omrøring ble tilsatt 1,38 ml trietylamin, og omrøringen ble fortsatt inntil blandin-gens temperatur var falt til ca. 60°C. De utskilte penicillinkrystal-ler ble frafiltrert og tørket ved ca. 62°C. Man fikk 2,71 g dehydratisert krystallinsk D(-)-a-aminobenzylpenicillin med et infrarødt spektrum som lignet spektret ifølge fig. 3. Utbyttet: 78 % av det teoretiske. 4 g of hydrated D(-)-α-aminobenzylpenicillin, whose infrared spectrum resembles the spectrum according to fig. 1., in 10 ml of 1 N hydrochloric acid was heated to 70°C, whereupon 1.38 ml of triethylamine was added at this temperature with stirring, and the stirring was continued until the temperature of the mixture had fallen to approx. 60°C. The secreted penicillin crystals were filtered off and dried at approx. 62°C. 2.71 g of dehydrated crystalline D(-)-α-aminobenzylpenicillin with an infrared spectrum similar to the spectrum according to fig. 3. The yield: 78% of the theoretical.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2491963A GB1016875A (en) | 1963-06-22 | 1963-06-22 | ª‡-aminobenzyl penicillin |
| GB3505463 | 1963-09-05 | ||
| GB3562663 | 1963-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO116085B true NO116085B (en) | 1969-01-27 |
Family
ID=27258379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO15373664A NO116085B (en) | 1963-06-22 | 1964-06-19 |
Country Status (13)
| Country | Link |
|---|---|
| AT (1) | AT249867B (en) |
| BE (1) | BE649197A (en) |
| BR (1) | BR6459876D0 (en) |
| CH (1) | CH450430A (en) |
| DE (1) | DE1279021B (en) |
| DK (1) | DK106973C (en) |
| ES (1) | ES301096A1 (en) |
| FI (1) | FI44613C (en) |
| FR (1) | FR1406104A (en) |
| GB (1) | GB1016875A (en) |
| NL (2) | NL6406859A (en) |
| NO (1) | NO116085B (en) |
| SE (1) | SE313814B (en) |
-
0
- NL NL123293D patent/NL123293C/xx active
-
1963
- 1963-06-22 GB GB2491963A patent/GB1016875A/en not_active Expired
-
1964
- 1964-06-10 BR BR15987664A patent/BR6459876D0/en unknown
- 1964-06-12 BE BE649197D patent/BE649197A/xx unknown
- 1964-06-13 FI FI129164A patent/FI44613C/en active
- 1964-06-15 DE DEB77261A patent/DE1279021B/en active Pending
- 1964-06-15 CH CH776964A patent/CH450430A/en unknown
- 1964-06-16 SE SE733764A patent/SE313814B/xx unknown
- 1964-06-16 ES ES301096A patent/ES301096A1/en not_active Expired
- 1964-06-17 NL NL6406859A patent/NL6406859A/xx unknown
- 1964-06-17 FR FR978598A patent/FR1406104A/en not_active Expired
- 1964-06-18 DK DK306664A patent/DK106973C/en active
- 1964-06-19 NO NO15373664A patent/NO116085B/no unknown
- 1964-06-19 AT AT526364A patent/AT249867B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| SE313814B (en) | 1969-08-25 |
| BE649197A (en) | 1964-10-01 |
| FI44613B (en) | 1971-08-31 |
| ES301096A1 (en) | 1964-12-01 |
| BR6459876D0 (en) | 1973-08-14 |
| FI44613C (en) | 1974-05-13 |
| AT249867B (en) | 1966-10-10 |
| FR1406104A (en) | 1965-07-16 |
| NL123293C (en) | |
| CH450430A (en) | 1968-01-31 |
| GB1016875A (en) | 1966-01-12 |
| NL6406859A (en) | 1964-12-23 |
| DK106973C (en) | 1967-04-10 |
| DE1279021B (en) | 1968-10-03 |
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