NO155867B - IN STEREO DECODER. - Google Patents
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- NO155867B NO155867B NO81813943A NO813943A NO155867B NO 155867 B NO155867 B NO 155867B NO 81813943 A NO81813943 A NO 81813943A NO 813943 A NO813943 A NO 813943A NO 155867 B NO155867 B NO 155867B
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 21
- 239000004098 Tetracycline Substances 0.000 claims description 21
- 229960002180 tetracycline Drugs 0.000 claims description 21
- 229930101283 tetracycline Natural products 0.000 claims description 21
- 235000019364 tetracycline Nutrition 0.000 claims description 21
- 150000003522 tetracyclines Chemical class 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- -1 aminomethyl- Chemical group 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- NWXMGUDVXFXRIG-PMXORCKASA-N (4r,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-PMXORCKASA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 210000003205 muscle Anatomy 0.000 description 5
- 206010030113 Oedema Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- WKXRHAACRPUBIC-UHFFFAOYSA-N 2-piperidin-1-ium-3-ylacetate Chemical compound OC(=O)CC1CCCNC1 WKXRHAACRPUBIC-UHFFFAOYSA-N 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
- XJLSEXAGTJCILF-UHFFFAOYSA-N nipecotic acid Chemical compound OC(=O)C1CCCNC1 XJLSEXAGTJCILF-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HMEYVGGHISAPJR-IAHYZSEUSA-N rolitetracycline Chemical compound O=C([C@@]1(O)C(O)=C2[C@@H]([C@](C3=CC=CC(O)=C3C2=O)(C)O)C[C@H]1[C@@H](C=1O)N(C)C)C=1C(=O)NCN1CCCC1 HMEYVGGHISAPJR-IAHYZSEUSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
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- Compression, Expansion, Code Conversion, And Decoders (AREA)
- Stereo-Broadcasting Methods (AREA)
Description
Fremgangsmåte til fremstilling av delvis Method for the production of partial
nye aminometylderivater av tetracyklin. new aminomethyl derivatives of tetracycline.
Foreliggende oppfinnelse vedrorer en ny fremgangsmåte til fremstilling av delvis nye aminometylderivater av antibistikumet tetracyklin. The present invention relates to a new process for the production of partially new aminomethyl derivatives of the antibiotic tetracycline.
Det er kjent å fremstille vannopploselige tetracyklinderi-vater ved Mannich-reaksjonen. Denne reaksjon består i å kondensere en forbindelse som inneholder aktive hydrogenatomer med formaldehyd og et primært eller sekundært amin, under dannelse av forbindelser som er kjent under.den alminnelige definisjon Mannich-baser. For tetracyklin, ble Mannich-basene fremstilt med utgangsmateriale be-stående i mange organiske baser, enten alifatiske, aromatiske eller heterocykliske, som beskrevet f.eks. i de tyske patenter 1 044 806, It is known to prepare water-soluble tetracycline derivatives by the Mannich reaction. This reaction consists in condensing a compound containing active hydrogen atoms with formaldehyde and a primary or secondary amine, forming compounds known by the general definition Mannich bases. For tetracycline, the Mannich bases were prepared with starting material consisting of many organic bases, either aliphatic, aromatic or heterocyclic, as described e.g. in the German patents 1 044 806,
1 O63 598 og 1 O88 Q. 8l. Selv om disse derivater er temmelig godt opploselige i vann, har de imidlertid alle en lav stabilitet, og flere av dem er ikke egnet for administrering ad parenteral vei. 1 O63 598 and 1 O88 Q. 8l. Although these derivatives are fairly well soluble in water, they all have a low stability, and several of them are not suitable for parenteral administration.
For å forbedre stabiliteten og muligheten av administrering parenteralt (toleransen), ble det fremstilt andre derivater som inneholdt en karboksylgruppe, ved som utgangsmateriale å bruke noen aminosyrer. Selv om det herved ble.oppnådd forbindelser som var mer stabile, gikk den antibiotiske aktivitet mer eller mindre ned. Dette skyldtes at ved de betingelser som hersket ved de fremstillinger som er beskrevet i litteraturen, vil tetracyklin lett omdannes til den in-aktive isomer. epitetracyklin. In order to improve the stability and possibility of parenteral administration (tolerance), other derivatives containing a carboxyl group were prepared by using as starting material some amino acids. Although compounds were thereby obtained that were more stable, the antibiotic activity more or less decreased. This was due to the fact that under the conditions prevailing in the preparations described in the literature, tetracycline will easily be converted into the inactive isomer. epitetracycline.
Ved foreliggende fremgangsmåte oppnåes det produkter i et hoyt utbytte og disse produkter omfatter et hoyt innhold av aktiv anti-biotisk forbindelse og et lavt innhold av praktisk talt inaktiv epimer. De fremstilte forbindelser har en bedre topisk toleranse etter intramuskulær administrasjon enn tidligere kjente forbindelser og de innehar den enestående egenskap at de kan administreres ad rektal vei. De nye fremstilte forbindelser har også en storre stabilitet innen et bredt pH-område enn nevnte tidligere kjente forbindelser. With the present method, products are obtained in a high yield and these products comprise a high content of active antibiotic compound and a low content of practically inactive epimer. The manufactured compounds have a better topical tolerance after intramuscular administration than previously known compounds and they have the unique property that they can be administered by rectal route. The new manufactured compounds also have a greater stability within a wide pH range than said previously known compounds.
Ifolge foreliggende oppfinnelse er det således tilveiebragt en fremgangsmåte til fremstilling av delvis nye aminometylderivater av tetracyklin og med formelen: hvor enten R er hydrogen og R-^ er resten av en alifatisk eller aromatisk aminosyre eller R og R-^ danner sammen med nitrogenet en substituert heterocyklisk ring med formelen: According to the present invention, a method is thus provided for the production of partially new aminomethyl derivatives of tetracycline and with the formula: where either R is hydrogen and R-^ is the residue of an aliphatic or aromatic amino acid or R and R-^ together with the nitrogen form a substituted heterocyclic ring with the formula:
hvor n er 0 - 3, ved omsetning av 1 mol tetracyklin, 1-2 mol formaldehyd og omtrent 1 mol av en alifatisk eller aromatisk aminosyre eller en piperidinkarboksylsyre med ovenfor angitte formel, ved en temperatur på mellom 10° og 50°C i et tidsrom på fra 5 "til 15 minutter, kjennetegnet ved at omsetningen foretaes i nærvær av en tertiær aminbase i en mengde where n is 0 - 3, by reacting 1 mol of tetracycline, 1-2 mol of formaldehyde and approximately 1 mol of an aliphatic or aromatic amino acid or a piperidine carboxylic acid with the above formula, at a temperature of between 10° and 50°C in a period of from 5" to 15 minutes, characterized in that the reaction is carried out in the presence of a tertiary amine base in an amount
som er tilstrekkelig til å gi reaksjonsblandingen en pH-verdi på 7-5 - 8.5, og at det, etter at reaksjonen er avsluttet, tilsettes saltsyre i en mengde som akkurat er tilstrekkelig til å noytralisere den tertiære aminbase, hvoretter det utskilte aminometylderivat av tetracyklin fraskilles. which is sufficient to give the reaction mixture a pH value of 7-5 - 8.5, and that, after the reaction has ended, hydrochloric acid is added in an amount just sufficient to neutralize the tertiary amine base, after which the separated aminomethyl derivative of tetracycline be divorced.
Selv om reaksjonen går ganske tilfredsstillende i alle opplosningsmidler som vanligvis benyttes i Mannich-reaksjonen, oppnåes de beste resultater ved å arbeide i en lavere alifatisk alkohol, slik som metanol eller etanol. Som tertiær organisk base er det hensikts-messig å anvende trietylamin, trimetylamin eller pyridin, hvilket således gjor at blandingen blir svakt alkalisk. Med slike betingelser som definert ovenfor dannes det meget lite epitetracyklin, og etter tilsetning av en mineralsyre som gir pH lik 4 - 5> felles produktet ut og oppsamles. Utbyttet er vanligvis meget h5yt. Although the reaction proceeds quite satisfactorily in all solvents commonly used in the Mannich reaction, the best results are obtained by working in a lower aliphatic alcohol, such as methanol or ethanol. As a tertiary organic base, it is appropriate to use triethylamine, trimethylamine or pyridine, which thus makes the mixture slightly alkaline. With such conditions as defined above, very little epitetracycline is formed, and after the addition of a mineral acid which gives a pH equal to 4 - 5> the product is precipitated and collected. The yield is usually very high.
Folgende er en tabell som sammenligner utbytter og epi-tetracyklindannelse oppnådd ved A) oppfinnelsens fremgangsmåte, B) ved fremgangsmåten beskrevet i Farmaco, Fd. Prat l6, 65, 196l, °g C) ved fremgangsmåten beskrevet i US patent nr. 3 042 7lS til fremstilling av y-aminosyrederivatene, under anvendelse av noen representative utgangsstoffer. The following is a table comparing yields and epi-tetracycline formation obtained by A) the method of the invention, B) by the method described in Farmaco, Fd. Prat 16, 65, 196l, °g C) by the method described in US patent no. 3,042 71S for the production of the y-amino acid derivatives, using some representative starting substances.
De mest interessante derivater er de som fremstilles ut fra 3-piperidinkarboksylsyre, 4-piperidinkarboksylsyre og 3-piperidineddiksyre, hvor det antibakterielle eller baktericide spektrum over-for noen representative bakterier er vist i nedenstående tabell, sammenlignet med tetracyklin. The most interesting derivatives are those prepared from 3-piperidinecarboxylic acid, 4-piperidinecarboxylic acid and 3-piperidineacetic acid, where the antibacterial or bactericidal spectrum for some representative bacteria is shown in the table below, compared to tetracycline.
De nye Mannich-baser av tetracyklin med nevnte piperidin-syrer viser en stabilitet som ligger meget hSyere enn for Mannich-baser med organiske baser som pyrrolidin, morfolin, N-hydroksyetyl-piperazin og basiske aminosyrer som lysin. De er meget opploselige i vann ved pH mellom 3 og 8. De vandige oppløsninger gir ingen felling ved henstand og det kan ikke observeres noen hydrolyse av de opp-loste forbindelser. The new Mannich bases of tetracycline with the aforementioned piperidine acids show a stability that is much higher than for Mannich bases with organic bases such as pyrrolidine, morpholine, N-hydroxyethyl piperazine and basic amino acids such as lysine. They are very soluble in water at a pH between 3 and 8. The aqueous solutions do not precipitate on standing and no hydrolysis of the dissolved compounds can be observed.
Den topiske toleranse etter intramuskulær administrasjon er bedre enn for alle andre tetracyklin Mannich-baser. Det folgende er The topical tolerance after intramuscular administration is better than for all other tetracycline Mannich bases. The following is
en sammenligning på dette grunnlag mellom (3-karboksymetyl-l-piperidino)-metyltetracyklin og andre kommersielt vanlige Mannich-baser av tetracyklin. Stoffene ble innsproytet intramuskulært i mus (grupper på 5 dyr) i en konsentrasjon som tilsvarer lOOmg tetracyklin per ml opplosning. a comparison on this basis between (3-carboxymethyl-1-piperidino)-methyltetracycline and other commercially common Mannich bases of tetracycline. The substances were injected intramuscularly into mice (groups of 5 animals) in a concentration corresponding to 100 mg of tetracycline per ml of solution.
( 3- karboksymetyl- l- piperidino) - metyltetracyklin {.opplost i 2%- ig vandig NaHCO^, pH 7.75). Produktet ble godt absorbert. Svak blodning i muskulærmassen. Musklene får svakt oket volum. /~ 4-( P- hydroksyetyl)- l- piperidino7- metyltetracyklin (vandig opplosning (3-carboxymethyl-1-piperidino)-methyltetracycline (dissolved in 2% aqueous NaHCO3, pH 7.75). The product was well absorbed. Weak bleeding in the muscle mass. The muscles get a slight increase in volume. /~ 4-( P- hydroxyethyl)- 1-piperidino7- methyltetracycline (aqueous solution
pH 5»9)« Svakt gul farve på grunn av noe residumprodukt. I noen dyr, små mengder av et grotaktig produkt. Musklene får oket volum. Subkutant odem, noen ganger tilstede. pH 5»9)« Faint yellow color due to some residue product. In some animals, small amounts of a cavernous product. The muscles gain increased volume. Subcutaneous edema, sometimes present.
Pyrrolidinometyltetracyklin (vandig opplosning pH 5»6), rester av gult residum-produkt, en smule blodning i muskulærmassen. Musklene får oket volum. Subkutant odem, leilighetsvis med utbredt odem-væske. Lysinometyltetracyklin (vandig opplosning pH 4«5)- Spor av rester-ende grotlignende produkt, i noen tilfeller meget utbredt. Sterkt markert odem i to tilfeller. Mindre blodninger i muskulærmassen. Pyrrolidinomethyltetracycline (aqueous solution pH 5»6), remains of yellow residum product, a little bleeding in the muscular mass. The muscles gain increased volume. Subcutaneous oedema, occasionally with widespread oedema-fluid. Lysinomethyltetracycline (aqueous solution pH 4-5)- Traces of residual slag-like product, in some cases very widespread. Strongly marked edema in two cases. Less bleeding in the muscle mass.
Vårt produkt var derfor den eneste forbindelse under obser-vasjon som ble helt absorbert etter intramuskulær administrasjon. Our product was therefore the only compound under observation that was completely absorbed after intramuscular administration.
En annen enestående egenskap for oppfinnelsens forbindelser er muligheten for administrering ad rektal vei. Det er velkjent at tetracyklin-antibiotika ikke absorberes når det gis i form av suppo-sitorier. Derimot gir karboksypiperidinmetyltetracykliner meget tilfredsstillende blodnivåer for antibiotikumene. Another outstanding feature of the compounds of the invention is the possibility of administration by rectal route. It is well known that tetracycline antibiotics are not absorbed when given in the form of suppositories. In contrast, carboxypiperidine methyltetracyclines provide very satisfactory blood levels for the antibiotics.
Folgendetabell angir blodbildet i mennesket ved forskjellige' tidspunkter etter administrering av et suppositorium som inneholder 500 mg (3-karboksy-^-piperidino)-metyltetracyklin. Verdiene ut-trykkes i Y/ml og er middelverdien av de observerte verdier for 10 pasienter: The following table indicates the blood picture in man at various times after administration of a suppository containing 500 mg of (3-carboxy-^-piperidino)-methyltetracycline. The values are expressed in Y/ml and are the mean value of the observed values for 10 patients:
Blodbildet etter The blood picture after
Disse tall tilsvarer de terapeutisk anvendbare doser av tetracyklin. These figures correspond to the therapeutically applicable doses of tetracycline.
Folgende eksempler gis for bedre å illustrere oppfinnelsen: Eksempel 1 ( 4- karboksy- l- piperidino)- metyltetracyklin The following examples are given to better illustrate the invention: Example 1 (4-carboxyl-piperidino)-methyltetracycline
En blanding av 2.2 g tetracyklin, 0.7 ml trietylamin og 40 ml etanol varmes til /\ 0°C og tilsettes deretter O.65 g 4_PiPeridin-karboksylsyre i 1.5 ml vann, fulgt av 0.5 ml /{. 0%- lg vandig formaldehyd. Etter 5 minutter ved 40°C kjoles oppløsningen ned til 25°C og det tilsettes 0.5 ml 10 N saltsyre. Den lysegule krystallinske felling oppsamles og torkes. Utbytte 2.25 g, med spektrofotometrisk im-hold på 72.7 %• Prosentvis innhold epitetracyklin er 1.2% bestemt ved kromatografi. A mixture of 2.2 g of tetracycline, 0.7 ml of triethylamine and 40 ml of ethanol is heated to /\ 0°C and then 0.65 g of 4-PiPeridine carboxylic acid in 1.5 ml of water is added, followed by 0.5 ml of /{. 0% aqueous formaldehyde. After 5 minutes at 40°C, the solution is cooled to 25°C and 0.5 ml of 10 N hydrochloric acid is added. The pale yellow crystalline precipitate is collected and dried. Yield 2.25 g, with a spectrophotometric im-content of 72.7%• The percentage content of epitetracycline is 1.2% determined by chromatography.
Eksempel 2 ( 3- karboksymetyl- l- piperidino)- metyltetracyklin Example 2 (3-carboxymethyl-1-piperidino)-methyltetracycline
En blanding av 11.0 g tetracyklin, 3-5 ml trietylamin og 25O ml etanol varmes til 40°C, hvoretter tilsettes en opplosning av 3.6 g 3-piperidineddiksyre i 7 «5 ral vann, fulgt av 2.5 ml 40%-ig vandig formaldehyd. Etter 5 minutter ved 40° C kjoles oppløsningen ned til 25°C og det tilsettes 2.5 ml 10 N saltsyre. Det gule kry- A mixture of 11.0 g of tetracycline, 3-5 ml of triethylamine and 250 ml of ethanol is heated to 40°C, after which a solution of 3.6 g of 3-piperidineacetic acid in 7 "5 ral of water is added, followed by 2.5 ml of 40% aqueous formaldehyde. After 5 minutes at 40° C, the solution is cooled to 25° C and 2.5 ml of 10 N hydrochloric acid is added. The yellow cry-
stallinske utfellingsprodukt oppsamles og torkes. Utbyttet 10.5 g, stalinic precipitation product is collected and dried. Yield 10.5 g,
med et spektrofotometrisk innhold på 73»9$- Prosentvis innhold av et epitetracyklin ifolge kromatografisk bestemmelse er under 1 %. with a spectrophotometric content of 73»9$- Percentage content of an epitetracycline according to chromatographic determination is below 1%.
Eksempel 3 ( 3- karboksy- l- piperidino)- metyltetracyklin Example 3 (3-carboxyl-1-piperidino)-methyltetracycline
En blanding av 22.0 g tetracyklin, 7-0 g trietylamin og 500 A mixture of 22.0 g tetracycline, 7-0 g triethylamine and 500
ml etanol varmes til 40°C, og tilsettes deretter en opplosning av 6.5 g 3-piperidinkarboksylsyre i 15 ml vann fulgt av 5 ml 40$-ig vandig formaldehyd. Etter 5 minutter ved 40°C kjoles opplosningen ned til 25°C og tilsettes 5 ml 10 N saltsyre. Det gule krystallinske fellingsprodukt oppsamles og torkes. Utbyttet 22 g, med et spektro- ml of ethanol is heated to 40°C, and a solution of 6.5 g of 3-piperidinecarboxylic acid in 15 ml of water is then added, followed by 5 ml of 40% aqueous formaldehyde. After 5 minutes at 40°C, the solution is cooled to 25°C and 5 ml of 10 N hydrochloric acid is added. The yellow crystalline precipitate is collected and dried. Yield 22 g, with a spectro-
fotometrisk innhold på 76.9%- Prosentinnholdet epitetracyklin som bestemt ved kromatografisk analyse er 1.4$. photometric content of 76.9%- The percentage content of epitetracycline as determined by chromatographic analysis is 1.4$.
Eksempel 4 ( V- karboksypropylamino)- metyltetracyklin Example 4 (V-carboxypropylamino)-methyltetracycline
En blanding av 22 g tetracyklin, 7 ml trietylamin og 400 ml A mixture of 22 g of tetracycline, 7 ml of triethylamine and 400 ml
etanol varmes til 40°C, og tilsettes deretter 5.1 g Y-aminosmorsyre opplost i 8 ml vann, fulgt av 5 ml 40$ vandig formaldehyd. Etter 5 minutter ved 40°C kjoles opplosningen til 25°C og det tilsettes ethanol is heated to 40°C, and then 5.1 g of Y-aminobutyric acid dissolved in 8 ml of water is added, followed by 5 ml of 40% aqueous formaldehyde. After 5 minutes at 40°C, the solution is cooled to 25°C and added
5 ml 10 N saltsyre. Den lysegule krystallinske felling oppsamles og 5 ml of 10 N hydrochloric acid. The pale yellow crystalline precipitate is collected and
torkes. Utbyttet 20.5 g> med spektrofotometrisk innhold på 77«3$« Epitetracyklininnholdet er under 1%. dried. The yield 20.5 g> with a spectrophotometric content of 77«3$« The epitetracycline content is below 1%.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/133,189 US4371747A (en) | 1980-03-24 | 1980-03-24 | AM Stereophonic decoder |
PCT/US1981/000111 WO1981002822A1 (en) | 1980-03-24 | 1981-01-21 | Am stereophonic decoder |
Publications (3)
Publication Number | Publication Date |
---|---|
NO813943L NO813943L (en) | 1981-11-20 |
NO155867B true NO155867B (en) | 1987-03-02 |
NO155867C NO155867C (en) | 1987-06-10 |
Family
ID=26764292
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO813943A NO155867C (en) | 1980-03-24 | 1981-11-20 | IN STEREO DECODER. |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU535856B2 (en) |
NO (1) | NO155867C (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6184933A (en) * | 1984-10-03 | 1986-04-30 | Pioneer Electronic Corp | Am stereo demodulator |
-
1981
- 1981-01-21 AU AU70705/81A patent/AU535856B2/en not_active Expired
- 1981-11-20 NO NO813943A patent/NO155867C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO155867C (en) | 1987-06-10 |
AU535856B2 (en) | 1984-04-05 |
AU7070581A (en) | 1981-10-09 |
NO813943L (en) | 1981-11-20 |
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