NO124162B - - Google Patents
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- NO124162B NO124162B NO96571A NO96571A NO124162B NO 124162 B NO124162 B NO 124162B NO 96571 A NO96571 A NO 96571A NO 96571 A NO96571 A NO 96571A NO 124162 B NO124162 B NO 124162B
- Authority
- NO
- Norway
- Prior art keywords
- carbon atoms
- thionyl chloride
- formula
- production
- acid addition
- Prior art date
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 4
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical class CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical class OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 229960001595 lincomycin hydrochloride Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
l-thio-3,4-0-cyklisk sulfit-a-D-galacto-pyranosider for anvendelse som utgangsmaterialer for fremstilling av 1incomycinderivater, og fremgangsmåte ved fremstilling derav. 1-thio-3,4-0-cyclic sulphite-α-D-galacto-pyranosides for use as starting materials for the production of 1incomycin derivatives, and method for the production thereof.
Foreliggende oppfinnelse angår en gruppe nye l-thio-3 ,4-0-cyklisk sulfit-a-D-galacto-pyranosider som kan anvendes som utgangsmaterialer for fremstilling av lincomycinderivater, og en ny fremgangsmåte ved fremstilling av disse. The present invention relates to a group of new l-thio-3,4-0-cyclic sulphite-α-D-galacto-pyranosides which can be used as starting materials for the production of lincomycin derivatives, and a new method for the production of these.
De nye forbindelser ifølge oppfinnelsen har den generelle formel: The new compounds according to the invention have the general formula:
hvor R er alkyl med inntil 8 carbonatomer, eventuelt alkylsubstituert cycloalkyl med 3-8 carbonatomer eller aralkyl med inntil 12 carbonatomer, og where R is alkyl with up to 8 carbon atoms, optionally alkyl-substituted cycloalkyl with 3-8 carbon atoms or aralkyl with up to 12 carbon atoms, and
Y er HC1-H- eller acylradikalet av en 4-substituert L-2-pyrrolidin-carboxylsyre av formelen: Y is the HC1-H or acyl radical of a 4-substituted L-2-pyrrolidine carboxylic acid of the formula:
hvor R.^ er alkyliden med inntil 8 carbonatomer, where R.^ is the alkylidene with up to 8 carbon atoms,
R2 er alkylen med inntil 8 carbonatomer, og R^ er hydrogen, methyl eller ethyl, og syreaddisjonssalter derav. R2 is the alkylene with up to 8 carbon atoms, and R^ is hydrogen, methyl or ethyl, and acid addition salts thereof.
Ifølge oppfinnelsen fremstilles ovenstående forbindelser av formel I ved at en forbindelse av den generelle formel: According to the invention, the above compounds of formula I are prepared by a compound of the general formula:
hvor R og Y er som ovenfor angitt, eller et syreaddisjonssalt derav, omsettes med thionylklorid, idet temperaturen, når et overskudd av thionylklorid over den støkiometriske mengde er tilstede, holdes på IO - 30°C. where R and Y are as indicated above, or an acid addition salt thereof, is reacted with thionyl chloride, the temperature, when an excess of thionyl chloride above the stoichiometric amount is present, being kept at 10 - 30°C.
Ved foreliggende fremgangsmåte blandes et utgangsmateriale av formel il, vortrinnsvis i form av et syreaddisjonssalt, f.eks. hydrokloridet, med thionylklorid, og reaksjonsblandingen omrøres ved ca. 25°c, fortrinnsvis i en inert atmosfære, f.eks. under nitrogen. Carbontetraklorid kan anvendes effektivt som oppløsningsmiddel, men andre inerte oppløsningsmidler som kloroform, methylenklorid, ethylenklorid, ether, benzen, og lignende, kan anvendes. En til-fredsstillende fremgangsmåte er å røre reaksjonsblandingen ved vær-elset emperatur i lengre tid, f.eks. fra 1 til 18 timer, eller så lenge som er nødvendig for å få en rimelig klar oppløsning. Det dannede lincomycin-3,4-O-cycliske sulfit kan så felles fra oppløs-ningen f . eks . ved tilsetning av diethylether. In the present method, a starting material of formula II is mixed, preferably in the form of an acid addition salt, e.g. the hydrochloride, with thionyl chloride, and the reaction mixture is stirred at approx. 25°c, preferably in an inert atmosphere, e.g. under nitrogen. Carbon tetrachloride can be used effectively as a solvent, but other inert solvents such as chloroform, methylene chloride, ethylene chloride, ether, benzene, and the like can be used. A satisfactory method is to stir the reaction mixture at room temperature for a longer time, e.g. from 1 to 18 hours, or as long as is necessary to obtain a reasonably clear solution. The formed lincomycin-3,4-O-cyclic sulphite can then be separated from the solution f . e.g. by addition of diethyl ether.
Hvis thionylklorid tilsettes i en mengde ikke over den støkio-metriske, dannes bare 3,4-0-cyklisk sulfit uavhengig av den anvendte temperatur. Når imidlertid et overskudd av thionylklorid anvendes, må temperaturen holdes på IO - 30°C ellers vil 7-hydroxygruppen kloreres. If thionyl chloride is added in an amount not above stoichiometric, only 3,4-O-cyclic sulfite is formed regardless of the temperature used. However, when an excess of thionyl chloride is used, the temperature must be kept at 10 - 30°C otherwise the 7-hydroxy group will be chlorinated.
Foreliggende forbindelser kan så overføres til terapeutisk aktive 7-klor-7-Oesoxylincomyciner ved oppvarmning med thionylklorid ved 50 - lOO°C for å overføre 7-hydroxygruppen til en 7-klorgruppe, og derpå underkaste den erholdte 7-ktor-3/f-0-cyklisk sulfitforbindelse basisk hydrolyse ved pH ca. 11, hvorefter eventuelt substituenten Y innføres. The present compounds can then be converted to therapeutically active 7-chloro-7-Oesoxylincomycins by heating with thionyl chloride at 50 - 100°C to transfer the 7-hydroxy group to a 7-chloro group, and then subjecting the obtained 7-ktor-3/f- 0-cyclic sulfite compound basic hydrolysis at pH approx. 11, after which optionally the substituent Y is introduced.
Eksempel Example
Lincomycin- 3, 4- O- cyklisk sulfit Lincomycin- 3, 4- O- cyclic sulfite
En suspensjon av 221^0 g (0,5 mol) lincomycin-hydroklorid i A suspension of 221^0 g (0.5 mole) of lincomycin hydrochloride i
5 1 carbontetraklorid ble omrørt godt ved 25°C under nitrogen. 900 ml thionylklorid ble tilsatt på en gang og omrøringen fortsatt i 2 timer. I løpet av denne tid oppløstes det faste stoff, og man fikk en klar oppløsning. 5 1 carbon tetrachloride was stirred well at 25°C under nitrogen. 900 ml of thionyl chloride was added at once and stirring continued for 2 hours. During this time, the solid dissolved, and a clear solution was obtained.
Reaksjonsoppløsningen ble så tilsatt et stort overskudd (45 1) diethylether, og lincomycin-3,4-O-cyklisk sulfit-hydroklorid-mono- A large excess (45 L) of diethyl ether was then added to the reaction solution, and lincomycin-3,4-O-cyclic sulfite-hydrochloride-mono-
hydrat feltes som et hvitt, fast stoff, som ved alkalisk hydrolyse (nøyt ral isasjon til ca. pH 11 med NaOH) ga lincomycin, og som videre kjennetegnes ved følgende analyse: hydrate is precipitated as a white solid, which on alkaline hydrolysis (neutralization to approx. pH 11 with NaOH) gave lincomycin, and which is further characterized by the following analysis:
Anal.: Beregn, for C^H^^OyS-HC1-H20: Anal.: Calculate, for C^H^^OyS-HC1-H20:
C 42,63; H 6,96; cl 6,99; N 5,53; S 12,65. C 42.63; H 6.96; cl 6.99; N 5.53; S 12.65.
Funnet: C 42,4o; H 6,70; Cl 7,44; N 5,65; S 12,84. Found: C 42.4o; H 6.70; Cl 7.44; N 5.65; S 12.84.
Molvekt: 452 (massespek.) Molecular weight: 452 (mass spec.)
452 (beregn.) 452 (calc.)
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO96571A NO124162B (en) | 1965-02-08 | 1971-03-15 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US43118465A | 1965-02-08 | 1965-02-08 | |
US51128865A | 1965-12-01 | 1965-12-01 | |
NO161593A NO123608B (en) | 1965-02-08 | 1966-02-07 | |
NO96571A NO124162B (en) | 1965-02-08 | 1971-03-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO124162B true NO124162B (en) | 1972-03-13 |
Family
ID=27483964
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO96571A NO124162B (en) | 1965-02-08 | 1971-03-15 |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO124162B (en) |
-
1971
- 1971-03-15 NO NO96571A patent/NO124162B/no unknown
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