NO124241B - - Google Patents
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- NO124241B NO124241B NO16281166A NO16281166A NO124241B NO 124241 B NO124241 B NO 124241B NO 16281166 A NO16281166 A NO 16281166A NO 16281166 A NO16281166 A NO 16281166A NO 124241 B NO124241 B NO 124241B
- Authority
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- Norway
- Prior art keywords
- ether
- solution
- water
- xanthogenic acid
- acid
- Prior art date
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 3
- IAOBHRLYOHUQBT-AFPISRSTSA-N 2-[(8R,9S,10S,13S,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethenol Chemical class C(=CC1=CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)O IAOBHRLYOHUQBT-AFPISRSTSA-N 0.000 claims 1
- DBMUNIJZUYVPCQ-XFNFOBRPSA-N pregnan-21-ol Chemical class C1CCC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)CCO)[C@@H]4[C@@H]3CCC21 DBMUNIJZUYVPCQ-XFNFOBRPSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 35
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000000155 melt Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 9
- 238000002211 ultraviolet spectrum Methods 0.000 description 8
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 7
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 7
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 7
- 229960004544 cortisone Drugs 0.000 description 7
- 229960000890 hydrocortisone Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000003470 adrenal cortex hormone Substances 0.000 description 4
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- GMVAAADTMXYSDE-XFNFOBRPSA-N 2-[(8R,9S,10S,13S,14S,17R)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethenol Chemical compound OC=C[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C GMVAAADTMXYSDE-XFNFOBRPSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- -1 amine salts Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 230000008023 solidification Effects 0.000 description 3
- 238000007711 solidification Methods 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 150000008522 N-ethylpiperidines Chemical class 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical class CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical class CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F9/00—Making metallic powder or suspensions thereof
- B22F9/02—Making metallic powder or suspensions thereof using physical processes
- B22F9/06—Making metallic powder or suspensions thereof using physical processes starting from liquid material
- B22F9/08—Making metallic powder or suspensions thereof using physical processes starting from liquid material by casting, e.g. through sieves or in water, by atomising or spraying
- B22F9/082—Making metallic powder or suspensions thereof using physical processes starting from liquid material by casting, e.g. through sieves or in water, by atomising or spraying atomising using a fluid
Landscapes
- Manufacture Of Metal Powder And Suspensions Thereof (AREA)
- Steroid Compounds (AREA)
Description
Fremgangsmåte til fremstilling av kortisonvirksomme derivater fra kortikoider. Process for the production of cortisone-active derivatives from corticoids.
Det er kjent, at kortison og beslektede It is known that cortisone and related
stoffer som 21-hydroksypregnener eller substances such as 21-hydroxypregnene or
-pregnadiener har en gunstig virkning på -pregnadiens have a beneficial effect on
pasienter som lider under nerves jokk. Ved patients suffering from nervous shock. By
behandling av slik sykdom er det dog ønskelig, at virkningen inntrer hurtig. Denne treatment of such a disease, however, it is desirable that the effect occurs quickly. This
hurtige virkning av disse substanser van-skeliggjøres imidlertid ved at de bare er however, the rapid effect of these substances is made difficult by the fact that they are only
lite oppløselige i vann, og således ikke kan sparingly soluble in water, and thus cannot
innføres direkte i blodkretsløpet i form av introduced directly into the bloodstream in the form of
vandige oppløsninger. Det var derfor vanlig aqueous solutions. It was therefore common
å oppløse kortison og beslektede stoffer i to dissolve cortisone and related substances in
etanol, og injisere den slik erholdte opp-løsning i egnet fortynnet tilstand intrave-nøst. Denne metode har dog betraktelige ethanol, and inject the thus obtained solution in a suitable diluted state intravenously. However, this method has considerable drawbacks
ulemper, særlig på grunn av de store disadvantages, especially due to the large ones
væskemengder som er nødvendige. Dess-uten kan en slik injeksjon vanligvis ikke amounts of liquid that are necessary. Without it, such an injection usually cannot
utføres utenfor hospital, skjønt dette i performed outside hospital, although this in
mange tilfeller ville være ønskelig, f. eks. many cases would be desirable, e.g.
på et ulykkessted. at an accident scene.
Det vilde til disse og andre formål være It would be for these and other purposes
ønskelig å ha oppløsninger til disposisjon, desirable to have solutions available,
i hvilke den nødvendige dose kan rummes in which the required dose can be accommodated
i få ml av en i blodbanen injiserbar væske in a few ml of a liquid that can be injected into the bloodstream
i en slik form, at det virksomme stoff til-strekkelig hurtig gjøres tilgjengelig for or-ganismens behov. in such a form that the active substance is made available quickly enough for the body's needs.
Forbindelser av kortikoider med større Compounds of corticoids with larger
oppløslighet i vandige fluida enn kortikoidet selv, men ikke nødvendigvis meget solubility in aqueous fluids than the corticoid itself, but not necessarily much
lettoppløslige, kan finne anvendelse for andre formål, f. eks. til fremstilling av kortisonvirksomme salver, f. eks. til bruk mot easily soluble, can be used for other purposes, e.g. for the production of cortisone-active ointments, e.g. for use against
eksemer. eczema.
Det har nå vist seg, at der kan fremstilles hittil ukjente forbindelser av slike It has now been shown that previously unknown compounds of this type can be produced
kortikoider, som er 21-hydroksypregnener eller -pregnadiener, hvilke forbindelser er oppløslige med baser i vann, og at fremstillingen av disse skjer ved, at der i 21-stillingen i kortikoidet innføres gruppen -O-CS-SH, hvorved der dannes xantogenater eller xantogensyrer, som inneholder den angjeldende steroide alkoholrest. corticoids, which are 21-hydroxypregnenes or -pregnadienes, which compounds are soluble with bases in water, and that the production of these takes place by introducing the group -O-CS-SH in the 21-position of the corticoid, whereby xanthogenates or xanthogenic acids, which contain the steroidal alcohol residue in question.
De ved denne fremgangsmåte oppnådde forbindelser kan oppfattes som estre av ditiokullsyre ved dennes hydroksylgruppe, i hvilke estre ditiokullsyrens sure sulfhy-drylgruppe er fri, hvorfor de kan løses opp i vann ved hjelp av baser som xantogenater, idet dog oppløsligheten er avhengig av ba-sens natur. Det har vist seg, at xantogenatene meget hurtig hydrolyseres i nærvær av vann ved pH-verdier nær nøytralpunktet, hvorved kortikoidet frigjøres, samt at der ved intravenøs injeksjon av xantogenatene i den menneskelige organisme meget hurtig inntrer kortisonvirkning. The compounds obtained by this method can be understood as esters of dithiocarbonic acid at its hydroxyl group, in which esters the acidic sulfhydryl group of dithiocarbonic acid is free, which is why they can be dissolved in water with the help of bases such as xanthogenates, although the solubility is dependent on the base's nature. It has been shown that the xanthogens are hydrolysed very quickly in the presence of water at pH values close to the neutral point, thereby releasing the corticoid, and that when the xanthogens are injected intravenously into the human organism, cortisone action occurs very quickly.
På grunn av xantogenatoppløsningenes hurtige hydrolyse må de nye stoffer til te-rapeutisk bruk dispenseres enten som tørr-stoff, som kan løses opp i vann, eller som den frie xantogensyre, som umiddelbart før bruken blandes med en vandig oppløs-ning av en base, eller som salver som inneholder et mere eller mindre oppløslig xantogenat og bestemt til utvortes bruk. Due to the rapid hydrolysis of the xanthogenate solutions, the new substances for therapeutic use must be dispensed either as a dry substance, which can be dissolved in water, or as the free xanthogenic acid, which immediately before use is mixed with an aqueous solution of a base, or as ointments containing a more or less soluble xanthogenate and intended for external use.
Innføringen av -O-CS-SH-gruppen i 21-stillingen i 21-hydroksypregnener eller -pregnadiener kan skje ved, at disse i et flytende medium omsettes med et alkalimetallhydroksyd og kullstoffsulfid. The introduction of the -O-CS-SH group in the 21 position in 21-hydroxypregnenes or -pregnadienes can take place by reacting these in a liquid medium with an alkali metal hydroxide and carbon sulphide.
På denne måte kan der fra de tilsvarende kortikoider fremstilles xantogensyrer .av A^-S^O-diketo-na^l-dihydroksy-pregnener og -pregnadiener, herunder såvel A4-pregnen-3,ll,20-triketo-17a,21-diol-21-xantogensyre og A4-pregnen-3,20-dike-to-ll,17a,21-triol-21-xantogensyre (hvor In this way, from the corresponding corticoids, xanthogenic acids can be produced from A^-S^O-diketo-na^l-dihydroxy-pregnenes and -pregnadienes, including both A4-pregnene-3,11,20-triketo-17a,21 -diol-21-xanthogenic acid and A4-pregnene-3,20-dike-to-11,17a,21-triol-21-xanthogenic acid (where
11-hydroksyl-gruppen kan være i a- eller p-stilling), som Al,4-pregnadien-3,ll,20-triketo-17a,21-diol-21-xantogensyre og A i,4-pregnadien-3,20-diketo-ll,17a,21-triol-xantogensyre (11-hydroksyl-gruppen kan være likeledes i a- eller p-stilling), såvel som beslektede forbindelser. Som eksempel på slike kan nevnes de i 6a-stillingen me-tylsubstituerte forbindelser svarende til de ovennevnte. Også av disse kan der på samme måte fremstilles xantogensyre og xantogenater, som har bibeholdt den forøkede kortisonvirkning, som er eiendommelig for dc slik substituerte kortikoider. The 11-hydroxyl group can be in the a- or p-position), such as A1,4-pregnadiene-3,11,20-triketo-17a,21-diol-21-xanthogenic acid and A1,4-pregnadiene-3, 20-diketo-11,17a,21-triol-xanthogenic acid (the 11-hydroxyl group may also be in the a- or p-position), as well as related compounds. As examples of such, mention may be made of the methyl-substituted compounds in the 6a position corresponding to those mentioned above. Also from these, xanthogenic acid and xanthogenates can be prepared in the same way, which have retained the increased cortisone effect, which is peculiar to dc substituted corticoids.
Ved utførelsen av fremgangsmåten ifølge oppfinnelsen kan der anvendes forskjellige reaksjonsmedier, som dog skal kunne løse opp steroidet og ikke selv må kunne omsettes med alkali og kullstoffdi-oksyd til xantogenat. Oppløsningsmidler, som inneholder alkoholgrupper, kan derfor i alminnelighet ikke anvendes. Det har vi-dere vist seg, at reaksjonsmediet må ha en viss blandbarhet med vann, og det er for-delaktig, at denn blandbarhet er så stor, at det kan løses opp minst 5—10 pst. vann. Således kan der under forøvrig samme be-tingelser kun oppnås 1/3 så stort utbytte av xantogenat ved anvendelse av metylisobutylketon som reaksjonsmiddel som ved anvendelse av f. eks. dioksan, svarende til det førstnevnte oppløsningsmiddels langt mindre blandbarhet med vann. Som eksempel på anvendelige reaksjonsmedier foruten de nevnte kan anføres aceton og andre ketoner som f. eks. metyletylketon, samt dimetylformamid. Aceton og dimetylformamid gir i alle prøvede tilfeller like så gode utbytter som dioksan. When carrying out the method according to the invention, different reaction media can be used, which must, however, be able to dissolve the steroid and must not themselves be able to react with alkali and carbon dioxide to xanthogenate. Solvents, which contain alcohol groups, cannot therefore generally be used. It has also been shown to you that the reaction medium must have a certain miscibility with water, and it is advantageous that this miscibility is so great that it can dissolve at least 5-10 percent water. Thus, under otherwise the same conditions, only 1/3 as large a yield of xanthogenate can be achieved when using methyl isobutyl ketone as a reaction agent as when using e.g. dioxane, corresponding to the first-mentioned solvent's far less miscibility with water. As examples of usable reaction media, in addition to those mentioned, acetone and other ketones such as e.g. methyl ethyl ketone, as well as dimethyl formamide. Acetone and dimethylformamide give as good yields as dioxane in all tested cases.
Reaksjonen utføres hensiktsmessig ved, at oppløsningen av steroidet i det valgte organiske oppløsningsmiddel, som er i det minste delvis blandbart med vann, behandles med et alkalimetallhydroksyd, og det derved dannede alkoholat omsettes med kullstoffdisulfid, hvorefter xantogenatet eller (efter tilsetning av en syre) den frie xantogensyre isoleres fra oppløsningen. Under reaksjonen anvendes der hensiktsmessig kjøling, eventuelt til temperaturer omkring oppløsningsmidlets frysepunkt. Man kan først tilsette alkalimetallhydrok-sydet i vandig oppløsning, og efter kort tids gjennemblanding av de to faser tilsette kullstoffdisulfid eller en oppløsning av dette i det samme oppløsningsmiddel, som er The reaction is conveniently carried out by treating the solution of the steroid in the selected organic solvent, which is at least partially miscible with water, with an alkali metal hydroxide, and the resulting alcoholate is reacted with carbon disulphide, after which the xanthogenate or (after addition of an acid) the free xanthogenic acid is isolated from the solution. During the reaction, appropriate cooling is used, possibly to temperatures around the solvent's freezing point. You can first add the alkali metal hydroxide in an aqueous solution, and after mixing the two phases for a short time, add carbon disulphide or a solution of this in the same solvent, which is
brukt til oppløsningen av steroidet eller et used for the dissolution of the steroid or et
annet med liknende egenskaper. Efter inn-virkning av kullstoffdisulfidet i noen tid er xantogenatet dannet, og den vandige fase skilles fra. Den organiske fase kan nå behandles på forskjellig måte for å skille ut enten xantogenatet av den anvendte base eller fri xantogensyre. I førstnevnte tilfelle kan oppløsningen tørres og dampes inn til tørrhet, eller der kan tilsettes et oppløsningsmiddel, f. eks. eter, som ned-setter blandingens oppløsningsevne for xantogenat, hvorved dette skilles ut. I sistnevnte tilfelle kan der tilsettes en sterk syre som f. eks. saltsyre eller svovelsyre, og et oppløsningsmiddel og, efter fornyet fra-skillelse av den vandige fase, kan den organiske fase dampes inn til tørrhet (eventuelt efter borttørring av vannet, for å undgå hydrolyse), eller der kan tilsettes oppløsningsmidler, som bringer den frie syre til utskillelse, f. eks. aceton. Det dannede xantogenat eller xantogensyren kan omkrystalliseres, og av syren kan der eventuelt fremstilles salter ved oppløsning i den tilsvarende base. other with similar properties. After exposure to the carbon disulphide for some time, the xanthogenate is formed, and the aqueous phase is separated. The organic phase can now be treated in different ways to separate out either the xanthogenate of the base used or free xanthogenic acid. In the former case, the solution can be dried and evaporated to dryness, or a solvent can be added, e.g. ether, which reduces the solubility of the mixture for xanthogenate, whereby this is separated. In the latter case, a strong acid such as e.g. hydrochloric acid or sulfuric acid, and a solvent and, after renewed separation of the aqueous phase, the organic phase can be evaporated to dryness (possibly after drying off the water, to avoid hydrolysis), or solvents can be added, which bring the free acid for excretion, e.g. acetone. The formed xanthogenate or xanthogenic acid can be recrystallized, and salts can possibly be produced from the acid by dissolving in the corresponding base.
De frie xantogensyrer er tungt oppløs-lige i vann, men mange av saltene er lett oppløslige og kan på grunn av deres store oppløslighet og tilbøyelighet til å flyte ut, være vanskelig å fremstille i ren, krystal-linsk tilstand. Således er natriumsaltene utflytende, mens kaliumsaltene, som dog stadig er meget lett oppløslige, lettere kan fås i ren tilstand. Også kalsiumsaltet og sinksaltet kan lett fremstilles i fast form, men visse aminsalter utmerker seg ved, at de forholdsvis lett kan oppnås i ren kry-stallinsk form, skjønt de er lett oppløslige, f eks. salter av etanolamin, dietylamin eller N-etylpiperidinsaltene. Også kvater-nære ammoniumsalter kan fremstilles. The free xanthogenic acids are poorly soluble in water, but many of the salts are easily soluble and, due to their high solubility and tendency to flow out, can be difficult to produce in a pure, crystalline state. Thus, the sodium salts are liquid, while the potassium salts, which are still very easily soluble, can more easily be obtained in a pure state. The calcium salt and the zinc salt can also be easily produced in solid form, but certain amine salts are distinguished by the fact that they can relatively easily be obtained in pure crystalline form, although they are easily soluble, e.g. salts of ethanolamine, diethylamine or the N-ethylpiperidine salts. Quaternary ammonium salts can also be prepared.
Av tungt oppløslige aminsalter kan nevnes di-isopropyl-aminsaltene og saltene av dimetylaminopropylamin, n-butylamin eller trietanolamin. Of poorly soluble amine salts, mention may be made of the di-isopropylamine salts and the salts of dimethylaminopropylamine, n-butylamine or triethanolamine.
Til belysning av oppløsligheten av en rekke av de lettoppløslige salter, særlig aminsalter, skal anføres den mengde av en vandig oppløsning av forskjellige baser, i hvilken 50 mg hydrokortisonxantogensyre kan løses opp under saltdannelse: To clarify the solubility of a number of the easily soluble salts, especially amine salts, the amount of an aqueous solution of various bases in which 50 mg of hydrocortisone xanthogenic acid can be dissolved during salt formation must be stated:
Fremstillingen av xantogensyrene og forskjellige salter av disse skal i det føl-gende belyses ved noen utførelseseksempler. The production of the xanthogenic acids and various salts thereof will be explained in the following with some design examples.
Eksempel 1. Example 1.
A4- pregnen- 3, ll, 20- trion- l 7a, 21 - diol- 21 - A4- pregnene- 3, ll, 20- trione- l 7a, 21 - diol- 21 -
xantogensyre. xanthogenic acid.
3,0 g kortison oppløses under svak oppvarmning i 90 ml peroksyd dioksan, og opp-løsningen avkjøles i en blanding av is og vann til dioksanets størkningspunkt. Der tilsettes under kraftig omrøring en forut kjø-let oppløsning av 3,0 g kaliumhydroksyd i 30 ml vann. Efter omrøring og kjøling i 5 min. tilsettes så en oppløsning av 3,0 g kullstoffdisulfid i 5 ml dioksan. Der røres påny 3.0 g of cortisone is dissolved under gentle heating in 90 ml of peroxide dioxane, and the solution is cooled in a mixture of ice and water to the solidification point of dioxane. A previously cooled solution of 3.0 g of potassium hydroxide in 30 ml of water is added with vigorous stirring. After stirring and cooling for 5 min. a solution of 3.0 g of carbon disulphide in 5 ml of dioxane is then added. It is stirred again
om i 15 min., hvoretter reaksjonsblandingen fortynnes med -200 ml benzen og surgjæres ved tilsetning av 9 ml kons. saltsyre. Den vandige fase skilles fra, og benzenoppløs-ningen vaskes tre ganger med vann Efter overnatriumsulfat, dampes oppløsningen inn til tørrhet i vakuum ved romtemperatur, og inndampningsresten krystalliseres ved tilsetning av aceton. Krystallene filtreres fra og tørres i tynt lag i luften ved romtemperatur. Utbyttet av det tørrede pro-dukt er 2,55 g. Stoffet smelter ved 127— 130° C, men størkner ved fortsatt opphetning og smelter påny ved 230—232° C. about for 15 min., after which the reaction mixture is diluted with -200 ml of benzene and acidified by adding 9 ml of conc. hydrochloric acid. The aqueous phase is separated, and the benzene solution is washed three times with water. After excess sodium sulfate, the solution is evaporated to dryness in vacuum at room temperature, and the evaporation residue is crystallized by adding acetone. The crystals are filtered off and dried in a thin layer in the air at room temperature. The yield of the dried product is 2.55 g. The substance melts at 127-130° C, but solidifies on continued heating and melts again at 230-232° C.
Eksempel 2. Example 2.
A4- pregnen- 3, 20- dion, l 1 fi, l 7a, 21- triol- 21 - A4- pregnene- 3, 20- dione, l 1 fi, l 7a, 21- triol- 21 -
xantogensyre. xanthogenic acid.
3,0 g hydrokortison behandles som i eksempel 1 med den forskjell, at reaksjonsblandingen fortynnes med 300 ml eter i stedet for med 200 ml eter i stedet for med 200 ml benzen. Ved vaskning av oppløs-ningen med vann felles hydrokortison-21-xantogensyren ut. Bunnfallet filtreres fra, vaskes med eter og lufttørres ved romtemperatur. Utbytte 3,0 g. Produktet smelter ved 110—113° C, men størkner ved ytterligere opphetning og smelter igjen ved 210 —231° C. 3.0 g of hydrocortisone is treated as in example 1 with the difference that the reaction mixture is diluted with 300 ml of ether instead of with 200 ml of ether instead of with 200 ml of benzene. When washing the solution with water, the hydrocortisone-21-xanthogenic acid precipitates. The precipitate is filtered off, washed with ether and air-dried at room temperature. Yield 3.0 g. The product melts at 110-113° C, but solidifies on further heating and melts again at 210-231° C.
Eksempel 3. Example 3.
/\ 1, 4- pregnadien- 3, 11, 20- trion- 17 a, 21- diol-21 - xantogensyre. /\ 1, 4- pregnadiene- 3, 11, 20- trione- 17 a, 21- diol-21 - xanthogenic acid.
3,00 g 1-dehydrokortison løses opp i 180 ml dioksan, og oppløsningen kjøles til dioksanets størkningspunkt, hvorefter der tilsettes en oppløsning av 3,00 g kaliumhydroksyd i 60 ml vann under kraftig om-røring. Omrøringen fortsettes i 5 min., hvorefter der på en gang tilsettes en opp-løsning av 3,0 g kullstoffdisulfid i 5 ml dioksan. Efter ytterligere omrøring i 15 min. fortynnes reaksjonsblandingen med 300 ml eter og surgjøres ved tilsetning av 9 ml kons. saltsyre. Den vandige fase skilles fra og eterfasen vaskes 3 ganger med vann. Efter tørring over natriumsulfat dampes 3.00 g of 1-dehydrocortisone is dissolved in 180 ml of dioxane, and the solution is cooled to the dioxane's solidification point, after which a solution of 3.00 g of potassium hydroxide in 60 ml of water is added with vigorous stirring. Stirring is continued for 5 min., after which a solution of 3.0 g of carbon disulphide in 5 ml of dioxane is added all at once. After further stirring for 15 min. the reaction mixture is diluted with 300 ml of ether and acidified by adding 9 ml of conc. hydrochloric acid. The aqueous phase is separated and the ether phase is washed 3 times with water. After drying over sodium sulphate, evaporate
oppløsningen inn til tørrhet i vakuum ved romtemperatur, og der tilsettes 9 ml aceton til inndampningsresten. Efter henstand ved 0° C i noen tid filtreres krystallene av xantogensyren fra og lufttørres ved romtemperatur. Utbytte: 1,95 g. Produktet smelter ved 120—122° C, men størkner ved fortsatt opphetning og smelter igjen ved 222—224° C under spaltning. the solution to dryness in vacuum at room temperature, and 9 ml of acetone is added to the evaporation residue. After standing at 0° C for some time, the crystals of the xanthogenic acid are filtered off and air-dried at room temperature. Yield: 1.95 g. The product melts at 120-122° C, but solidifies on continued heating and melts again at 222-224° C during cleavage.
Eksempel 4. Example 4.
Al, 4- pregnadien- 3, 20- dion- ll$, 17a, 21- triol-21 - xantogensyre. Al, 4- pregnadiene- 3, 20- dione- ll$, 17a, 21- triol-21 - xanthogenic acid.
3,00 g prednisolen løses ved svak oppvarmning opp i 90 ml peroksydfri dioksan, og oppløsningen kjøles i en blanding av is og vann til dioksanets størkningspunkt. Der tilsettes under kraftig omrøring en forut kjølet oppløsning av 3,0 g kaliumhydroksyd i 30 ml vann. Efter 5 min. omrø-ring tilsettes en oppløsning av 3,0 g kullstoffdisulfid i 5 ml dioksan. Efter ytterligere omrøring i 15 min. fortynnes reaksjonsblandingen med 500 ml eter og surgjæres ved tilsetning av 9 ml kons. saltsyre. Den vandige fase fjernes og eterfasen vaskes tre ganger med vann. Efter kort tids henstand felles prednisolen-21-xantogensyre ut. Bunnfallet filtreres fra, vaskes med eter og lufttørres ved romtemperatur. The 3.00 g of prednisolone is dissolved by gentle heating in 90 ml of peroxide-free dioxane, and the solution is cooled in a mixture of ice and water to the dioxane's solidification point. A previously cooled solution of 3.0 g of potassium hydroxide in 30 ml of water is added with vigorous stirring. After 5 min. stirring, a solution of 3.0 g of carbon disulphide in 5 ml of dioxane is added. After further stirring for 15 min. the reaction mixture is diluted with 500 ml of ether and acidified by adding 9 ml of conc. hydrochloric acid. The aqueous phase is removed and the ether phase is washed three times with water. After a short period of time, prednisolone-21-xanthogenic acid precipitates. The precipitate is filtered off, washed with ether and air-dried at room temperature.
Utbytte: 2,1 g. Produktet smelter ved 127— 128° C, men størkner ved fortsatt opphetning og smelter påny ved 227—228° C. Yield: 2.1 g. The product melts at 127-128° C, but solidifies on continued heating and melts again at 227-228° C.
Eksempel 5. Example 5.
/ S4- pregnen- 3, 20- dion- lla, 17a, 21- triol- 21-xantogensyre. / S4- pregnene- 3, 20- dione- lla, 17a, 21- triol- 21-xanthogenic acid.
5 g av det ovennevnte stoff løses ved svak oppvarmning opp i 150 ml dioksan og oppløsningen kjøles i en blanding av is og vann til dioksanets frysepunkt Derefter tilsettes under sterk omrøring en forut kjølet oppløsning av 4 g natriumhydroksyd i 50 ml vann. Efter omrøring i 5 min. tilsettes på en gang en oppløsning av 8 ml kullstoffdisulfid i 10 ml dioksan. Efter fortsatt omrøring i 15 min. fortynnes reaksjonsblandingen med 5 g of the above-mentioned substance is dissolved in 150 ml of dioxane by gentle heating and the solution is cooled in a mixture of ice and water to the freezing point of dioxane Then, with vigorous stirring, a pre-cooled solution of 4 g of sodium hydroxide in 50 ml of water is added. After stirring for 5 min. a solution of 8 ml of carbon disulphide in 10 ml of dioxane is added at once. After continued stirring for 15 min. dilute the reaction mixture with
850 ml eter og surgjæres med 15 ml kons. 850 ml ether and leaven with 15 ml conc.
saltsyre. Vannfasen fjernes og eterfasen vaskes to ganger med vann. 21-xantogensyren faller ut og filtreres fra efter henstand i kort tid ved 0° C, hvorefter bunnfallet vaskes med eter og lufttørres ved romtemperatur. Utbytte: 3,5 g. Produktet smelter ved 135—137° C, men størkner ved fortsatt opphetning og smelter igjen ved 216—217° C. hydrochloric acid. The water phase is removed and the ether phase is washed twice with water. The 21-xanthogenic acid precipitates and is filtered off after standing for a short time at 0° C, after which the precipitate is washed with ether and air-dried at room temperature. Yield: 3.5 g. The product melts at 135-137° C, but solidifies on continued heating and melts again at 216-217° C.
Eksempel 6. Example 6.
A' i- pregnen- 3, ll, 20- trion- 17a, 21- diol- 21-xantogensyre. A' i- pregnene- 3, 11, 20-trione- 17a, 21-diol- 21-xanthogenic acid.
1,0 g kortison løses under oppvarmning opp i 200 ml metylisobutylketon og oppløs-ningen kjøles til romtemperatur. Der tilsettes under kraftig omrøring 1 ml kullstoffdisulfid og 1 g kaliumhydroksyd opp-løst i 10 ml vann. Omrøringen fortsettes i 45 min., hvorefter den nedre fase fjernes og metylisobutylketonet vaskes med 1 N-saltsyre. Efter tørring av metylisobutylketonet med natriumsulfat og filtrering tilsettes petroleter. Efter henstand i noen tid ved 0° C filtreres de dannede krystaller fra og tørres i luft ved romtemperatur. Utbytte: 0,3 g. 1.0 g of cortisone is dissolved while heating in 200 ml of methyl isobutyl ketone and the solution is cooled to room temperature. With vigorous stirring, 1 ml of carbon disulphide and 1 g of potassium hydroxide dissolved in 10 ml of water are added. Stirring is continued for 45 min., after which the lower phase is removed and the methyl isobutyl ketone is washed with 1 N hydrochloric acid. After drying the methyl isobutyl ketone with sodium sulphate and filtering, petroleum ether is added. After standing for some time at 0° C, the formed crystals are filtered off and dried in air at room temperature. Yield: 0.3 g.
Eksempel 7. Example 7.
Kaliumsaltet av 6a- metyl- kortison- 21-xantogensyre. The potassium salt of 6a-methylcortisone-21-xanthogenic acid.
3 g 6a-metylkortison løses opp i 9 ml dimetylformamid. Ved romtemperatur tilsettes under kraftig omrøring først 3 g kaliumhydroksyd oppløst i 2,3 ml vann og derefter 3 ml kullstoffdisulfid. Omrøringen 3 g of 6a-methylcortisone is dissolved in 9 ml of dimethylformamide. At room temperature, first 3 g of potassium hydroxide dissolved in 2.3 ml of water and then 3 ml of carbon disulfide are added with vigorous stirring. The stirring
fortsettes i 45 min., hvorefter den nedre fase skilles fra, og der tilsettes eter til dimetylformamidfasen. Efter kort tids henstand dekanteres eteren fra et i oppløsnin-gen dannet bunnfall. Til bunnfallet settes aceton, hvorefter der filtreres og moder-niten bunnfelles nok en gang med eter. Efter frafiltrering vaskes det utfelte stoff med eter og tørres ved romtemperatur i vakuum over fosforpentoksyd. Utbytte 2,7 g. is continued for 45 min., after which the lower phase is separated, and ether is added to the dimethylformamide phase. After a short period of time, the ether is decanted from a precipitate formed in the solution. Acetone is added to the precipitate, after which it is filtered and the modernite is precipitated once more with ether. After filtration, the precipitated substance is washed with ether and dried at room temperature in vacuum over phosphorus pentoxide. Yield 2.7 g.
Det ultraviolette spektrum av en frisk fremstillet vandig oppløsning av det erholdte kaliumsalt har maksimum ved 240 mj.i (e = 15100) og ved 304 m^ (E = 13500). The ultraviolet spectrum of a freshly prepared aqueous solution of the obtained potassium salt has a maximum at 240 mj.i (e = 15100) and at 304 m^ (E = 13500).
Eksempel 8. Example 8.
Kaliumsaltet av hydrokortisonxantogensyre. The potassium salt of hydrocortisone xanthogenic acid.
3 g hydrokortison løses opp i 9 ml dimetylformamid. Under sterk omrøring tilsettes ved romtemperatur 3 g kaliumhydroksyd i 2,3 ml vann og derefter 3 ml kullstoffdisulfid. Omrøringen fortsettes i 45 min. Den nedre fase skilles fra, og der tilsettes eter til dimetylformamidfasen. Herved dannes et bunnfall, og eteren dekanteres fra. Til bunnfallet settes aceton, hvor- 3 g of hydrocortisone are dissolved in 9 ml of dimethylformamide. With vigorous stirring, 3 g of potassium hydroxide in 2.3 ml of water and then 3 ml of carbon disulphide are added at room temperature. Stirring is continued for 45 min. The lower phase is separated, and ether is added to the dimethylformamide phase. This forms a precipitate, and the ether is decanted from it. Acetone is added to the precipitate, where-
efter der filtreres og moderluten bunnfelles nok en gang med eter. Bunnfallet filtreres fra, vaskes med eter og tørres ved romtemperatur i vakuum over fosforpentoksyd. Utbytte 2,7 g av kaliumsaltet. after that it is filtered and the mother liquor is precipitated once more with ether. The precipitate is filtered off, washed with ether and dried at room temperature in vacuum over phosphorus pentoxide. Yield 2.7 g of the potassium salt.
Eksempel 9. Example 9.
Kaliumsaltet av prednisolon- 21- xantogensyre. The potassium salt of prednisolone-21-xanthogenic acid.
Til en blanding av 2 g prednisolon og 60 ml aceton settes 620 mg pulverisert kaliumhydroksyd og 2 ml kullstoffdisulfid. Efter omrøring i 10 min. filtreres reaksjonsblandingen og helles i eter. Det derved dannede bunnfall filtreres fra, vaskes med eter og tørres ved romtemperatur i vakuum over fosforpentoksyd. Utbytte 2,1 g av kaliumsaltet. 620 mg of powdered potassium hydroxide and 2 ml of carbon disulphide are added to a mixture of 2 g of prednisolone and 60 ml of acetone. After stirring for 10 min. the reaction mixture is filtered and poured into ether. The resulting precipitate is filtered off, washed with ether and dried at room temperature in a vacuum over phosphorus pentoxide. Yield 2.1 g of the potassium salt.
Eksempel 10. Example 10.
Kaliumsaltet av kortison- 21- xantogensyre. The potassium salt of cortisone-21-xanthogenic acid.
Av 3,00 g kortison fremstilles der på den i eksempel 1 angitte måte en med vann vasket og over natriumsulfat tørret oppløs-ning av xantogensyren i benzen. Denne oppløsning anbringes ved romtemperatur i vakuum i 30 min. for å fjerne overskudd av kullstoffdisulfid, hvorefter der tilsettes 42 ml av en 1,6 pst.s alkoholisk oppløsning av kaliumhy dr oksyd. Efter noen tids henstand filtreres det dannede bunnfall fra, vaskes med benzen og lufttørres uten oppvarmning, hvorved der oppnås 2,4 g av det ønskede stoff, som har smeltepunkt 165— 167° C (under spaltning), og hvis innhold av svovel er 13,60 pst., mens det beregnede innhold er 13,51 pst. S. From 3.00 g of cortisone, a solution of the xanthogenic acid in benzene, washed with water and dried over sodium sulfate, is prepared in the manner indicated in example 1. This solution is placed at room temperature in a vacuum for 30 min. to remove excess carbon disulphide, after which 42 ml of a 1.6% alcoholic solution of potassium hydroxide are added. After some time has passed, the precipitate formed is filtered off, washed with benzene and air-dried without heating, whereby 2.4 g of the desired substance is obtained, which has a melting point of 165-167° C (during decomposition), and whose sulfur content is 13 .60 per cent, while the calculated content is 13.51 per cent S.
i in
Eksempel 11. Example 11.
Kaliumsaltet av hydrokortisonxantogensyre. The potassium salt of hydrocortisone xanthogenic acid.
1,50 g av det ved fremgangsmåten ifølge eksempel 2 fremstilte hydrokortison-21-xantogensyre røres ut med 10 ml 2 pst.'s alkoholisk oppløsning av kaliumhydroksyd, hvorved syren løses opp. Efter henstand i noen tid, skiller kaliumsaltet seg ut, frafil-treres, vaskes med eter og tørres. Utbytte: 1,30 g 8,12 pst. K (beregnet: 8,20 pst. k). 1.50 g of the hydrocortisone-21-xanthogenic acid produced by the method according to example 2 is stirred with 10 ml of a 2% alcoholic solution of potassium hydroxide, whereby the acid dissolves. After standing for some time, the potassium salt separates, is filtered off, washed with ether and dried. Yield: 1.30 g 8.12 percent K (calculated: 8.20 percent k).
Eksempel 12. Example 12.
Kaliumsaltet av prednisolon- 21- xantogensyre. The potassium salt of prednisolone-21-xanthogenic acid.
1,50 g prednisolon-21-xantogensyre blandes med 10 ml 2 pst.s alkoholisk oppløsning av kaliumhydroksyd, hvorved syren løses opp. Efter noen tids henstand skilles kaliumsaltet ut, filtreres fra, vaskes med eter og tørres. Utbytte: 1,40 g. 1.50 g of prednisolone-21-xanthogenic acid is mixed with 10 ml of a 2% alcoholic solution of potassium hydroxide, whereby the acid dissolves. After some time has passed, the potassium salt is separated, filtered off, washed with ether and dried. Yield: 1.40 g.
Det ultraviolette spektrum av en vandig oppløsning viser maksima ved 244 mu, = 15.200 og ved 304 mu, e = 13.400. The ultraviolet spectrum of an aqueous solution shows maxima at 244 mu, = 15,200 and at 304 mu, e = 13,400.
Eksempel 13. Example 13.
Etanolaminsaltet av hydrokortison- 21-xantogensyre. The ethanolamine salt of hydrocortisone-21-xanthogenic acid.
Til 4,0 g frisk fremstillet hydrokortison-21-xantogensyre settes 20 ml av en 3,1 pst.'s oppløsning av etanolamin i 99 pst.s etanol. Herved løses xantogensyren opp, men efter få minutters forløp dannes der et bunnfall. Efter noen tids henstand filtreres bunnfallet fra, vaskes grundig først med 99 pst.s etanol, derefter med eter og tørres i vakuum over fosforpentoksyd. Utbytte 2,7 g. En friskt tilberedt vandig oppløsning av saltet viser følgende maksima i det ultraviolette spektrum: 245 mp (e = 17500) og 304 mu (e = 14400). To 4.0 g of freshly prepared hydrocortisone-21-xanthogenic acid is added 20 ml of a 3.1% solution of ethanolamine in 99% ethanol. This dissolves the xanthogenic acid, but after a few minutes a precipitate forms. After some time has passed, the precipitate is filtered off, washed thoroughly first with 99% ethanol, then with ether and dried in vacuum over phosphorus pentoxide. Yield 2.7 g. A freshly prepared aqueous solution of the salt shows the following maxima in the ultraviolet spectrum: 245 mp (e = 17500) and 304 mu (e = 14400).
Eksempel 14. Example 14.
Dietylaminsaltet av hydrokortison- 21-xantogensyre. The diethylamine salt of hydrocortisone-21-xanthogenic acid.
Til 4,0 g frisk fremstillet hydrokortison-21-xantogensyre settes 27 ml av en 2,5 pst.s appløsning av dietylamin i 99 pst.s etanol. Xantogensyren løses opp, og der dannes jerefter et bunnfall, som filtreres fra efter loen tids henstand, vaskes grundig med 59 pst.s etanol og derefter med eter og tør-res i vakuum over fosforpentoksyd. Utbytte: 3.5 g. En friskt tilberedt vandig opp-løsning av saltet viser følgende maksima i det ultraviolette spektrum: 246 mu (s = 18200) Og 304 mu (e = 14400). To 4.0 g of freshly prepared hydrocortisone-21-xanthogenic acid, add 27 ml of a 2.5% solution of diethylamine in 99% ethanol. The xanthogenic acid is dissolved, and a precipitate is then formed, which is filtered off after a period of time, washed thoroughly with 59% ethanol and then with ether and dried in vacuum over phosphorus pentoxide. Yield: 3.5 g. A freshly prepared aqueous solution of the salt shows the following maxima in the ultraviolet spectrum: 246 mu (s = 18200) and 304 mu (e = 14400).
Eksempel 15. Example 15.
Tetraetylammoniumsaltet av hydrokortison- 21 - xantogensyre. The tetraethylammonium salt of hydrocortisone-21-xanthogenic acid.
5,0 g tetraetylammoniumjodid løses opp i 80 ml metanol og der tilsettes 1 ml vann og 3,5 g sølvoksyd. Efter omrøring i 3 ti-mer filtreres blandingen, og filtratet fortynnes med metanol til 100 ml. Til 4,0 g hydrokortison-21-xantogensyre settes 48 Dissolve 5.0 g of tetraethylammonium iodide in 80 ml of methanol and add 1 ml of water and 3.5 g of silver oxide. After stirring for 3 hours, the mixture is filtered, and the filtrate is diluted with methanol to 100 ml. 48 is added to 4.0 g of hydrocortisone-21-xanthogenic acid
ml av det fortynnede filtrat. Xantogensyren oppløses og efter noen minutters for-løp tilsettes eter, hvorved der dannes et oljeaktig bunnfall. Væsken dekanteres fra og bunnfallet løses opp i aceton. Der tilsettes påny eter og det derved utfelte stoff filtreres fra, vaskes grundig med eter og tørres i vakuum over fosforpentoksyd. En friskt tilberedt vandig oppløsning av saltet viser følgende maksima i det ultraviolette spektrum: 245 mu (s = 17500) og 303 mu. (e = 14000). ml of the diluted filtrate. The xanthogenic acid is dissolved and after a few minutes ether is added, whereby an oily precipitate is formed. The liquid is decanted off and the precipitate is dissolved in acetone. Ether is added again and the substance thus precipitated is filtered off, washed thoroughly with ether and dried in vacuum over phosphorus pentoxide. A freshly prepared aqueous solution of the salt shows the following maxima in the ultraviolet spectrum: 245 mu (s = 17500) and 303 mu. (e = 14000).
Eksempel 16. Example 16.
N- etylpiperidinsaltet av hydrokortison-21 - xantogensyre. The N-ethylpiperidine salt of hydrocortisone-21-xanthogenic acid.
Til 4,0 g frisk fremstillet hydrokortison-21-xantogensyre settes 4,0 g N-etylpiperidin oppløst i 20 ml 99 pst.'s etanol, hvorved xantogensyren løses opp og et bunnfall dannes efter få minutters forløp. Bunnfallet filtreres fra og vaskes med eter samt tørres i vakuum over fosforpentoksyd. Utbytte 4,4 g. En frisk tilberedt vandig opp-løsning av saltet viser følgende maksima i det ultraviolette spektrum: 246 mu (s = 17600) Og 303 mu (E = 13800). To 4.0 g of freshly prepared hydrocortisone-21-xanthogenic acid is added 4.0 g of N-ethylpiperidine dissolved in 20 ml of 99% ethanol, whereby the xanthogenic acid dissolves and a precipitate forms after a few minutes. The precipitate is filtered off and washed with ether and dried in vacuum over phosphorus pentoxide. Yield 4.4 g. A freshly prepared aqueous solution of the salt shows the following maxima in the ultraviolet spectrum: 246 mu (s = 17600) and 303 mu (E = 13800).
Eksempel 17. Example 17.
i Kalsiumsaltet av hydrokortison-21- xantogensyre. i The calcium salt of hydrocortisone-21-xanthogenic acid.
I en morter blandes 85 mg kalsium-hydroksyd med 1 g frisk tilberedt hydrokortison-21-xantogensyre og 10 ml 99 pst.'s etanol. Det røres om med pistillen i 5 min., og blandingen filtreres derpå, hvorefter det frafiltrerte stoff vaskes med 99 pst.'s etanol og med eter og tørres i vakuum ved romtemperatur over fosforpentoksyd. Utbytte: 1 g. En frisk tilberedt vandig opp-løsning av saltet viser følgendt maksima i det ultraviolette spektrum: 245 mu (e = 30000) og 304 mu (e = 22000). In a mortar, mix 85 mg of calcium hydroxide with 1 g of freshly prepared hydrocortisone-21-xanthogenic acid and 10 ml of 99 percent ethanol. It is stirred with the pestle for 5 min., and the mixture is then filtered, after which the filtered substance is washed with 99% ethanol and with ether and dried in vacuum at room temperature over phosphorus pentoxide. Yield: 1 g. A freshly prepared aqueous solution of the salt shows the following maxima in the ultraviolet spectrum: 245 mu (e = 30000) and 304 mu (e = 22000).
Eksempel 18. Example 18.
Sinksaltet av hydrokortison-21 - xantogensyre. The zinc salt of hydrocortisone-21 - xanthogenic acid.
Til 452 mg sinkhydroksyd settes der i en morter 40 ml 99 pst.'s etanol og 4,0 g frisk tilberedt hydrokortison-21-xantogensyre. Der røres om med pistillen i 5 min., hvorefter blandingen filtreres og det frafiltrerte stoff vaskes med 99 pst.'s etanol og med eter og tørres i vakuum over fosforpentoksyd. Utbytte 3,9 g. En frisk tilberedt oppløsning av saltet i 0,1 N-vandig NaOH-oppløsning viser følgende maksima i det ultraviolette spektrum: 245 mu (e = 30400) og 304 m(x (e = 28100). To 452 mg of zinc hydroxide, add 40 ml of 99% ethanol and 4.0 g of freshly prepared hydrocortisone-21-xanthogenic acid in a mortar. Stir with the pestle for 5 minutes, after which the mixture is filtered and the filtered material is washed with 99% ethanol and with ether and dried in vacuum over phosphorus pentoxide. Yield 3.9 g. A freshly prepared solution of the salt in 0.1 N aqueous NaOH solution shows the following maxima in the ultraviolet spectrum: 245 mu (e = 30400) and 304 m(x (e = 28100).
Vandige oppløsninger av kaliumsaltet eller dietanolaminsaltet hydrolyseres hurtig, idet halveringstiden ved pH 7,2 og 37° C er 15 min. Herved frigjøres steroidhormo-net f. eks. hydrokortison. Når oppløsninger av disse og andre liknende salter injiseres intravenøst i et lite omfang, vil hydrokor-tisonet eller i alminnelighet det kortikoid, som inngår i xantogenatet efter kort tid være frigjort i blodet. Aqueous solutions of the potassium salt or the diethanolamine salt are rapidly hydrolysed, the half-life at pH 7.2 and 37° C being 15 min. This releases steroid hormones, e.g. hydrocortisone. When solutions of these and other similar salts are injected intravenously to a small extent, the hydrocortisone or, in general, the corticoid, which is part of the xanthogenate, will be released into the blood after a short time.
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DEK56083A DE1285681B (en) | 1965-05-11 | 1965-05-11 | Ring slot nozzle for atomizing molten material |
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US4988464A (en) * | 1989-06-01 | 1991-01-29 | Union Carbide Corporation | Method for producing powder by gas atomization |
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US1501449A (en) * | 1917-12-20 | 1924-07-15 | Metals Disintegrating Co | Metal-disintegrating apparatus |
US1659291A (en) * | 1917-12-20 | 1928-02-14 | Metals Disintegrating Co | Process for disintegrating metal |
DE949859C (en) * | 1940-06-19 | 1956-09-27 | Norddeutsche Affinerie | Process for the production of brittle metal powders |
DE917226C (en) * | 1943-10-24 | 1954-08-26 | Mannesmann Ag | Process and ring slot nozzle for atomizing liquid metals |
DE1178679B (en) * | 1954-03-26 | 1964-09-24 | Mannesmann Ag | Process for the optional production of conical or spattered metal powder |
US2956304A (en) * | 1956-12-06 | 1960-10-18 | Vanadium Alloys Steel Co | Apparatus for atomizing molten metal |
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