NO116143B - - Google Patents
Info
- Publication number
- NO116143B NO116143B NO160356A NO16035665A NO116143B NO 116143 B NO116143 B NO 116143B NO 160356 A NO160356 A NO 160356A NO 16035665 A NO16035665 A NO 16035665A NO 116143 B NO116143 B NO 116143B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- reaction
- pseudo
- steroid
- molecule
- Prior art date
Links
- 238000006243 chemical reaction Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- -1 saturated aliphatic monocarboxylic acid Chemical class 0.000 claims description 9
- GMBQZIIUCVWOCD-WWASVFFGSA-N Sarsapogenine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@H](C)CO1 GMBQZIIUCVWOCD-WWASVFFGSA-N 0.000 claims description 8
- QVZULXNXCIFMTL-IXCVKQQLSA-N 4802-74-8 Chemical compound O([C@@H]1[C@@H]([C@]2(CC(=O)[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 QVZULXNXCIFMTL-IXCVKQQLSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 150000001735 carboxylic acids Chemical class 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- RTMWIZOXNKJHRE-UHFFFAOYSA-N Tigogenin Natural products CC1COC2CC(C)(OC12)C3CCC4C5CCC6CC(O)CCC6(C)C5CCC34C RTMWIZOXNKJHRE-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- QOLRLLFJMZLYQJ-LOBDNJQFSA-N Hecogenin Chemical compound O([C@@H]1[C@@H]([C@]2(C(=O)C[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 QOLRLLFJMZLYQJ-LOBDNJQFSA-N 0.000 claims description 3
- OXLGJTRVVNGJRK-UHFFFAOYSA-N Hecogenin Natural products CC1CCC2(CC3CC4C5CCC6CC(O)CCC6(C)C5CC(=O)C4(C)C3C2C)OC1 OXLGJTRVVNGJRK-UHFFFAOYSA-N 0.000 claims description 3
- UVLDESQWQRMYKD-UHFFFAOYSA-N Neobotogenin Natural products CC1C(C2(C(=O)CC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 UVLDESQWQRMYKD-UHFFFAOYSA-N 0.000 claims description 3
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 claims description 3
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 150000003431 steroids Chemical class 0.000 description 10
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 229960002446 octanoic acid Drugs 0.000 description 7
- 238000009835 boiling Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- INLFWQCRAJUDCR-IQVMEADQSA-N (1R,2S,4S,5'S,6R,7S,8R,9S,12S,13S)-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.02,9.04,8.013,18]icosane-6,2'-oxane] Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@H](C)CO1 INLFWQCRAJUDCR-IQVMEADQSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 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 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229960004544 cortisone Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- NWMIYTWHUDFRPL-UHFFFAOYSA-N sapogenin Natural products COC(=O)C1(CO)C(O)CCC2(C)C1CCC3(C)C2CC=C4C5C(C)(O)C(C)CCC5(CCC34C)C(=O)O NWMIYTWHUDFRPL-UHFFFAOYSA-N 0.000 description 3
- GMBQZIIUCVWOCD-UQHLGXRBSA-N (25R)-5beta-spirostan-3beta-ol Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 GMBQZIIUCVWOCD-UQHLGXRBSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- FLJFMDYYNMNASJ-UHFFFAOYSA-N 6-methyl-5,6-dihydrothieno[2,3-b]thiopyran-4-one Chemical compound S1C(C)CC(=O)C2=C1SC=C2 FLJFMDYYNMNASJ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- RAFYDKXYXRZODZ-UHFFFAOYSA-N octanoyl octanoate Chemical compound CCCCCCCC(=O)OC(=O)CCCCCCC RAFYDKXYXRZODZ-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- VUXXCVWHUXQPFJ-UHFFFAOYSA-N 1-methylsulfanyl-4-methylsulfinyl-6,7-dihydro-5h-cyclopenta[d]pyridazine Chemical compound CSC1=NN=C(S(C)=O)C2=C1CCC2 VUXXCVWHUXQPFJ-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- IQDKIMJGXXRZGR-UHFFFAOYSA-N Pseudotigogenin Natural products C1CC2CC(O)CCC2(C)C(CCC23C)C1C3CC1C2C(C)=C(CCC(CO)C)O1 IQDKIMJGXXRZGR-UHFFFAOYSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- IQDKIMJGXXRZGR-HUEIYZRMSA-N pseudosmilagenin Chemical compound C([C@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3C[C@H]2[C@@H]1C(C)=C(CC[C@H](CO)C)O2 IQDKIMJGXXRZGR-HUEIYZRMSA-N 0.000 description 1
- IQDKIMJGXXRZGR-MEBFULDVSA-N pseudotigogenin Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3C[C@H]2[C@@H]1C(C)=C(CC[C@H](CO)C)O2 IQDKIMJGXXRZGR-MEBFULDVSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229950002323 smilagenin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical group OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
- G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
- G09B3/00—Manually or mechanically operated teaching appliances working with questions and answers
- G09B3/02—Manually or mechanically operated teaching appliances working with questions and answers of the type wherein the student is expected to construct an answer to the question which is presented or wherein the machine gives an answer to the question presented by a student
- G09B3/04—Manually or mechanically operated teaching appliances working with questions and answers of the type wherein the student is expected to construct an answer to the question which is presented or wherein the machine gives an answer to the question presented by a student of chart form
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
- B41L—APPARATUS OR DEVICES FOR MANIFOLDING, DUPLICATING OR PRINTING FOR OFFICE OR OTHER COMMERCIAL PURPOSES; ADDRESSING MACHINES OR LIKE SERIES-PRINTING MACHINES
- B41L1/00—Devices for performing operations in connection with manifolding by means of pressure-sensitive layers or intermediaries, e.g. carbons; Accessories for manifolding purposes
- B41L1/20—Manifolding assemblies, e.g. book-like assemblies
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B42—BOOKBINDING; ALBUMS; FILES; SPECIAL PRINTED MATTER
- B42D—BOOKS; BOOK COVERS; LOOSE LEAVES; PRINTED MATTER CHARACTERISED BY IDENTIFICATION OR SECURITY FEATURES; PRINTED MATTER OF SPECIAL FORMAT OR STYLE NOT OTHERWISE PROVIDED FOR; DEVICES FOR USE THEREWITH AND NOT OTHERWISE PROVIDED FOR; MOVABLE-STRIP WRITING OR READING APPARATUS
- B42D19/00—Movable-strip writing or reading apparatus
Description
Fremgangsmåte til fremstilling av pseudo-isosapogeniner og estere av sådanne. Process for the production of pseudo-isosapogenins and esters thereof.
Foreliggende oppfinnelse angår en The present invention relates to a
fremgangsmåte til av steroid-isosapogeniner å fremstille pseudoisosapogeniner og deres estere, dvs. steroidforbindelser hvis D-ring og den sidekjerne som er forbundet med denne kan representeres ved den generelle formel method for preparing pseudoisosapogenins and their esters from steroid isosapogenins, i.e. steroid compounds whose D-ring and the side nucleus connected to it can be represented by the general formula
i hvilken R betegner en hydroksylgruppe eller en acyloksygruppe. Isosapogeniner skiller seg fra normale sapogeniner ved en forskjell i spiral-ketal-sidekj edens konfigurasjon, idet denne kan ha både 22- og 25-stillingene. Denne for-skjellighets nøyaktige natur er på det nå-værende tidspunkt uviss. Isosapogeninets sidekjede tegnes i alminnelighet således: mens det normale sapogenins sidekjede tegnes slik: in which R represents a hydroxyl group or an acyloxy group. Isosapogenins differ from normal sapogenins by a difference in the configuration of the helical ketal side chain, as this can have both the 22 and 25 positions. The exact nature of this difference is currently uncertain. The side chain of the isosapogenin is generally drawn like this: while the side chain of the normal sapogenin is drawn like this:
Sapogeniner med iso-konfigurasjon omfatter flere naturlig forekommende forbindelser som er verdifulle som utgangsmateriale for syntese av viktige steroidforbindelser. Således er f. eks. hecogenin et verdifullt utgangsmateriale for syntese av kortison og dermed beslektede forbindelser. Sapogenins with iso-configuration comprise several naturally occurring compounds that are valuable as starting material for the synthesis of important steroid compounds. Thus, e.g. hecogenin a valuable starting material for the synthesis of cortisone and related compounds.
Et vesentlig trekk ved bruken av ste-roidsapogeniner til fremstilling av mange hormoner, som kortison og kjønnshormo-nene, er fjernelsen av disse stoffers karak-teristiske sidekjede som består av 5- og 6-leddede heterocykliske ringer som er forbundet med D-ringen, hvilket kan vises som følger: An essential feature of the use of steroid sapogenins for the production of many hormones, such as cortisone and the sex hormones, is the removal of these substances' characteristic side chain consisting of 5- and 6-membered heterocyclic rings which are connected to the D-ring, which can be shown as follows:
Det er tidligere foreslått som et første trinn av denne av avbygning å overføre sapogeniner, særlig isosapogeniner, til pseudosapogeniner ved å oppvarme sapogeninet med et syreanhydrid, som eddiksyreanhydrid, i en autoklav eller under til-bakeløpskjøling og i nærvær av en kata-lysator, hvorved man får pseudosapogeninet ved at den 6-leddede heterocykliske ring åpnes. Det er også foreslått som et føl-gende trinn i denne avbygning å oksydere pseudosapogeninet for eksempel med krom-trioksyd, så at man får et substituert 20-oksosteroid inneholdende følgende sidekjede: It has previously been proposed as a first step of this degradation to convert sapogenins, particularly isosapogenins, to pseudosapogenins by heating the sapogenin with an acid anhydride, such as acetic anhydride, in an autoclave or under reflux and in the presence of a catalyst, whereby the pseudosapogenin is obtained by opening the 6-membered heterocyclic ring. It is also proposed as a next step in this degradation to oxidize the pseudosapogenin, for example with chromium trioxide, so that a substituted 20-oxosteroid containing the following side chain is obtained:
Denne sistnevnte forbindelse kan så be-handles med syre eller alkali, hvorved man får et A<1G->20-keto-steroid som er kjent å være nyttig ved syntese av forskjellige hormoner. Foreliggende oppfinnelse befatter seg med det første av disse avbygnings-trinn, nemlig overføringen av steroid-isosapogeniner til pseudo-isosapogeniner. This latter compound can then be treated with acid or alkali, whereby an A<1G->20-keto-steroid is obtained which is known to be useful in the synthesis of various hormones. The present invention deals with the first of these degradation steps, namely the transfer of steroid isosapogenins to pseudo-isosapogenins.
Det er funnet at denne overføring be-kvemt og effektivt kan utføres ved å bruke karbonsyrer i stedet for de syreanhydrider som det er foreslått å bruke og som er blitt brukt tidligere. Bruken av syrer i stedet for anhydrider medfører flere fordeler, blant hvilke kan nevnes at syrer i alminnelighet er lettere tilgjengelige og betyde-lig billigere enn deres tilsvarende anhydrider. Syrer lar seg også lettere fjerne og gjenvinne etter reaksjonens utførelse, idet de lett ekstraheres med alkali. Videre viser de mindre tilbøyelighet til å spaltes ved de reaksjonsbetingelser som brukes. Mange karbonsyrer er egnet for anvendelse i fremgangsmåten ifølge oppfinnelsen, forutsatt at de ikke på uønsket måte innvirker på steroidforbindelsene i en annen del av deres molekyler under de anvendte reaksjonsbetingelser. I alminnelighet er sterke, orga-niske syrer ikke egnet. Det foretrekkes således f. eks. ikke å bruke syrer som inne-holder en nitrogruppe eller en sulfonsyregruppe eller halogen. Det er funnet at karbonsyrer inneholdende fra 2—20 kullstoffatomer er egnet. It has been found that this transfer can be conveniently and efficiently carried out by using carboxylic acids instead of the acid anhydrides which it is proposed to use and which have been used in the past. The use of acids instead of anhydrides entails several advantages, among which can be mentioned that acids are generally more readily available and considerably cheaper than their corresponding anhydrides. Acids can also be more easily removed and recovered after the reaction has been carried out, as they are easily extracted with alkali. Furthermore, they show less tendency to split under the reaction conditions used. Many carboxylic acids are suitable for use in the method according to the invention, provided that they do not adversely affect the steroid compounds in another part of their molecules under the reaction conditions used. In general, strong organic acids are not suitable. It is thus preferred, e.g. not to use acids containing a nitro group or a sulphonic acid group or halogen. It has been found that carboxylic acids containing from 2-20 carbon atoms are suitable.
Verdien av karbonsyrer med hensyn til å oppnå høye utbytter av pseudosapogeniner fra sapogeniner er overraskende nok begrenset til isosapogeninene. Således kan utbytter på 80 % og mer oppnåes i fremgangsmåten ifølge foreliggende oppfinnelse, mens utbyttet av pseudosapogenin fra sarsasapogenin, et nornalt sapogenin, bare er 27 % under anvendelse av kaprylsyre, og Marker og medarbeidere (J.A.C.S., 1940, 62, 518) ikke kunne utvinne noe pseu-dosarsasapogenin ved oppvarmning av sarsasapogenin med eddiksyre i 7 timer ved 210° C. The value of carboxylic acids in obtaining high yields of pseudosapogenins from sapogenins is surprisingly limited to the isosapogenins. Thus, yields of 80% and more can be obtained in the method according to the present invention, while the yield of pseudosapogenin from sarsasapogenin, a normal sapogenin, is only 27% using caprylic acid, and Marker et al. (J.A.C.S., 1940, 62, 518) could not recover some pseudo-dose sarsasapogenin by heating sarsasapogenin with acetic acid for 7 hours at 210°C.
Fremgangsmåten ifølge foreliggende oppfinnelse til fremstilling av pseudo-isosapogeniner og deres estere er følgelig i sitt hovedtrekk karakterisert ved at man oppvarmer et steroid-isosapogenin eller en ester av et sådant i et flytende medium hovedsakelig bestående av en eller flere karbonsyrer med 2—20 kullstoffatomer i molekylet. The method according to the present invention for the production of pseudo-isosapogenins and their esters is consequently characterized in its main feature by heating a steroid isosapogenin or an ester thereof in a liquid medium mainly consisting of one or more carboxylic acids with 2-20 carbon atoms in the molecule.
Det foretrekkes å bruke en mettet alifatisk monokarbonsyre inneholdende fra 6 til 12 kullstoffatomer. It is preferred to use a saturated aliphatic monocarboxylic acid containing from 6 to 12 carbon atoms.
Fremgangsmåten ifølge oppfinnelsen kan i sin alminnelighet anvendes på alle steroid-isosapogeniner, forutsatt at det i steroidets molekyl ikke er til stede substi-tuenter som er utstabile ved de anvendte reaksjonsbetingelser. Når hydroksylgrupper eller forestrede hydroksylgrupper, f. eks. en 3-hydroksylgruppe eller -forestret hydroksylgruppe er til stede i molekylet, kan for-estring eller omforestring finne sted under reaksjonen. Estergrupper som er dannet på denne måte kan imidlertid om så ønskes lett forsåpes under pseudoisosapogeninets isolering. Alternativt kan man la slike estergrupper forbli i molekylet og utføre forsåpningen f. eks. på det tidspunkt da et 20-keto-steroid dannes av et substituert 20-okso-steroid med den foran angitte formel III og som er fremstillet av et pseudo-iso-sapogenin erholdt ved hjelp av fremgangsmåten ifølge oppfinnelsen. The method according to the invention can generally be applied to all steroid isosapogenins, provided that there are no substituents present in the steroid's molecule which are unstable under the reaction conditions used. When hydroxyl groups or esterified hydroxyl groups, e.g. a 3-hydroxyl group or -esterified hydroxyl group is present in the molecule, esterification or transesterification can take place during the reaction. Ester groups formed in this way can, however, if desired, be easily saponified during the isolation of the pseudoisosapogenin. Alternatively, you can let such ester groups remain in the molecule and carry out the saponification, e.g. at the time when a 20-keto-steroid is formed from a substituted 20-oxo-steroid with the above-mentioned formula III and which is produced from a pseudo-iso-sapogenin obtained by means of the method according to the invention.
Når fremgangsmåten ifølge oppfinnelsen skal brukes ved syntese av kortison og med dette beslektede stoffer, kan det steroid-iso-sapogenin som brukes som utgangsmateriale hensiktsmessig være en av de følgende forbindelser eller en ester av en av disse: 3(3-hydroksy-5a:22a-spirostan-12-on (hecogenin), 3(3-hydroksy-5a:22a-spiro-stan (tigogenin), 3(3-hydroksy-5ct:22a-spi-rostan-ll-on (11-ketotigogenin), 3(3-hydroksy-5a: 22a-spirost-9-en (A<9>^<11>)-dehydro-tigogenin), 3(3:lla-dihydroksy-5a:22a-spi-rostan (lla-hydroksytigogenin) eller 3(3-hydroksy-22a-spirost-5-en ( diosgenin). When the method according to the invention is to be used for the synthesis of cortisone and related substances, the steroid iso-sapogenin used as starting material can conveniently be one of the following compounds or an ester of one of these: 3(3-hydroxy-5a: 22a-spirostan-12-one (hecogenin), 3(3-hydroxy-5a:22a-spiro-stan (tigogenin), 3(3-hydroxy-5ct:22a-spi-rostan-ll-one (11-ketotigogenin) , 3(3-hydroxy-5a:22a-spirost-9-ene (A<9>^<11>)-dehydro-tigogenin), 3(3:lla-dihydroxy-5a:22a-spirostane (lla- hydroxytigogenin) or 3(3-hydroxy-22a-spirost-5-ene (diosgenin).
Den laveste temperatur ved hvilken det er hensiktsmessig å utføre fremgangsmåten ifølge oppfinnelsen er omkring 150° C. Under denne temperatur er reaksjonstiden meget lang. Den øvre grense for temperaturen fastsettes bare av syrens, steroid-iso-sapogeninets og pseudo-iso-sapogeninets stabilitet. Det vil derfor forståes at den optimale temperatur varierer med den særlige syre og det særlige iso-sapogenin som brukes og bør bestemmes ved et forhånds-forsøk i hvert enkelt tilfelle. Det er funnet at i alminnelighet er temperaturer innen området fra 160—350° C egnet. Når syrens kokepunkt er høyere enn 160° C og lavere enn 350° C er det hensiktsmessig å utføre reaksjonen ved kokning under tilbakeløps-kjøling. Når man bruker laverekokende syrer er det selvfølgelig nødvendig å bruke et lukket kar som en autoklav. The lowest temperature at which it is appropriate to carry out the method according to the invention is around 150° C. Below this temperature, the reaction time is very long. The upper limit of the temperature is determined only by the stability of the acid, the steroid iso-sapogen and the pseudo-iso-sapogen. It will therefore be understood that the optimum temperature varies with the particular acid and the particular iso-sapogenin used and should be determined by a preliminary trial in each individual case. It has been found that, in general, temperatures within the range of 160-350°C are suitable. When the boiling point of the acid is higher than 160° C and lower than 350° C, it is appropriate to carry out the reaction by boiling under reflux cooling. When using lower-boiling acids, it is of course necessary to use a closed vessel such as an autoclave.
Den tid som kreves for reaksjonens fullførelse varierer likeledes med det anvendte steroid-iso-sapogenins og den anvendte syres natur og med den temperatur ved hvilken reaksjonen utføres. Også reaksjonstiden må bestemmes ved forsøk. Reaksjonens forløp kan følges polarimetrisk da overføringen av steroid-iso-sapogeninet til pseudo-iso-sapogeninet medfører en økning i den spesifikke dreiningsevne og reaksjonen kan betraktes som fullstendig når man når maksimalverdien for den spesifikke dreiningsevne. Det er således funnet at når man f. eks. går ut fra 11-keto-tigogenin og utfører reaksjonen under tilbakeløpskjøling under anvendelse av kapronsyre (kokepunkt 205° C) er den optimale tid 5—6 timer, ved anvendelse av kaprylsyre (kokepunkt 240° C) 2 timer og ved anvendelse av kaprinsyre (kokepunkt 270° C) 1 time. The time required for the completion of the reaction also varies with the nature of the steroid iso-sapogenin used and the acid used and with the temperature at which the reaction is carried out. The reaction time must also be determined by trial. The course of the reaction can be followed polarimetrically as the transfer of the steroid iso-sapogenin to the pseudo-iso-sapogenin leads to an increase in the specific turning ability and the reaction can be considered complete when the maximum value for the specific turning ability is reached. It has thus been found that when one e.g. starts from 11-keto-tigogenin and carries out the reaction under reflux using caproic acid (boiling point 205° C) the optimal time is 5-6 hours, when using caprylic acid (boiling point 240° C) 2 hours and when using capric acid ( boiling point 270° C) 1 hour.
Det foretrekkes å utføre reaksjonen i nærvær av en mengde syreanhydrid som er ekvivalent med den mengde vann som dannes under reaksjonen. Syreanhydridet kan tilsvare den syre som brukes eller kan være anhydridet av en annen syre. I sistnevnte tilfelle kan det f. eks. brukes en blanding av en mettet alifatisk monokarbonsyre inneholdende fra 6—12 kullstoffatomer som kaprylsyre og en mengde eddiksyreanhydrid som er ekvivalent med den mengde vann som dannes under reaksjonen. Det anvendte syreanhydrid bør i alminnelighet ikke være anhydridet av en sterk organisk syre og — som det også er tilfelle med de syrer som brukes i fremgangsmåten ifølge oppfinnelsen — foretrekkes det ikke å bruke anhydrider av syrer inneholdende en nitrogruppe eller en sulfonsyregruppe eller halogen. It is preferred to carry out the reaction in the presence of an amount of acid anhydride equivalent to the amount of water formed during the reaction. The acid anhydride may correspond to the acid used or may be the anhydride of another acid. In the latter case, it can e.g. a mixture of a saturated aliphatic monocarboxylic acid containing from 6 to 12 carbon atoms such as caprylic acid and an amount of acetic anhydride equivalent to the amount of water formed during the reaction is used. The acid anhydride used should generally not be the anhydride of a strong organic acid and — as is also the case with the acids used in the method according to the invention — it is preferred not to use anhydrides of acids containing a nitro group or a sulfonic acid group or halogen.
Når reaksjonen er fullstendig kan syren lett skilles fra pseudo-iso-sapogeninet ved ekstraksjon med alkali, som det vil bli beskrevet i eksemplene i det følgende. Når det ønskes å få estere av pseudo-iso-sapogeninet kan disse isoleres fra reaksjonsproduktet etter fjernelse av syren fra dette ved hjelp av den nevnte ekstraksjon med alkali. Alternativt kan, når det ønskes å fremstille selve pseudo-iso-sapogeninet, nevnte reaksjonsprodukt fortrinnsvis underkastes alkalisk hydrolyse, f. eks. med alkoholisk eller vandig-alkoholisk etsalkali som kaliumhydroksyd oppløst i metanol og pseudo-iso-sapogeninet isoleres fra hydrolysatet. I alminnelighet foretrekkes det å gå frem over slik hydrolyse med alkali, da rensnin-gen av reaksjonsproduktet herved lettes, idet det isolerte og rensede pseudo-iso-sapogenin forestres påny ved hjelp av hvilken som helst passende metode når det ønskes å få pseudo-iso-sapogeninestere. When the reaction is complete, the acid can be easily separated from the pseudo-iso-sapogenin by extraction with alkali, as will be described in the examples below. When it is desired to obtain esters of the pseudo-iso-sapogenin, these can be isolated from the reaction product after removing the acid from it by means of the aforementioned extraction with alkali. Alternatively, when it is desired to produce the pseudo-iso-sapogenin itself, said reaction product can preferably be subjected to alkaline hydrolysis, e.g. with alcoholic or aqueous-alcoholic caustic alkali such as potassium hydroxide dissolved in methanol and the pseudo-iso-sapogenin is isolated from the hydrolyzate. In general, it is preferred to proceed over such hydrolysis with alkali, as the purification of the reaction product is thereby facilitated, the isolated and purified pseudo-iso-sapogenin being re-esterified by any suitable method when it is desired to obtain pseudo-iso -sapogen esters.
I det følgende beskrives som eksempler noen utførelsesformer for fremgangsmåten ifølge oppfinnelsen: Eksempel 1: 3fi:26- dihydroksy- ll- keto- 5å- furost- 20( 22)- en. ll-ketotigogeninacetat (5 g) ble oppvarmet under kvelstoffatmosfære i n-kapronsyre (10 ml) i 6 timer. Etter dette tids-rom hadde dreiningsevnen, som ble bestemt ved å ta ut en prøve på 1 ml og fortynne denne til 10 ml med kloroform, nådd en maksimalverdi (observert a = + 1.55). In the following, some embodiments of the method according to the invention are described as examples: Example 1: 3fi:26-dihydroxy-ll-keto-5å- furost- 20( 22)- one. 11-ketotigogenin acetate (5 g) was heated under a nitrogen atmosphere in n-caproic acid (10 ml) for 6 hours. After this period of time, the rotatability, which was determined by taking a sample of 1 ml and diluting this to 10 ml with chloroform, had reached a maximum value (observed a = + 1.55).
Reaksjonsoppløsningen ble avkjølt og tilsatt eter (200 ml), hvorpå den resulterende blanding ble vasket med tre porsjoner 0,5 N natriumhydroksyd (totalt 600 ml) en gang med vann og tørret over MgS04. Oppløsningsmidlet ble fjernet i vakuum og man fikk en blekgul olje. The reaction solution was cooled and ether (200 mL) was added, after which the resulting mixture was washed with three portions of 0.5 N sodium hydroxide (total 600 mL) once with water and dried over MgSO 4 . The solvent was removed in vacuo and a pale yellow oil was obtained.
Denne olje ble oppvarmet under til-bakeløpskjøling i 30 minutter med en opp-løsning av kaliumhydroksyd (2,5 g) i metanol (50 ml), hvorpå varmt vann (omkring 400 cm<3>) ble tilsatt langsomt. Man lot derpå det hele avkjøle til romtemperatur. Det utfelte faste stoff ble oppsamlet ved filtrering og vasket med flere porsjoner varmt vann som var gjort ganske lite alkalisk med kaliumhydroksyd, derpå sluttelig vasket med destillert vann. Det faste stoff ble tørret i vakuum over natriumhydrok-sydgranuler og derpå vasket med eter (omkring 30 cm<3>). Etter ytterligere tørring fikk man 3|3: 26-dihydroksy-l l-keto-5a-f urost-20-(22)-en som et hvitt pulver (3,70 g; 81%), sm.p. 183—190° [a] n = + 74° (c = 2 i CHCl;,). This oil was heated under reflux for 30 minutes with a solution of potassium hydroxide (2.5 g) in methanol (50 ml), after which hot water (about 400 cm<3>) was added slowly. The whole thing was then allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with several portions of hot water made slightly alkaline with potassium hydroxide, then finally washed with distilled water. The solid was dried in vacuo over sodium hydroxide granules and then washed with ether (about 30 cm<3>). After further drying, 3|3: 26-dihydroxy-1 l -keto-5α-furost-20-(22)-ene was obtained as a white powder (3.70 g; 81%), m.p. 183—190° [a] n = + 74° (c = 2 in CHCl;,).
Ved ytterligere krystallisasjon fra aceton fikk man nåler med sm.p. 194—196° C som av analysen viser seg å være et sol-vent (kombinasjon av oppløsningsmiddel og oppløst stoff i et visst mengdeforhold). Ved analysen ble det funnet C, 74.1; H, 10.0. C27H4204.CaH80 tilsvarer C 73.7% og H 9.9 %. Further crystallization from acetone gave needles with m.p. 194-196° C which from the analysis turns out to be a sol-vent (combination of solvent and solute in a certain quantity ratio). The analysis found C, 74.1; H, 10.0. C27H4204.CaH80 corresponds to C 73.7% and H 9.9%.
Ved omkrystallisasjon fra metanol fikk man prismer med sm.p. 194—196° C, [a] D 20 By recrystallization from methanol, prisms were obtained with m.p. 194—196° C, [a] D 20
EtOH = + 76° (c 2.0 i kloroform), Amaks 217 mu (- 5,300). Ved analyse av dette stoff ble det funnet C, 75.0% og H 9,7%. Formelen C27H42O4 tilsvarer C. 75.3 %, H. 9.8 % EtOH = + 76° (c 2.0 in chloroform), Amax 217 mu (- 5.300). When analyzing this substance, C, 75.0% and H 9.7% were found. The formula C27H42O4 corresponds to C. 75.3%, H. 9.8%
Eksempel 2: Example 2:
Utførelse av reaksjonen under anvendelse av eddiksyre. 11-ketotigogeninacetat (3 g) suspen-dert i iseddik (6 ml) ble oppvarmet i et Carius-glassrør til 270° C med en tempera- turstigning på 145° C pr. time. I det øye-blikk temperaturen nådde 270° C ble glass-røret avkjølt raskt til romtemperatur. Opp-løsningsmidlet ble fjernet i vakuum og den resulterende olje oppvarmet under tilbake-løpskjøling i 30 minutter med kaliumhydroksyd (1.5 g) i metanol (30 ml). Man lot reaksjonsoppløsningen avkjøle, hvorpå man kjølte den i flere timer. Det krystallinske faste stoff ble oppsamlet, vasket med litt kold metanol og tørret i vakuum. Man fikk 3(3:26-dihydroksy-ll-a-keto-5a-furost-20-(22)-en som nåler (0,96 g; tilsvarer et utbytte på 35%. Forbindelsens sm.p. var 186— 190° C. [a]D = + 77° (c, 1.0 i kloroform). 11-ketotigogeninacetat (5 g), iseddik (8,5 ml) og eddiksyreanhydrid (1,5 ml) be-handlet på nøyaktig samme måte som ovenfor beskrevet ga furosten-diolen (1.95 g 43%), sm.p. 186—191° C, [a]D = +73° (c, = 1.0 i kloroform). Performance of the reaction during use of acetic acid. 11-ketotigogenin acetate (3 g) suspended in glacial acetic acid (6 ml) was heated in a Carius glass tube to 270° C. with a temperature rise of 145° C per hour. As soon as the temperature reached 270° C, the glass tube was cooled quickly to room temperature. The solvent was removed in vacuo and the resulting oil heated under reflux for 30 minutes with potassium hydroxide (1.5 g) in methanol (30 mL). The reaction solution was allowed to cool, after which it was cooled for several hours. The crystalline solid was collected, washed with a little cold methanol and dried in vacuo. 3(3:26-dihydroxy-11-α-keto-5α-furost-20-(22)-ene was obtained as needles (0.96 g; corresponding to a yield of 35%). The m.p. of the compound was 186— 190° C. [a]D = + 77° (c, 1.0 in chloroform). 11-ketotigogenin acetate (5 g), glacial acetic acid (8.5 ml) and acetic anhydride (1.5 ml) treated in exactly the same manner as described above gave the furostene diol (1.95 g 43%), m.p. 186—191° C, [a]D = +73° (c, = 1.0 in chloroform).
Eksempel 4: 3{ 5:26- dihydroksy- 5a- spirost- 20( 22)- en. Example 4: 3{5:26-dihydroxy-5a-spirost-20(22)-ene.
( Pseudotigogenin.) (Pseudotigogenin.)
3(3-acetoksy-5a:22a-spirostan (10.0 g) i kaprylsyre (13,2 ml) inneholdende kapryl-syreanhydrid (6.8 ml) ble oppvarmet til kokning under tilbakeløpskjøling og under kvelstoff i en time. Etter avkjøling ble pro-duktet tatt opp i eter (200 ml), vasket med 2N natriumhydroksydoppløsning (4 x 50 ml), og derpå med vann (4 x 100 ml), tørret over magnesiumsulfat og inndampet under redusert trykk. Residuet (12.35 g) 1 metanol (250 ml) ble hydrolysert ved å oppvarme det under tilbakeløpskjø-ling med en 10 %'s vandig natriumhydr-oksydoppløsning (32 ml), i 30 minutter. Halvparten av metanolet ble derpå fjernet under redusert trykk, diolen utfelt med vann (500 ml) og frafiltrert etter avkjøling. Bunnfallet ble vasket med varm fortynnet natriumhydroksydoppløsning og derpå med varmt vann (8,93 g). Produktets sm.p. var 165—178° C. Ved krystallisasjon fra metanol som ikke var sur fikk man rent 3(3,26-dihydroksy-5a : spirost-20(22)en med sm.p. 179—189° C. 3-(3-acetoxy-5α:22α-spirostane (10.0 g) in caprylic acid (13.2 mL) containing caprylic anhydride (6.8 mL) was heated to reflux under nitrogen for one hour. After cooling, the product taken up in ether (200 ml), washed with 2N sodium hydroxide solution (4 x 50 ml), and then with water (4 x 100 ml), dried over magnesium sulfate and evaporated under reduced pressure The residue (12.35 g) 1 methanol (250 ml ) was hydrolysed by heating it under reflux with a 10% aqueous sodium hydroxide solution (32 ml) for 30 minutes. Half of the methanol was then removed under reduced pressure, the diol precipitated with water (500 ml) and filtered off after cooling. The precipitate was washed with warm dilute sodium hydroxide solution and then with hot water (8.93 g). The m.p. of the product was 165-178° C. Crystallization from methanol, which was not acidic, gave pure 3(3.26 -dihydroxy-5a : spirost-20(22)ene with m.p. 179-189° C.
[a] 2° = +24 (C, 0,47 i CHCla) [a] 2° = +24 (C, 0.47 in CHClCl)
EtOH „,„ _ 1 % ,,AEtOH „,„ _ 1% ,,A
1 maks. 218 m^ 1 cm 114- 1 max. 218 m^ 1 cm 114-
Ved analyse ble det funnet: C. 77,93 % og H. 10,51 %. De beregnede verdier for C27 H4403 er C. 77,83 % og H. 10,65 %. On analysis it was found: C. 77.93% and H. 10.51%. The calculated values for C27 H4403 are C. 77.83% and H. 10.65%.
Eksempel 5: 3fi:26- hydroksy- 12- keto- 5a- spirost-20 ( 22)- en 12-ketotigogeninacetat («hecogeninace-tat», 10 g) ble oppvarmet under tilbake-løpskjøling i kaprylsyre (13,2 ml) og ka-prylsyreanhydrid (6,8 ml) under kvelstoff i 2 timer. Detter gik kman frem som beskrevet i eksempel 1, hvorved det etter forsåpningen skilte seg ut 3(3 26-dihydroksy-12-keto-5a-spirost-20(22)-en som et hvitt fast stoff (8,3 g tilsvarer et utbytte på 92%). Forbindelsens sm.p. var 189—190° C. Example 5: 3fi:26-hydroxy-12-keto-5a-spirost-20 (22)-one 12-ketotigogeninacetate ("hecogeninacetate", 10 g) was heated under reflux in caprylic acid (13.2 ml) and caprylic anhydride (6.8 mL) under nitrogen for 2 hours. This was carried out as described in example 1, whereby after the saponification 3(3 26-dihydroxy-12-keto-5a-spirost-20(22)-ene separated out as a white solid (8.3 g corresponding to a yield of 92%). The m.p. of the compound was 189-190° C.
20 20
[a] D = +100° (c = 1,8 i CHCI3). Ved krystallisasjon fra vandig aceton fikk man et rent produkt i form av plater med sm.p. 190—191° C. [a]D = +103° (c = 1,5% i CHCI3). [a] D = +100° (c = 1.8 in CHCl3). Crystallization from aqueous acetone gave a pure product in the form of plates with m.p. 190-191° C. [a]D = +103° (c = 1.5% in CHCl 3 ).
Eksempel 6: Example 6:
En blanding av 11-ketotigogenin (50 g), eddiksyreanhydrid (25 ml) og kaprylsyre (95 ml) ble oppvarmet under tilbakeløps-kjøling idet man brukte et Dean og Stark rør inneholdende kaprylsyre. Reaksjons-blandingens temperatur steg langsomt til 220° C, hvoretter man fortsatte oppvarmningen i ytterligere 2 timer. Reaksjonsblandingen ble så avkjølt, helt i benzol (350 ml) og den resulterende oppløsning vasket med vandig natriumhydroksyd (8 %'s, 2 x 350 ml). Det vandige ekstrakt ble ekstrahert med bensol, benzolekstraktene forenet, vasket med vann, (250 ml) og inndampet til tørrhet. Residuet ble oppvarmet under til-bakeløpskjøling med en 5 %'s oppløsning av kaliumhydroksyd i metanol (500 ml) i 45 minutter. Det ble derpå tilsatt varmt vann (400 ml) og det faste stoff som herved falt ut frafiltrert, vasket med vann (3000 ml) og tørret ved 40° C i vakuum i 16 timer. Man fikk 3(3:26-dihydroksy-ll-keto-5a-furost-20(22)-en (45,8 g, 91,6%), forbindelsens sm.p. var 183—188° C, [a]D = +68,2° A mixture of 11-ketotigogenin (50 g), acetic anhydride (25 ml) and caprylic acid (95 ml) was heated under reflux using a Dean and Stark tube containing caprylic acid. The temperature of the reaction mixture rose slowly to 220° C., after which the heating was continued for a further 2 hours. The reaction mixture was then cooled, poured into benzene (350 mL) and the resulting solution washed with aqueous sodium hydroxide (8%, 2 x 350 mL). The aqueous extract was extracted with benzol, the benzol extracts combined, washed with water (250 ml) and evaporated to dryness. The residue was heated under reflux with a 5% solution of potassium hydroxide in methanol (500 mL) for 45 minutes. Hot water (400 ml) was then added and the solid which thereby precipitated was filtered off, washed with water (3000 ml) and dried at 40° C. in vacuum for 16 hours. 3(3:26-dihydroxy-11-keto-5a-furost-20(22)-ene (45.8 g, 91.6%) was obtained, the m.p. of the compound was 183-188° C, [a ]D = +68.2°
(c = 1,0% i kloroform). (c = 1.0% in chloroform).
Eksempel 7: Example 7:
Smilagenin (1,7 g), n-kaprylsyreanhy-drid (2,46 ml) og n-kaprylsyre (5 ml) ble oppvarmet under tilbakeløpskjøling og i kvelstoffatmosfære i 1% time etter hvilken 20 tid oppløsningens [a] D forble konstant ved +5°. Etter avkjøling ble reaksjonsblandingen ekstrahert med eter og eterekstrak-tene ble etter vaskning med vandig natriumhydroksyd og vann inndampet, hvorved det ble tilbake et gummiaktig stoff. Dette stoff ble fordampet ved oppvarmning under tilbakeløpskjøling i en 5 %'s oppløsning av kaliumhydroksyd i metanol (20 ml) og i kvelstoffatmosfære i 30 minutter. Ved til-setning av varmt vann utfeltes et fast stoff som ble frafiltrert, vasket med ganske lite alkalisk varm, vandig metanol og tørret, hvorved man fikk 3(3:26-dihydroksy-5a : 25D-furost-20(22)-en (pseudosmilagenin). Denne forbindelses sm.p er 158—161° C. Smilagenin (1.7 g), n-caprylic anhydride (2.46 ml) and n-caprylic acid (5 ml) were heated under reflux and in a nitrogen atmosphere for 1% hour after which 20 hours the [a] D of the solution remained constant at +5°. After cooling, the reaction mixture was extracted with ether and the ether extracts were evaporated after washing with aqueous sodium hydroxide and water, leaving behind a gummy substance. This material was evaporated by heating under reflux in a 5% solution of potassium hydroxide in methanol (20 ml) and under a nitrogen atmosphere for 30 minutes. On addition of hot water, a solid precipitated which was filtered off, washed with slightly alkaline warm, aqueous methanol and dried, whereby 3(3:26-dihydroxy-5a : 25D-furost-20(22)-ene was obtained (pseudosmilagenin). The melting point of this compound is 158-161° C.
22 22
[a] D = +24° (c = 0,98 i kloroform). [a] D = +24° (c = 0.98 in chloroform).
Eksempel 8: Example 8:
Diosgenin (4 g) ble oppløst i en blanding av n-kaprylsyre (27 ml) og n-kapryl-syreanhydrid (10 ml) og blandingen ble oppvarmet under tilbakeløpskjøling i 1% time. Etter avkjøling ble oppløsningen ekstrahert med eter, eterekstraktet vasket Diosgenin (4g) was dissolved in a mixture of n-caprylic acid (27ml) and n-caprylic anhydride (10ml) and the mixture was heated under reflux for 1% hour. After cooling, the solution was extracted with ether, the ether extract washed
med 2N natriumhydroksydoppløsning og with 2N sodium hydroxide solution and
vann, derpå igjen med vann og inndampet water, then again with water and evaporated
til tørrhet. Som residum fikk man gummiaktig stoff som ble forsåpet ved oppvarmning i 30 minutter under tilbakeløpskjøling to dryness. A rubbery substance was obtained as a residue, which was saponified by heating for 30 minutes under reflux cooling
i en 6 %'s oppløsning av kaliumhydroksyd in a 6% solution of potassium hydroxide
i metanol (50 cm<:!>). Det ble derpå tilsatt in methanol (50 cm<:!>). It was then added
varmt vann, filtrert påny fra ganske lite hot water, filtered again from quite a bit
alkalisk metanol og sluttelig omkrystalli-sert fra vandig metanol. Man fikk 3(3 : 26-dihydroksy-furosta-5 : 20(22)-dien (pseudo-diosgenin) (3,47 g tilsvarende et utbytte alkaline methanol and finally recrystallized from aqueous methanol. 3(3 : 26-dihydroxy-furosta-5 : 20(22)-diene (pseudo-diosgenin) (3.47 g corresponding to a yield
på 87 %). Produktets sm.p. var 157—163° C. of 87%). The product's m.p. was 157-163° C.
Ved smeltning påny 174—177° C (Kofler), When melting again 174-177° C (Kofler),
18 18
[a] D = -36° (c, 1,7 i kloroform). [a] D = -36° (c, 1.7 in chloroform).
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DER39196A DE1254893B (en) | 1964-11-09 | 1964-11-09 | Exercise sheet with solution control |
DER40956A DE1295252B (en) | 1964-11-09 | 1965-06-26 | Assignment sheet |
Publications (1)
Publication Number | Publication Date |
---|---|
NO116143B true NO116143B (en) | 1969-02-03 |
Family
ID=25991837
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO160356A NO116143B (en) | 1964-11-09 | 1965-11-05 |
Country Status (10)
Country | Link |
---|---|
BE (1) | BE671831A (en) |
CH (2) | CH435822A (en) |
DE (2) | DE1254893B (en) |
DK (1) | DK117186B (en) |
ES (1) | ES123092Y (en) |
FI (1) | FI41696B (en) |
GB (1) | GB1109650A (en) |
NL (1) | NL6513680A (en) |
NO (1) | NO116143B (en) |
SE (1) | SE309868B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3736006A (en) * | 1971-06-16 | 1973-05-29 | Polsky N | Envelope |
JPS5524607Y2 (en) * | 1977-03-02 | 1980-06-12 | ||
GB2125336B (en) * | 1982-08-17 | 1986-03-05 | Martin Brockley | Devices for making written records |
CN108053723B (en) * | 2017-11-24 | 2022-02-22 | 辽宁工业大学 | English translation teaching auxiliary device |
-
1964
- 1964-11-09 CH CH1442064A patent/CH435822A/en unknown
- 1964-11-09 DE DER39196A patent/DE1254893B/en not_active Withdrawn
-
1965
- 1965-06-26 DE DER40956A patent/DE1295252B/en not_active Withdrawn
- 1965-10-22 NL NL6513680A patent/NL6513680A/xx unknown
- 1965-10-26 GB GB45240/65A patent/GB1109650A/en not_active Expired
- 1965-11-03 FI FI2641/65A patent/FI41696B/fi active
- 1965-11-04 BE BE671831A patent/BE671831A/xx unknown
- 1965-11-05 SE SE14300/65A patent/SE309868B/xx unknown
- 1965-11-05 NO NO160356A patent/NO116143B/no unknown
- 1965-11-06 DK DK572265AA patent/DK117186B/en unknown
- 1965-11-06 ES ES123092U patent/ES123092Y/en not_active Expired
- 1965-12-20 CH CH1761165A patent/CH468049A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CH468049A (en) | 1969-01-31 |
DE1254893B (en) | 1967-11-23 |
FI41696B (en) | 1969-09-30 |
SE309868B (en) | 1969-04-08 |
CH435822A (en) | 1967-05-15 |
DE1295252B (en) | 1969-05-14 |
BE671831A (en) | 1966-03-01 |
ES123092Y (en) | 1967-08-01 |
GB1109650A (en) | 1968-04-10 |
ES123092U (en) | 1966-10-16 |
NL6513680A (en) | 1966-05-09 |
DK117186B (en) | 1970-03-23 |
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