HRP20192000T1 - Postupak dobivanja ingenol-3-angelata - Google Patents
Postupak dobivanja ingenol-3-angelata Download PDFInfo
- Publication number
- HRP20192000T1 HRP20192000T1 HRP20192000TT HRP20192000T HRP20192000T1 HR P20192000 T1 HRP20192000 T1 HR P20192000T1 HR P20192000T T HRP20192000T T HR P20192000TT HR P20192000 T HRP20192000 T HR P20192000T HR P20192000 T1 HRP20192000 T1 HR P20192000T1
- Authority
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- Croatia
- Prior art keywords
- ingenol
- iii
- process according
- ketal
- angeloyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims 17
- VDJHFHXMUKFKET-UHFFFAOYSA-N Ingenol mebutate Natural products CC1CC2C(C)(C)C2C2C=C(CO)C(O)C3(O)C(OC(=O)C(C)=CC)C(C)=CC31C2=O VDJHFHXMUKFKET-UHFFFAOYSA-N 0.000 title claims 3
- VDJHFHXMUKFKET-WDUFCVPESA-N ingenol mebutate Chemical compound C[C@@H]1C[C@H]2C(C)(C)[C@H]2[C@@H]2C=C(CO)[C@@H](O)[C@]3(O)[C@@H](OC(=O)C(\C)=C/C)C(C)=C[C@]31C2=O VDJHFHXMUKFKET-WDUFCVPESA-N 0.000 title claims 3
- 229960002993 ingenol mebutate Drugs 0.000 title claims 3
- -1 ketal Chemical group 0.000 claims 36
- 150000001875 compounds Chemical class 0.000 claims 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 9
- 229910052739 hydrogen Inorganic materials 0.000 claims 8
- 239000001257 hydrogen Substances 0.000 claims 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 6
- TUNLYEHIVPWOHK-ARJAWSKDSA-N (z)-2-methylbut-2-enoyl chloride Chemical compound C\C=C(\C)C(Cl)=O TUNLYEHIVPWOHK-ARJAWSKDSA-N 0.000 claims 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- ADPMHRDERZTFIN-UHFFFAOYSA-N epinastine hydrobromide Chemical compound Br.C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 ADPMHRDERZTFIN-UHFFFAOYSA-N 0.000 claims 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 4
- 239000002904 solvent Substances 0.000 claims 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical group [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- BPNXYQJXBPWIKW-UTCJRWHESA-N [(z)-2-methylbut-2-enoyl] 2,4,6-trichlorobenzoate Chemical compound C\C=C(\C)C(=O)OC(=O)C1=C(Cl)C=C(Cl)C=C1Cl BPNXYQJXBPWIKW-UTCJRWHESA-N 0.000 claims 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Chemical group CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 3
- 239000003054 catalyst Substances 0.000 claims 3
- VEBVPUXQAPLADL-POYOOMFHSA-N ingenol Chemical compound C1=C(CO)[C@@H](O)[C@]2(O)[C@@H](O)C(C)=C[C@]32[C@H](C)C[C@H]2C(C)(C)[C@H]2[C@H]1C3=O VEBVPUXQAPLADL-POYOOMFHSA-N 0.000 claims 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 3
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 2
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 claims 2
- VEBVPUXQAPLADL-UHFFFAOYSA-N Ingenol Natural products C1=C(CO)C(O)C2(O)C(O)C(C)=CC32C(C)CC2C(C)(C)C2C1C3=O VEBVPUXQAPLADL-UHFFFAOYSA-N 0.000 claims 2
- 239000002841 Lewis acid Substances 0.000 claims 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- UIERETOOQGIECD-ARJAWSKDSA-N angelic acid Chemical compound C\C=C(\C)C(O)=O UIERETOOQGIECD-ARJAWSKDSA-N 0.000 claims 2
- 125000005601 angeloyl group Chemical group 0.000 claims 2
- 150000008064 anhydrides Chemical class 0.000 claims 2
- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims 2
- 230000032050 esterification Effects 0.000 claims 2
- 238000005886 esterification reaction Methods 0.000 claims 2
- 150000002148 esters Chemical group 0.000 claims 2
- 150000007517 lewis acids Chemical class 0.000 claims 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims 2
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 1
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 claims 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 claims 1
- LIHLSLRANKCHLV-SFECMWDFSA-N [(z)-2-methylbut-2-enoyl] (z)-2-methylbut-2-enoate Chemical compound C\C=C(\C)C(=O)OC(=O)C(\C)=C/C LIHLSLRANKCHLV-SFECMWDFSA-N 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 claims 1
- JTGAUXSVQKWNHO-UHFFFAOYSA-N ditert-butylsilicon Chemical group CC(C)(C)[Si]C(C)(C)C JTGAUXSVQKWNHO-UHFFFAOYSA-N 0.000 claims 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims 1
- YYJWBYNQJLBIGS-PLNGDYQASA-N methyl (z)-2-methylbut-2-enoate Chemical compound COC(=O)C(\C)=C/C YYJWBYNQJLBIGS-PLNGDYQASA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 150000002905 orthoesters Chemical class 0.000 claims 1
- DKTXXUNXVCHYDO-UHFFFAOYSA-N phenoxyborinic acid Chemical compound OBOC1=CC=CC=C1 DKTXXUNXVCHYDO-UHFFFAOYSA-N 0.000 claims 1
- 239000003223 protective agent Substances 0.000 claims 1
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Substances COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
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- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/88—Hydrazones having also the other nitrogen atom doubly-bound to a carbon atom, e.g. azines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/54—Preparation of carboxylic acid anhydrides
- C07C51/567—Preparation of carboxylic acid anhydrides by reactions not involving carboxylic acid anhydride groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- C07C2603/95—Spiro compounds containing "not free" spiro atoms
- C07C2603/98—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Claims (16)
1. Postupak dobivanja ingenol-3-angelata ((1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihidroksi-4-(hidroksimetil)-1,1,7,9-tetrametil-11-okso-1a,2,5,5a,6,9,10,10a-oktahidro-1H-2,8a- metanociklopenta[a]ciklopropa[e]ciklodecen-6-il estra 2-metil-2(Z)-butenske kiseline) (I) iz ingenola (II)
koji obuhvaća korake:
(a) reagiranja jedne ili obje hidroksilne skupine u položajima 5 i 20 ingenola s odgovarajućim hidroksilnim zaštitnim sredstvima, istim ili različitim, da bi se dobio spoj opće formule (III) ili (IV)
gdje R1 predstavlja vodik ili hidroksilnu zaštitnu skupinu i R2 predstavlja vodik ili hidroksilnu zaštitnu skupinu, uz uvjet da oba R1 i R2 ne predstavljaju vodik,
ili gdje D predstavlja dihidroksilnu zaštitu skupinu
(b) esterifikacije hidroksilne skupine u položaju 3 spoja (III) ili (IV) da bi se dobio spoj opće formule (V) ili (VI)
gdje R1, R2 i D su kao što je gore opisano, i gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV) s:
(i) metil angelatom,
(ii) angeloil kloridom u prisustvu baze, u odgovarajućem otapalu,
(iii) anhidridom angelinske kiseline , ili
(iv) mješovitim anhidridom angelinske kiseline ;
i
(c) uklanjanja hidroksilnih zaštitnih skupina R1 ili R2, ili R1 i R2, ili D iz spoja (V) ili (VI) da bi se dobio ingenol-3-angelat (I).
2. Postupak prema zahtjevu 1, gdje R1 predstavlja vodik ili etersku, acetalnu, ketalnu, sililetersku, estersku, karbonatnu, ili sulfenatnu hidroksilnu zaštitnu skupinu i R2 predstavlja vodik ili etersku, acetalnu, ketalnu, sililetersku, estersku, karbonatnu, ili sulfenatnu hidroksilnu zaštitnu skupinu.
3. Postupak prema zahtjevu 1, gdje D predstavlja acetalnu, ketalnu, diacetalnu, diketalnu, orto estersku, sililnu, boronatnu ili karbonatnu dihidroksilnu zaštitnu skupinu.
4. Postupak prema zahtjevu 1 ili 2, gdje je R1 izabran iz skupine koju čine vodik ili [(3,4- dimetoksibenzil)oksi]metil, gvaiakolmetil, 2-metoksietoksimetil, tetrahidropiranil, tetrahidrofuranil, 1-etoksietil, 1-metil-1-metoksietil, alil, prenil, p-metoksibenzil, trifenilmetil, 2-(trimetilsilil)etoksimetil, trietilsilil, triizopropilsilil, terc-butildimetilsilil, dimetilizopropilsilil, dietilizopropilsilil, terc-butildifenilsilil, trifenilsilil, acetil, kloroacetil, fenoksiacetil ili angeloil.
5. Postupak prema zahtjevu 1, 2 ili 4, gdje je R2 izabran iz skupine koju čine vodik ili [(3,4- dimetoksibenzil)oksi]metil, gvaiakolmetil, 2-metoksietoksimetil, tetrahidropiranil, tetrahidrofuranil, 1etoksietil, 1-metil-1-metoksietil, alil, prenil, p-metoksibenzil, trifenilmetil, 2-(trimetilsilil)etoksimetil, trietilsilil, triizopropilsilil, terc-butildimetilsilil, dimetilizopropilsilil, dietilizopropilsilil, terc-butildifenilsilil, trifenilsilil, acetil, kloroacetil, fenoksiacetil ili angeloil.
6. Postupak prema zahtjevu 1 ili 3, gdje je D izabran iz skupine koju čine izopropiliden, ciklopentiliden, cikloheksiliden, p-metoksibenziliden, metoksimetilen, 2-oksaciklopentiliden, 2,3-dimetoksibutan-2,3-di-il, 1,2-dimetoksicikloheksan-1,2-di-il, oktahidro-[2,2']-bipiran-2,2'-di-il, di-terc-butilsililen, 1,3-(1,1,3,3-tetraizopropildisiloksaniliden), fenil boronat, 3-pentiliden, 2,4-dimetil-3-pentiliden, 2,6-dimetil-4-heptiliden, 3,3-dimetil-2-butiliden, 1-fenil-1-etiliden, benziliden, 2,4-dimetoksibenziliden,4-nitrobenziliden, 2,4,6-trimetilbenziliden, 2,2-dimetil-1-propiliden, etoksimetilen ili izopropoksimetilen.
7. Postupak prema zahtjevu 6, gdje je D izopropiliden.
8. Postupak prema zahtjevu 1, 2 ili 4, gdje R1 predstavlja hidroksilnu zaštitnu skupinu i R2 predstavlja vodik.
9. Postupak prema zahtjevu 1, 2, 4 ili 5, gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV), s metil angelatom, angeloil kloridom, anhidridom angelinske kiseline, [(Z)-2-metilbut-2-enoil] 2,4,6-triklorobenzoatom ili angeloil 4-nitrobenzoil anhidridom.
10. Postupak prema zahtjevu 1, 2, 4 ili 5 gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV) s angeloil kloridom, anhidridom angelinske kiseline , [(Z)-2-metilbut-2-enoil] 2,4,6-triklorobenzoatom ili angeloil 4-nitrobenzoil anhidridom.
11. Postupak prema zahtjevu 1, 2, 4 ili 5, gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV) s anhidridom angelinske kiseline:
(i) bez katalizatora; ili
(ii) u prisustvu kiselog katalizatora, na primjer, kiselinom kao što je perklorna kiselina ili Lewisova kiselina kao što je skandij (III) triflat ili bizmut (III) triflat; ili
(iii) u prisustvu baze kao što je natrij hidrogenkarbonat, trietilamin, litij heksametildisilazid, natrij heksametildisilazid, kalij heksametildisilazid, piridin, cezij karbonat ili 4-(dimetilamino)piridin;
u odgovarajućem otapalu kao što je tetrahidrofuran, MeCN, piridin ili metil terc-butil eter.
12. Postupak prema zahtjevu 11, gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV) s anhidridom angelinske kiseline u prisustvu baze izabrane između natrij hidrogenkarbonata, trietilamina, litij heksametildisilazida, natrij heksametildisilazida, kalij heksametildisilazida, piridina, cezij karbonata i 4-(dimetilamino)piridina.
13. Postupak prema zahtjevu 1, 2, 3, 4, 5, 6, 7 ili 8, gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV) s mješovitim anhidridom angelinske kiseline izabranim između angeloil 2,4,6-triklorobenzoil anhidrida, [(Z)-2-metilbut-2-enoil]2,4,6-triklorobenzoata, i angeloil 4-nitrobenzoil anhidrida:
(i) bez katalizatora; ili
(ii) u prisustvu kiselog katalizatora koji koristi kiselinu kao što je perklorna kiselina ili Lewisova kiselina kao što je skandij (III) triflat ili bizmut (III) triflat; ili
(iii) u prisustvu baze kao što je natrij hidrogenkarbonat ili trimetilamin;
u odgovarajućem otapalu kao što je toluen.
14. Postupak prema zahtjevu 1, 2, 3, 4, 5, 6, 7 ili 8, gdje korak (b) obuhvaća reagiranje spoja (III) ili (IV) s angeloil kloridom.
15. Postupak prema zahtjevu 14, gdje se esterifikacija reakcijom s angeloil kloridom odvija:
u prisustvu baze kao što je piridin, trietilamin, litij heksametildisilazid ili 4-(dimetilamino)piridin; u odgovarajućem otapalu kao što je piridin ili tetrahidrofuran.
16. Postupak prema bilo kojem od zahtjeva 1 ili 9-15, gdje je spoj opće formule (IV) izabran iz skupine koju čine
Ingenol-5,20-(3-pentiliden)-ketal,
Ingenol-5,20-(2,4-dimetil-3-pentiliden)-ketal,
Ingenol-5,20-(2,6-dimetil-4-heptiliden)-ketal,
Ingenol-5,20-ciklopentiliden-ketal,
Ingenol-5,20-cikloheksiliden-ketal,
Ingenol-5,20-(3,3-dimetil-2-butiliden)-ketal,
Ingenol-5,20-(1-fenil-1-etiliden)-ketal,
Ingenol-5,20-benziliden-acetal,
Ingenol-5,20-(4-metoksibenziliden)-acetal,
Ingenol-5,20-(2,4-dimetoksibenziliden)-acetal,
Ingenol-5,20-(4-nitrobenziliden)-acetal,
Ingenol-5,20-(2,4,6-trimetilbenziliden)-acetal,
Ingenol-5,20-(2,2-dimetil-1-propiliden)-acetal,
Ingenol-5,20-metil-ortoformijat,
Ingenol-5,20-etil-ortoformijat,
Ingenol-5,20-(prop-2-il)-ortoformijat,
Ingenol-5,20-(di(terc-butil)sililen)-eter.
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| US36601810P | 2010-07-20 | 2010-07-20 | |
| PCT/DK2011/000081 WO2012010172A1 (en) | 2010-07-20 | 2011-07-08 | A method of producing ingenol-3-angelate |
| EP11738152.5A EP2595948B1 (en) | 2010-07-20 | 2011-07-08 | A method of producing ingenol-3-angelate |
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| US (3) | US8901356B2 (hr) |
| EP (2) | EP2595948B1 (hr) |
| JP (1) | JP5816279B2 (hr) |
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| HR (1) | HRP20192000T1 (hr) |
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| GB0525680D0 (en) | 2005-12-16 | 2006-01-25 | Peplin Ltd | Therapeutic compositions |
| BR112013001245B1 (pt) | 2010-07-20 | 2021-06-15 | Leo Laboratories Limited | Método de produção de ingenol-3-angelato a partir de ingenol |
| JP2014507396A (ja) | 2010-12-22 | 2014-03-27 | レオ・ラボラトリーズ・リミテッド | イノゲノール−３−アシラートｉ |
| EP2807263A1 (en) * | 2012-01-25 | 2014-12-03 | Leo Laboratories Limited | Process for the preparation of ingenol-3-angelate |
| EP2872477B1 (en) | 2012-07-16 | 2018-09-05 | Leo Laboratories Limited | Process for the preparation of ingenol-3-angelate from 20-deoxy-ingenol |
| CN103483193A (zh) * | 2013-09-10 | 2014-01-01 | 南京奇鹤医药科技有限公司 | 一种巨大戟醇甲基丁烯酸酯的制备方法 |
| EP3145903A4 (en) * | 2014-05-23 | 2018-01-03 | Alphora Research Inc. | A continuous flow process for the preparation of ingenol-3-mebutate |
| CN104649901B (zh) * | 2015-02-09 | 2017-03-29 | 中国科学院昆明植物研究所 | 一种治疗光化性角化病的原料药物巨大戟醇甲基丁烯酸酯的制备方法 |
| WO2016191836A1 (pt) * | 2015-06-03 | 2016-12-08 | Amazônia Fitomedicamentos Ltda. | Método de preparação de ingenol-3-dodecanoato, método de preparação de 3-etinil-3-hidroxi-4.7.7-trimetilbiciclo[4.1.0]heptano-2-carbaldeído e método de preparação de 2,2-dimetil-4-etinil-5-trifenilfosforanilideno-1,3-dioxano |
| WO2016191835A1 (pt) * | 2015-06-03 | 2016-12-08 | Amazônia Fitomedicamentos Ltda. | Método de preparação de ingenol-5,20-acetonida, método de preparação de 3-etinil-3-hidroxi-4.7.7-trimetilbiciclo[4.1.0] heptano-2-carbaldeído, método de preparação do composto 2,2-dimetil-4-etinil-5 -trifenilfosforanilideno-1,3-dioxano e composto intermediário |
| WO2016191837A1 (pt) * | 2015-06-03 | 2016-12-08 | Amazônia Fitomedicamentos Ltda. | Método de preparação de ingenol-3-hexanoato, método de preparação de 3-etinil-3-hidroxi-4.7.7-trimetilbiciclo[4.1.0]heptano-2-carbaldeído e método de preparação do composto 2,2-dimetil-4-etinil-5-trifenilfosforanilideno-1,3-dioxano |
| WO2017108927A1 (en) * | 2015-12-22 | 2017-06-29 | Leo Laboratories Limited | Process for preparation of ingenol 3-(3.5-diethylisoxazole-4-carboxylate) |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| US11753363B2 (en) | 2017-06-09 | 2023-09-12 | Tianjin Pharmaceutical Da Ren Tang Group Corp., Ltd. Traditional Chinese Medicine Research Institute | 13-oxidized ingenol derivative and use thereof |
| WO2022192521A1 (en) * | 2021-03-10 | 2022-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Synthesis of tigilanol tiglate and analogs thereof |
| CN113336628B (zh) * | 2021-04-16 | 2023-02-10 | 云南省中医中药研究院 | 一种二醇蔷薇烷、其制备方法及用途 |
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| JPS5920247A (ja) * | 1982-07-28 | 1984-02-01 | Taiyo Koryo Kk | アンゲリカ酸不飽和エステル類及びその香料組成物 |
| JPS6036479A (ja) * | 1983-08-08 | 1985-02-25 | Kotobuki Seiyaku Kk | １，３−ジオキサン誘導体、本化合物を有効成分とする抗潰瘍剤及びその製造方法 |
| JP3773578B2 (ja) * | 1996-02-29 | 2006-05-10 | 三共株式会社 | タキソール合成中間体 |
| AUPQ801700A0 (en) | 2000-06-07 | 2000-06-29 | Peplin Research Pty Ltd | Enzyme and viral activation |
| AUPQ923100A0 (en) * | 2000-08-07 | 2000-08-31 | Peplin Research Pty Ltd | Treatment of prostate cancer |
| WO2007009055A2 (en) * | 2005-07-13 | 2007-01-18 | Salvia Sciences, Inc. | Ester prodrugs of prostratin and related phorbol compounds |
| CA2541903A1 (en) * | 2006-04-20 | 2007-10-20 | Peplin Research Pty. Ltd. | A method of diagnosis and treatment |
| JP4952208B2 (ja) | 2006-11-16 | 2012-06-13 | 株式会社ツムラ | プラエルプトリンａの製造方法 |
| ES2633814T3 (es) * | 2010-04-16 | 2017-09-25 | Leo Pharma A/S | Mebutato de ingenol cristalino ortorrómbico |
| BR112013001245B1 (pt) | 2010-07-20 | 2021-06-15 | Leo Laboratories Limited | Método de produção de ingenol-3-angelato a partir de ingenol |
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