HRP20151301T1 - Postupci za proäśišä†avanje trans-(-)-delta9-tetrahidrokanabinola i trans-(+)-delta9-tetrahidrokanabinola - Google Patents
Postupci za proäśišä†avanje trans-(-)-delta9-tetrahidrokanabinola i trans-(+)-delta9-tetrahidrokanabinola Download PDFInfo
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- HRP20151301T1 HRP20151301T1 HRP20151301TT HRP20151301T HRP20151301T1 HR P20151301 T1 HRP20151301 T1 HR P20151301T1 HR P20151301T T HRP20151301T T HR P20151301TT HR P20151301 T HRP20151301 T HR P20151301T HR P20151301 T1 HRP20151301 T1 HR P20151301T1
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- 238000000034 method Methods 0.000 title claims 19
- 239000000203 mixture Substances 0.000 claims 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 33
- 238000002360 preparation method Methods 0.000 claims 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 12
- IRMPFYJSHJGOPE-UHFFFAOYSA-N olivetol Chemical compound CCCCCC1=CC(O)=CC(O)=C1 IRMPFYJSHJGOPE-UHFFFAOYSA-N 0.000 claims 12
- 239000012074 organic phase Substances 0.000 claims 9
- 239000012071 phase Substances 0.000 claims 9
- 238000002156 mixing Methods 0.000 claims 8
- 238000006243 chemical reaction Methods 0.000 claims 7
- 239000003495 polar organic solvent Substances 0.000 claims 7
- 238000003756 stirring Methods 0.000 claims 7
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 4
- 230000002051 biphasic effect Effects 0.000 claims 4
- 238000001816 cooling Methods 0.000 claims 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 3
- 239000002841 Lewis acid Substances 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 239000003518 caustics Substances 0.000 claims 3
- 238000002425 crystallisation Methods 0.000 claims 3
- 230000008025 crystallization Effects 0.000 claims 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 3
- 238000002955 isolation Methods 0.000 claims 3
- 150000007517 lewis acids Chemical class 0.000 claims 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 3
- 238000000926 separation method Methods 0.000 claims 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 3
- 235000005074 zinc chloride Nutrition 0.000 claims 3
- 239000011592 zinc chloride Substances 0.000 claims 3
- 239000004215 Carbon black (E152) Substances 0.000 claims 2
- 230000005526 G1 to G0 transition Effects 0.000 claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 2
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims 2
- 239000003377 acid catalyst Substances 0.000 claims 2
- 238000007033 dehydrochlorination reaction Methods 0.000 claims 2
- 239000012156 elution solvent Substances 0.000 claims 2
- 229930195733 hydrocarbon Natural products 0.000 claims 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 2
- QHMBSVQNZZTUGM-MSOLQXFVSA-N 2-[(1s,6s)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@@H]1[C@@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-MSOLQXFVSA-N 0.000 claims 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 230000005587 bubbling Effects 0.000 claims 1
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims 1
- 229950011318 cannabidiol Drugs 0.000 claims 1
- 229930003827 cannabinoid Natural products 0.000 claims 1
- 239000003557 cannabinoid Substances 0.000 claims 1
- 229940065144 cannabinoids Drugs 0.000 claims 1
- 229940043350 citral Drugs 0.000 claims 1
- 239000012024 dehydrating agents Substances 0.000 claims 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims 1
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 claims 1
- 239000005457 ice water Substances 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Claims (18)
1. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola koji sadrži:
omogućavanje kristalizacije trans-(-)-Δ9-tertahidrokanabinola i trans-(+)-Δ9-tertahidrokanabinola iz prvog pripravka koji sadrži trans-(-)-Δ9-tertahidrokanabinol, trans-(+)-Δ9-tertahidrokanabinol, te nepolarno organsko otapalo da se dobije kristalizirani (±)-Δ9-tertahidrokanabinol,
naznačen time da je prvi pripravak dobiven pomoću:
(1) konverzije (-)-p-ment-2,8-dien-1-ola u trans-(+)-Δ9-tertahidrokanabinol uz
(i) miješanje smjese olivetola, cinkovog klorida i bezvodnog diklorometana na 40°C tijekom jednog sata, dodavanje otopine (-)-p-ment-2,8-dien-1-ola i bezvodnog diklorometana kap po kap tijekom 1 sata na 40°C u miješanu smjesu koja sadrži olivetol, te miješanje nastale smjese tijekom dodatnih 40 minuta na 40°C,
(ii) hlađenje smjese na -10°C, dodavanje otopine BF3·Et2O u bezvodnom diklorometanu kap po kap tijekom 1 sata na -10°C, te miješanje smjese tokom 30 minuta na -10°C, te
(iii) dodavanje hladne vode, miješanje nastale dvofazne smjese tokom 20 minuta na 0°C, te izoliranje sirovog trans-(+)-Δ9-tertahidrokanabinola iz organske faze;
(2) stvaranje dvofaznog pripravka koji sadrži (i) prvu organsku fazu, i (ii) alkoholno-kaustičnu fazu koja sadrži sirovi trans-(+)-Δ9-tertahidrokanabinol koji proizlazi iz koraka (1) i trans-(-)-Δ9-tertahidrokanabinol;
(4) separaciju Δ9-tertahidrokanabinola iz nastale faze koja sadrži Δ9-tertahidrokanabinol; i
(5) spajanje Δ9-tertahidrokanabinola iz koraka (4) s nepolarnim organskim otapalom da se dobije prvi pripravak.
2. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola koji sadrži:
omogućavanje kristalizacije trans-(-)-Δ9-tertahidrokanabinola i trans-(+)-Δ9-tertahidrokanabinola iz prvog pripravka koji sadrži trans-(-)-Δ9-tertahidrokanabinol, trans-(+)-Δ9-tertahidrokanabinol, te nepolarno organsko otapalo da se dobije provide kristalizirani (±)-Δ9-tertahidrokanabinol,
naznačen time da je prvi pripravak dobiven pomoću:
(1) konverzije cis/trans smjese (+)-p-ment-2,8-dien-1-ola u trans-(-)-Δ9-tertahidrokanabinol pomoću reakcije cis/trans smjese (+)-p-ment-2,8-dien-1-ola s olivetolom u prisutnosti kiselog katalizatora i sredstva za dehidraciju;
(2) stvaranje dvofaznog pripravka koji sadrži (i) prvu organsku fazu, i (ii) alkoholno-kaustičnu fazu koja sadrži sirovi trans-(-)-Δ9-tertahidrokanabinol koji proizlazi iz koraka (1) i trans-(+)-Δ9-tertahidrokanabinol;
(4) separaciju Δ9-tertahidrokanabinola iz nastale faze koja sadrži Δ9-tertahidrokanabinol; i
(5) spajanje Δ9-tertahidrokanabinola iz koraka (4) s nepolarnim organskim otapalom da se dobije prvi pripravak.
3. Postupak prema zahtjevu 2, naznačen time da kiseli katalizator je para-toluensulfonska kiselina ili BF3·Et2O.
4. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola koji sadrži:
omogućavanje kristalizacije trans-(-)-Δ9-tertahidrokanabinola i trans-(+)-Δ9-tetra-hidrokanabinola iz prvog pripravka koji sadrži trans-(-)-Δ9-tertahidrokanabinol, trans-(+)-Δ9-tertahidrokanabinol, te nepolarno organsko otapalo da se dobije kristalizirani (±)-Δ9-tertahidrokanabinol,
naznačen time da je prvi pripravak dobiven pomoću:
(1) konverzije (±)-p-ment-2,8-dien-1-ola u trans-(±)-Δ9-tertahidrokanabinol pomoću
(i) miješanja smjese olivetola, cinkovog klorida i bezvodnog diklorometana na 40°C tijekom jednog sata, dodavanje otopine (±)-p-ment-2,8-dien-1-ola i bezvodnog diklorometana kap po kap tijekom 1 sata na 40°C u miješanu smjesu koja sadrži olivetol, i miješanje dobivene smjese tijekom dodatnih 40 minuta na 40°C,
(ii) hlađenja smjese na -10°C, dodavanje otopine BF3·Et2O u bezvodnom diklorometanu kap po kap tijekom 1 sata na -10°C, i miješanje smjese tijekom 30 minuta na -10°C, i
(iii) dodavanja hladne vode, miješanja dobivene dvofazne smjese tijekom 20 minuta na 0°C, te izoliranja sirovog trans-(±)-Δ9-tertahidrokanabinola iz organske faze;
(2) stvaranje dvofaznog pripravka koji sadrži (i) prvu organsku fazu, i (ii) alkoholno-kaustičnu fazu koja sadrži sirovi trans-(±)-Δ9-tertahidrokanabinol koji proizlazi iz koraka (1);
(4) razdvajanje Δ9-tertahidrokanabinola iz nastale faze koja sadrži Δ9-tertahidrokanabinol; i
(5) spajanje Δ9-tertahidrokanabinola iz koraka (4) s nepolarnim organskim otapalom da se dobije prvi pripravak.
5. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 2, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
1. reakcijom (-)-kanabidiola s Lewisovom kiselinom u inertnom otapalu pod bezvodnim uvjetima u sirovi trans-(-)-Δ9-tertahidrokanabinol koji je korišten u koraku (2).
6. Postupak prema zahtjevu 5, naznačen time da Lewisova kiselina je BF3·Et2O.
7. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 1, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
(1) dodavanje otopine BF3·Et2O u bezvodnom diklorometanu kap po kap uz miješanje tijekom 1 sata u otopinu (+)-kanabidiola u bezvodnom diklorometanu na -5°C, miješanje nastale smjese tijekom 1.5 sata na -5°C, dodavanje smjese u smjesu leda i 7% NaHCO3, te izoliranje iz organske faze sirovog trans-(+)-Δ9-tertahidrokanabinola koji je korišten u koraku (2).
8. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 4, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
1. dodavanje otopine BF3·Et2O u bezvodnom diklorometanu kap po kap uz miješanje tijekom 1 sata u otopinu (±)-kanabidiola u bezvodnom diklorometanu na -5°C, miješanje nastale smjese tijekom 1.5 sata na -5°C, dodavanje smjese u 7% NaHCO3, te izoliranje iz organske faze sirovog trans-(±)-Δ9-tertahidrokanabinola koji je korišten u koraku (2).
9. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 1, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
1. reakcija (+)-Δ8-tertahidrokanabinola s HCl nakon čega slijedi dehidrokloriranje u sirovi trans-(+)-Δ9-tertahidrokanabinol koji je korišten u koraku (2).
10. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 2, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
(1) reakcija (-)-Δ8-tertahidrokanabinola s HCl nakon čega slijedi dehidrokloriranje u sirovi trans-(-)-Δ9-tertahidrokanabinol koji je korišten u koraku (2).
11. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 4, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
(1)
(i) miješanje smjese (±)-A8-tertahidrokanabinola, cinkovog klorida, i bezvodnog diklorometana tijekom 0.5 sata na 25°C pod Ar atmosferom, hlađenje smjese na 0°C, brabotiranje plinovitog vodikovog klorida kroz smjesu tokom 1.5 sata, ulijevanje smjese u ledenu kupelj i miješanje nastale dvofazne smjese tijekom 1 sata na 0 do 5°C, izoliranje dobivenog (±)-9-kloro-trans-heksahidrokanabinola iz organske faze,
(ii) miješanje smjese izoliranog (±)-9-kloro-trans-heksahidrokanabinola s kalijevim-tert-amilatom i bezvodnim toluenom tijekom 75 minuta na 65°C, hlađenje smjese i njegovo ulijevanje u ledenu vodu, te izolaciju iz organske faze nastalog sirovog trans-(±)-Δ9-tertahidrokanabinola koji je korišten u koraku (2).
12. Postupak za dobivanje kristalnog (±)-Δ9-tertahidrokanabinola prema zahtjevu 4, naznačen time da je korak (1) zamijenjen sa slijedećim korakom (1):
(1) reakcija citrala s olivetolom u prisutnosti Lewisove kiseline do sirovog trans-(±)-Δ9-tertahidrokanabinola koji je korišten u koraku (2).
13. Postupak za pripravu pripravka trans-(-)-Δ9-tertahidrokanabinola, koji se sastoji od:
omogućavanja da se pripravak koji sadrži (±)-Δ9-tertahidrokanabinol i otapalo za eluiranje razdvoje na kiralnoj stacionarnoj fazi da se dobije pripravak trans-(-)-Δ9-tertahidrokanabinola, ili
pripravka trans-(+)-Δ9-tertahidrokanabinola, koji se sastoji od:
omogućavanja da se pripravak koji sadrži (±)-Δ9-tertahidrokanabinol i otapalo za eluiranje razdvoje na kiralnoj stacionarnoj fazi da se dobije pripravak trans-(+)-Δ9-tertahidrokanabinola,
naznačen time da je (±)-Δ9-tertahidrokanabinol dobiven iz kristaliziranog (±)-Δ9-tertahidrokanabinola, te pri čemu je kristalizirani (±)-Δ9-tertahidrokanabinol dobiven postupkom prema bilo kojem od zahtjeva 1 do 12.
14. Postupak prema bilo kojem od zahtjeva 1 do 13, naznačen time da je trans-(-)-Δ9-tertahidrokanabinol prisutan u prvom pripravku u količini od 0.75 do 1.25 molarnih ekvivalenata, poželjno od 0.9 do 1.1 molarnih ekvivalenata, poželjnije od 0.95 do 1.05 molarnih ekvivalenata i čak još poželjnije 1 molarni ekvivalent po molarnom ekvivalentu trans-(+)-Δ9-tertahidrokanabinola.
15. Postupak prema bilo kojem od zahtjeva 1 do 14, naznačen time da (±)-Δ9-tertahidrokanabinol sadrži barem 95%, poželjno barem 98%, poželjnije barem 99% težinski trans-(-)-Δ9-tertahidrokanabinola i trans-(+)-Δ9-tertahidrokanabinola u odnosu na ukupnu količinu kanabinoida.
16. Postupak prema bilo kojem od zahtjeva 1 do 15, naznačen time da je nepolarno organsko otapalo (C4-C10)alifatski ugljikovodik s ravnim-lancem ili razgranatim-lancem, (C4-C10)cikloalifatski ugljikovodik, ili bilo koja njihova mješavina, pri čemu je ugljikovodik s ravnim-lancem ili razgranatim-lancem poželjno pentan, heksan, heptan, izooktan, ili bilo koja njihova mješavina, te je poželjnije n-heptan.
17. Dvofazni pripravak dobiven iz koraka (2) postupkom prema bilo kojem od zahtjeva 1 do 12.
18. Pripravak koji sadrži trans-(-)-Δ9-tertahidrokanabinol, trans-(+)-Δ9-tertahidrokanabinol, organsko otapalo koje se ne miješa s vodom, alkohol koji se miješa s vodom, vodu, te hidroksid alkalijskog metala, naznačen time da je trans-(-)-Δ9-tertahidrokanabinol prisutan u količini od 0.75 do 1.25 molarnih ekvivalenata po molarnom ekvivalentu trans-(+)-Δ9-tertahidrokanabinola.
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| EP10179360.2A EP2289509B1 (en) | 2004-11-22 | 2005-11-18 | Methods for purifying trans-(-)-delta9-tetrahydrocannabinol and trans-(+)-delta9-tetrahydrocannabinol |
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2010
- 2010-01-21 AU AU2010200227A patent/AU2010200227A1/en not_active Abandoned
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2011
- 2011-05-17 CY CY20111100473T patent/CY1111471T1/el unknown
- 2011-05-24 HR HR20110385T patent/HRP20110385T1/hr unknown
- 2011-08-29 HK HK11109114.9A patent/HK1154796A1/xx unknown
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2012
- 2012-01-03 HK HK12100001.3A patent/HK1159500A1/xx unknown
- 2012-03-26 JP JP2012068947A patent/JP2012180350A/ja active Pending
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2013
- 2013-02-22 US US13/774,955 patent/US8937097B2/en active Active
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2015
- 2015-01-13 US US14/596,034 patent/US9278083B2/en active Active
- 2015-11-30 HR HRP20151301TT patent/HRP20151301T1/hr unknown
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2016
- 2016-03-04 US US15/061,780 patent/US9744151B2/en active Active
- 2016-03-04 US US15/061,859 patent/US9675581B2/en active Active
- 2016-03-04 US US15/061,891 patent/US20160199344A1/en not_active Abandoned
- 2016-03-23 HR HRP20160300TT patent/HRP20160300T1/hr unknown
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