CN116368127A - 大麻素类化合物的纯化方法 - Google Patents
大麻素类化合物的纯化方法 Download PDFInfo
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- CN116368127A CN116368127A CN202180073353.2A CN202180073353A CN116368127A CN 116368127 A CN116368127 A CN 116368127A CN 202180073353 A CN202180073353 A CN 202180073353A CN 116368127 A CN116368127 A CN 116368127A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 229930003827 cannabinoid Natural products 0.000 title claims abstract description 13
- 239000003557 cannabinoid Substances 0.000 title claims abstract description 13
- 229940065144 cannabinoids Drugs 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- -1 triethylsilyl Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 229910052710 silicon Inorganic materials 0.000 claims description 8
- 239000010703 silicon Substances 0.000 claims description 8
- 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 description 8
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 8
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 6
- 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 description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 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 description 14
- 229940125904 compound 1 Drugs 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-VVKOMZTBSA-N Dideuterium Chemical compound [2H][2H] UFHFLCQGNIYNRP-VVKOMZTBSA-N 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 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 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 229950011318 cannabidiol Drugs 0.000 description 2
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 2
- 229960004242 dronabinol Drugs 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/685—Processes comprising at least two steps in series
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/82—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by solid-liquid treatment; by chemisorption
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/88—Use of additives, e.g. for stabilisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- 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
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- 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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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/20—Purification, separation
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Abstract
公开了大麻素类化合物的纯化方法，采用该方法获得大麻素类化合物更经济，纯化效果更好。
Description
本申请涉及化合物纯化领域，具体涉及纯化大麻素化合物的方法。
大麻素类化合物在制药中具有巨大的应用价值，例如对Lennox-Gastaut综合征相关的癫痫、结节性硬化症相关的癫痫、自闭症、创伤后应激障碍、炎症性心脏病、创伤性脑损伤、结肠癌等适应症具有医疗效果或潜力。
合成和提取得到的大麻素含有多种杂质，通常采用色谱法分离纯化大麻素化合物。然而，色谱法在工业化中不仅需要使用大量溶剂，而且纯化效果也难以达到预期，极大限制了分离方法的规模和效率。此外，大多数大麻素类化合物不稳定，在室温条件下也容易发生重排及氧化，给大麻素类化合物的分离和储存带来困难，特别是应用最为广泛的大麻二酚(CBD)和四氢大麻酚(THC)。
目前亟需经济有效并且适用于大规模纯化大麻素类化合物的方法。
发明内容
本申请的目的在于提供纯化大麻素化合物的方法，与现有纯化方法相比，具有纯化效果好、适用于工业化生产的特点。
本申请的一个或多个实施方式提供了大麻素类化合物、其立体异构体或者其氘代物或盐的纯化方法，其包括：
其中
其中：
R
0为C
1-6烷基或C
1-6羟烷基；
R为H或C
1-12烷基；
R
1为H或-COOH；
R
2为H、-COOH或C1-6烷基；
R
3和R
3′各自独立地为OH或C
1-6烷氧基，且R
3和R
3′中至的少一个为C
1-6烷氧基；
R4为OH、C
1-6烷氧基、-COOH或-OCOC
1-6烷基；
G为硅基保护基；
R
3a和R
3b各自独立地为-OG或C
1-6烷氧基，且R
3a和R
3b中的至少一个为-OG；
n为1或2。
在一个或多个实施方式中，在所述第一步中加入三乙基氯硅烷。
在一个或多个实施方式中，在所述第二步中加入四正丁基氟化铵。
在一个或多个实施方式中，
其中：
R
0为甲基或-CH
2OH；
R为H或C
1-8烷基；
R
1为H或-COOH；
R
2为H；
R
3和R
3′各自独立地为OH或-OCH
3，且R
3和R
3′中的至少一个为OH；
G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基；
R
3a和R
3b各自独立地为-OG或-OCH
3，且R
3a和R
3b中的至少一个为-OG；
n为1或2。
在一个或多个实施方式中，
其中：
G为三乙基硅基或叔丁基二甲基硅基。
在一个或多个实施方式中，所述C
1-6烷基为甲基，所述C
1-6羟烷基为-CH2OH。
在一个或多个实施方式中，所述C
1-12烷基为戊烷基。
在一个或多个实施方式中，所述戊烷基为正戊烷基。
在一个或多个实施方式中，所述C
1-6烷氧基为-OCH
3。
在一个或多个实施方式中，所述硅基保护基为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基。
在一个或多个实施方式中，n为2。
本申请的一个或多个实施方式提供了具有以下结构的化合物：
其中
R
0为C
1-6烷基或C
1-6羟烷基；
R为H或C
1-12烷基；
R
1为H或-COOH；
R
2为H、-COOH或C
1-6烷基；
R
3和R
3′各自独立地为OH或
C1-6烷氧基，且R
3和R
3′中至的少一个为C
1-6烷氧基；
R
4为OH、C
1-6烷氧基、-COOH或-OCOC
1-6烷基；
G为硅基保护基；
R
3a和R
3b各自独立地为-OG或C
1-6烷氧基，且R
3a和R
3b中的至少一个为-OG。
在一个或多个实施方式中，所述C
1-6烷基为甲基，所述C
1-6羟烷基为-CH
2OH，所述C
1-12烷基为戊烷基，所述C
1-6烷氧基为-OCH
3，所述硅基保护基为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基。
在一个或多个实施方式中：
R
0为甲基或-CH
2OH；
R为H或C
1-8烷基；
R
1为H或-COOH；
R
2为H；
R
3和R
3′各自独立地为OH或-OCH
3，且R
3和R
3′中的至少一个为OH；
G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基；
R
3a和R
3b各自独立地为-OG或-OCH
3，且R
3a和R
3b中的至少一个为-OG。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢或氧均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢或氧任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括
12C、
13C和
14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括
16O、
17O和
18O。
“烷基”是指1至20个碳原子(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子)的直链或支链饱和脂肪族烃基，例如为1至8个碳原子的烷基，1至6个碳原子的烷基，1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。
“羟烷基”是指烷基至少被一个羟基取代。所述的烷基定义与上文所述的“烷基”定义相同。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
实施例1
(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)
(1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol
第一步：
(((1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二基)双(氧基))双(叔丁基二甲基硅烷)(1b)
(((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-bip-henyl]-2,6-diyl)bis(oxy))bis(tert-butyldimethylsilane)
将混有杂质的(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇1a(化合物1粗品)(0.1g)和咪唑(87mg,1.28mmol)溶于二氯甲烷(0.7ml)中，在0℃下加入叔丁基二甲基氯硅烷(TBDMSCl)(116mg,0.76mmol)，40℃下反应3小时。TLC监测反应完全，停止反应。将溶剂旋干，并用硅胶柱色谱分离提纯(二氯甲烷/正己烷(v/v)＝1/19)，得到标题化合物(((1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二基)双(氧基))双(叔丁基二甲基硅烷)1b(146mg，84％产率，淡黄色油状物)。
1H NMR(300MHz,Chloroform-d)δ6.19(s,2H),5.22(t,1H),4.45-4.52(m,2H),3.89–3.94(m,1H),3.02(td,1H),2.39–2.44(m,2H),1.94–2.14(m,2H),1.66–1.78(m,2H),1.44-1.61(m,8H),1.24-1.34(m,6H),0.84-1.05(s,21H),0.15-0.23(m,12H)。
LC-MS m/z(ESI)＝543.45[M+1]。
第二步
(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)
(1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol
将(((1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二基)双(氧基))双(叔丁基二甲基硅烷)1b(146mg，0.27mmol)溶解于二氯甲烷(1ml)，在0℃下加入四正丁基氟化铵的四氢呋喃溶液(0.54ml,0.54mmol)，0℃下反应30分钟。TLC监测反应完全，停止反应。将溶剂旋干，并用硅胶柱色谱分离提纯(乙酸乙酯/正己烷(v/v)＝2/8)，得到标题化合物(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)(80mg，95％产率，纯度>99％，白色固体)。
1H NMR(300MHz,DMSO-d
6)δ8.61(s,2H),5.99(s,2H),5.06(s,1H),4.38–4.47(m,2H),3.80(d,1H),2.96-3.04(m,1H),2.25–2.30(m,2H),1.86–2.07(m,2H),1.42–1.64(m, 10H),1.20–1.28(m,4H),0.83(t,3H)。
LC-MS m/z(ESI)＝315.47[M+1]。
实施例2
(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)
(1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
第一步
(((1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二基)双(氧基))双(三乙基硅烷)(1c)
(((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-bip-henyl]-2,6-diyl)bis(oxy))bis(triethylsilane)
将混有杂质的(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇1a(化合物1粗品)(0.26g)和咪唑(0.17g,2.5mmol)溶解于二氯甲烷(1.8ml)中，在0℃下加入三乙基氯硅烷(TESCl)(320mg,2.1mmol)，40℃下反应3小时。TLC监测反应完全，停止反应。将溶剂旋干，并用硅胶柱色谱分离提纯(二氯甲烷/正己烷(v/v)＝1/19)，得到标题化合物(((1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二基)双(氧基))双(三乙基硅烷)1c(433mg，99％产率，淡黄色油状物)。
1H NMR(300MHz,Chloroform-d)δ6.16(s,2H),5.19(s,1H),4.45–4.49(m,2H),3.85–3.89(m,1H),2.91-2.99(m,1H),2.42(t,2H),1.94–2.14(m,2H),1.48-1.79(m,12H),1.18-1.35(m,4H),0.69-0.99(m,33H)。
LC-MS m/z(ESI)＝543.45[M+1]。
第二步：
(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)
(1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol
将(((1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二基)双(氧基))双(三乙基硅烷)1c(433mg，0.8mmol)溶解于无水四氢呋喃(4ml)，在0℃下加入四正丁基氟化铵的四氢呋喃溶液(1.8ml,1.8mmol)，0℃下反应30分钟。TLC监测反应完全，停止反应。将溶剂旋干，并用硅胶柱色谱分离提纯(乙酸乙酯/正己烷(v/v)＝2/8)，得到标题化合物(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二醇(化合物1)(250mg，99％产率，纯度>99％，白色固体)。
1H NMR(300 MHz,DMSO-d
6)δ8.61(s,2H),5.99(s,2H),5.06(s,1H),4.38–4.47(m,2H),3.80(d,1H),2.96-3.04(m,1H),2.25–2.30(m,2H),1.86–2.07(m,2H),1.42–1.64(m,10H),1.20–1.28(m,4H),0.83(t,3H)。
LC-MS m/z(ESI)＝315.47[M+1]。
Claims (10)
- 大麻素类化合物、其立体异构体或者其氘代物或盐的纯化方法，其包括：
其中为：
为：
其中：为单键或双键；
R 0为C 1-6烷基或C 1-6羟烷基；R为H或C 1-12烷基；R 1为H或-COOH；R 2为H、-COOH或C 1-6烷基；R 3和R 3′各自独立地为OH或C 1-6烷氧基，且R 3和R 3′中至的少一个为C 1-6烷氧基；R 4为OH、C 1-6烷氧基、-COOH或-OCOC 1-6烷基；G为硅基保护基；R 3a和R 3b各自独立地为-OG或C 1-6烷氧基，且R 3a和R 3b中的至少一个为-OG；n为1或2。 - 如权利要求1所述的纯化方法，其中为：
为：
其中：为单键或双键；
R 0为甲基或-CH 2OH；R为H或C 1-8烷基；R 1为H或-COOH；R 2为H；R 3和R 3′各自独立地为OH或-OCH 3，且R 3和R 3′中的至少一个为OH；G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基；R 3a和R 3b各自独立地为-OG或-OCH 3，且R 3a和R 3b中的至少一个为-OG；n为1或2。 - 如权利要求1或2所述的纯化方法，其中
其中：G为三乙基硅基或叔丁基二甲基硅基。 - 如权利要求1所述的纯化方法，其中所述C 1-6烷基为甲基，所述C 1-6羟烷基为-CH 2OH。
- 如权利要求1所述的纯化方法，其中所述C 1-12烷基为戊烷基，优选地所述戊烷基为正戊烷基。
- 如权利要求1所述的纯化方法，其中所述C 1-6烷氧基为-OCH 3。
- 如权利要求1所述的纯化方法，其中所述硅基保护基为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基。
- 如权利要求1所述的纯化方法，其中n为2。
- 化合物，其具有以下结构：
其中为单键或双键；
R 0为C 1-6烷基或C 1-6羟烷基；R为H或C 1-12烷基；R 1为H或-COOH；R 2为H、-COOH或C 1-6烷基；R 3和R 3′各自独立地为OH或C 1-6烷氧基，且R 3和R 3′中至的少一个为C 1-6烷氧基；R 4为OH、C 1-6烷氧基、-COOH或-OCOC 1-6烷基；G为硅基保护基；R 3a和R 3b各自独立地为-OG或C 1-6烷氧基，且R 3a和R 3b中的至少一个为-OG；优选地，所述C 1-6烷基为甲基，所述C 1-6羟烷基为-CH 2OH，所述C 1-12烷基为戊烷基，所述C 1-6烷氧基为-OCH 3，所述硅基保护基为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁 基二甲基硅基或叔丁基二苯基硅基。 - 如权利要求9所述的化合物，其中为单键或双键；
R 0为甲基或-CH 2OH；R为H或C 1-8烷基；R 1为H或-COOH；R 2为H；R 3和R 3′各自独立地为OH或-OCH 3，且R 3和R 3′中的至少一个为OH；G为三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基；R 3a和R 3b各自独立地为-OG或-OCH 3，且R 3a和R 3b中的至少一个为-OG。
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