CN112142556A - (1s,4r)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法 - Google Patents
(1s,4r)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法 Download PDFInfo
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- CN112142556A CN112142556A CN202011076960.8A CN202011076960A CN112142556A CN 112142556 A CN112142556 A CN 112142556A CN 202011076960 A CN202011076960 A CN 202011076960A CN 112142556 A CN112142556 A CN 112142556A
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- benzyl
- methyl
- methylvinyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- -1 1-methylvinyl Chemical group 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 24
- XMGQYMWWDOXHJM-JTQLQIEISA-N (+)-α-limonene Chemical compound CC(=C)[C@@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-JTQLQIEISA-N 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000005406 washing Methods 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 23
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 14
- MKPMHJQMNACGDI-VHSXEESVSA-N (1S,4R)-p-Mentha-2,8-dien-1-ol Chemical compound CC(=C)[C@@H]1CC[C@](C)(O)C=C1 MKPMHJQMNACGDI-VHSXEESVSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000013067 intermediate product Substances 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 7
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 claims description 4
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical group ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 4
- 229940073608 benzyl chloride Drugs 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 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 4
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 230000002083 iodinating effect Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000003379 elimination reaction Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 36
- 239000000243 solution Substances 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 13
- 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 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 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 11
- 229950011318 cannabidiol Drugs 0.000 description 11
- 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 11
- 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 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000007599 discharging Methods 0.000 description 7
- 229940087305 limonene Drugs 0.000 description 7
- 235000001510 limonene Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229930007453 limonene-1,2-epoxide Natural products 0.000 description 5
- CCEFMUBVSUDRLG-UHFFFAOYSA-N limonene-1,2-epoxide Chemical compound C1C(C(=C)C)CCC2(C)OC21 CCEFMUBVSUDRLG-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000008399 tap water Substances 0.000 description 5
- 235000020679 tap water Nutrition 0.000 description 5
- 239000004593 Epoxy Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 244000025254 Cannabis sativa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 150000002978 peroxides Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 229940099369 (+)- limonene Drugs 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000218236 Cannabis Species 0.000 description 1
- 235000008697 Cannabis sativa Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000223198 Humicola Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AKEKKCGPLHMFCI-UHFFFAOYSA-L potassium sodium hydrogen carbonate Chemical compound [Na+].[K+].OC([O-])=O.OC([O-])=O AKEKKCGPLHMFCI-UHFFFAOYSA-L 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- 150000003346 selenoethers Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
- C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
- C07C35/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings with unsaturation at least in the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/04—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides onto unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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Abstract
本发明公开一种(1S,4R)‑1‑甲基‑4‑(1‑甲基乙烯基)‑2‑环己烯‑1‑醇的制备方法,所述方法以D‑柠檬烯为原料经双键加成、羟基保护制备得到中间体化合物;再经消除反应并继续脱保护最终制备得到产物。所述方法两步连续反应,工艺路线短,副产物少,获得的产物手性选择性高,收率达70%以上,较目前已有工艺有较大提升。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法。
背景技术
大麻二酚(CBD)是植物大麻中的主要化学成分,是大麻中的非成瘾性成分,具有抗痉挛、抗焦虑、抗炎、止痛等药理作用,医用CBD用于治疗癫痫、帕金森等疾病,也可添加到食品、新型烟草等消费品。当前时点,伴随全球医用大麻合法化推进,CBD需求正快速增长,预计2022年全球CBD产值达220亿美元,相比2019年复合增速为57%。
目前工业生产CBD的方法主要是通过从天然植物大麻的花叶中提取,但该方法工业规模化生产的局限性较大,且提取得到的CBD中均有不同含量的THC,影响CBD的开发使用。因此,通过化学合成的方法获得CBD是提高CBD产量的必要途径。
(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇是合成CBD的重要原料,获得手性选择性好、纯度高、可工业化大量生产(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法是合成CBD的前提条件。
中国专利文献CN109734554A公开了一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法,所述方法制备工艺如下:
具体包括以柠檬烯为原料,以脂肪酶催化氧化制得1,2-环氧柠檬烯;1,2-环氧柠檬烯在硼氢化钠和二苯基二硒存在下开环形成柠檬烯硒化物;柠檬烯硒化物在氧化剂作用下形成硒氧化物然后发生消除反应制得产物。
美国专利文献US4433183A公开的一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇制备工艺路线如下:
非专利文献Tetrahedron Letters 54(2013)52–54公开的(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇制备工艺路线如下:
分析上述工艺路线可以发现,具有代表性的(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇合成工艺都是以柠檬烯为起始物料,经过环氧、开环、氧化、消除4个步骤反应最终获得产物,已经公开的合成反应类型基本大同小异。发明人对现有工艺进行分析及对部分工艺的重复实验中发现,现已报道的工艺存在如下缺陷:(1)已有的合成路线都需经过1,2-环氧柠檬烯,制备环氧柠檬烯需要使用到双氧水、间氯过氧苯甲酸等过氧化物,应用于工业化生产存在较大的安全隐患;(2)制备环氧化合物过程,由于原料中存在2个双键,副产物也较多,目前已明确的副产物包括但不限于等;(3)最后消除反应步骤一般需要高温高真空,反应条件较苛刻,不易达成;(4)传统工艺路线长、副反应多、产物手性选择性较低,普遍只有50-60%,产率相对较低,4步反应总收率仅有30-40%。
为了改善现有技术的缺陷,本发明提供一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备工艺,所述方法完全避免了环氧化物的制备,革除了过氧化物的使用,大大提高了实验的安全性。另外,革除了消除制备的工艺,避免了高温高真空蒸馏的弊端,缩短工艺路线短,副产物少,获得的产物选择性高,收率较现有技术有较大提升。
发明内容
本发明的一个目的是提供一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法,本发明另一个目的是提供一种合成(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇中间体及其制备方法。
第一方面,本发明提供一种合成(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇中间体,所述中间体为通式Ⅰ所示的化合物:
其中,X选自Cl、Br、I,Y选自苄基、TMS、TBDMS、乙酰基、苯甲酰基、对硝基苯甲酰基、对甲苯磺酰基。
第二方面,本发明提供一种合成(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇中间体的制备方法,所述方法包括如下步骤:
(1)将D-柠檬烯溶于有机溶剂,控制体系温度为-5~0℃,加入加成试剂卤素单质或卤代酰胺类试剂进行加成反应;
(2)反应结束后采用非质子类溶剂萃取,合并有机相后室温下加入羟基保护试剂反应3-4小时,洗涤、干燥后得到中间体产物。
所述步骤(1)中的卤素单质选自Br2、I2,卤代酰胺类试剂选自氯化试剂N-氯代丁二酰亚胺(NCS)、溴化试剂N-溴代丁二酰亚胺(NBS)、碘化试剂N-碘代丁二酰亚胺(NIS)。
所述有机溶剂选自四氢呋喃、乙腈、丙酮、二氧六环、甲醇、乙醇中的一种或两种以上的组合。
所述步骤(2)中的羟基保护试剂包括但不限于酰基试剂、硅醚保护基试剂、苄基试剂。优选的,所述酰基试剂选自苯甲酰氯、对硝基苯甲酰氯、乙酰氯、乙酸酐;硅醚保护基试剂选自TMSCl、TBDMSCl、TBDPSC、TMSOTf;苄基试剂选自苄氯、苄溴、对甲氧基苄溴。
所述非质子类溶剂选自二氯甲烷、氯仿、正己烷、环己烷、乙酸乙酯中的一种或两种以上的组合。
第三方面,本发明提供一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法,反应路线如下:
其中,X选自Cl、Br、I,Y选自苄基、TMS、TBDMS、苯甲酰基、对硝基苯甲酰基、对甲苯磺酰基、乙酰基。
所述制备方法包括如下步骤:
(1)将D-柠檬烯溶于有机溶剂,控制体系温度为-5~0℃,加入加成试剂卤素单质或卤代酰胺类试剂进行加成反应;
(2)反应结束后采用非质子类溶剂萃取,合并有机相后室温下加入羟基保护试剂反应3-4小时,洗涤、干燥后得到中间体产物;
(3)将中间体产物溶于醇溶剂中,加入当量弱碱回流反应2-3小时消除X取代基;
(4)待体系温度降至室温后进行羟基保护基脱保护反应,洗涤除去碱和盐类物质即得(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇。
所述步骤(1)中的卤素单质选自Br2、I2,卤代酰胺类试剂选自氯化试剂N-氯代丁二酰亚胺(NCS)、溴化试剂N-溴代丁二酰亚胺(NBS)、碘化试剂N-碘代丁二酰亚胺(NIS)。
所述有机溶剂选自四氢呋喃、乙腈、丙酮、二氧六环、甲醇、乙醇中的一种或两种以上的组合。
所述步骤(2)中的羟基保护试剂包括但不限于酰基试剂、硅醚保护基试剂、苄基试剂。优选的,所述酰基试剂选自苯甲酰氯、对硝基苯甲酰氯、乙酰氯、乙酸酐、;硅醚保护基试剂选自TMSCl、TBDMSCl、TBDPSC、TMSOTf;苄基试剂选自苄氯、苄溴、对甲氧基苄溴。
所述非质子类溶剂选自二氯甲烷、氯仿、正己烷、环己烷、乙酸乙酯中的一种或两种以上的组合。
所述步骤(3)中弱碱包括有机碱和无机碱,有机碱选自如三乙胺、乙二胺、二异丙基乙胺中的一种或两种以上的组合,无机碱选自醋酸钠、磷酸钠、碳酸钾碳酸钠中的一种或两种以上的组合。
步骤(4)所述的羟基保护基脱保护反应,本领域技术人员可根据有机合成基本知识依具体保护基采取不同措施。
本发明提供的(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇制备方法具有如下效果优势:(1)中间体的制备完全避免了环氧化物的制备,革除了过氧化物的使用,提高实验安全性;(2)中间体制备采用了连续反应法,中间态不经提纯,提高了收率并简化了处理流程;(3)消除与脱保护步骤目前无文献报道,本发明避免了高温高真空蒸馏的弊端;(4)本发明提供的制备方法可工业化大量生产(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇,改革了现有小规模实验室合成现状。
发明人将本发明制备的(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇与标准品通过第三方检测机构进行检测,结果如其他证明文件所示。标准品出峰时间在6.506min,本发明合成的产品在6.509min出现峰面积为92.47%的峰,说明本发明合成的产品纯度为92.47%。
附图说明
图1实施例3制备产物的H1核磁共振谱图
图2实施例4制备产物的H1核磁共振谱图
图3实施例5制备产物的H1核磁共振谱图
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明使用的化合物缩写
SM | D-柠檬烯 | NIS | N-碘代丁二酰亚胺 |
DCM | 二氯甲烷 | TBDMSCl | 叔丁基二甲基氯硅烷 |
NCS | N-氯代丁二酰亚胺 | TMSOTf | 三氟甲磺酸三甲基硅脂 |
NBS | N-溴代丁二酰亚胺 | TMSCl | 三甲基氯硅烷 |
TBDPSC | 叔丁基二苯基氯硅烷 |
实施例1中间体的制备
S1:在1000ml三口反应瓶中加入SM液体133g、四氢呋喃400ml、水100ml,搅拌混匀后体系开始制冷降温,待体系内温降低至-3℃时,控制反应温度在-3~0℃之间,分批加入NIS粉末固体290g,维持温度搅拌反应1个小时,TLC确认原料SM反应完毕。放料,减压浓缩除去四氢呋喃,残余物过滤,除去固体不溶物质。滤液补加自来水150ml,使用DCM搅拌萃取分液300ml*2次,合并有机相后用饱和食盐水洗涤50ml*1次,分液,有机相用无水硫酸钠20g搅拌干燥4小时,过滤收集滤液;
S2:滤液转回洗净干燥的1000ml三口反应瓶中,室温下加入三乙胺110g,搅拌下分批加入TBDMSCl固体170g,2小时加完并继续搅拌反应3小时,TLC监控反应完毕,放料,DCM溶液使用自来水洗涤150ml*2次,洗涤时体系中出现少量的絮状沉淀,使用硅藻土过滤除去,二氯甲烷溶液再用5%碳酸氢钠水溶液洗涤150ml*1次,饱和食盐水洗涤150ml*1次,分液后二氯甲烷溶液使用无水硫酸钠20g搅拌干燥4小时。过滤,用40ml二氯甲烷洗涤滤饼,合并滤液,减压蒸馏除去溶剂,得浅黄色半固体411g,即为中间体粗品,收率>100%,GC纯度90%。
实施例2(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备
取实施例1制备的中间体粗品400g加入2000ml三口反应瓶中,加入1200ml甲醇,搅拌混匀后加入结晶醋酸钠150g,搅拌混匀,体系呈混悬液状态,搅拌下回流反应2小时,TLC监控中间体已反应完毕,降低体系温度至室温,补加配置好的2N盐酸水溶液300ml,搅拌反应约3小时,TLC监控中间态消失为止。放料,用碳酸氢钠溶液调节Ph值为6~7,减压蒸馏除去溶剂甲醇,水相中有淡黄色油状物悬浮,用甲基叔丁基醚进行萃取120ml*3次,合并有机相,有机相用5%碳酸氢钠水溶液洗涤100ml*1次,饱和食盐水洗涤100ml*1次,分液有机相使用无水硫酸钠20g搅拌干燥4小时,过滤,用40ml甲基叔丁基醚洗涤滤饼,合并滤液,减压蒸馏除去溶剂,纯化得浅黄色油状物115.3g,GC纯度92%,手性纯度99.5%,整体收率75.8%。
实施例3中间体的制备
100L反应釜中加入SM液体15.0kg、四氢呋喃33.1kg、水10.5kg,搅拌混匀后开始制冷降温,待体系内温降低至-3℃时,控制反应温度在-3~0℃之间,分批加入NCS粉末固体18.7kg,维持温度,搅拌反应1个小时,TLC确认原料SM反应完毕。放料,减压浓缩除去四氢呋喃,残余物过滤除去固体不溶物质。滤液补加自来水15.0L,使用DCM搅拌萃取分液20.0L*2次,合并有机相,用饱和食盐水洗涤5.0L*1次,分液,有机相用无水硫酸钠800g搅拌干燥4小时,过滤收集滤液;
滤液转回洗净干燥的100L反应釜中,室温下加入TMSOTf液体245g,搅拌反应10min后,搅拌下滴加醋酸酐12.37kg,2小时滴加完毕并继续搅拌反应3小时,TLC监控反应完毕,放料,二氯甲烷溶液使用自来水洗涤10.0L*2次,洗涤时体系中出现少量的絮状沉淀,使用硅藻土过滤除去,二氯甲烷溶液再用5%碳酸氢钠水溶液洗涤5.0L*1次,饱和食盐水洗涤5.0L*1次,分液后二氯甲烷溶液使用无水硫酸钠2kg搅拌干燥4小时,过滤,使用4.0L二氯甲烷洗涤滤饼,合并滤液,减压蒸馏除去溶剂,得黄色油状物28.4kg,即为中间体粗品,收率>100%,GC纯度91%;
实施例4(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备
取实施例3制备的中间体粗品14.0kg加入100L玻璃反应釜中,加入56.0L甲醇,搅拌混匀后加入结晶醋酸钠8.2kg,搅拌混匀,体系呈混悬液状态,搅拌下回流反应2小时,TLC监控中间体已反应完毕。降低体系温度至35±3℃,补加配置好的50%氢氧化钠水溶液8.0kg,搅拌反应约3小时,TLC监控中间态消失为止。反应完毕后降至室温,放料,使用2N的稀盐酸调节体系pH值为7~8,减压蒸馏,除去溶剂甲醇,水相中有淡黄色油状物悬浮,用甲基叔丁基醚进行萃取10.0L*3次,萃取完毕后合并有机相。有机相用5%碳酸氢钠水溶液洗涤5.0L*1次,饱和食盐水洗涤5.0L*1次,分液有机相使用无水硫酸钠2kg搅拌干燥4小时,过滤,用4.0L甲基叔丁基醚洗涤滤饼,合并滤液,减压蒸馏除去溶剂,纯化得浅黄色油状物6430g,GC纯度92%,手性纯度99.5%,整体收率76.7%。
实施例5中间体的制备
200L搪玻璃反应釜中加入SM液体15.0kg、1,4-二氧六环40.0kg、水10.5kg,搅拌混匀后开始制冷降温,待体系内温降低至-3℃时,控制反应温度在-3~0℃之间,滴加溴素18.0kg(1.02eq),维持温度,搅拌反应1个小时,TLC确认原料SM反应完毕。加入10%亚硫酸钠水溶液20L,搅拌洗涤10分钟,溶液褪色,放料,减压浓缩除去二氧六环,使用环己烷搅拌萃取分液20.0L*3次,合并有机相,用5%碳酸氢钠水溶液洗涤5.0L*1次,再用饱和食盐水洗涤5.0L*1次,分液,有机相用无水硫酸钠2kg搅拌干燥4小时,过滤收集滤液;
滤液转回洗净干燥的200L反应釜中,室温下加入TMSOTf液体245g,搅拌反应10min后,搅拌下分批缓慢加入对硝基苯甲酰氯22.00kg(密闭加料),3小时加完毕并继续搅拌反应1小时,TLC监控反应完毕,放料,环己烷溶液使用自来水洗涤10.0L*2次,再用5%碳酸氢钠水溶液洗涤10.0L*1次,饱和食盐水洗涤10.0L*1次,分液后环己烷溶液使用无水硫酸钠2kg搅拌干燥4小时,过滤,使用4.0L环己烷洗涤滤饼,合并滤液,减压蒸馏除去溶剂,得浅黄色半固体状物44.4kg,即为中间体粗品,收率>100%,GC纯度90%;
实施例6(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备
取实施例5制备的中间体粗品44.4kg加入300L搪玻璃反应釜中,加入112.0L甲醇,搅拌混匀后加入乙二胺3.64kg,搅拌混匀,体系溶清,搅拌下回流反应2小时,体系逐渐有少量固体析出,TLC监控中间体已反应完毕。降低体系温度至40±3℃,加碳酸钾固体15.0kg,补水5.0L,搅拌反应约3小时,TLC监控中间态消失为止。反应完毕后降至室温,放料,过滤,除去不溶固体物质,再使用2N的稀盐酸调节体系pH值为7~8,减压蒸馏,除去溶剂甲醇,加水40L进行稀释,水相中有淡黄色油状物悬浮,用甲基叔丁基醚进行萃取20.0L*3次,萃取完毕后合并有机相。有机相用5%碳酸氢钠水溶液洗涤10.0L*1次,饱和食盐水洗涤10.0L*1次,分液有机相使用无水硫酸钠3kg搅拌干燥4小时,过滤,用6.0L甲基叔丁基醚洗涤滤饼,合并滤液,减压蒸馏除去溶剂,纯化得浅黄色油状物12.76kg,GC纯度92%,手性纯度99.6%,整体收率76.1%。
对比实施例1
参照CN109734554A制备(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇
S1:向(+)-柠檬烯133g、纯化水450ml和肉豆蔻酸22.8g的混合体系中加入Humicolasp脂肪酶5.3g,然后再在23℃下缓慢加入浓度为30%的双氧水122ml,控制加入时间为16小时,加完后继续反应2小时停止反应,加入浓度为16.7%的亚硫酸钠水溶液淬灭,用甲基叔丁基醚萃取、分液两次,合并所得有机相,依次用饱和碳酸氢钠水溶液和水洗,最后将水洗后的有机相减压蒸馏后得反式1,2-环氧柠檬烯80.1g(纯度89.2%,收率54%;顺式1,2-环氧柠檬烯含量2.7%);
S2:在氮气保护下,将二苯基二硒化物93.6g和850ml无水乙醇混合,温度降至8℃,分三次加入硼氢化钠26g,控制温度在8℃,继续搅拌1小时后将步骤S1制得的1,2-环氧柠檬烯滴入,滴完后升温至80℃回流反应4小时;停止反应,降温至6℃;
S3:向步骤S2的体系中加入无水四氢呋喃310ml,并继续上在上述温度下滴加30%双氧水70g,滴加完毕后升温至20℃,搅拌6小时;加水静置分液,水相用正己烷萃取,合并有机相并用10%碳酸钠水溶液、饱和食盐水洗后浓缩除去有机溶剂,向浓缩液中加入乙醇,再次浓缩,重复操作两次后降温至3℃,搅拌3小时,过滤得滤饼,将滤饼加入到660ml氯仿中,加热至62℃回流反应过夜后减压蒸馏(110~130℃),得产物51.1g(纯度97.5%,对映体过量ee=96.4%,非对映体过量de=81.3%)。
经计算,由化合物2(1,2-环氧柠檬烯)至化合物5(反式-薄荷基-2,8-二烯-1-醇)的反应总收率为60.2%。由原料1(柠檬烯)至化合物5(反式-薄荷基-2,8-二烯-1-醇)的总收率为32.5%。
将对比实施例1的合成结果与本发明实施例结果相对比可以发现:1,本发明提供的制备方法制备得到的(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇总收率均在75%以上,最高达到76.7%,而对比实施例1的总收率仅为32.5%;2,本发明实施例得到的产物手性纯度好,在99.5-99.6%之间,而对比实施例1产物ee=96.4%,说明其手性纯度只有98%左右;3,本发明提供的制备方法可进行放大生产,如实施例3-6所示,原料加入量都在15kg,而对比实施例1中合成中用到双氧水和酶等,此方法仅适用于实验室少量合成,若进入放大生产将困难重重。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
2.一种权利要求1所述的合成(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇中间体的制备方法,所述方法包括如下步骤:
(1)将D-柠檬烯溶于有机溶剂,控制体系温度为-5~0℃,加入加成试剂卤素单质或卤代酰胺类试剂进行加成反应;
(2)反应结束后采用非质子类溶剂萃取,合并有机相后室温下加入羟基保护试剂反应3-4小时,洗涤、干燥后得到中间体产物。
3.根据权利要求2所述的制备方法,其特征在于,所述步骤(1)中有机溶剂选自四氢呋喃、乙腈、丙酮、二氧六环、甲醇、乙醇中的一种或两种以上的组合。
4.根据权利要求2所述的制备方法,其特征在于,所述步骤(1)中的卤素单质选自Br2、I2,卤代酰胺类试剂选自氯化试剂N-氯代丁二酰亚胺(NCS)、溴化试剂N-溴代丁二酰亚胺(NBS)、碘化试剂N-碘代丁二酰亚胺(NIS)。
5.根据权利要求2所述的制备方法,其特征在于,所述步骤(2)中的羟基保护试剂包括但不限于酰基试剂、硅醚保护基试剂、苄基试剂。优选的,所述酰基试剂选自苯甲酰氯、对硝基苯甲酰氯、乙酰氯、乙酸酐;硅醚保护基试剂选自TMSCl、TBDMSCl、TBDPSC、TMSOTf;苄基试剂选自苄氯、苄溴、对甲氧基苄溴。
6.一种(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的制备方法,所述制备方法包括如下步骤:
(1)将D-柠檬烯溶于有机溶剂,控制体系温度为-5~0℃,加入加成试剂卤素单质或卤代酰胺类试剂进行加成反应;
(2)反应结束后采用非质子类溶剂萃取,合并有机相后室温下加入羟基保护试剂反应3-4小时,洗涤、干燥后得到中间体产物;
(3)将中间体产物溶于醇溶剂中,加入当量弱碱回流反应2-3小时消除X取代基;
(4)待体系温度降至室温后进行羟基保护基脱保护反应,洗涤除去碱和盐类物质即得(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇;
所述中间体结构式如下所示
其中,X选自Cl、Br、I,Y选自苄基、TMS、TBDMS、苯甲酰基、对硝基苯甲酰基、乙酰基、对甲苯磺酰基。
7.根据权利要求6所述的制备方法,其特征在于,所述步骤(1)中有机溶剂选自四氢呋喃、乙腈、丙酮、二氧六环、甲醇、乙醇中的一种或两种以上的组合。
8.根据权利要求6所述的制备方法,其特征在于,所述步骤(1)中的卤素单质选自Br2、I2,卤代酰胺类试剂选自氯化试剂N-氯代丁二酰亚胺(NCS)、溴化试剂N-溴代丁二酰亚胺(NBS)、碘化试剂N-碘代丁二酰亚胺(NIS)。
9.根据权利要求6所述的制备方法,其特征在于,所述步骤(2)中的羟基保护试剂包括但不限于酰基试剂、硅醚保护基试剂、苄基试剂。优选的,所述酰基试剂选自苯甲酰氯、对硝基苯甲酰氯乙酰氯、乙酸酐;硅醚保护基试剂选自TMSCl、TBDMSCl、TBDPSC、TMSOTf;苄基试剂选自苄氯、苄溴、对甲氧基苄溴;所述非质子类溶剂选自二氯甲烷、氯仿、正己烷、环己烷、乙酸乙酯中的一种或两种以上的组合。
10.根据权利要求6所述的制备方法,其特征在于,所述步骤(3)中弱碱包括有机碱和无机碱,有机碱选自如三乙胺、乙二胺、二异丙基乙胺中的一种或两种以上的组合,无机碱选自醋酸钠、磷酸钠、碳酸钾碳酸钠中的一种或两种以上的组合。
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