WO2021181420A1 - Process for the synthesis of cannabidiol and intermediates thereof - Google Patents
Process for the synthesis of cannabidiol and intermediates thereof Download PDFInfo
- Publication number
- WO2021181420A1 WO2021181420A1 PCT/IN2021/050242 IN2021050242W WO2021181420A1 WO 2021181420 A1 WO2021181420 A1 WO 2021181420A1 IN 2021050242 W IN2021050242 W IN 2021050242W WO 2021181420 A1 WO2021181420 A1 WO 2021181420A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- formula
- compound
- methyl
- aryl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 30
- 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 title claims abstract description 30
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 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 title abstract description 29
- 239000000543 intermediate Substances 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title description 19
- 238000003786 synthesis reaction Methods 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 238000002360 preparation method Methods 0.000 claims abstract description 49
- 238000005859 coupling reaction Methods 0.000 claims abstract description 23
- 230000008878 coupling Effects 0.000 claims abstract description 12
- 238000010168 coupling process Methods 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 86
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 239000011541 reaction mixture Substances 0.000 claims description 40
- -1 cannabidiol compound Chemical class 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 22
- 239000004305 biphenyl Substances 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- IULRDYBWNXHIMR-UHFFFAOYSA-N CC1(C(CC(CC1)C(=C)C)[Se]C1=CC=CC=C1)O Chemical compound CC1(C(CC(CC1)C(=C)C)[Se]C1=CC=CC=C1)O IULRDYBWNXHIMR-UHFFFAOYSA-N 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 238000007306 functionalization reaction Methods 0.000 claims description 17
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012363 selectfluor Substances 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 230000008030 elimination Effects 0.000 claims description 13
- 238000003379 elimination reaction Methods 0.000 claims description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 11
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 11
- 235000010290 biphenyl Nutrition 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- CBDBKVCXIINDGL-UHFFFAOYSA-N 1-methyl-2-phenylselanyl-4-propan-2-ylcyclohexan-1-ol Chemical compound C1C(C(C)C)CCC(C)(O)C1[Se]C1=CC=CC=C1 CBDBKVCXIINDGL-UHFFFAOYSA-N 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- MKPMHJQMNACGDI-UHFFFAOYSA-N 1-methyl-4-prop-1-en-2-ylcyclohex-2-en-1-ol Chemical compound CC(=C)C1CCC(C)(O)C=C1 MKPMHJQMNACGDI-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- LCEFEIBEOBPPSJ-UHFFFAOYSA-N phenyl selenohypobromite Chemical compound Br[Se]C1=CC=CC=C1 LCEFEIBEOBPPSJ-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- XZYAJJRPTOHPEO-UHFFFAOYSA-N FC(C(=O)OC(C)(C)C1C=CC(CC1)(C)O)(F)F Chemical compound FC(C(=O)OC(C)(C)C1C=CC(CC1)(C)O)(F)F XZYAJJRPTOHPEO-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 230000001172 regenerating effect Effects 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- IZXYHAXVIZHGJV-UHFFFAOYSA-N 2-p-Menthen-1-ol Chemical compound CC(C)C1CCC(C)(O)C=C1 IZXYHAXVIZHGJV-UHFFFAOYSA-N 0.000 claims description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 6
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229920001429 chelating resin Polymers 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- YZCTXAASHZYYGI-UHFFFAOYSA-N OC(C)(C)C1CC(C(CC1)(O)C)[Se]C1=CC=CC=C1 Chemical compound OC(C)(C)C1CC(C(CC1)(O)C)[Se]C1=CC=CC=C1 YZCTXAASHZYYGI-UHFFFAOYSA-N 0.000 claims description 5
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 5
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- ASAXRKSDVDALDT-UHFFFAOYSA-N propan-2-yl 2,2,2-trifluoroacetate Chemical compound CC(C)OC(=O)C(F)(F)F ASAXRKSDVDALDT-UHFFFAOYSA-N 0.000 claims description 5
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 5
- 229910004749 OS(O)2 Inorganic materials 0.000 claims description 4
- BPVYMDMPLCOQPJ-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)mercury Chemical compound [Hg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BPVYMDMPLCOQPJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 claims description 4
- WJCXADMLESSGRI-UHFFFAOYSA-N phenyl selenohypochlorite Chemical compound Cl[Se]C1=CC=CC=C1 WJCXADMLESSGRI-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 239000010457 zeolite Substances 0.000 claims description 4
- 241000269350 Anura Species 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000003957 anion exchange resin Substances 0.000 claims description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical class C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003729 cation exchange resin Substances 0.000 claims description 3
- 150000001768 cations Chemical group 0.000 claims description 3
- 229910001919 chlorite Inorganic materials 0.000 claims description 3
- 229910052619 chlorite group Inorganic materials 0.000 claims description 3
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052900 illite Inorganic materials 0.000 claims description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052622 kaolinite Inorganic materials 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- MCVFFRWZNYZUIJ-UHFFFAOYSA-M lithium;trifluoromethanesulfonate Chemical compound [Li+].[O-]S(=O)(=O)C(F)(F)F MCVFFRWZNYZUIJ-UHFFFAOYSA-M 0.000 claims description 3
- 229910003455 mixed metal oxide Inorganic materials 0.000 claims description 3
- 229910052674 natrolite Inorganic materials 0.000 claims description 3
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 3
- ZKATWMILCYLAPD-UHFFFAOYSA-N niobium pentoxide Inorganic materials O=[Nb](=O)O[Nb](=O)=O ZKATWMILCYLAPD-UHFFFAOYSA-N 0.000 claims description 3
- VGIBGUSAECPPNB-UHFFFAOYSA-L nonaaluminum;magnesium;tripotassium;1,3-dioxido-2,4,5-trioxa-1,3-disilabicyclo[1.1.1]pentane;iron(2+);oxygen(2-);fluoride;hydroxide Chemical compound [OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[F-].[Mg+2].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[K+].[K+].[K+].[Fe+2].O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2 VGIBGUSAECPPNB-UHFFFAOYSA-L 0.000 claims description 3
- 229910000273 nontronite Inorganic materials 0.000 claims description 3
- 230000000737 periodic effect Effects 0.000 claims description 3
- 150000003003 phosphines Chemical class 0.000 claims description 3
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 229910052903 pyrophyllite Inorganic materials 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 229910000275 saponite Inorganic materials 0.000 claims description 3
- 229910000276 sauconite Inorganic materials 0.000 claims description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 150000008648 triflates Chemical class 0.000 claims description 3
- 229910052902 vermiculite Inorganic materials 0.000 claims description 3
- 239000010455 vermiculite Substances 0.000 claims description 3
- 235000019354 vermiculite Nutrition 0.000 claims description 3
- LEHFSLREWWMLPU-UHFFFAOYSA-B zirconium(4+);tetraphosphate Chemical class [Zr+4].[Zr+4].[Zr+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LEHFSLREWWMLPU-UHFFFAOYSA-B 0.000 claims description 3
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 claims description 2
- MFQRWZGVUIOPHH-UHFFFAOYSA-N FC(C(=O)OC(C)(C)C1CC(C(CC1)(C)O)[Se]C1=CC=CC=C1)(F)F Chemical compound FC(C(=O)OC(C)(C)C1CC(C(CC1)(C)O)[Se]C1=CC=CC=C1)(F)F MFQRWZGVUIOPHH-UHFFFAOYSA-N 0.000 claims description 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 description 2
- 229910052901 montmorillonite Inorganic materials 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 43
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- IRMPFYJSHJGOPE-UHFFFAOYSA-N Olivetol Natural products CCCCCC1=CC(O)=CC(O)=C1 IRMPFYJSHJGOPE-UHFFFAOYSA-N 0.000 description 25
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 239000013058 crude material Substances 0.000 description 17
- 239000003480 eluent Substances 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- 229910001868 water Inorganic materials 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 0 CC(*)C(C)C1CC(*c2ccccc2)C(*)CC1 Chemical compound CC(*)C(C)C1CC(*c2ccccc2)C(*)CC1 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- XMGQYMWWDOXHJM-JTQLQIEISA-N D-limonene Natural products CC(=C)[C@@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-JTQLQIEISA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- XMGQYMWWDOXHJM-SNVBAGLBSA-N (-)-α-limonene Chemical compound CC(=C)[C@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-SNVBAGLBSA-N 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- 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 7
- OKKJLVBELUTLKV-MZCSYVLQSA-N deuterated methanol Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 7
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 6
- 229960004242 dronabinol Drugs 0.000 description 6
- 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 description 5
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 240000004308 marijuana Species 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- MKPMHJQMNACGDI-ZJUUUORDSA-N (1r,4s)-1-methyl-4-prop-1-en-2-ylcyclohex-2-en-1-ol Chemical compound CC(=C)[C@H]1CC[C@@](C)(O)C=C1 MKPMHJQMNACGDI-ZJUUUORDSA-N 0.000 description 4
- UIMAEYMKYMNCGW-UHFFFAOYSA-N (R)-p-Mentha-1,8-dien-10-ol Chemical compound CC1=CCC(C(=C)CO)CC1 UIMAEYMKYMNCGW-UHFFFAOYSA-N 0.000 description 4
- 101150041968 CDC13 gene Proteins 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000000707 stereoselective effect Effects 0.000 description 4
- 229940099369 (+)- limonene Drugs 0.000 description 3
- 229960003595 (-)- limonene Drugs 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 229930003827 cannabinoid Natural products 0.000 description 3
- 239000003557 cannabinoid Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 150000002627 limonene derivatives Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- WUOACPNHFRMFPN-SECBINFHSA-N (S)-(-)-alpha-terpineol Chemical compound CC1=CC[C@@H](C(C)(C)O)CC1 WUOACPNHFRMFPN-SECBINFHSA-N 0.000 description 2
- FAMJUFMHYAFYNU-UHFFFAOYSA-N 1-methyl-4-(propan-2-yl)cyclohex-1-ene Chemical compound CC(C)C1CCC(C)=CC1 FAMJUFMHYAFYNU-UHFFFAOYSA-N 0.000 description 2
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- UWNRDSGNBZDZAQ-UHFFFAOYSA-N 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate Chemical compound CC1=CCC(C(C)(C)OC(=O)C(F)(F)F)CC1 UWNRDSGNBZDZAQ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- 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
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/14—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by addition reactions, i.e. reactions involving at least one carbon-to-carbon unsaturated bond
-
- 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
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- C07C37/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by exchange of hydrocarbon groups, which may be substituted, from the same of other compounds, e.g. transalkylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
- C07C391/02—Compounds containing selenium having selenium atoms bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention relates to process for the preparation of cannabidiol of formula (A) involving the coupling of compound of formula (D) and compound of formula (E) through the intermediates of formula (C) and formula (D) starting from compound of formula (B).
- the invention further relates to the novel compounds of formulae (B), (C), (D) and (E) and reagents used in this process. More specifically, this invention provides the process for the preparation of cannabidiol of formula (A) in milligram to gram or kilogram scale.
- Cannabis has been associated with Indian culture and medicine since ancient time; however, due to its abuse as psycho-active substance, it has been banned worldwide for decades and put under narcotic list in India also (J.Gould, Nature, 525, (2015), 52- 53; M.Grayson, Nature outlook, 525, Issue no. 7570). Cannabis is well known for the occurrence of a unique class of terpenophenolic compounds named as phytocannabinoids. About 104 phytocannabinoids have been isolated from the plant till date (R.Mechaulam et.al., Chemical Reviews, 1976,76 ); (L.O.Hanus et.al., Nat. Prod.
- CBD and THC are found throughout the seeds, stalk and flowers of cannabis plants, including hemp and marijuana varieties of cannabis.
- phytocannabinoids particularly ⁇ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) isolated from cannabis sp.
- THC phytocannabinoids
- CBD cannabidiol
- CBD is totally devoid of psycho-active properties (T.A.Iseger and M.G. Bossong, Schizophrenia Research 162, 153-161, 2015).
- four drugs namely Nabiximols, Dronabinol, Nabilone and Cannabidiol has been approved by regulatory bodies; and many others, such as Ajulemic acid and Dexanabinol are under process of regulatory approval.
- Cannabidiol being non-psychotic is the first choice among academic and industrial researchers throughout the world (Hawkes 2018). In most of the CBD preparation available around the globe, isolation from a natural source is the best choice.
- the low selectivity, cost, multi-steps, poor yields of previous methods demonstrates the manufacturing of cannabinoid compounds difficult.
- the cause of difficulties also includes the chromatographic purification and instability of cannabidiol, which leads to the formation of other related unwanted phytocannabinoids and their derivatives.
- the present invention relates to the process for the stereoselective preparation of cannabidiol and its related compounds starting from inexpensive starting material limonene and related compounds via three steps sequence difunctionalization, elimination and condensation.
- the main objective of the present invention is to provide a stereoselective route for the production of (+) or (-) cannabidiol and related compounds thereof.
- the (+) or (-) cannabidiol and related compounds thereof can be prepared via three steps sequences di-functionalization of (+) or (-) limonene or limonene derivative thereof, elimination to (+) or (-) menthadienol or derivatives thereof, and metal triflate or acid or hetero-acids catalyzed condensation of (+) or (-) menthadienol or menthadienol derivatives with olivetol or olivetol derivativesthereof.
- Scheme 1 General scheme for the preparation of cannabidiol and related compounds wherein R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; Ri , R 2, R 3 and R 4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl; X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl; Y is independently selected from S, SO, Se, SeO, Cl, Br, I, /V-di alkyl, /V-aryl, or /V-heteroaryl; R 5 , R 6 , R 7 , R 8 , R 9 are independently selected from H, halogen, -CN, -NO 2 , -OH, alkyl, - O-alkyl, -COOH, -C(O),
- alkyl refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents.
- Preferred alkyl groups 1 to 6 carbon atoms include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
- aryl refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents.
- Preferred aryl groups include, without limitation, phenyl, naphthyl, indanyl, biphenyl, and the like.
- arylalkyl refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents and have 7 to 15 carbon atoms.
- Preferred arylalkyl groups include, without limitation, -CH 2 C 6 H 5 , - C2H4C6H5, and the like.
- arylalkyl and aralkyl may be used interchangeably.
- heterocyclyl refers to a heterocyclic ring radical which may be optionally substituted by one or more substituents.
- the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
- heterocyclyl refers to a stable 3 to 15 membered rings radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
- the heterocyclic ring radical may be monocyclic, bicyclic or tricyclic ring systems, and the nitrogen, phosphorus, carbon, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
- heteroaryl refers to an aromatic heterocyclic ring radical as defined above.
- the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.
- fused heterocyclyl refers to monocyclic or polycyclic ring
- polycyclic ring system refers to a ring system containing 2 or more rings, preferably bicyclic or tricyclic rings, in which rings can be fused, bridged or spiro rings or any combinations thereof.
- a fused ring as used herein means that the two rings are linked to each other through two adjacent ring atoms common to both rings.
- the fused ring can contain 1-4 hetero atoms independently selected from N, O, and S.
- the rings can be either fused by nitrogen or -CH- group.
- cycloalkyl refers to non-aromatic mono or polycyclic ring system of about 3 to 7 carbon atoms, which may be optionally substituted by one or more substituents.
- the polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures.
- Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched chain having about 2 to 6 carbon atoms, which may be optionally substituted by one or more substituents.
- Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl- 1 -propenyl, 1-butenyl, 2-butenyl and the like.
- alkynyl refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-6 carbon atoms, which may be optionally substituted by one or more substituents.
- Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.
- R group of the acyl includes but not limited to alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, arylalkyl, heteroaryl, heterocyclyl and the like.
- R group includes but not limited to alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, arylalkyl, heteroaryl, heterocyclyl and the like.
- Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
- a temperature in the range of -40 °C to 60 °C should be interpreted to include not only the explicitly recited limits of -40°C to 60 °C but also to include sub-ranges, such as -30 °C to 50 °C, -10°C to 40°C, 0°C to 35 °C and so forth, as well as individual amounts, within the specified ranges, such as 19.6 °C, and 27.3 °C.
- R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl
- Ri , R2 , R3 and R4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl
- X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl
- Y is independently selected from S, SO, Se, SeO, Cl, Br, I, /V-di alkyl, A-aryl, or A-heteroaryl
- R5 , R 6 , R7 , Rs , R9 are independently selected from H, halogen, -CN, -NO 2 , -OH, alkyl, -O-alkyl, -CO
- metal triflates selected from AgOTf, Ni(OTf) 2 ,
- the coupling reaction is carried out in the presence of a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, preferably dichloroethane; and the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 0.1 to 48 hours at a temperatyure in the range of -40° C to 60° C.
- a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, Hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like, preferably dichloroethane.
- a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein wherein the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 0.1 to 48 hours.
- the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 1 to about 3 hours, or about 6 to about 48 hours, or about 12 to about 24 hours, or about 14 to about 18 hours, preferably for 5 - 10 h.
- a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein wherein the coupling reaction is carried out at a temperature in the range of -40° C to 60° C.
- a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein wherein the coupling reaction is carried out at a temperature in the range of -40°C. to 40° C, or -35° C. to -25° C, or -0° C to 50° C, preferably at 10 °C to 35 °C.
- a process for the preparation of compound of formula (D) from compound of formula (C) comprisng the steps of: regenerating of double bond by elimination of group (Y) of compound formula (C) and conversion to compound formula (D) in the presence of oxidants selected from mCPBA, Oxone, DDQ, CAN, /V-hydroxy succinamide, /-Butyl hydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF 4 , PyF-OTf, TMPyF- OTf, or PIFA, preferably Selectfluor, and Hydrogen peroxide.
- oxidants selected from mCPBA, Oxone, DDQ, CAN, /V-hydroxy succinamide, /-Butyl hydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF 4 , PyF-OTf, TMPyF- OTf, or PIFA, preferably
- a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein wherein elimination is carried out in the presence of a solvent or a mixture of solvents, selected from H2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroe thane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like.
- a solvent or a mixture of solvents selected from H2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroe thane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like.
- a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein wherein regenerating of double bond by elimination is carried out by stirring the reaction mixture for a time period in the range of 0.1 to 48 hours.
- a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein wherein regenerating of double bond by elimination is carried out by stirring the reaction mixture for a time period in the range of 1 to 3 hours, or 6 to 48 hours, or 12 to 24 hours, or 14 to 18 hours.
- a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein wherein regenerating of double bond by elimination is carried out at a temperature in the range of -40° C to 60° C.
- a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein wherein regenerating of double bond by elimination is carried out at a temperature in the range of -40°C to 40° C, or - 35° C. to -25° C, or -0° C to 5, preferably at -10 °C to 35 °C.
- process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein wherein the bi-functionalization is carried out in the presence of a solvent or a mixture of solvents, selected from H2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like.
- a solvent or a mixture of solvents selected from H2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like.
- process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein wherein the bi-functionalization is carried out by stirring the reaction mixture for a time period in the range of 0.1 h - 48 h.
- process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein wherein the bi-functionalization is carried out by stirring the reaction mixture for a time period in the range of 1 to 3 hours, or 6 to 48 hours, or 12 to 24 hours, or 14 to 18 hours, preferably 12 - 24 h.
- Step 1 Bi-functionalization of (+) or (-) limonene or limonene derivatives.
- Examplel To a stirred solution of (R)-(+)-limonene (Bl) (1.2g, 7.0 mmol) in ACNiPhO (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (lg, 4.5 mmol) in ACN and allowed to stir at the same temperature. After the initiation of reaction, hydrogen peroxide (2.1 mmol) as an activator was addedto the reaction mixture The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times).
- Example20 To a stirred solution of (S)-(-)-limonene(B2) (544 mg, 4.0 mmol) in ACN:H 2 0 (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na 2 S0 4 and concentrated in vaccum.
- Example 22 To a stirred solution of (+) a-terpineol (B3) (616mg, 4.0 mmol) in ACN:H 2 O (98:2, 6ml) at -30 to -35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na 2 SO 4 and concentrated in vaccum.
- B3 (+) a-terpineol (B3) (616mg, 4.0 mmol) in ACN:H 2 O (98:2, 6ml) at -30 to -35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the
- Example25 To a stirred solution of 2-(4-methylcyclohex-3-en-l-yl)propan-2- yl 2,2,2-trifluoroacetate (B4) ( lg, 4.0 mmol) in ACNithO (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times).
- Example 27 To a stirred solution of (+)-4-isopropyl-l-methylcyclohex-l-ene (B5) ( 552 mg, 4.0 mmol) in ACN:H 2 0 (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na 2 S0 4 and concentrated in vaccum.
- STEP 2 Regeneration of the double bond by elimination (C-D).
- Example29 The solution of (+)-l-methyl-2-(phenylselenyl)-4-(prop-l-en-2- yl)cyclohexan-l-ol (Cl) (155 mg, 0.5 mmol) in THF (5ml) was allowed to stir for 10 min. Then, Selectfluor (531 mg, 1.5 mmol) was added to the reaction. The reaction mixture was stirred for 9- 10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate.
- Example37 The solution of (-)-l-methyl-2-(phenylselenyl)-4-(prop-l-en-2- yl)cyclohexan-l-ol (C2) (155 mg, 0.5 mmol) in THF (5mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9- 10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate.
- Example 38 The solution of (+)-2-(4-hydroxy-4-methyl-3-
- Example 40 The solution of (+)-4-isopropyl-l-methyl-2- (phenylselanyl)cyclohexan-l-ol (C4) (156 mg, 0.5 mmol) in THF (5mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate.
- STEP 3 Condensation of olivetol or derivatives with menthadienol or derivatives to prepare cannabidiol or derivatives.
- Example 43 To a solution of Silver bis(trifluoromethanesulfonyl)imide (AgNTf 2 )(20 mol%) in anhydrous DCE was added (+)-l-methyl-4-(prop-l-en-2- yl)cyclohex-2-en- 1 -ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (El) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- Example 44 To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol(Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (El) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- Example 52 To a solution of silver triflate (20 mol%) in anhydrous DCE was added (-)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol(D2) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- Example 54 To a solution of silver triflate (20 mol%) in anhydrous DCE was added 2-(4-hydroxy-4-methylcyclohex-2-en- 1 -yl)propan-2-yl 2,2,2-trifluoroacetate (D3) (133 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (180 mg, 1 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- D3 2-(4-hydroxy-4-methylcyclohex-2-en- 1 -yl)propan-2-yl 2,2,2-trifluoroacetate
- Example 56 To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) 4-isopropyl- l-methylcyclohex-2-en-l-ol(D4) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (El) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- Example58 To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, 5-propoxybenzene-l,3-diol (E2) (100 mg, 0.6 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- Example 59- To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, 5-(dodecyloxy)benzene-l,3-diol(E3)(118mg,0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- Example 60 To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, Orcinol(E4) (50 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc.
- the present invention deals with a novel process development for the production of a (+) or (-) Cannabidiol and related compounds thereof.
- the (+) or (-) cannabidiol and related compounds thereof can be prepared via three steps sequence bi-functionalization of (+) or (-) limonene or limonene derivative thereof, elimination to (+) or (-) menthadienol or derivatives thereof, and metal triflate or acid or heteroacid catalyzed condensation of (+) or (-) menthadienol or menthadienol derivatives with olivetol or olivetol derivatives thereof.
- the processes of the present disclosure provide a number of advantages over current methods.
- the main advantage of the present disclosure are i) inexpensive and commercially available starting materials, ii) accessibility of the (+) or (-) cannabidiol or derivatives, iii) high selectivity in condensation reaction, and iv) high overall yield.
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Abstract
The present invention relates to process for the preparation of cannabidiol (A) from the coupling of (D) and (E) through the intermediates (C) and (D) starting from compound (B). The invention further relates to the novel compounds (B), (C), (D) and (E) and reagents used in this process. More specifically, this invention provides the manufacturing of Cannabidiol (A) in milligram to gram or kilogram scale.
Description
PROCESS FOR THE SYNTHESIS OF CANNABIDIOL AND INTERMEDIATES THEREOF
FIELD OF INVENTION
[0001] The present invention relates to process for the preparation of cannabidiol of formula (A) involving the coupling of compound of formula (D) and compound of formula (E) through the intermediates of formula (C) and formula (D) starting from compound of formula (B). The invention further relates to the novel compounds of formulae (B), (C), (D) and (E) and reagents used in this process. More specifically, this invention provides the process for the preparation of cannabidiol of formula (A) in milligram to gram or kilogram scale.
BACKGROUND OF THE INVENTION:
[0002] Cannabis has been associated with Indian culture and medicine since ancient time; however, due to its abuse as psycho-active substance, it has been banned worldwide for decades and put under narcotic list in India also (J.Gould, Nature, 525, (2015), 52- 53; M.Grayson, Nature outlook, 525, Issue no. 7570). Cannabis is well known for the occurrence of a unique class of terpenophenolic compounds named as phytocannabinoids. About 104 phytocannabinoids have been isolated from the plant till date (R.Mechaulam et.al., Chemical Reviews, 1976,76 ); (L.O.Hanus et.al., Nat. Prod. Rep., 2016, 33, 1357);(J.P.Marcu, An Overview of Major and Minor
Phytocannabinoids Chapter 62, 672- 678). However, the major ones, as well as most studied and medicinally useful are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD and THC are found throughout the seeds, stalk and flowers of cannabis plants, including hemp and marijuana varieties of cannabis. Scientific discoveries have confirmed that phytocannabinoids particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) isolated from cannabis sp., have several therapeutic indications (pain management including rheumatic, reduce nausea and vomiting, suppress seizure activity, combat anxiety, depression, psychosis disorders, anti-inflammatory properties, anti-tumoral properties and antioxidant properties that could fight neurodegenerative disorders) apart from psychoactive properties which come from THC (R.Hosking and J.Zajicek J. Nat .Rev. Neurol. 8 July 2014; M.E. Gerich et al.,Am J Gastroenterol, 9 September 2014; Joseph Maroon 2018), however on the other hand, CBD is totally devoid of psycho-active properties (T.A.Iseger and M.G. Bossong, Schizophrenia Research 162, 153-161, 2015). In last decades, four drugs namely Nabiximols, Dronabinol, Nabilone and Cannabidiol has been approved by regulatory bodies; and many others, such as Ajulemic acid and Dexanabinol are under process of regulatory approval. Cannabidiol being non-psychotic is the first choice among academic and industrial researchers throughout the world (Hawkes 2018). In most of the CBD preparation available around the globe, isolation from a natural source is the best choice. However, its occurrence is highly varied among the accession and is influenced by number of factors. Considering the importance of cannabidiol, a synthetic approach could be a better opportunity, and number of researchers has developed many synthetic strategies. In this direction, the first total synthesis is developed by Mechoulam, and Gaoni (J Am Chem Soc 1965, 87, 3237-5) which involves the addition of 1,3 -dime thoxy-olivetol to geranial followed by cyclization and demethylation leads to the formation of (±)-cannabidiol. In nature, cannabidiol is present as (-)-enantiomers and therefore stereo-selective route for its synthesis is required. To develop an stereo-selective approach, coupling of chiral terpenes were used as coupling partner and coupled with resorcinol derivative in the presence of
number of Lewis-acids [Lukas Dialer et al., (US20170008868A1); Hong Gu et al., (US2006/0194761A1); Gutman, Arie et al., (WO 2006053766A1); Reekie, Tristan et al., (WO2019/033164A1); Bencivenga, Marc et al., (WO2019/046806); Burdick, DavidC et al., (EP2578561); Seung-Hwa Baek et al., Tetrahedron letters, 26, 1985, 1083-1086). These methods lead to the formation of cannabidiol with natural configuration but other phytocannabinoids were also being formed by either cyclization of products or coupling form other position.
[0003] In other attempts, the issue of selectivity was addressed by using substituted coupling partners. D. Burdick et al., (W02007041167 A3) and D. Daniel et al., (US2017/0349518) coupled 6-carbethoxyolivetol withmenthadienol in the presence of dimethylformamide anddineopentylacetal as a catalyst with improved selectivity with a yield of 42% of cannabidiol-carboxylic acid ethyl ester. In another route, Crombie et. al., (chemischer Informationsdienst 1977, 8, No. 38, Abstract 361) coupled olivetol carboxylic ester with unsaturated hydrocarbons, alcohols, ketones, or derivatives thereof which gave corresponding carboxylic acid ester of cannabinoids, which in final step underwent decarboxylation to furnish ester-free cannabinoids (J. Chem. Researchll4, 1301-1345 1977). In another approach, Burdick, David C et al., (EP2578561A1) describes the synthesis of CBD from (+)-limonene oxide and dihalo- olivetol via the four-step sequences, epoxide opening and elimination of dimethylamino to menthadienol, condensation with olivetol derivative by using protic acid or Lewis acid, and reductive dehalogenation.
[0004] The low selectivity, cost, multi-steps, poor yields of previous methods demonstrates the manufacturing of cannabinoid compounds difficult. The cause of difficulties also includes the chromatographic purification and instability of cannabidiol, which leads to the formation of other related unwanted phytocannabinoids and their derivatives. The present invention relates to the process for the stereoselective preparation of cannabidiol and its related compounds starting from inexpensive starting material limonene and related compounds via three steps sequence difunctionalization, elimination and condensation.
OBJECTIVE OF THE INVENTION:
[0005] The main objective of the present invention is to provide a stereoselective route for the production of (+) or (-) cannabidiol and related compounds thereof. The (+) or (-) cannabidiol and related compounds thereof can be prepared via three steps sequences di-functionalization of (+) or (-) limonene or limonene derivative thereof, elimination to (+) or (-) menthadienol or derivatives thereof, and metal triflate or acid or hetero-acids catalyzed condensation of (+) or (-) menthadienol or menthadienol derivatives with olivetol or olivetol derivativesthereof.
SUMMARY OF THE INVENTION:
[0006] In an aspect of the present invention, there is provided a process for the preparation of cannabidiol of following formula (A) and intermediates thereof:
Scheme 1: General scheme for the preparation of cannabidiol and related compounds wherein R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; Ri, R2, R3 and R4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl; X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl; Y is independently selected from S, SO, Se, SeO, Cl, Br, I, /V-di alkyl, /V-aryl, or /V-heteroaryl;
R5, R6, R7, R8, R9 are independently selected from H, halogen, -CN, -NO2, -OH, alkyl, - O-alkyl, -COOH, -C(O), -C alkyl, -C(O)OC, S-alkyl, -SO-alkyl, -SO2-alkyl, S-aryl, - SO-aryl, -SO2-aryl, SO-heteroaryl, -SO2-N-aryl, -N-SO2-aryl NR'R", alkenyl, alkynyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the alkyl or aryl or heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, -O-alkyl, -COOH, -C(O), -C alkyl, - C(O)OC, alkyl, NR'R", and -(CH2)nNR'R"; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, acyl, acyloxy, aryl, arylalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Ql; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(N Ra) NRbRc, -ORa, -OC(O) Ra, -OC(O)ORa, OC(O)NRbRc, -OC(=N Ra)NRbRc, -OS(O) Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -N Ra C(O)Rd, -N Ra C(O)ORd, -N Ra (O)NRbRc, -NRaC(=NRd)NRbRc , -N Ra S(O)Rd, -N Ra S(O)2Rd, -N Ra S(O)NRbRc, -N Ra S(O)2NRbRc, -SRa, -S(O) Ra, -S(O)2Ra, - S(O)NRbRc, and -S(O)2NRbRc, or -(CH2)nNR'R"; wherein Ra, Rb, Rc, and Rdis independently selected from (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15arylalkyl, heteroaryl, or hterocyclyl, optionally substituted with one or more substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached from heterocyclyl, optionally substituted with one or more substituents Q1; wherein Q1 is independently selected from the group consisting of (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7- 15arylalkyl, heteroaryl, or heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, - C(N Re) NRfRg, -ORe, -OC(O) Re, -OC(O)ORe, OC(O)NRfRg, -OC(=N Re)NRfRg, - OS(O) Re, - OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -N Re C(O)Rh, -N Re C(O)ORh, -N Re (O)NRfRg, -NReC(=NRh)NRfRg, -N Re S(O)Rh, -N Re S(O)2Rh, -N Re
S(O)NRfRg, -N Re S(O)2NRfRg, -SRe, -S(O) Re, -S(O)2Re, -S(O)NRfRg, or - S(O)2NRfRg; wherein Re, Rf, Rg, and Rhis independently selected from (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15aryl al kyl , heteroaryl, or heterocyclyl; (iii) Rf and Rg together with the N atom to which they are attached from heterocyclyl; wherein each represents a single or double bond; provided that both - groups
are not double bonds, and wherein denoted, dash marks indicate the points of attachment; wherein,
represents a single bond, above the plane or below the plane or both above the plane or both below the plane or one is above the plane and one is below the plane.
[0007] These and other features, aspects, and advantages of the present subject matter will be better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.
DETAILED DESCRIPTION OF THE INVENTION:
[0008] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Definitions'.
[0009] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized
and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
[0010] The articles "a", "an" and "the" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
[0011] The terms "comprise" and "comprising" are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as "consists of only".
[0012] Throughout this specification, unless the context requires otherwise the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
[0013] The term “alkyl” refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents. Preferred alkyl groups 1 to 6 carbon atoms include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
[0014] The term “aryl” refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents. Preferred aryl groups include, without limitation, phenyl, naphthyl, indanyl, biphenyl, and the like.
[0015] The term “arylalkyl” refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents and have 7 to 15
carbon atoms. Preferred arylalkyl groups include, without limitation, -CH2C6H5, - C2H4C6H5, and the like. The terms arylalkyl and aralkyl may be used interchangeably.
[0016] The term “heterocyclyl” refers to a heterocyclic ring radical which may be optionally substituted by one or more substituents. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
[0017] Furthermore, the term “heterocyclyl” refers to a stable 3 to 15 membered rings radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be monocyclic, bicyclic or tricyclic ring systems, and the nitrogen, phosphorus, carbon, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
[0018] The term “heteroaryl” refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.
[0019] The term “fused heterocyclyl” refers to monocyclic or polycyclic ring, polycyclic ring system refers to a ring system containing 2 or more rings, preferably bicyclic or tricyclic rings, in which rings can be fused, bridged or spiro rings or any combinations thereof. A fused ring as used herein means that the two rings are linked to each other through two adjacent ring atoms common to both rings. The fused ring can contain 1-4 hetero atoms independently selected from N, O, and S. The rings can be either fused by nitrogen or -CH- group.
[0020] The term “cycloalkyl” refers to non-aromatic mono or polycyclic ring system of about 3 to 7 carbon atoms, which may be optionally substituted by one or more substituents. The polycyclic ring denotes hydrocarbon systems containing two or more
ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0021] The term “alkenyl” refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched chain having about 2 to 6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl- 1 -propenyl, 1-butenyl, 2-butenyl and the like.
[0022] The term “alkynyl” refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.
[0023] The term “acyl” refers to a group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids and it has a double -bonded oxygen atom and R group (R-C=0). R group of the acyl includes but not limited to alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, arylalkyl, heteroaryl, heterocyclyl and the like.
[0024] The term “acyloxy” refers to the acyl group bonded to oxygen: R-C(=0)-0- wherein R-C(=0) is the acyl group. R group includes but not limited to alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, arylalkyl, heteroaryl, heterocyclyl and the like.
[0025] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the
numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a temperature in the range of -40 °C to 60 °C should be interpreted to include not only the explicitly recited limits of -40°C to 60 °C but also to include sub-ranges, such as -30 °C to 50 °C, -10°C to 40°C, 0°C to 35 °C and so forth, as well as individual amounts, within the specified ranges, such as 19.6 °C, and 27.3 °C.
[0026] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally-equivalent products, compositions, and methods are clearly within the scope of the disclosure, as described herein.
[0027] In an embodiment of the present disclosure, there is provided a process for the preparation of the compound of Formula (A)
wherein R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; Ri, R2, R3 and R4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl; X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl; Y is independently selected from S, SO, Se, SeO, Cl, Br, I, /V-di alkyl, A-aryl, or A-heteroaryl; R5, R6, R7, Rs, R9 are independently selected from H, halogen, -CN, -NO2, -OH, alkyl, -O-alkyl, -COOH, -C(O), -C alkyl, -C(O)OC, S-alkyl,
1SO-alkyl, -SCh-alkyl, S-aryl, -SO-aryl, -SO2-aryl, SO-heteroaryl, -SC2-N-aryl, -N- SO2-aryl NR'R", alkenyl, alkynyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the alkyl, aryl or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, -O-alkyl, -COOH, -C(O), -C alkyl, -C(O)OC, alkyl, NR'R", and -(CH2)nNR'R"; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, acyl, acyloxy, aryl, arylalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more in one embodiment, one, two, three, or four substituents Q1; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(N Ra) NRbRc, -ORa, - OC(O) Ra, -OC(O)ORa, OC(O)NRbRc, -OC(=N Ra)NRbRc, -OS(O)Ra, -OS(O)2Ra, - OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -N Ra C(O)ORd, -NRa (O)NRbRc, -NRaC(=NRd)NRbRc, -N RaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRa S(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc,-S(O)2NRbRc, or -(CH2)nNR'R"; wherein, Ra, Rb, Rc, and Rd are independently selected from (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6- aryl, C7 i5arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached from heterocyclyl, optionally substituted with one or more substituents Q1; wherein, Q1 is independently selected from the group consisting of (a) cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-1 aryl, C7 i5arylalkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(NRe) NRfRg, -ORe, -OC(O) Re, -OC(O)ORe, OC(O)NRfRg, -OC(=NRe)NRfRg, -OS(O) Re, -OS(O)2Re, -
Rf, Rg, and Rhis independently selected from (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6- 14 aryl, C7-i5arylalkyl, heteroaryl, or heterocyclyl; (iii)
Rf and Rg together with the N atom to which they are attached from heterocyclyl; wherein, each
represents a single or double bond; provided that both - groups are not double bonds, and wherein denoted, dash marks indicate the points of attachment; wherein,
represents a single bond, above the plane or below the plane or both above the plane or both below the plane or one is above the plane and one is below the plane.
[0028] In an embodiment of the present invention there is provided the process as disclosed herein, wherein the compounds are selected from a) (+)- 1 -methyl-2-(phenylselanyl)-4-(prop- 1 -en-2-yl)cyclohexan- 1 -ol b) (-)- 1 -methyl-2-(phenylselanyl)-4-(prop- 1 -en-2-yl)cyclohexan- 1 -ol c) 4-(2-hydroxypropan-2-yl)- 1 -methyl-2-(phenylselanyl)cyclohexan- 1 -ol d) (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2- trifluoroacetate e) 4-isopropyl- 1 -methyl-2-(phenylselanyl)cyclohexan- 1 -ol f) (+)- 1 -methyl-4-(prop- 1 -en-2-yl)cyclohex-2-en- 1 -ol g) (+)- l-methyl-2-(phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol (D2) h) (+)-2-(4-hydroxy-4-methylcyclohex-2-en-l-yl)propan-2-yl 2,2,2- trifluoroacetate i) (+)-4-isopropyl- 1 -methylcyclohex-2-en- 1 -ol j) (-)-5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)- 1',2',3',4'-tetrahydro-[ 1,1'- biphenyl] -2 , 6-diol k) (+Z)-5'-methyl-4-pentyl-2'-(prop- 1 -en-2-yl)- 1 ',2',3',4'-tetrahydro-[ 1,1'- biphenyl] -2 , 6-diol l) (-)-2-((lR,2R)-2',6'-dihydroxy-5-methyl-4'-pentyl- 1 ,2,3, 4-tetrahydro-[ 1,1'- biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate m) (-)-( 1 'S,2'S)-2'-isopropyl-5'-methyl-4-pentyl- 1 ',2',3',4'-tetrahydro-[ 1 , 1 '- biphenyl] -2 , 6-diol n) (-)-5'-methyl-2'-(prop-l-en-2-yl)-4-propoxy-1',2',3',4'-tetrahydro-[1,1'- biphenyl] -2 , 6-diol
o) (-)-4-(dodecyloxy)-5'-methyl-2'-(prop-l-en-2-yl)-T,2',3',4'-tetrahydro-[l,T- biphenyl] -2 , 6-diol p) (-)-4,5'-dimethyl-2'-(prop-l-en-2-yl)-T,2',3',4'-tetrahydro-[l,T-biphenyl]- 2, 6-diol
[0029] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E):
wherein the coupling reaction occurs with metal triflates selected from AgOTf, Ni(OTf)2, Hg(OTf)2, LiOTf, Bi(OTf)3, Ln(OTf)3, or Ac(OTf)x, preferably AgOTf or along with ligands selected from bipyridyl, substituted bipyridyl phenanthrolene, substituted phenanthrolene, pyridine, substituted pyridine, BINAP, QINAP, PINAP, PI13P or like phosphines or with heterogeneous acids selected from mixed metal oxides, SiO2-S03H/C0Fe204, SiO2-Pr-S03H, zeolites, zeotype materials, OMR-
[C4HMTA][S03H], MPD-SO3H-IL, MeAPSO, MeAPO, SAPO, ALPO4, Natrolite, ZSM-5, H-ZSM-5, periodic mesoporous organosilicas (PMOs), mesoporous silicas (PMSs), H3PW12O40, H4S1W12O40, CS2HPW12O40, HPW/ZrO2, HPW/Nb2O5,
Montmorillonite, pyrophyllite, Talc, Vermiculite, Sauconite, Saponite, Nontronite, Kaolinite, Chlorite, Illite, SAPO-34, Zirconium phosphates or sulphates, cation/anion exchange resins amberlyst, amberlite, preferably montmorillonite clay; the coupling reaction is carried out in the presence of a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, preferably dichloroethane; and
the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 0.1 to 48 hours at a temperatyure in the range of -40° C to 60° C.
[0030] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction can occur alone with metal triflates (AgOTf, Ni(OTf)2, Hg(OTf)2, LiOTf, Bΐ(OTί¾, Ln(OTf)3, or Ac(OTf)x) preferably AgOTf, or along with ligands selected from bipyridyl, substituted bipyridyl phenanthrolene, substituted phenanthrolene, pyridine, substituted pyridine, BINAP, QINAP, PINAP, PtnP or like phosphines or with heterogeneous acids, mixed metal oxides, SiO2-S03H/C0Fe204, SiO2-Pr-S03H, Zeolites, zeotype materials (0MR-[C4HMTA][S03H], MPD-SO3H-IL, MeAPSO, MeAPO, SAPO, ALP04,Natrolite, ZSM-5, H-ZSM-5, periodic mesoporous organosilicas (PMOs), mesoporous silicas (PMSs), H3PW12O40, H4S1W12O40, CS2HPW12O40, HPW/Zr02, HPW/NI52O5), Mantmorillonite, pyrophyllite, Talc, Vermiculite, Sauconite, Saponite, Nontronite, Kaolinite, Chlorite, Illite, SAPO-34, Zirconium phosphates or sulphates, cation/anion exchange resins amberlyst, or amberlite, preferably montmorillonite clay. [0031] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction occur in a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, Hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like, preferably dichloroethane.
[0032] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 0.1 to 48 hours. In another embodiment of the present invention, there is provided a process as disclosed herein wherein the coupling reaction is carried out with stirring the reaction mixture
for time period in the range of 1 to about 3 hours, or about 6 to about 48 hours, or about 12 to about 24 hours, or about 14 to about 18 hours, preferably for 5 - 10 h.
[0033] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction is carried out at a temperature in the range of -40° C to 60° C. In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction is carried out at a temperature in the range of -40°C. to 40° C, or -35° C. to -25° C, or -0° C to 50° C, preferably at 10 °C to 35 °C.
[0034] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) comprisng the steps of:
regenerating of double bond by elimination of group (Y) of compound formula (C) and conversion to compound formula (D) in the presence of oxidants selected from mCPBA, Oxone, DDQ, CAN, /V-hydroxy succinamide, /-Butyl hydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF4, PyF-OTf, TMPyF- OTf, or PIFA, preferably Selectfluor, and Hydrogen peroxide.
[0035] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein elimination is carried out in the presence of a solvent or a mixture of
solvents, selected from H2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroe thane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like.
[0036] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out by stirring the reaction mixture for a time period in the range of 0.1 to 48 hours. In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out by stirring the reaction mixture for a time period in the range of 1 to 3 hours, or 6 to 48 hours, or 12 to 24 hours, or 14 to 18 hours.
[0037] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out at a temperature in the range of -40° C to 60° C. In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out at a temperature in the range of -40°C to 40° C, or - 35° C. to -25° C, or -0° C to 5, preferably at -10 °C to 35 °C.
[0038] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B):
wherein the bi-functionalization of double bond is carried out in the presence of by a reagent selected from PhSeSePh, ZPhSeSePhZ, HetArSeSeHetAr, PhSSPh, ZPhSSPhZ, HetArSSHetAr, PhSeBr, ZPhSeBr HetArSeBr, PhSeCl, ZPhSeCl, HetArSeCl, PhSCl, ZPhSCl, HetArSCl, PhSBr, ZPhSBr HetArSBr, NBS, NIS, or NCS, along with oxidants or without oxidants, for example mCPBA, Oxone, DDQ, CAN, A- Hydroxy succinamide, /-Butyl hydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF4, PyF-OTf, TMPyF-OTf preferably with PhSeBr, PhSeCl, PhSCl, PhSBr, PhSSPh/AgOTf, PhSSPh/Selectfluor, PhSeSePh/AgOTf, PhSeSePh/Selectfluor, or the like and wherein Z is independently halogen, -CN, - N(Me)2, -NO2, -OH, alkyl, -O-alkyl, -COOH, -C(O), -C alkyl.
[0039] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out in the presence of a solvent or a mixture of solvents, selected from H2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichlorome thane, chloroform, ethyl acetate, or toluene, and the like.
[0040] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out by stirring the reaction mixture for a time period in the range of 0.1 h - 48 h. In another embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out by stirring the reaction mixture for a time period in the range of 1 to 3 hours, or 6 to 48 hours, or 12 to 24 hours, or 14 to 18 hours, preferably 12 - 24 h.
[0041] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of
compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out at a temperature in the range of -80° C to 60° C, preferably -40 °C to- 10 °C. [0042] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compound of formula (D) and compound of formula (E):
[0043] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C):
[0044] In an embodiment the present invention, there is provided a process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B):
[0045] In an embodiment of the present invention, there is provided a compound of formula (C):
[0046] In an embodiment of the present invention, there is provided a compound of following formula (D):
[0047] In an embodiment of the present invention, there is provided a compound of following formula (A):
[0048] In an embodiment of the present invention, there is provided a compound of following formula (C):
[0049] In an embodiment of the present invention, there is provided a compound of following formula (D):
[0050] In an embodiment of the present invention, there is provided a compound of following formula (A):
[0051] In an embodiment of the present invention, there is provided a compounds of following formula:
List of abbreviations:
THC- Tetrahydrocannabinol CBD- Cannabidiol
BINAP-(2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl)
DCE- Dichloroethane m-CPBA- meta chloroperbenzoic acid
DDQ-2,3-Dichloro-5,6-dicyano-l,4-benzoquinone
CAN- Cerric ammonium nitrate
BIAB- (Diacetoxyiodo)benzene
NFSI- N-Fluorobenzenesulfonimide
OTf-trifluoromethanesulfonate
CDCh-Deuterated chloroform
CD3OD- Deuterated methanol
NMR- Nuclear Magnetic Resonance
PPM- Parts Per Million
TFC- Thin Fayer Chromatography
HRMS-High Resolution Mass Spectrometry
THF- Tetrahydrofuran
DCM- Dichloromethane
ACN -Acetonitrile
DEPT-Distortionless Enhancement of Polarization Transfer UV- Ultraviolet
ESI-MS- Electrospray ionization mass specrometry LC-MS- Liquid chromatography- mass spectrometry MS- Mass Spectrometry MHz- Megahertz
TOF- Turnover Frequency
OCOCF3-- Trifluoroacetoxy
EtOAc- Ethyl acetate
AgOTf- Silver Trifluoromethanesulfonate
ESI- Electronspray ionisation
Ni(OTf)2- Nickel (II) trifluoromethanesulfonate
Hg(OTf)2 - Mercury triflate
LiOTf- Lithium trifluoromethanesulfonate
Bi(OTf)2-Bismuth(III) trifluoromethanesulfonate
Ln(OTf>2- Lanthanide trifluoromethanesulfonate
Ac(OTf>2 - Actanide trifluoromethanesulfonate
PMO- Polarized Molecular Orbital
ZSM- Zeolite Socony Mobil-5
SAPO- Silicoaluminophosphate
PyF-BF4 -N-Fluoropyridinium triflate
TMSOTf- Trimethylsilyl trifluoromethanesulfonate
NBS- N- Bromosuccinimide
NIS- N- Iodosuccinimide
NCS- N-Chlorosuccinimide
Material and method used in experiments:
[0052] All the product mixtures were analysed by thin layer chromatography. UV inactive compounds were visualized in staining solution and UV active compounds were detected with UV lamp (}= 254 nm). All the reactions were performed under inert atmosphere wherever required. Anhydrous solvents like THF, toluene, dichloroethane were dried in standard way. NMR spectra ( 1 HNMR, 13C, DEPT) were recorded in 400 MHz spectrometer using CDCE and CD3OD solvent. ES 1-MS and HRMS spectra were
recorded on LC-MS/MS and HRMS-6540-UHD machines. Optical rotations were measured on a Perkin Elmer polarimeter. Column chromatography was carried out with silica gel (60-120, 230-400 mesh)
EXAMPLES:
[0053] The present invention is further defined in the following Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only.
Step 1: Bi-functionalization of (+) or (-) limonene or limonene derivatives.
Preparation of (+)-l-methyl-2-(phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol
[0054] Examplel: To a stirred solution of (R)-(+)-limonene (Bl) (1.2g, 7.0 mmol) in ACNiPhO (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (lg, 4.5 mmol) in ACN and allowed to stir at the same temperature. After the initiation of reaction, hydrogen peroxide (2.1 mmol) as an activator was addedto the reaction mixture The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and
extracted with ethyl acetate (3 times). The organic layer was dried over Na2SC>4 and concentrated in vaccum. The crude material was subjected to silica gel column chromatography Rf = 0.4 EtOAc:Hexane (0.3-9.7) as an eluent to afford the title compound (+) l-methyl-2-(phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol (Cl) (638 mg, 49% ) as a yellow oil. ¾ NMR (400 MHz, CDCb): δ(ppm) = 7.58 (dd, 7=4 Hz, 2H), 7.27 ( m, 3H), 4.71 (d, J= 13.6 Hz, 2H), 3.44 (t, J= 4Hz, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 1.85 (m, 2H), 1.68 (s, 3H), 1.64 (m, 3H), 1.41 (s, 3H), 1.26(bs, 1H);13C NMR (100 MHz, CDCb): δ(ppm) = 149.03, 134.41, 130.55, 129.13, 127.39, 109.29, 72.59, 54.62, 39.54, 35.24, 33.70, 29.55, 26.24, 21.35; [a]D 20 = + 129 (c = 1.0, CHCb); LC-MS: (ESI+): m/z calcd for Ci6H22OSe 310.084; found 327.25.
Table 1: Reaction conditions for synthesis of compound formula (+)-Cl from R-(+)- B1
Preparation of (-)-l-methyl-2-(phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol
(C2):
[0055] Example20: To a stirred solution of (S)-(-)-limonene(B2) (544 mg, 4.0 mmol) in ACN:H20 (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na2S04 and concentrated in vaccum. The crude material was subjected to silica gel column chromatography Rf = 0.4 EtOAc:Hexane(0.3-9.7) as an eluent to afford the title compound (-)-l-methyl-2- (phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol (C2) (39% ) as a yellow oil. *H NMR (400 MHz, CDCb): δ(ppm) = 7.58 (dd, j=4 Hz, 2H), 7.27 ( m, 3H), 4.71 (d, j = 13.6 Hz, 2H), 3.44 (t , j= 4Hz, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 1.85 (m, 2H), 1.68 (s, 3H), 1.64 (m, 3H), 1.41 (s, 3H), 1.26(bs, 1H); 13C NMR (100 MHz, CDCb): δ(ppm) = 149.03, 134.41, 130.55, 129.13, 127.39, 109.29, 72.59, 54.62, 39.54, 35.24, 33.70, 29.55, 26.24, 21.35; [a]D 20 = - 138 (c = 1.0, CHCb); LC-MS: (ESI+): m/z calcd for Ci6H22OSe 310.084; found 327.25.
Table 2: Reaction conditions for synthesis of compound formula (-)-C2 from S-(-)-B2
Preparation of (+) 4-(2-hydroxypropan-2-yl)-l-methyl-2-
(pheny lselanyl)cyclohexan- 1 -ol (C3) :
(+)-B3 (+)-C3
[0056] Example 22: To a stirred solution of (+) a-terpineol (B3) (616mg, 4.0 mmol) in ACN:H2O (98:2, 6ml) at -30 to -35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na2SO4 and concentrated in vaccum. The crude material was subjected to silica gel column chromatography Rf = 0.5 EtOAc:Hexane (0.2-9.8) as a eluent to afford title compound (+) 4-(2- hydroxypropan-2-yl)-l-methyl-2-(phenylselanyl)cyclohexan-l-ol (C3) (268 mg, 82%) as a dark yellow oil. 1H NMR (400 MHz, CDC13):δ(ppm) =7.55 (dd, /= 4 Hz, 2H), 7.25 ( m, 3H), 3.54 (t, /= 4Hz, 1H), 2.63 (m, 1H), 2.24 (m, 1H), 1.65 (m, 2H), 1.55 (m, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.12(s, 3H). [a]D 20 = +79 (c = 1.0, CHC13); LC-MS: (ESI+): m/z calcd for calcd Ci6H24O2Se 327.094; found 293.25
Table 3: Reaction conditions for synthesis of compound formula (+)-C3 from (+)-B3
Preparation of (+)-2-(4-hydroxy-4-methyl-3-
(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate (C4) :
[0057] Example25: To a stirred solution of 2-(4-methylcyclohex-3-en-l-yl)propan-2- yl 2,2,2-trifluoroacetate (B4) ( lg, 4.0 mmol) in ACNithO (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na2SC>4 and concentrated in 3vaccum. The crude material was subjected to silica gel column chromatography Rf = 0.3 EtOAc:Hexane (0.4-9.6) as an eluent to afford the title compound (+)-2-(4-hydroxy-4-methyl-3-
(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate(C4) (138.24 mg, 59%) as a yellow oil;1!! NMR (400 MHz, CDCb): δ(ppm) = 7.58 (dd, /= 4 Hz, 2H), 7.27 ( m, 3H), 3.45 (d, /= 4Hz, 1H), 2.39 (m, 1H), 2.11 (m, 1H), 1.73 (m, 2H), 1.67(m, 3H)1.52 (s, 3H), 1.48 (s, 3H), 1.45 (s, 3H); [a]D 20 = + 111 (c = 1.0, CHCI3); 19F NMR (376 MHz, CDCb): δ(ppm)= -75.65
Table 4: Reaction conditions for synthesis of compound formula (+)-C4 from (+)-B4
Preparation of 4-isopropyl-l-methyl-2-(phenylselanyl)cyclohexan-l-ol (C5)
(+)-B5 (+)-C5
[0058] Example 27: To a stirred solution of (+)-4-isopropyl-l-methylcyclohex-l-ene (B5) ( 552 mg, 4.0 mmol) in ACN:H20 (98:2, 6ml) at -30 to - 35 °C was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na2S04 and concentrated in vaccum. The crude material was subjected to silica gel column chromatography Rf = 0.5 EtOAc:Hexane (0.4-9.6) as an eluent to afford the title compound (+)-4-isopropyl-l-methyl-2-(phenylselanyl)cyclohexan-l-ol (C5) (138.24 mg, 86% ) as a yellow oil. ¾ NMR (400 MHz, CDC13): δ(ppm) = 7.60 (dd, /= 4 Hz, 2H), 7.28 ( m, 3H), 3.44 (t, /= 4Hz, 1H), 2.03 (m, 1H), 1.81 (m, 3H), 1.57 (m, 3H), 1.40 (s, 3H), 0.88(d, j= 4Hz, 3H), 0.83(d, j= 4 Hz, 3H) 13C NMR (100 MHz, CDC13): 134.53, 130.94, 129.31, 127.31, 72.68, 55.14, 39.22, 35.25, 32.37, 30.72, 29.10, 24.82, 20.14, 20.05; [a]D20= - 101 (c =1.0, CHC13); LC-MS: (ESI+): m/z calcd for Ci6H24OSe; 295 [M - OH]+.
Table 5: Reaction conditions for synthesis of compound formula (+)-C5 from (+)-B5
STEP 2: Regeneration of the double bond by elimination (C-D).
Preparation of (+)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl):
[0059] Example29: The solution of (+)-l-methyl-2-(phenylselenyl)-4-(prop-l-en-2- yl)cyclohexan-l-ol (Cl) (155 mg, 0.5 mmol) in THF (5ml) was allowed to stir for 10 min. Then, Selectfluor (531 mg, 1.5 mmol) was added to the reaction. The reaction mixture was stirred for 9- 10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography Rf = 0.4 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (+)-l- methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (64.9 mg, 85%) as light yellow oil.1!! NMR (400 MHz, CDCb): δ(ppm) = 5.71 (dd, 1H), 5.66 (dd, 1H), 4.78 (d, 7=16
Hz, 1H), 4.75 (d, J= 8Hz, 1H), 2.66 (m, 1H), 1.80 (m, 2H), 1.74 (s,3H), 1.59 (m, 1H), 1.49 (br, OH, 1H), 1.30 (s,3H).13C NMR (100 MHz, CDCL3): δ(ppm) = 148.125 (C- 8), 134.13 (C-2), 132.20 (C-l), 110.74 (C-9), 67.41 (C-3), 43.34 (C-6), 36.77 (C-4), 29.70 (C-5), 27.10 (C-10), 20.81 (C-7); [a]D 20Experimental= + 146 (c = 1.0, CHC13); literature = +53.8 (CHC13);
HRMS (ESI-TOF) m/z: [M - OH]"calcd for C10H16O; 152.120; found 135.15.
Table 6: Reaction conditions for synthesis of compound formula (+)-Dl from (+)-Cl
Preparation of (+)- l-methyl-2-(phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol
(D2):
(-)-C2 (->02
[0060] Example37: The solution of (-)-l-methyl-2-(phenylselenyl)-4-(prop-l-en-2- yl)cyclohexan-l-ol (C2) (155 mg, 0.5 mmol) in THF (5mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9- 10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography, Rf = 0.4 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (-)-l-methyl- 4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (D2) (81%) as light yellow oil.'H NMR (400 MHz, CDCb): δ(ppm) = 5.71 (dd, 1H), 5.66 (dd, 1H), 4.78 (d,/=16 Hz, 1H), 4.75 (d, /= 8Hz, 1H), 2.66 (m, 1H), 1.80 (m, 2H), 1.74 (s,3H), 1.59 (m, 1H), 1.49 (br, OH, 1H), 1.30 (s,3H); 13C NMR (100 MHz, CDCb): δ(ppm) = 148.125 (C-8), 134.13 (C-2), 132.20 (C-l), 110.74 (C-9), 67.41 (C-3), 43.34 (C-6), 36.77 (C-4), 29.70 (C-5), 27.10 (C-10), 20.81 (C-7); [a]D20Experimental= - 92(c = 1.0, CHCI3); LC-MS: (ESI+): m/z calcd for C10H16O; 152.120; found 135.15.
Preparation of (+)-2-(4-hydroxy-4-methylcyclohex-2-en-l-yl)propan-2-yl 2,2,2- trifluoroacetate (D3):
(+)- C3 (+)- D3
[0061] Example 38: The solution of (+)-2-(4-hydroxy-4-methyl-3-
(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate (C3) (212 mg, 0.5 mmol)
in THF (5mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography Rf = 0.3 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (+)-2-(4-hydroxy-4-methylcyclohex-2-en-l-yl)propan-2-yl 2,2,2-trifluoroacetate (D3) (79 mg, 59.3%) as light yellow oil.'HNMR (400 MHz, CDCb): δ(ppm) = 5.79 (m, 1H), 5.67 (m, 1H), 2.72 (s, 1H), 2.49 (s, 1H) 1.80 (m, 3H), 1.57(d,/= 12Hz, 3H), 1.52(d, /= 8Hz, 3H) 1.29 (d,/= 8Hz,3H). 19F NMR (376 MHz, CDCb): δ(ppm)= -75.65; [a]h20= + 51(c = 1.0, CHCb)
Table 7: Reaction conditions for synthesis of compound formula (+)-D3 from (+)-C3
Preparation of (+)-4-isopropyl-l-methylcyclohex-2-en-l-ol (D4):
[0062] Example 40:The solution of (+)-4-isopropyl-l-methyl-2- (phenylselanyl)cyclohexan-l-ol (C4) (156 mg, 0.5 mmol) in THF (5mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column
chromatography Rf = 0.5 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (+)-4-isopropyl-l-methylcyclohex-2-en-l-ol (D4) (63%) as light yellow oΐI.Ή NMR (400 MHz, CDCb): δ(ppm) = ¾ NMR (400 MHz, CDCb): d 5.66 (m, 2H), 1,84 (m, 2H), 1.62 (m, 2H), 1.47 (m, 2H), 1.26 (s, 3H), 0.89 (m, 6H); 13C NMR (100 MHz, CDCb): 133.64, 133.08, 67.59, 42.23, 37.36, 31.74, 29.74, 21.67, 19.65, 19.31; [a]D20Experimental= + 48(c = 1.0, CHCb);LC-MS: (ESI+): m/z calcd for CIOHI80; 154.136; found 137.136
Table 8: Reaction conditions for synthesis of compound formula (+)-D4 from (+)-C4
STEP 3: Condensation of olivetol or derivatives with menthadienol or derivatives to prepare cannabidiol or derivatives.
Preparation of (-)-5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro- [l,l'-biphenyl]-2,6-diol (Al):
[0063] Example 43: To a solution of Silver bis(trifluoromethanesulfonyl)imide (AgNTf2)(20 mol%) in anhydrous DCE was added (+)-l-methyl-4-(prop-l-en-2- yl)cyclohex-2-en- 1 -ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (El) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.5 EtO Ac/hexane (0.1:9.9) as an eluent to afford the title compound (-) 5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)- l',2',3',4'-tetrahydro-[l,T-biphenyl]-2,6-diol(Al)(67.18 mg, 43%) as a yellow oiEH NMR (400 MHz, CDC13): δ(ppm) = 6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, IH,OH), 4.66 (s, 1H), 4.56( s, 1H), 3.86 (dd, /= 8Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83(m, 2H), 1.79 (s, 3H), 1.66(s, 3H), 1.56(t, 3H), 1.30 (m, 4H), 0.88 (t,3H); 13C NMR (100 MHz,CD3OD):δ(ppm) = 156.13, 148.90, 141.36, 133.20, 125.86, 114.61, 109.23, 107.02, 45.06, 36.13, 35.19,31.23, 30.64,30.31, 29.30, 22.29, 22.17, 18.17, 12.97; [a]h20= - 43 (c =1.0, CHCb); LC-MS: (ESI+): m/z calcd for C21H31O2; 314.225; found 315.2317.
[0064] Example 44: To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol(Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (El) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of
reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.5 EtO Ac/hexane (0.1:9.9) as an eluent to afford the title compound (-) 5'-methyl-4- pentyl-2'-(prop-l-en-2-yl)-l',2',3',4'-tetrahydro-[l,l'-biphenyl]-2,6-diol(Al)(62.5 mg, 36%) as a yellow oil.
Table 9: Reaction conditions for synthesis of compound formula (-)-Al from (+)-Dl.
Preparation of (+Z)-5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro- [l,l'-biphenyl]-2,6-diol (A2):
[0065] Example 52 To a solution of silver triflate (20 mol%) in anhydrous DCEwas added (-)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol(D2) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf = 0.5 EtO Ac/hexane (0.1:9.9) as an eluent to afford the title compound (+)-5'-methyl- 4-pentyl-2'-(prop-l-en-2-yl)-l',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (A2) (56.25 mg, 36%) as a yellow oϋ.Ή NMR (400 MHz, CDCb): δ(ppm) = 6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, IH,OH), 4.66 (s, 1H), 4.56( s, 1H), 3.86 (dd, /= 8 Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83(m, 2H), 1.79 (s, 3H), 1.66(s, 3H), 1.56(t, 3H), 1.30 (m, 4H), 0.88 (t,3H); 13C NMR (100 MHz, CDCb): δ(ppm) = 161.11(2’C and 6’C), 149.37 (8 C), 142.99 (4-’C), 140.00 ( 3- C), 124.08 (2C), 113.87 (l’C), 110.92 (3’C and 5’C), 46.20 (6 C), 37.24 (1C), 35.50 (1” C),
32.51 (4 C), 30.61 (3” C), 30.42 (2” C), 28.44 (5C), 23.66 (7C), 22.55 (4” C), 20.47 (9 C), 14.03 (5” C);[a]D 20 = + 21 (c =1.0, CHCb); LC-MS: (ESI+): m/z calcd for C21H31O2; 314.225; found 315.2317.
Table 10: Reaction conditions for synthesis of compound formula (+)-Al from (-)-Dl.
Preparation of (-)-2-((lR,2R)-2',6'-dihydroxy-5-methyl-4'-pentyl-l,2,3,4- tetrahydro-[l,l'-biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate (A3):
(+)-D3 (-)-A3
[0066] Example 54: To a solution of silver triflate (20 mol%) in anhydrous DCE was added 2-(4-hydroxy-4-methylcyclohex-2-en- 1 -yl)propan-2-yl 2,2,2-trifluoroacetate (D3) (133 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (180 mg, 1 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.4 EtOAc/hexane (0.2:9.9) as an eluent to afford the title compound (-)-2-((lR,2R)-2',6'-dihydroxy-5-methyl-4'-pentyl- 1,2,3, 4-tetrahydro-[ 1,1'- biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate (A3) (81 mg, 41%) as a yellow oil.'H NMR (400 MHz, CDCls): δ(ppm) = 6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, IH,OH), 4.66 (s, 1H), 4.56( s, 1H), 3.86 (dd, /= 8Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83(m, 2H), 1.79 (s, 3H), 1.66(s, 3H), 1.56(t, 3H), 1.30 (m, 4H), 0.88 (t,3H); 19F NMR (376 MHz, CDCb): δ(ppm)= -75.65; 13C
NMR (100 MHz,CD3OD):δ(ppm) = 156.13, 148.90, 141.36, 133.20, 125.86, 114.61, 109.23, 107.02, 45.06, 36.13, 35.19,31.23, 30.64,30.31, 29.30, 22.29, 22.17, 18.17, 12.97; [a]h20= - 43 (c =1.0, CHCls).
Table 11: Reaction conditions for synthesis of compound formula (-)-A3 from (+)-D3
Preparation of (-)-(l'S,2'S)-2'-isopropyl-5'-methyl-4-pentyl-l',2',3',4'-tetrahydro-
[l,l'-biphenyl]-2,6-diol (A4):
[0067] Example 56: To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) 4-isopropyl- l-methylcyclohex-2-en-l-ol(D4) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (El) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.5 EtOAc/hexane (0.E9.9) as an eluent to afford the title compound (-)-( l'S,2'S)-2'-
isopropyl-5'-methyl-4-pentyl-l',2',3',4'-tetrahydro-[l,l'-biphenyl]-2,6-diol (A4) (39%) as a yellow oil.1!! NMR (400 MHz, CDC13): δ(ppm) = 6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, IH,OH), 3.86 (dd, /= 8Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83(m, 2H), 1.79 (s, 3H), 1.66(s, 6H), 1.56(t, 3H), 1.30 (m, 4H), 0.88 (t, 3H); [a]h20= - 48 (c =1.0, CHCE); LC-MS: (ESI+): m/z for C19H26O3; 317.240 [M + H]+.
Table 12: Reaction conditions for synthesis of compound formula (-)-A4 form (+)-D4
Preparation of (-)-5'-methyl-2'-(prop-l-en-2-yl)-4-propoxy-r,2',3',4'-tetrahydro- [l,l'-biphenyl]-2,6-diol (A5):
[0068] Example58- To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, 5-propoxybenzene-l,3-diol (E2) (100 mg, 0.6 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.4 EtO Ac/hexane (0.1:9.9) as an eluent to afford the title
compound (-)-5'-methyl-2'-(prop-l-en-2-yl)-4-propoxy-1',2',3',4'-tetrahydro-[l,T- biphenyl]-2,6-diol (A5) (62.2 mg, 41.05%) as a yellow oil.'H NMR (400 MHz, CDC13): δ(ppm) = 6.04 (bs, 2H), 5.59 (s, 1H), 4.74 (s, 1H), 4.62( s, 1H), 3.86 (t, 2H),
3.69 (m. 1H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83(m, 2H), 1.79 (s, 3H),
1.66(s, 3H), 1.30 (m, 2H), 1.06 (t, 3H); [a]o20= - 21 (c =1.0, CHCE); LC-MS: (ESI+): m/z calcd for C19H26O3; 303.40.
Preparation of (-)-4-(dodecyloxy)-5'-methyl-2'-(prop-l-en-2-yl)-r,2',3',4'- tetrahydro-[l,l'-biphenyl]-2,6-diol
(
[0069] Example 59- To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, 5-(dodecyloxy)benzene-l,3-diol(E3)(118mg,0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.4 EtO Ac/hexane (0.1:9.9) as an eluent to afford the title compound (-)-5'-methyl-2'-(prop-l-en-2-yl)-4-propoxy-T,2',3',4'-tetrahydro-[l,T- biphenyl]-2,6-diol (A6) (78mg, 36.4%) as a yellow oil.lHNMR (400 MHz, CDC13) δ(ppm)= 5.96 (s, 2H), 5.48 (s, 1H), 4.61 (s, 1H), 4.51 (s, 1H), 3.78 (t, 3H), 3.71 (m, 1H), 2.28 (m, 1H), 2.21 - 1.95 (m, 2H), 1.72 (s, 3H), 1.68 - 1.62 (m, 2H), 1.58 (s, 3H), 1.19 (s, 20H), 0.81 (s, 3H).13C NMR (101 MHz, CDCb) δ(ppm)= 159.03, 149.54,
140.21, 111.17, 108.98, 67.78, 46.35, 31.93, 30.41, 29.62, 29.30 12.4 28.44, 26.05, 23.04, 20.76, 14.44.LC-MS: (ESI+): m/z calcd for C21H31O2; 428.33; found 429.40.
Preparation of (-)-4,5'-dimethyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro-[l,l'- biphenyl] -2,6-diol(Cannabidiorcinol) (A 7)
[0070] Example 60- To a solution of silver triflate (20 mol%) in anhydrous DCE was added (+) l-methyl-4-(prop-l-en-2-yl)cyclohex-2-en-l-ol (Dl) (76 mg, 0.5 mmol) in solution form using syringe. Then, Orcinol(E4) (50 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography Rf 0.4 EtO Ac/hexane (0.1:9.9) as an eluent to afford the title compound (-)-4,5'-dimethyl- 2'-(prop-l-en-2-yl)-l',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Cannabidiorcinol) (A7) (41 mg, 39%)) as a yellow oil.lH NMR (400 MHz, CDCb) δ(ppm)= 6.15 (d, 2H), 5.89 (bs, OH), 5.48 (s, 1H), 4.59 (s, 1H), 4.49 (s, 1H), 3.78 (d, 1H), 2.33 (m,lH), 2.14 (s, 1H), 2.01 (m, 1H), 1.72 - 1.67 (m, 3H), 1.59 (s, 3H), 1.51 (s, 3H).13C NMR (101 MHz, CDCb) δ(ppm)=149.32, 137.95,113.89, 110.90, 46.02, 30.27, 21.35, 20.31.
ADVANTAGES OF THE PRESENT INVENTION:
[0071] The present invention deals with a novel process development for the production of a (+) or (-) Cannabidiol and related compounds thereof. The (+) or (-) cannabidiol and related compounds thereof can be prepared via three steps sequence bi-functionalization of (+) or (-) limonene or limonene derivative thereof, elimination to (+) or (-) menthadienol or derivatives thereof, and metal triflate or acid or heteroacid catalyzed condensation of (+) or (-) menthadienol or menthadienol derivatives with olivetol or olivetol derivatives thereof. The processes of the present disclosure provide a number of advantages over current methods. The main advantage of the present disclosure are i) inexpensive and commercially available starting materials, ii) accessibility of the (+) or (-) cannabidiol or derivatives, iii) high selectivity in condensation reaction, and iv) high overall yield.
Claims
1. A process for the preparation of cannabidiol compound of formula (A)
wherein
R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl;
R I R2, R3 and R4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl;
X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl;
Y is independently selected from S, SO, Se, SeO, Cl, Br, I, /V-di alkyl, X-aryl, or N- heteroaryl;
R5 Re, R7, R8, R9 are independently selected from H, halogen, -CN, -NO2, -OH, alkyl, -O-alkyl, -COOH, -C(O), -C alkyl, -C(O)OC, S-alkyl, -SO-alkyl, -SO2-alkyl, S-aryl, -SO-aryl, -SO2-aryl, SO-heteroaryl, -SO2-N-aryl, -N-SO2-aryl NR'R", alkenyl, alkynyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the alkyl, aryl or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, -O-alkyl, - COOH, -C(O), -C alkyl, -C(O)OC, alkyl, NR'R", or -(CH2)nNR'R"; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, acyl, acyloxy, aryl, arylalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) Ci_6 alkyl, C2-6 alkenyl,
C2-6 alkynyl, cycloalkyl, C6-u aryl, C7_i5 arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q1; and (c) -C(O)Ra, - C(O)ORa, -C(O)NRbRc, -C(N Ra) NRbRc, -ORa, -OC(O) Ra, -OC(O)ORa, OC(O)NRbRc, -OC(=N Ra)NRbRc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, - OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -N Ra C(O)ORd, -NRa (O)NRbRc, - NRaC(=NRd)NRbRc , -N RaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRa S(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc,-S(O)2NRbRc, or -(CH2)nNR'R"; wherein, Ra, Rb, Rc, and Rd are independently selected from (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, Ce-u aryl, C7- 13 aryl alkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached from heterocyclyl, optionally substituted with one or more substituents Q1; wherein, Q1 is independently selected from the group consisting of (a) cyano, halo, or nitro; (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, Ce-u aryl, C7- i5arylalkyl, heteroaryl, or heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, - C(NRe) NRfRg, -ORe, -OC(O) Re, -OC(O)ORe, OC(O)NRfRg, -OC(=NRe)NRfRg, - OS(O) Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -N Re C(O)Rh, -N Re C(O)ORh, -N Re (O)NRfRg, -NReC(=NRh)NRfRg, -N Re S(O)Rh, -N Re S(O)2Rh, -N Re S(O)NRfRg, -N Re S(O)2NRfRg, -SRe, -S(O) Re, -S(O)2Re, -S(O)NRfRg, or - S(O)2NRfRg; wherein Re, Rf, Rg, and Rhis independently selected from (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, Ce-u aryl, C7-15 arylalkyl, heteroaryl, or heterocyclyl; (iii) Rf and Rg together with the N atom to which they are attached from heterocyclyl; wherein, each - represents a single or double bond; provided that both - groups are not double bonds, and wherein denoted, dash marks indicate the points of attachment;
wherein, •™ w represents a single bond, above the plane or below the plane or both above the plane or both below the plane or one is above the plane and one is below the plane.
2. The process as claimed in claim 1, wherein the compounds are selected from: a) (+)- 1 -methyl-2-(phenylselanyl)-4-(prop- 1 -en-2-yl)cyclohexan- 1 -ol b) (-)- 1 -methyl-2-(phenylselanyl)-4-(prop- 1 -en-2-yl)cyclohexan- 1 -ol c) 4-(2-hydroxypropan-2-yl)-l-methyl-2-(phenylselanyl)cyclohexan-l-ol d) (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2- trifluoroacetate e) 4-isopropyl- 1 -methyl-2-(phenylselanyl)cyclohexan- 1 -ol f) (+)- 1 -methyl-4-(prop- 1 -en-2-yl)cyclohex-2-en- 1 -ol g) (+)- l-methyl-2-(phenylselanyl)-4-(prop-l-en-2-yl)cyclohexan-l-ol (D2) h) (+)-2-(4-hydroxy-4-methylcyclohex-2-en-l-yl)propan-2-yl 2,2,2- trifluoroacetate i) (+)-4-isopropyl- 1 -methylcyclohex-2-en- 1 -ol j) (-)-5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)-T,2',3',4'-tetrahydro-[l,T- biphenyl] -2 , 6-diol k) (+Z)-5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)-T,2',3',4'-tetrahydro-[l,T- biphenyl] -2 , 6-diol l) (-)-2-(( lR,2R)-2',6'-dihydroxy-5-methyl-4'-pentyl- 1 ,2,3 ,4-tetrahydro-[ 1 , T- biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate m) (-)-(TS,2'S)-2'-isopropyl-5'-methyl-4-pentyl-T,2',3',4'-tetrahydro-[l,T- biphenyl] -2 , 6-diol n) (-)-5'-methyl-2'-(prop-l-en-2-yl)-4-propoxy-T,2',3',4'-tetrahydro-[l,T- biphenyl] -2 , 6-diol o) (-)-4-(dodecyloxy)-5'-methyl-2'-(prop-l-en-2-yl)-T,2',3',4'-tetrahydro-[l,T- biphenyl] -2 , 6-diol
p) (-)-4,5'-dimethyl-2'-(prop-l-en-2-yl)-T,2',3',4'-tetrahydro-[l,T-biphenyl]-
2,6-diol
3. The process for preparation of cannabidiol compound of formula (A) as claimed in claim 1 , the preparation of formula (A) by coupling of compound of formula (D) and compound of formula (E) comprising the step of:
wherein the coupling reaction occurs with metal triflates selected from AgOTf, Ni(OTf)2, Hg(OTf)2, LiOTf, Bi(OTf)3, Ln(OTf)3, or Ac(OTf)x, preferably AgOTf or along with ligands selected from bipyridyl, substituted bipyridyl phenanthrolene, substituted phenanthrolene, pyridine, substituted pyridine, BINAP, QINAP, PINAP, Ph3P or like phosphines or with heterogeneous acids selected from mixed metal oxides, Si02-S03H/C0Fe204, Si02-Pr-S03H, zeolites, zeotype materials, OMR- [C4HMTA][S03H], MPD-SO3H-IL, MeAPSO, MeAPO, SAPO, ALPO4, Natrolite, ZSM-5, H-ZSM-5, periodic mesoporous organosilicas (PMOs), mesoporous silicas (PMSs), H3PW12O40, H4S1W 12O40, CS2HPW12O40, HPW/ZrO2, HPW/Nb205, Montmorillonite, pyrophyllite, Talc, Vermiculite, Sauconite, Saponite, Nontronite, Kaolinite, Chlorite, Illite, SAPO-34, Zirconium phosphates or sulphates, cation/anion exchange resins amberlyst, or amberlite, likewise preferably montmorillonite clay; the coupling reaction is carried out in the presence of a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroe thane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene, preferably
dichloroe thane; and with stirring the reaction mixture for time period in the range of 0.1 to 48 hours at a temperature in the range of -40° C to 60° C.
4. The process for preparation of cannabidiol compound of the formula (A) as claimed in claim 1, conversion of compound of formula (B) to compound of formula (C) via bi-functionalization of double bond :
(B) (C) wherein the bi-functionalization of double bond is carried out in the presence of reagent selected from PhSeSePh, ZPhSeSePhZ, HetArSeSeHetAr, PhSSPh, ZPhSSPhZ, HetArSSHetAr, PhSeBr, ZPhSeBr,HetArSeBr, PhSeCl, ZPhSeCl, HetArSeCl, PhSCl, ZPhSCl, HetArSCl, PhSBr, ZPhSBr, HetArSBr, NBS, NIS, or NCS, optionally with oxidants selected from mCPBA, Oxone, DDQ, CAN, N- Hydroxy succinamide, r- B uty 1 h ydroperox i de, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF4, PyF-OTf, TMPyF-OTf preferably with PhSeBr, PhSeCl, PhSCl, PhSBr, PhSSPh/AgOTf, PhSSPh/Selectfluor, PhSeSePh/AgOTf, or PhSeSePh/Selectfluor; wherein Z is independently selected from halogen, -CN, - N(Me)2, -NO2, -OH, alkyl, -O-alkyl, -COOH, -C(O), or -C alkyl; the bi-functionalization is carried out in the presence of a solvent or a mixture of solvents selected from H20, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroe thane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene; and with stirring the reaction mixture for time period in the range of 0.1 h - 48 h and at a temperature in the range of -80° C to 60° C.
5. The process for preparation of cannabidiol compound of the formula (A) as claimed in claim 1, the conversion of compound of formula (C) to compound of
regenerating double bond by elimination of group (Y) of compound of formula (C) and conversion to compound formula (D) in the presence of oxidants selected from mCPBA, Oxone, DDQ, CAN, /V-hydroxy succinamide, t- Butylhydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF- BF4, PyF-OTf, TMPyF-OTf, or PIFA, preferably Selectfluor, and Hydrogen peroxide; wherein the regenerating double bond by elimination is carried out in the presence of a solvent or a mixture of solvents selected from ¾0, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene; and with stirring the reaction mixture for a time period in the range of 0.1 to 48 hours at a temperature in the range of -40° C to 60° C.
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| WO2023084516A1 (en) * | 2021-11-11 | 2023-05-19 | Cannasoul Analytics Ltd. | Novel cannabinoid derivatives |
| WO2024028516A1 (en) | 2022-08-05 | 2024-02-08 | Salud & Semillas, S.L. | CANNABINOID SYNTHESIS STARTING OUT FROM OLIVETOL AND TERPENE IN DICHLOROMETHANE WITH FeCl3 * 6H2O AS CATALYST |
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