CN115353540B - Synthetic method and application of phenolic steroid compound - Google Patents
Synthetic method and application of phenolic steroid compound Download PDFInfo
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- CN115353540B CN115353540B CN202211157129.4A CN202211157129A CN115353540B CN 115353540 B CN115353540 B CN 115353540B CN 202211157129 A CN202211157129 A CN 202211157129A CN 115353540 B CN115353540 B CN 115353540B
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- -1 phenolic steroid compound Chemical class 0.000 title claims abstract description 19
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 89
- 239000002904 solvent Substances 0.000 claims description 76
- 239000000010 aprotic solvent Substances 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000007254 oxidation reaction Methods 0.000 claims description 28
- 230000009471 action Effects 0.000 claims description 26
- 239000007800 oxidant agent Substances 0.000 claims description 26
- 238000003786 synthesis reaction Methods 0.000 claims description 25
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 239000002798 polar solvent Substances 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000003849 aromatic solvent Substances 0.000 claims description 18
- 238000010511 deprotection reaction Methods 0.000 claims description 18
- 150000008282 halocarbons Chemical class 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 239000004210 ether based solvent Substances 0.000 claims description 14
- 229930014626 natural product Natural products 0.000 claims description 14
- 230000001590 oxidative effect Effects 0.000 claims description 13
- 229940125773 compound 10 Drugs 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 150000007530 organic bases Chemical class 0.000 claims description 11
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 10
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 150000002736 metal compounds Chemical class 0.000 claims description 10
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 9
- 125000000746 allylic group Chemical group 0.000 claims description 9
- 229940125797 compound 12 Drugs 0.000 claims description 9
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 239000003810 Jones reagent Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical group CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000007239 Wittig reaction Methods 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 5
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000005453 ketone based solvent Substances 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- UTRBHXSKVVPTLY-UHFFFAOYSA-N 4,5,6,7-tetrachloro-2-hydroxyisoindole-1,3-dione Chemical compound ClC1=C(Cl)C(Cl)=C(Cl)C2=C1C(=O)N(O)C2=O UTRBHXSKVVPTLY-UHFFFAOYSA-N 0.000 claims description 2
- DHDHJYNTEFLIHY-UHFFFAOYSA-N 4,7-diphenyl-1,10-phenanthroline Chemical compound C1=CC=CC=C1C1=CC=NC2=C1C=CC1=C(C=3C=CC=CC=3)C=CN=C21 DHDHJYNTEFLIHY-UHFFFAOYSA-N 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- WEXOMUHIFCRUIT-UHFFFAOYSA-N C(C)(C)(C)C1(NC(=CC=C1)C(C)(C)C)C1=NC=CC=C1 Chemical compound C(C)(C)(C)C1(NC(=CC=C1)C(C)(C)C)C1=NC=CC=C1 WEXOMUHIFCRUIT-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 150000002085 enols Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 2
- 238000006317 isomerization reaction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 239000011572 manganese Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 16
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 55
- 239000000243 solution Substances 0.000 description 40
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
- 238000005406 washing Methods 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000002390 rotary evaporation Methods 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 238000001035 drying Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- 229910052786 argon Inorganic materials 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- 238000001914 filtration Methods 0.000 description 11
- 125000001624 naphthyl group Chemical group 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000002156 mixing Methods 0.000 description 10
- 150000003431 steroids Chemical class 0.000 description 10
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 5
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 5
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- WXYYACUWOMKZQC-UHFFFAOYSA-N 1-benzyl-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC=C1 WXYYACUWOMKZQC-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 3
- JOFDSYLCZIHGGO-UHFFFAOYSA-N 4-[(4-cyclohexylphenyl)methyl-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetyl]amino]-2-hydroxybenzoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(=O)N(C=1C=C(O)C(C(O)=O)=CC=1)CC(C=C1)=CC=C1C1CCCCC1 JOFDSYLCZIHGGO-UHFFFAOYSA-N 0.000 description 3
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- 125000002252 acyl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
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- 125000006413 ring segment Chemical group 0.000 description 3
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- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 2
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
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- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 description 2
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- 125000004185 ester group Chemical group 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
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- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical group CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- HJKVPZJVBHWFCQ-UHFFFAOYSA-N phenolic steroid Chemical class C1CC2=CC(O)=CC=C2C2C1C1CCCC1(C)CC2 HJKVPZJVBHWFCQ-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing a phenolic steroid compound. Concrete embodimentsThe invention provides a method for synthesizing a phenolic steroid compound, which comprises the following steps.
Description
Technical Field
The present invention relates to the field of pharmaceutical chemistry. In particular, the invention relates to a method for synthesizing phenolic steroid compounds and application thereof.
Background
With elucidation of the structure of steroids in 1932 and chemical synthesis of marnaftoprostone in 1939, development of methods for artificially synthesizing steroids has been attracting attention. Today, the number of steroid drugs approved by the FDA exceeds 100, and they have a wide range of pharmaceutical values, both for the treatment of cancer, heart disease and craniocerebral injury, and for anti-inflammatory and analgesic, and also as oral contraceptives. It can be said that such drugs have become the most widely studied and successful natural product derived drugs. However, organic synthesis of steroids also presents a bottleneck, which limits the search for new molecules of pharmaceutical value.
Early industrial production of steroid drugs was semi-synthetic, i.e. the conversion of existing natural steroids to high value drugs by chemical means. For example, merck converts bile acid to cortisone, and Marker degradation converts diosgenin to testosterone, estrone, estradiol, progesterone, or cortisone. However, the natural products containing naphthalene ring structure in the steroid are less, and the synthesis report is less.
The natural product Myrmenaphtol A is a first isolated steroid marine natural product containing a naphthalene ring structure. Structurally, the catalyst has a unique naphthalene ring skeleton, and the A epoxidation state is positioned at a C2 position. Naphthalene ring structures are extremely rare in natural steroid compounds, and methods for constructing naphthalene ring skeletons in steroid compounds in the literature so far mainly comprise (1) oxidation or Pd/C hydrogenation of steroid natural products with known non-naphthalene ring skeletons by DDQ; (2) By coupling with compounds which themselves contain naphthalene ring structures; (3) Through acid catalyzed Friedel-crafts alkylation, but the synthesis in the literature is focused on the products of oxidation at the C3 position of the A ring; (4) The method utilizes gold catalysis to generate intramolecular [3+2] cyclization to construct a naphthalene ring structure, and the method is not suitable for gram-scale preparation by utilizing noble metal catalysis; (5) The naphthalene ring skeleton is constructed by using metal Ti as a catalyst, and the substrate of the method has no universality. In summary, the methods reported in the literature either utilize noble metals or are not universal. Therefore, the development of an efficient naphthalene ring framework construction method has important significance for the synthesis of steroid natural products.
Disclosure of Invention
In a first aspect of the present invention, there is provided a method for synthesizing a phenolic steroid compound, characterized by comprising the steps of:
b) In an aprotic solvent, under the action of a catalyst and a condensing agent, performing condensation reaction on the compound 2 and the compound 3 to obtain a compound 4;
c) In polar solvent or mixed solution of polar solvent and aprotic solvent, under the action of metal Ni catalyst and ligand and under the action of metal compound or organic base, compound 4 and compound 5 undergo decarboxylation coupling reaction to obtain compound 6;
d) In an aprotic solvent, under the action of acid and oxygen, carrying out ring closure reaction on the compound 6 to obtain a steroid compound 7;
wherein ,
for CH-H, C = O, CH-OH or c=chch 3 Preferably c=o;
R 2 and R3 Each independently is H OR'; r' is selected from the group consisting of: H. c (C) 1 -C 4 Alkyl, C 2 -C 4 Acyl, C 1 -C 4 alkoxy-C 1 -C 4 Alkyl, C 1 -C 4 alkyl-C 6 -C 10 Aryl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
and ,R2 and R3 Not simultaneously H;
each X is 1 Each independently H, cl;
X 2 is Cl, br, I or B (OH) 2 。
In some of the embodiments of the present invention,
in step b), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in step b), the volume molar ratio of the aprotic solvent to the compound 2 is 10 to 30L:0.8-1.2mol;
And/or, in step b), the catalyst is Dimethylaminopyridine (DMAP);
and/or, in step b), the molar ratio of the catalyst to the compound 2 is between 0.01 and 0.5:0.8-1.2;
and/or, in step b), the condensing agent is selected from the group consisting of: n, N' -Diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC); preferably, the molar ratio of the condensing agent to the compound 2 is 1-3: 0.8-1.2;
and/or, in the step b), the compound 3 is N-hydroxy phthalimide (NHPI) or N-hydroxy Tetrachlorophthalimide (TCNHPI); preferably, the molar ratio of the compound 3 to the compound 2 is 1-3: 0.8-1.2;
and/or in step b), the condensation reaction temperature is from 0 to 80 ℃, preferably from 10 to 50 ℃.
In some of the embodiments of the present invention,
in step c), the polar solvent is selected from the group consisting of: sulfoxide polar solvents, amide polar solvents, or combinations thereof; preferably, the sulfoxide polar solvent is dimethyl sulfoxide (DMSO), and the amide polar solvent is selected from the group consisting of: n, N '-Dimethylformamide (DMF), N' -dimethylacetamide (DMAc);
and/or, in step c), the volume molar ratio of the polar solvent to the compound 4 is between 5 and 20L:0.8-1.2mol;
And/or, in step c), said aprotic solvent is selected from the group consisting of: ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in the step c), when a mixed solution of a polar solvent and an aprotic solvent is used, the volume ratio of the polar solvent to the aprotic solvent is 1:5-10;
and/or, in the step c), the volume mole ratio of the polar solvent and aprotic solvent mixed solution to the compound 4 is 10-50L: 0.8-1.2mol;
and/or, in step c), the metallic Ni catalyst is selected from the group consisting of: niCl 2 ·6H 2 O、NiBr 2 DME, or NiBr 2 Diglyme; preferably, the molar ratio of the metal Ni catalyst to the compound 4 is 0.05-0.5: 0.8-1.2;
and/or, in step c), said ligand is selected from the group consisting of: 2, 6-di-tert-butylbipyridine, bipyridine, 2, 6-diphenyl bipyridine, 4, 7-diphenyl-1, 10-phenanthroline; preferably, the molar ratio of the ligand to the compound 4 is 0.05-0.5;
and/or, in step c), said metal compound is selected from the group consisting of: metallic zinc and metallic manganese; preferably, in the reaction, the molar ratio of the metal compound to the compound 4 is 0 to 0.5:0.8-1.2;
and/or, in step c), the organic base is selected from the group consisting of: triethylamine, tributylamine, N-diisopropylethylamine, or a combination thereof; preferably, in the reaction, the molar ratio of organic base to compound 4 is between 0 and 20:0.8-1.2; and/or, in step c), the molar ratio of the compound 5 to the compound 4 is 1-4: 0.8-1.2;
And/or, in step c), the decarboxylation coupling reaction temperature is between 0 and 100 ℃, preferably between 20 and 80 ℃.
In another preferred embodiment, in said step c), when X 2 When Cl, br and I are used, the molar ratio of the metal compound to the compound 4 is 0.05-0.5: 0.8-1.2.
In another preferred embodiment, in said step c), when X 2 Is B (OH) 2 When the reaction is carried out, no metal compound is added.
In another preferred embodiment, in said step c), when X 2 Is B (OH) 2 In the case of the organic base and the compound 4, the molar ratio is 10 to 20:0.8-1.2.
In another preferred embodiment, in said step c), when X 2 When Cl, br and I are used, no organic base is added in the reaction.
In some of the embodiments of the present invention,
in step d), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof; the volume mol ratio of the compound to the compound 6 is 10-50L/0.8-1.2 mol;
and/or, in step d), the acid is selected from the group consisting of: HCl, HClO 4 、PTSA.H 2 O、TiCl 4 Or PPA, more preferably PPA; preferably, the molar ratio of the acid to the compound 6 is 0.1 to 5:0.8-1.2;
and/or, in step d), the temperature of the ring closure reaction is 50-120 ℃, more preferably 80-120 ℃;
And/or, in the step d), the time of the ring closing reaction is 1-10 hours; preferably 5 to 10 hours.
In another preferred embodiment, in said step d), when said acid is PPA, the mass molar ratio of said acid to compound 6 is between 0.1 and 1g:0.8-1.2mmol; more preferably 0.6 to 1g:0.8-1.2mmol.
In some embodiments, the method further comprises: preparing a compound of formula 2 by the following step a):
a) In an alcohol solvent and water, under the action of alkali, carrying out hydrolysis reaction on the compound 1 to obtain a hydrolysis product; then adding an aprotic solvent, and carrying out oxidation reaction under the action of an oxidant to obtain a compound 2;
wherein ,R1 The definition of (2) is as described in the preceding.
In some of the embodiments of the present invention,
in step a), the alcoholic solvent is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, or combinations thereof;
and/or, in the step a), the volume ratio of the alcohol solvent to the water is 1-3: 0.8-1.2;
and/or, in the step a), the volume mole ratio of the alcohol solvent and water mixed solution to the compound 1 is 1-5L: 0.8-1.2mol;
and/or, in step a), the base is selected from the group consisting of: potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride, or a combination thereof; preferably, the mass ratio of the alkali to the compound 1 is 1-3: 0.8-1.2;
And/or, in step a), the temperature of the hydrolysis reaction is 25-80 ℃, preferably 50-80 ℃;
and/or, in step a), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in step a), the volume ratio of the aprotic solvent to the compound 1 is 1 to 20L:0.8-1.2mol;
and/or, in step a), the oxidizing agent is selected from the group consisting of: jones reagent, pyridinium chlorochromate (PCC), pyridinium Dichromate (PDC); preferably, the molar ratio of the oxidizing agent to the compound 1 is 1:1 to 3:1;
and/or, in step a), the temperature of the oxidation reaction is from 0 to 50 ℃, preferably from 0 to 25 ℃.
In some embodiments, the method further comprises the steps of:
e) In an aprotic solvent, under the action of a deprotection agent, carrying out deprotection reaction on the compound 7 to obtain a phenolic steroid compound 8;
wherein ,R1 Is as defined in the preceding description;
R 2 and R3 Each independently is H OR'; r' is selected from the group consisting of: c (C) 1 -C 4 Alkyl, C 2 -C 4 Acyl, C 1 -C 4 alkoxy-C 1 -C 4 Alkyl, C 1 -C 4 alkyl-C 6 -C 10 Aryl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl; and R is 2 and R3 Not simultaneously H;
R 4 、R 5 each independently is H or OH; and R is 4 and R5 And not H at the same time.
In some of the embodiments of the present invention,
in step e), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic solvents, naphthenic solvents, or combinations thereof; preferably, the volume mole ratio of the aprotic solvent to the compound 7 is 10 to 50L:0.8-1.2mol;
and/or, in the step e), the deprotection agent is sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium fluoride and boron tribromide; preferably, the molar ratio of the deprotection agent to the compound 7 is 1-5: 0.8-1.2;
and/or, in the step e), the temperature of the deprotection reaction is 0-100 ℃.
In a second aspect of the invention, there is provided a method of synthesizing a natural product Myrmenaphtol a, comprising the steps of:
i) In an aprotic solvent, under the action of alkali, performing a Wittig reaction on the compound 7 and the compound 9 to obtain a compound 10; wherein said compound 7 is prepared by a process according to the first aspect of the invention;
and the method further comprises: the natural product Myrmenaphtol A was prepared using the compound 10.
In some of the embodiments of the present invention,
in step I), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof; the volume mole ratio of the compound to the compound 7 is 10-50L: 0.8-1.2mol;
and/or, in step I), the base is selected from the group consisting of: potassium tert-butoxide, sodium tert-butoxide, KHMDS, naHMDS, liHMDS, naH; preferably, the molar ratio of the alkali to the compound 7 is 1-6: 0.8-1.2;
and/or, in step I), the molar ratio of compound 9 to compound 7 is 1 to 6:0.8-1.2;
and/or, in step I), the temperature of the Wittig reaction is 20-100 ℃, preferably 50-100 ℃;
in some embodiments, the preparation of the natural product Myrmenaphtol a from compound 7 is performed by the following steps:
II) in an aprotic solvent, under the action of an oxidant, carrying out allylic oxidation reaction on the compound 10 to obtain an intermediate, and then in the aprotic solvent, under the action of the oxidant, carrying out allylic hydroxyl oxidation reaction on the intermediate to obtain a compound 11;
III) in an aprotic solvent, under the action of alkali and an oxidant, carrying out a reaction of introducing hydroxyl into alpha position of carbonyl of the compound 11 to obtain a compound 12;
IV) in an aprotic solvent, under the action of an oxidant, carrying out enol isomerization reaction on the compound 12 to obtain a compound 13;
v) in aprotic solvent or alcohol solvent, under the action of deprotection agent, compound 13 is subjected to deprotection reaction to obtain natural product Myrmenaphtol A;
wherein ,
R 2 is as defined above;
x is Cl, br or I.
In some of the embodiments of the present invention,
in step II), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof; the volume mole ratio of the compound to the compound 10 is 10-50L: 0.8-1.2mol;
and/or, in step II), the oxidizing agent of the allylic oxidation reaction is selected from the group consisting of: seO (SeO) 2 t-BuOOH, PCC, PDC; preferably, the molar ratio of the oxidizing agent to the compound 10 is 0.5 to 8:0.8-1.2;
and/or, in the step II), the temperature of the allylic oxidation reaction is 0-80 ℃, preferably 15-50 ℃;
and/or, step II), said oxidizing agent of the oxidation of the allylic hydroxyl group is selected from the group consisting of: jones reagent, dess-martin reagent, manganese dioxide; the molar ratio of the compound to the compound 10 is 2-20: 0.8-1.2; preferably 5 to 10:0.8-1.2;
And/or, in the step II), the temperature of the allylic hydroxyl oxidation reaction is 0-80 ℃, and more preferably 0-50 ℃;
and/or, in step III), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbons, ethers, aromatic hydrocarbons, naphthenic hydrocarbon solvents, or combinations thereof; the volume mole ratio of the compound to the compound 11 is 6-20L: 0.8-1.2mol;
and/or, in step III), the oxidizing agent is selected from the group consisting of: davis reagent, oxygen; the molar ratio of the compound to the compound 11 is 1-3: 0.8-1.2;
and/or, in the step III), the alkali is KHMDS, naHMDS, potassium tert-butoxide, sodium tert-butoxide and Lithium Diisopropylamide (LDA); the molar ratio of the compound to the compound 11 is 1-3: 0.8-1.2;
and/or, in step III), the temperature of the oxidation reaction is preferably-20 to 50 ℃, preferably-15 to 25 ℃;
and/or, in the step IV), the aprotic solvent is one or more of halogenated hydrocarbon solvents, ethers solvents, ketones solvents, aromatic solvents and naphthenic solvents; the volume mole ratio of the compound to the compound 12 is 6-20L: 0.8-1.2mol;
and/or, in step IV), the oxidizing agent is selected from the group consisting of: swern reagent, jones reagent, PDC, PCC, dess-martin reagent; the molar ratio of the compound to the compound 12 is 2-20: 0.8-1.2; preferably 5-10:0.8-1.2;
And/or, in step IV), the temperature of the oxidation reaction is preferably-78 to 80 ℃, preferably-78 to 25 ℃;
and/or, in the step V), the aprotic solvent is one or more of halogenated hydrocarbon solvents, ethers solvents, aromatic solvents and naphthenic solvents; the volume mole ratio of the compound to the compound 13 is 10-50L: 0.8-1.2mol;
and/or, in the step V), the alcohol solvent is one or more of methanol, ethanol, n-propanol and isopropanol; the volume mole ratio of the compound to the compound 13 is 10-30L: 0.8-1.2mol.
And/or, in the step V), the deprotection agent is sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium fluoride and boron tribromide; the molar ratio of the compound to the compound 13 is 1-5: 0.8-1.2;
and/or, in the step V), the temperature of the deprotection reaction is 0-100 ℃.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies and have unexpectedly found a method for synthesizing a phenolic steroid compound and its use in synthesizing a natural product. The present invention has been completed on the basis of this finding.
Definition of the definition
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this context, the term "substituted" means that one or more hydrogen atoms on the group are replaced by substituents selected from the group consisting of: c (C) 1 ~C 8 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 8 Alkoxy, halogen, hydroxy, carboxyl, cyano, C 1 ~C 10 Aldehyde group, C 2 ~C 6 Acyl, C 2 ~C 10 An ester group, an amino group, a phenyl group; the phenyl group comprises unsubstituted phenyl or substituted phenyl with 1-3 substituents selected from the group consisting of: halogen, C 1 ~C 10 Alkyl, cyano, hydroxy, nitro, C 3 ~C 8 Cycloalkyl, C 1 ~C 8 Alkoxy, amino.
Unless otherwise specified, each chiral carbon atom in all compounds of the invention may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C 1 -C 6 Alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.
As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C 1 -C 6 Alkoxy "refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specified number of ring atoms (e.g., 3-10 ring atoms), and wherein 1-3 atoms are heteroatoms selected from N, S and O. It may be monocyclic or may be in the form of a double or multiple ring, for example in the form of a bridged or spiro ring. Specific examples may be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
As used herein, the term "aryl" refers to a cyclic aromatic group having a specified number of carbon atoms. For example, "C 6 -C 10 Aryl "refers to aryl groups having 6 to 10 carbon atoms, such as phenyl, naphthyl, or the like.
As used herein, the term "heteroaryl" refers to a cyclic aromatic group having a specified number of ring atoms, and wherein 1-3 atoms are heteroatoms selected from N, S and O. It may be a single ring or may be in the form of a fused ring. For example, "5-12 membered heteroaryl" refers to heteroaryl groups having 5-12 carbon atoms, such as pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolinyl, or the like.
As used herein, the term "acyl" refers to a-C (=o) R group having a specific number of carbon atoms. For example, C2-6 acyl refers to a-C (=O) R group having 2 to 6 carbon atoms, such as-C (=O) CH 3 、-C(=O)C 2 H 5 、-C(=O)C 3 H 7 、-C(=O)C 4 H 9 Or the like.
As used herein, the term "ester group" refers to an R-O-C (=o) -group having a specific number of carbon atoms. For example, C2-6 acyl refers to an R-O-C (=o) -group having 2 to 6 carbon atoms, such as-C (=o) OCH 3 、-C(=O)OC 2 H 5 、-C(=O)OC 3 H 7 、-C(=O)OC 4 H 9 Or the like.
As used herein, the term "alkenyl" refers to alkenyl groups having a particular number of carbon atoms, including straight or branched alkenyl groups. For example C 2 -C 6 Alkenyl refers to straight or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" refers to an alkynyl group having a particular number of carbon atoms, including straight or branched chain alkynyl groups. For example C 2 -C 6 Alkynyl refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
The term "amine group" as used herein refers to a-NR group having from 0 to 6 carbon atoms 1 R 2 Radicals, e.g. -NH 2 ,-NHCH 3 ,-NHC(=O)CH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 Or the like. Herein, amine groups are intended to include amino groups, i.e., -NH- 2 。
As used herein, the term "amide" refers to a-C (=o) NR having a carbon atom of a particular number of carbon atoms 1 R 2 Radicals, e.g. -C (=O) NH 2 、-C(=O)NHCH 3 、-C(=O)N(CH 3 ) 2 Or the like.
As used herein, the term "sulfonamide" refers to-S (=o) having a specified number of carbon atoms 2 NR 1 R 2 A group. For example C 1 -C 6 Sulfonamide refers to sulfonamide groups having 1 to 6 carbon atoms, such as-S (=o) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 Or the like.
As used herein, the term "halogen" refers to F, cl, br, and I.
Unless otherwise indicated, the formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers), such as R, S configuration containing an asymmetric center, the (Z), (E) isomers of double bonds and the conformational isomers of (Z), (E).
The term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton transfer) include interconversions by proton transfer, such as 1H-indazole with 2H-indazole, 1H-benzo [ d ] imidazole with 3H-benzo [ d ] imidazole, valence tautomers include interconversions by recombination of some bonding electrons.
In this context, a form such as "C1-C6" means that the group may have 1 to 6 carbon atoms, for example 1, 2, 3, 4, 5 or 6.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Examples
In the examples below, the operating temperatures, as not limited, were all carried out at room temperature. The room temperature is 0-35 ℃, preferably 20-30 ℃.
In the following examples, calculated for refers to the calculated value and found refers to the actual value.
EXAMPLE 1 Synthesis of Compound 2a
Compound 1a (5.0 g,22.52 mmol) was added to the flask, followed by potassium hydroxide (1.5 g,27.03mmol,1.2 equiv), 13.5mL of water and 13.5mL of ethanol were added to dissolve, reacted at 80℃for about 3 hours, the starting material was detected as disappeared by TLC, the solvent was spun-dried, additional water was dissolved, and further spun-dried, and repeated three times to remove ethanol as much as possible. A further 18mL of acetone was added and dissolved, and Jones reagent (13.5 mL,2.67M,1.6 equiv) was added under ice bath. Extracting with ethyl acetate for three times after reacting for 45-60min, mixing organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtration, vacuum rotary evaporation to remove solvent, column chromatography separation, and obtaining compound 2a,3.7g, yield 70%.
mp:109-111℃;
IR(KBr)ν=3130,2965,1731,1707,1218,1175,915,819cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ2.71–2.37(m,6H),2.31–2.17(m,1H),2.11–1.96(m,2H),1.95–1.73(m,4H),1.73–1.62(m,1H),1.18(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ218.0,210.6,179.3,49.5,49.1,47.7,37.5,36.2,31.8,30.5,22.4,21.3,13.6ppm;
HRMS(ESI-TOF,m/z):calcd for C 13 H 19 O 4 [M+H] + 239.1278;found 239.1278.
EXAMPLE 2 Synthesis of Compound 4a
Compound 2a (3.5 g,14.71 mmol), DMAP (179.7 mg,1.47mmol,0.1 equiv) and Compound 3a (2.6 g,16.18mmol,1.1 equiv) were added to a dry reaction flask, purged with argon, and dissolved in 147.0ml of dichloromethane. DIC (2.5 mL,16.18mmol,1.1 equiv) was added dropwise under ice bath, the reaction was warmed to room temperature and monitored by TLC. After the reaction is finished, insoluble substances are filtered and removed, then dichloromethane is used for extraction for three times, the organic phases are combined, water is used for washing until the solution becomes clear, saturated NaCl solution is used for washing, and anhydrous Na is used for washing 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove solvent, column chromatography separation, and obtaining compound 4a,3.8g, yield 68%.
IR(KBr)ν=2963,1814,1787,1742,1707,1186,1081,698cm -1 ;
1 H NMR(500MHz,CDCl 3 )δ7.88–7.82(m,2H),7.80–7.74(m,2H),2.94–2.75(m,2H),2.67(t,J=9.7Hz,1H),2.61–2.48(m,2H),2.42(ddd,J=15.4,5.4,1.7Hz,1H),2.27–2.15(m,1H),2.05–1.94(m,3H),1.89–1.76(m,3H),1.63(td,J=13.4,5.5Hz,1H),1.20(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ217.78,210.4,169.7,162.0,134.9,128.9,124.0,49.7,48.5,47.7,37.5,36.1,30.6,29.2,22.2,21.6,13.6ppm;
HRMS(ESI-TOF,m/z):calcd for C 21 H 22 NO 6 [M+H] + 384.1442;found 384.1448.
EXAMPLE 3 Synthesis of Compound 4a
Compound 2a (1 g,4.2 mmol), DMAP (102 mg,0.84mmol,0.2 equiv) and compound 3a (1.3 g,8.4mmol,2 equiv) were added to a dry reaction flask, purged with argon, and dissolved in 147.0ml of dichloromethane. DDC (1.3 mL,8.4mmol,2 equiv) was added dropwise under ice bath and the reaction monitored by TLC. After the reaction is finished, insoluble substances are filtered and removed, then dichloromethane is used for extraction for three times, the organic phases are combined, water is used for washing until the solution becomes clear, saturated NaCl solution is used for washing, and anhydrous Na is used for washing 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove solvent, column chromatography separation, and obtaining compound 4a,1.1g, yield 65%.
EXAMPLE 4 Synthesis of Compound 4b
Compound 2a (238.0 mg,1 mmol), DMAP (12.2 mg,0.1mmol,0.1 equiv) and compound 3b (300.9 mg,1.0mmol,1.0 equiv) were added to a dry reaction flask, purged with argon, and dissolved in 10.0ml of dichloromethane. DIC (0.17 mL,1.1mmol,1.1 equiv) was added dropwise at room temperature and the reaction monitored by TLC. After the reaction is finished, insoluble substances are filtered and removed, then dichloromethane is used for extraction for three times, the organic phases are combined, water is used for washing until the solution becomes clear, saturated NaCl solution is used for washing, and anhydrous Na is used for washing 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove solvent, column chromatography separation, and obtaining compound 4b,354.3mg, yield 68%.
mp:171-172℃;
IR(KBr)ν=2964,2883,1819,1747,1739,732cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ2.98–2.88(m,1H),2.88–2.78(m,1H),2.69–2.41(m,4H),2.30–2.17(m,1H),2.10–1.96(m,3H),1.93–1.75(m,3H),1.72–1.65(m,1H),1.22(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ217.7,210.4,169.4,157.7,141.3,130.7,124.9,49.8,48.7,47.9,37.6,36.2,30.7,29.2,22.4,21.8,13.7ppm;
HRMS(ESI-TOF,m/z):calcd for C 13 H 19 O 4 [M+NH 4 ] + 537.0148;found 537.0150.
EXAMPLE 5 Synthesis of Compound 6a
Compound 4a (3.8 g,9.92 mmol), compound 5a (2.8 g,11.91mmol,1.2 equiv.) and zinc powder (1.3 g,19.84mmol,2.0 equiv.) are added to the flask and purged with argon. NiBr is added to 2 (diglyme) (349.9 mg,0.99mmol,0.1 equiv), dtbpy (266.3 mg,0.99mmol,0.1 equiv) was added to another dry reaction flask, vented, argon protected, and 47.6mL DMAc was added and dissolved with stirring to give a blue-green solution. Adding the solution into a substrate reaction bottle, reacting at room temperature, and finishing the reaction. Filtering to remove zinc powder, extracting with ethyl acetate three times, mixing organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove solvent, column chromatography separation, and obtaining compound 6a,76.4mg, yield 65%.
IR(KBr)ν=2593,2835,1739,1706,1512,1245,1176,1036,830cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ7.12(d,J=8.5Hz,2H),6.83(d,J=8.5Hz,2H),3.79(s,3H),2.79–2.65(m,1H),2.61–2.43(m,5H),2.27–2.15(m,1H),2.05–1.82(m,4H),1.76–1.64(m,3H),1.13(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ218.1,210.6,157.8,134.3,129.3,113.8,55.3,49.3,49.3,47.5,37.4,36.1,32.5,30.4,28.3,22.5,13.2ppm;
HRMS(ESI-TOF,m/z):calcd for C 19 H 25 O 3 [M+H] + 301.1798;found 301.1796.
EXAMPLE 6 Synthesis of Compound 6a
NiBr is added to 2 (diglyme) (105.8 mg,0.3mmol,3.0 equiv), dtbpy (80.5 mg,0.3mmol,3 equiv) was dried in a reaction flask, purged with argon, and dissolved in 6mL of DMF, and stirred at room temperature for 30min to give a green solution. Can be used for several times in several days. In another reaction flask, compound 4b (52.1 mg,0.1mmol,1.0 equiv) and Compound 5b (45.6 mg,0.3mmol,3.0 equiv) were added, purged with argon, 4mL of dioxane was added to dissolve, followed by Et 3 N (139. Mu.L, 10.0 equiv) was allowed to settle after stirring for 2-5 minutes, then NiCl was added 2 Diglyme/ligands (0.05M in DMF,0.4mL,20mol%), stirred for 2 hours at 75℃in an oil bath. After cooling to room temperature, extraction with ethyl acetate was performed three times, the combined organic phases were washed with 1M aqueous HCl, washed with water, with saturated NaCl solution, with anhydrous Na 2 SO 4 Drying, suction filtration, vacuum rotary evaporation to remove the solvent, column chromatography separation, compound 6a,18.1mg, yield 60%.
EXAMPLE 7 Synthesis of Compound 6b
Into a reaction flask, compound 4a (70.0 mg,0.18mmol,1.0 equiv) and Compound 5c (65.7 mg,0.36mmol,2 equiv) were introduced, purged with argon, 6mL of tetrahydrofuran was added to dissolve, followed by Et 3 N (0.3 mL,12.0 equiv) was allowed to settle after stirring for 2-5 minutes, then NiCl was added 2 Diglyme/ligands (0.05M in DMF,1.1mL,30mol%), stirring for 6 hours at 60℃in an oil bath. After cooling to room temperature, extraction with ethyl acetate was performed three times, the combined organic phases were washed with 1M aqueous HCl, washed with water, with saturated NaCl solution, with anhydrous Na 2 SO 4 Drying, suction filtering, and removing solvent by rotary evaporation under reduced pressureColumn chromatography gave compound 6b,34.8mg, 58% yield.
IR(KBr)ν=1744,1687,1705,1401,1417,1196,887,986cm -1
1 H NMR(400MHz,CDCl3)δ7.22(dd,J=6.7,6.1Hz,1H),7.15(d,J=6.8Hz,2H),6.97(d,J=7.7Hz,1H),2.42(s,3H),2.41–2.34(m,2H),2.22–2.04(m,4H),1.97–1.87(m,4H),1.82–1.61(m,4H),1.36(s,3H);
13 C NMR(101MHz,CDCl3)δ212.4,192.4,155.7,148.4,141.8,125.3,120.3,110.2,82.4,75.6,72.9,51.7,46.8,41.3,41.7,38.1,28.6,26.1,17.4,9.9;
EXAMPLE 8 Synthesis of Compound 7a
Compound 6a (300.0 mg,1.00 mol) was added to a reaction flask, PPA (600 mg,0.60 g/mol) was added, 10.0mL toluene was added to dissolve, and the mixture was dissolved in O 2 Heating at 80deg.C, cooling to room temperature after the reaction is completed, quenching with water, extracting with ethyl acetate for three times, mixing organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove solvent, column chromatography separation, and obtaining the compound 7a,154.8mg, and the yield is 55%.
mp:168-170℃;
IR(KBr)ν=2958,2931,1736,1624,1514,1459,1228,1033,838cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ7.74(d,J=8.9Hz,1H),7.67(d,J=8.3Hz,1H),7.19(d,J=8.4Hz,2H),7.13(dd,J=8.9,2.4Hz,1H),3.94(s,3H),3.35–3.14(m,3H),2.71(dd,J=19.2,8.7Hz,1H),2.62–2.51(m,1H),2.46–2.34(m,1H),2.25(ddd,J=13.1,7.2,1.8Hz,1H),2.10–1.98(m,1H),1.97–1.85(m,1H),0.83(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ220.1,158.1,135.1,133.2,130.4,129.7,128.0,126.5,121.6,117.6,102.1,55.4,47.7,47.2,36.8,29.3,24.3,22.0,13.4ppm;
HRMS(ESI-TOF,m/z):calcd for C 19 H 21 O 2 [M+H] + 281.1536;found 281.1536.
EXAMPLE 9 Synthesis of Compound 7b
Compound 6b (328.0 mg,1.00 mol) was added to a reaction flask, PPA (800 mg,0.80 g/mol) was added, and 20.0mL benzene was added to dissolve in O 2 Heating at 75deg.C, cooling to room temperature, quenching with water, extracting with ethyl acetate for three times, mixing organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove the solvent, column chromatography separation, and obtaining the compound 7b,178.9mg, with a yield of 58%.
1 H NMR(400MHz,CDCl 3 )δ7.97(d,J=8.8Hz,1H),7.67(d,J=8.9Hz,1H),7.52(s,1H),7.30(dd,J=9.3,2.5Hz,1H),7.21(d,J=2.8Hz,1H),3.34–3.12(m,3H),2.69(dd,J=19.2,8.7Hz,1H),2.59–2.49(m,1H),2.49–2.32(m,1H),2.35(s,3H),2.23(ddd,J=13.2,7.4,2.0Hz,1H),2.10–1.99(m,1H),1.98–1.86(m,1H),0.81(s,3H)ppm;
13 C NMR(101MHz,CDCl3)δ220.0,170.1,157.1,133.6,132.3,131.2,127.4,125.6,124.9,124.6,118.8,106.7,47.6,46.8,46.5,36.7,29.2,24.2,22.1,13.2ppm;
HRMS(ESI-TOF,m/z):calcd for C 20 H 21 O 3 [M+H] + 309.1485;found 309.1485.
EXAMPLE 10 Synthesis of Compound 8a
Compound 7a (100.0 mg,0.36 mmol) was added to a dry reaction flask, purged with argon, dissolved in 6ml DCM, placed at 0deg.C and BBr added dropwise 3 (0.72 mL,0.72mmol,1.0M,2 equiv) and stirred at this temperature for 1.5 hours. Stopping the reaction when the raw materials are reacted completely. Dripping NaHCO at 0 DEG C 3 Quenching the saturated solution until the system turns brown to light, heating to room temperature, extracting with dichloromethane three times, mixing the organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, washing with anhydrous Na 2 SO 4 Drying, suction filtering, removing solvent by rotary evaporation under reduced pressure, and separating by column chromatography (SiO 2 Petroleum ether: etoac=1:1) to give compound 8a,84mg in 88% yield.
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J=8.9Hz,1H),7.68(d,J=8.3Hz,1H),7.20(d,J=8.4Hz,2H),7.14(dd,J=8.9,2.4Hz,1H),3.36–3.15(m,3H),2.73(dd,J=19.2,8.7Hz,1H),2.63–2.53(m,1H),2.48–2.35(m,1H),2.26(ddd,J=13.1,7.2,1.8Hz,1H),2.11–2.00(m,1H),1.98–1.86(m,1H),0.84(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ220.2,158.2,135.2,133.3,130.5,129.6,128.1,126.6,121.7,117.8,102.2,47.8,47.3,36.9,29.5,24.4,22.1,13.5ppm;
HRMS(ESI-TOF,m/z):calcd for C 18 H 19 O 2 [M+H] + 267.1380,found 267.1382.
EXAMPLE 11 Synthesis of Compound 8b
Compound 7b (100 mg,0.33 mmol) was added to a reaction flask, followed by potassium carbonate (134 mg,0.97mmol,3 equiv), 6mL of methanol was added, the reaction was carried out at 50℃for about 2 hours, TLC was used to detect disappearance of starting material, heating was stopped, after cooling to room temperature, the solvent was removed by rotary evaporation under reduced pressure, extraction with dichloromethane, adjustment to neutrality with dilute aqueous hydrochloric acid solution, washing of the combined organic phase with water, washing with saturated NaCl solution, washing with anhydrous Na 2 SO 4 Drying, suction filtering, removing solvent by rotary evaporation under reduced pressure,column chromatography gave compound 8b,79.46mg in 92% yield.
m.p.:250–252℃;
1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.02(d,J=9.8Hz,1H),6.75(d,J=8.3Hz,1H),6.42(d,J=8.3Hz,1H),6.31(dq,J=5.1,2.6Hz,2H),2.48–2.24(m,3H),1.83(dd,J=18.9,8.5Hz,1H),1.69–1.61(m,1H),1.52(dt,J=18.6,8.9Hz,1H),1.21(dd,J=12.9,6.4Hz,1H),1.12–0.89(m,2H),0.03(s,3H)ppm;
13 C NMR(101MHz,DMSO-d6)δ219.4,155.0,134.0,131.8,130.8,126.6,125.2,125.2,124.6,119.0,110.0,47.2,46.2,36.5,29.1,24.0,21.9,13.2ppm;
HRMS(ESI-TOF,m/z):calcd for C 18 H 19 O 2 [M+H] + 267.1380,found 267.1380.
EXAMPLE 12 Synthesis of Compound 10a
PPh is added into a dry reaction bottle 3 EtBr (596.0 mg,1.61mmol,3.0 equiv), vented under argon, THF 1.35mL was added and potassium tert-butoxide (1.61 mL.1.0M,3.0 equiv) was added rapidly at room temperature and stirred for 30min. Compound 7a (150.0 mg,0.54 mmol) was added to the flask, purged with argon, and dissolved in 5.4mL of THF. The substrate was added to the reaction flask and heated at 80 ℃. After the raw materials are reacted completely, cooling to room temperature, adding NH 4 After Cl quenching, the mixture was extracted three times with ethyl acetate and the combined organic phases were washed with water until the solution became clear, with saturated NaCl solution, with anhydrous Na 2 SO 4 Drying, suction filtration, vacuum rotary evaporation to remove the solvent, column chromatography separation, and 10a,128.3mg of the compound is obtained, and the yield is 82%.
IR(KBr)ν=2949,1625,1515,1223,836cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J=8.9Hz,1H),7.62(d,J=8.3Hz,1H),7.21(d,J=2.3Hz,1H),7.17(d,J=8.3Hz,1H),7.11(dd,J=8.9,2.4Hz,1H),5.31(qt,J=7.1,2.0Hz,0.9H),5.27–5.20(m,0.1H),3.95(s,3H),3.35–3.17(m,2H),3.04(dd,J=12.9,6.1Hz,1H),2.77–2.45(m,3H),2.31–2.10(m,2H),1.83–1.69(m,4H),0.80(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ157.8,149.1,137.2,133.0,130.3,129.6,127.7,125.8,122.5,117.0,114.8,102.1,99.2,55.4,52.0,44.1,34.6,32.4,24.9,24.7,16.6,13.5ppm;
HRMS(ESI-TOF,m/z):calcd for C 21 H 23 O 2 [M+H] + 293.1900;found 293.1900.
EXAMPLE 13 Synthesis of Compound 10a
PPh is added into a dry reaction bottle 3 EtI (1.19 g,2.85mmol,4.0 equiv), vented under argon, THF 3mL was added and KHMDS (2.85 mL.1.0M,4.0 equiv) was added rapidly at room temperature and stirred for 30min. Compound 7a (200.0 mg,0.71 mmol) was added to the flask, purged with argon, and dissolved in 8mL THF. The substrate was added to the reaction flask and heated at 70 ℃. After the raw materials are reacted completely, cooling to room temperature, adding NH 4 After Cl quenching, the mixture was extracted three times with ethyl acetate and the combined organic phases were washed with water until the solution became clear, with saturated NaCl solution, with anhydrous Na 2 SO 4 Drying, suction filtration, reduced pressure rotary evaporation to remove solvent, column chromatography separation, 10a,166.8mg of compound was obtained, yield 80%.
EXAMPLE 14 Synthesis of Compound 11a
Compound 10a (100.0 mg,0.34 mmol) was added to a reaction flask and SeO was added 2 (18.9 mg,0.17mmol,0.5 equiv.) under argon, addAdding 3.4mL DCM, reacting at room temperature for 30min, standing at 0deg.C, adding TBHP (0.2mL,5.5M in hexane,3.0equiv), heating to room temperature for 3h, adding NaHCO 3 Extracting with dichloromethane three times after quenching, mixing the organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtering, and removing the solvent by rotary evaporation under reduced pressure to obtain a crude product. The crude product was taken up in 3.4mL of DCM solvent and MnO was added 2 (297.7 mg,3.42mmol,10.0 equiv.) at room temperature, filtering after completion of the reaction, removing the solvent by rotary evaporation under reduced pressure, and separating by column chromatography to give compound 11a,48.2mg in 48% yield.
IR(KBr)ν=2956,2840,1721,1650,1624,1516,1462,1231,1221,835cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J=8.9Hz,1H),7.66(d,J=8.3Hz,1H),7.21(d,J=2.1Hz,1H),7.14(dd,J=8.9,2.4Hz,1H),7.05(d,J=8.3Hz,1H),6.70(q,J=7.5Hz,1H),3.96(s,3H),3.43–3.21(m,3H),2.77(ddd,J=19.9,14.4,7.1Hz,2H),2.53(dd,J=16.9,14.5Hz,1H),2.30(dd,J=21.9,9.3Hz,1H),1.98(d,J=7.5Hz,3H),0.90(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ205.6,158.1,147.2,134.4,133.0,130.7,130.4,129.3,128.0,126.4,122.2,117.5,101.9,55.4,45.9,42.9,38.1,33.9,24.0,17.3,13.6ppm;
HRMS(ESI-TOF,m/z):calcd for C 21 H 23 O 2 [M+H] + 307.1693;found 307.1693.
EXAMPLE 15 Synthesis of Compound 11a
Compound 10a (100.0 mg,0.34 mmol) was added to the flask, PCC (18.9 mg,1.02mmol,3 equiv) was added, purged with argon, 5mL of DCM was added, and reacted at 40℃for 5h. Filtering with diatomite Removing solid, quenching with water, extracting with dichloromethane three times, mixing organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtering, and removing the solvent by rotary evaporation under reduced pressure to obtain a crude product. The crude product was taken up in 5mL of DCM and NaHCO was added 3 (142.8 mg,1.70mmol,5.0 equiv) and dess-Martin reagent (721.0 mg,1.70mmol,5.0 equiv), at 0deg.C for 3h, quenched with water, extracted three times with dichloromethane, the combined organic phases washed with water until the solution becomes clear, washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, rotary evaporation under reduced pressure, and column chromatography gave compound 11a,41.9mg in 40% yield.
EXAMPLE 16 Synthesis of Compound 12a
Compound 11a (20 mg,0.065 mmol) was added to a reaction flask, 0.65mL dioxane was added, and 2.4 μ L H 2 O, 1 drop of acetic acid, seO 2 (14.5 mg,0.13mmol,2.0 equiv) was heated at 100deg.C. Stopping heating when the raw materials react completely, and cooling to room temperature. Filtering to remove insoluble solid, extracting with ethyl acetate three times, mixing organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtration, rotary evaporation under reduced pressure to remove solvent, column chromatography separation, and obtaining 12a,14.6mg of compound with a yield of 70%.
IR(KBr)ν=3458,2933,1724,1645,1624,1515,1462,1222,1111,1078,833cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ7.76(d,J=8.9Hz,1H),7.70(d,J=8.3Hz,1H),7.61(d,J=8.4Hz,1H),7.20(d,J=2.2Hz,1H),7.15(dd,J=8.9,2.3Hz,1H),6.88(q,J=7.5Hz,1H),4.48(dd,J=12.6,2.1Hz,1H),3.96(s,3H),3.41–3.22(m,2H),3.12(d,J=12.4Hz,1H),2.93(d,J=2.1Hz,1H),2.75–2.64(m,1H),2.31–2.21(m,1H),2.03(d,J=7.5Hz,3H),0.98(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ205.7,158.0,143.4,134.1,133.3,133.0,130.5,129.3,128.2,126.7,122.8,117.4,102.0,75.5,55.5,52.8,39.8,34.4,23.9,18.9,14.1ppm;
HRMS(ESI-TOF,m/z):calcd for C 21 H 23 O 3 [M+H] + 323.1642;found 323.1642.
EXAMPLE 17 Synthesis of Compound 13a
In a dry reaction flask, DMSO (25. Mu.L, 0.35mmol,10.0 equiv) was added under argon, dissolved in 0.1ml DCM, and TFAA (15. Mu.L, 0.11mmol,3.0 equiv) was added dropwise at-78deg.C and stirred at this temperature for 30min. Compound 12a (10 mg,0.031 mmol) was added to a dry reaction flask, purged with argon, dissolved in 0.15mL DCM, stirred for 1.5h at-78deg.C, DIPEA (61. Mu.L, 0.35mmol,10.0 equiv) was added dropwise at a temperature at which the starting materials reacted to completion, na was added at-78deg.C 2 S 2 O 3 Quenching, heating to room temperature, extracting with dichloromethane three times, mixing the organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtering, removing solvent by rotary evaporation under reduced pressure, and separating by column chromatography (SiO 2 Petroleum ether: etoac=5:1) to give compound 13a,8.1mg in 82% yield.
IR(KBr)ν=3254,2919,1677,1621,1397,1227cm -1 ;
1 H NMR(400MHz,CDCl 3 )δ8.10(d,J=8.6Hz,1H),7.75(dd,J=13.5,8.7Hz,2H),7.30(d,J=2.3Hz,1H),7.21(dd,J=8.9,2.4Hz,1H),6.78(q,J=7.5Hz,1H),6.50(br s,1H),3.96(s,3H),3.45–3.20(m,2H),2.69–2.57(m,1H),2.07(d,J=7.5Hz,3H),1.92(td,J=12.6,6.5Hz,1H),1.36(s,3H)ppm;
13 C NMR(101MHz,CDCl 3 )δ189.0,158.3,146.8,142.2,140.8,133.1,131.4,130.8,130.4,129.1,127.0,126.7,124.6,118.8,103.1,55.5,40.1,31.8,24.1,22.1,14.7ppm;
HRMS(ESI-TOF,m/z):calcd for C 21 H 21 O 3 [M+H] + 321.1485;found 321.1486.
EXAMPLE 18 Synthesis of the Natural product Myrmenaphtol A
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Compound 13a (10.0 mg,0.031 mmol) was added to a dry reaction flask, purged with argon, dissolved in 0.3ml DCM, and BBr was added dropwise at 0deg.C 3 (47. Mu.L, 0.047mmol,1.0M,1.5 equiv) was stirred at this temperature for 30min. Stopping the reaction when the raw materials are reacted completely. Dripping NaHCO at 0 DEG C 3 Quenching the saturated solution until the system turns brown to light, heating to room temperature, extracting with dichloromethane three times, mixing the organic phases, washing with water until the solution becomes clear, washing with saturated NaCl solution, washing with anhydrous Na 2 SO 4 Drying, suction filtering, removing solvent by rotary evaporation under reduced pressure, and separating by column chromatography (SiO 2 Petroleum ether: etoac=1:1) to give the compound Myrmenaphtol a,8.6mg, 90% yield.
IR(KBr)ν=3425,1667,1620,1420,1222cm -1 ;
1 H NMR(400MHz,MeOD)δ8.08(d,J=8.5Hz,1H),7.71(d,J=8.8Hz,1H),7.66(d,J=8.7Hz,1H),7.35(d,J=2.2Hz,1H),7.11(dd,J=8.8,2.3Hz,1H),6.65(q,J=7.5Hz,1H),3.29–3.17(m,2H),2.69(dd,J=13.0,5.9Hz,1H),2.07(d,J=7.6Hz,3H),1.88–1.77(m,1H),1.33(s,3H)ppm;
13 C NMR(101MHz,CD 3 OD)δ190.8,157.1,149.3,144.1,143.3,134.7,131.9,131.2,130.8,129.6,128.2,127.3,124.7,119.6,106.9,40.8,33.0,24.8,22.4,14.7ppm;
HRMS(ESI-TOF,m/z):calcd for C 20 H 19 O 3 [M+H] + 307.1329;found 307.1328.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (24)
1. The synthesis method of the phenolic steroid compound is characterized by comprising the following steps:
b) In an aprotic solvent, under the action of a catalyst and a condensing agent, performing condensation reaction on the compound 2 and the compound 3 to obtain a compound 4;
c) In polar solvent or mixed solution of polar solvent and aprotic solvent, under the action of metal Ni catalyst and ligand and under the action of metal compound or organic base, compound 4 and compound 5 undergo decarboxylation coupling reaction to obtain compound 6; the metal compound is selected from the following group: metallic zinc and metallic manganese; the organic base is selected from the following group: triethylamine, tributylamine, N-diisopropylethylamine, or a combination thereof; the ligand is selected from the group consisting of: 2, 6-di-tert-butylbipyridine, bipyridine, 2, 6-diphenyl bipyridine, 4, 7-diphenyl-1, 10-phenanthroline;
d) In an aprotic solvent, under the action of acid and oxygen, carrying out ring closure reaction on the compound 6 to obtain a steroid compound 7;
wherein ,
c=o;
R 2 and R3 Each independently is H OR'; r' is selected from the group consisting of: H. c (C) 1 -C 4 Alkyl, C 2 -C 4 Acyl, C 1 -C 4 alkoxy-C 1 -C 4 Alkyl, C 1 -C 4 alkyl-C 6 -C 10 Aryl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
and ,R2 and R3 Not simultaneously H;
each X is 1 Each independently H, cl;
X 2 is Cl, br, I or B (OH) 2 。
2. The synthesis method according to claim 1, wherein,
in step b), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in step b), the volume molar ratio of the aprotic solvent to the compound 2 is 10 to 30L:0.8-1.2mol;
and/or, in step b), the catalyst is Dimethylaminopyridine (DMAP);
and/or, in step b), the molar ratio of the catalyst to the compound 2 is between 0.01 and 0.5:0.8-1.2;
and/or, in step b), the condensing agent is selected from the group consisting of: n, N' -Diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC);
and/or, in the step b), the compound 3 is N-hydroxy phthalimide (NHPI) or N-hydroxy Tetrachlorophthalimide (TCNHPI);
And/or, in step b), the condensation reaction temperature is 0-80 ℃.
3. The synthesis method according to claim 1, wherein,
in the step b), the molar ratio of the compound 3 to the compound 2 is 1-3: 0.8-1.2;
and/or, in the step b), the condensation reaction temperature is 10-50 ℃;
and/or the molar ratio of the condensing agent to the compound 2 is 1-3: 0.8-1.2.
4. The synthesis method according to claim 1, wherein,
in step c), the polar solvent is selected from the group consisting of: sulfoxide polar solvents, amide polar solvents, or combinations thereof;
and/or, in step c), the volume molar ratio of the polar solvent to the compound 4 is between 5 and 20L:0.8-1.2mol;
and/or, in step c), said aprotic solvent is selected from the group consisting of: ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in the step c), when a mixed solution of a polar solvent and an aprotic solvent is used, the volume ratio of the polar solvent to the aprotic solvent is 1:5-10;
and/or, in the step c), the volume mole ratio of the polar solvent and aprotic solvent mixed solution to the compound 4 is 10-50L: 0.8-1.2mol;
And/or, in step c), the metallic Ni catalyst is selected from the group consisting of: niCl 2 ·6H 2 O、NiBr 2 DME, or NiBr 2 ·diglyme;
And/or, in the reaction, the molar ratio of the organic base to the compound 4 is 0 to 20:0.8-1.2; and/or, in step c), the molar ratio of the compound 5 to the compound 4 is 1-4: 0.8-1.2;
and/or, in the step c), the decarboxylation coupling reaction temperature is 0-100 ℃.
5. The synthesis method according to claim 4, wherein,
in step c), the sulfoxide-based polar solvent is dimethyl sulfoxide (DMSO), and the amide-based polar solvent is selected from the group consisting of: n, N '-Dimethylformamide (DMF), N' -dimethylacetamide (DMAc);
and/or, in the step c), the molar ratio of the metal Ni catalyst to the compound 4 is 0.05-0.5: 0.8-1.2;
and/or, in step c), the molar ratio of the ligand to the compound 4 is between 0.05 and 0.5;
and/or, in step c), the molar ratio of the metal compound to the compound 4 is 0 to 0.5:0.8-1.2;
and/or, in step c), the molar ratio of the organic base to the compound 4 is between 0 and 20:0.8-1.2; and/or, in the step c), the decarboxylation coupling reaction temperature is 20-80 ℃.
6. The synthesis method according to claim 4, wherein,
in said step c), when X 2 When Cl, br and I are used, the molar ratio of the metal compound to the compound 4 is 0.05-0.5: 0.8-1.2.
7. The synthesis method according to claim 4, wherein,
in said step c), when X 2 Is B (OH) 2 When the reaction is carried out, no metal compound is added.
8. The synthesis method according to claim 4, wherein,
in said step c), when X 2 Is B (OH) 2 In the case of the organic base and the compound 4, the molar ratio is 10 to 20:0.8-1.2.
9. The synthesis method according to claim 4, wherein,
in said step c), when X 2 When Cl, br and I are used, no organic base is added in the reaction.
10. The synthesis method according to claim 1, wherein,
in step d), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof; the volume mol ratio of the compound to the compound 6 is 10-50L/0.8-1.2 mol;
and/or, in step d), the acid is selected from the group consisting of: HCl, HClO 4 、PTSA.H 2 O、TiCl 4 Or PPA;
and/or, in the step d), the temperature of the ring closing reaction is 50-120 ℃;
And/or, in the step d), the time of the ring closing reaction is 1-10 hours.
11. The synthesis method according to claim 10, wherein,
in step d), the acid is PPA; the molar ratio of the acid to the compound 6 is 0.1-5: 0.8-1.2;
and/or, in the step d), the temperature of the ring closing reaction is 80-120 ℃;
and/or, in the step d), the time of the ring closing reaction is 5-10 hours.
12. The method of claim 10, wherein in the step d), when the acid is PPA, the mass molar ratio of the acid to the compound 6 is 0.1 to 1g:0.8-1.2mmol.
13. The method of claim 10, wherein in the step d), when the acid is PPA, the mass molar ratio of the acid to the compound 6 is 0.6 to 1g:0.8-1.2mmol.
14. The method of synthesis according to claim 1, wherein the method further comprises: preparing a compound of formula 2 by the following step a):
a) In an alcohol solvent and water, under the action of alkali, carrying out hydrolysis reaction on the compound 1 to obtain a hydrolysis product; then adding an aprotic solvent, and carrying out oxidation reaction under the action of an oxidant to obtain a compound 2;
wherein ,R1 Is defined as in claim 1.
15. The synthesis method according to claim 14, wherein,
in step a), the alcoholic solvent is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, or combinations thereof;
and/or, in the step a), the volume ratio of the alcohol solvent to the water is 1-3: 0.8-1.2;
and/or, in the step a), the volume mole ratio of the alcohol solvent and water mixed solution to the compound 1 is 1-5L: 0.8-1.2mol;
and/or, in step a), the base is selected from the group consisting of: potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride, or a combination thereof;
and/or, in the step a), the temperature of the hydrolysis reaction is 25-80 ℃;
and/or, in step a), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in step a), the volume ratio of the aprotic solvent to the compound 1 is 1 to 20L:0.8-1.2mol;
and/or, in step a), the oxidizing agent is selected from the group consisting of: jones reagent, pyridinium chlorochromate (PCC), pyridinium Dichromate (PDC);
And/or, in the step a), the temperature of the oxidation reaction is 0-50 ℃.
16. The synthesis method according to claim 15, wherein,
in the step a), the mass ratio of the alkali to the compound 1 is 1-3: 0.8-1.2;
and/or, in the step a), the temperature of the hydrolysis reaction is 50-80 ℃;
and/or, in the step a), the molar ratio of the oxidant to the compound 1 is 1:1-3:1;
and/or, in the step a), the temperature of the oxidation reaction is 0-25 ℃.
17. The method of synthesis according to claim 1, further comprising the step of:
e) In an aprotic solvent, under the action of a deprotection agent, carrying out deprotection reaction on the compound 7 to obtain a phenolic steroid compound 8;
wherein ,R1 、R 2 and R3 Is as defined in claim 1;
R 4 、R 5 each independently is H or OH; and R is 4 and R5 And not H at the same time.
18. The synthesis method according to claim 17, wherein,
in step e), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic solvents, naphthenic solvents, or combinations thereof;
and/or, in the step e), the deprotection agent is sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium fluoride and boron tribromide;
And/or, in the step e), the temperature of the deprotection reaction is 0-100 ℃.
19. The synthesis method according to claim 18, wherein,
in step e), the volume molar ratio of the aprotic solvent to the compound 7 is 10 to 50L:0.8-1.2mol;
and/or, in step e), the molar ratio of the deprotection agent to the compound 7 is 1-5: 0.8-1.2.
20. The synthesis method of the natural product Myrmenaphtol A is characterized by comprising the following steps of:
synthesizing compound 7' by the method of claim 1;
and the method further comprises:
i) In an aprotic solvent, under the action of alkali, performing a Wittig reaction on the compound 7' and the compound 9 to obtain a compound 10;
II) in an aprotic solvent, under the action of an oxidant, carrying out allylic oxidation reaction on the compound 10 to obtain an intermediate, and then in the aprotic solvent, under the action of the oxidant, carrying out allylic hydroxyl oxidation reaction on the intermediate to obtain a compound 11;
III) in an aprotic solvent, under the action of alkali and an oxidant, carrying out a reaction of introducing hydroxyl into alpha position of carbonyl of the compound 11 to obtain a compound 12;
IV) in an aprotic solvent, under the action of an oxidant, carrying out enol isomerization reaction on the compound 12 to obtain a compound 13;
V) in aprotic solvent or alcohol solvent, under the action of deprotection agent, compound 13 is subjected to deprotection reaction to obtain natural product Myrmenaphtol A;
wherein ,
R 2 is as defined in claim 1;
x is Cl, br or I.
21. The method of claim 20, wherein,
in step I), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof; the volume mole ratio of the compound to the compound 7' is 10-50L: 0.8-1.2mol;
and/or, in step I), the base is selected from the group consisting of: potassium tert-butoxide, sodium tert-butoxide, potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS), lithium hexamethyldisilazide (LiHMDS), naH;
and/or, in step I), the molar ratio of compound 9 to compound 7' is 1 to 6:0.8-1.2;
and/or, in the step I), the temperature of the Wittig reaction is 20-100 ℃.
22. The method of claim 21, wherein,
in step I), the molar ratio of the base to the compound 7' is 1 to 6:0.8-1.2;
and/or, in step I), the molar ratio of compound 9 to compound 7' is 1 to 6:0.8-1.2;
And/or, in the step I), the temperature of the Wittig reaction is 50-100 ℃.
23. The method of claim 20, wherein,
in step II), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic solvents, naphthenic solvents, or combinations thereof; the volume mole ratio of the compound to the compound 10 is 10-50L: 0.8-1.2mol;
and/or, in step II), the oxidizing agent of the allylic oxidation reaction is selected from the group consisting of: seO (SeO) 2 /t-BuOOH、PCC、PDC;
And/or, in the step II), the temperature of the allylic oxidation reaction is 0-80 ℃;
and/or, step II), said oxidizing agent of the oxidation of the allylic hydroxyl group is selected from the group consisting of: jones reagent, dess-martin reagent, manganese dioxide; the molar ratio of the compound to the compound 10 is 2-20: 0.8-1.2;
and/or, in the step II), the temperature of the allylic hydroxyl oxidation reaction is 0-80 ℃;
and/or, in step III), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbons, ethers, aromatic hydrocarbons, naphthenic hydrocarbon solvents, or combinations thereof; the volume mole ratio of the compound to the compound 11 is 6-20L: 0.8-1.2mol;
and/or, in step III), the oxidizing agent is selected from the group consisting of: davis reagent, oxygen; the molar ratio of the compound to the compound 11 is 1-3: 0.8-1.2;
And/or, in the step III), the alkali is KHMDS, naHMDS, potassium tert-butoxide, sodium tert-butoxide and Lithium Diisopropylamide (LDA); the molar ratio of the compound to the compound 11 is 1-3: 0.8-1.2;
and/or, in the step III), the temperature of the oxidation reaction is-20-50 ℃;
and/or, in the step IV), the aprotic solvent is one or more of halogenated hydrocarbon solvents, ethers solvents, ketones solvents, aromatic solvents and naphthenic solvents; the volume mole ratio of the compound to the compound 12 is 6-20L: 0.8-1.2mol;
and/or, in step IV), the oxidizing agent is selected from the group consisting of: swern reagent, jones reagent, pyridinium Dichromate (PDC), pyridinium chlorochromate (PCC), dess-Martin reagent; the molar ratio of the compound to the compound 12 is 2-20: 0.8-1.2;
and/or, in the step IV), the temperature of the oxidation reaction is-78-80 ℃;
and/or, in the step V), the aprotic solvent is one or more of halogenated hydrocarbon solvents, ethers solvents, aromatic solvents and naphthenic solvents; the volume mole ratio of the compound to the compound 13 is 10-50L: 0.8-1.2mol;
and/or, in the step V), the alcohol solvent is one or more of methanol, ethanol, n-propanol and isopropanol; the volume mole ratio of the compound to the compound 13 is 10-30L: 0.8-1.2mol;
And/or, in the step V), the deprotection agent is sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium fluoride and boron tribromide; the molar ratio of the compound to the compound 13 is 1-5: 0.8-1.2;
and/or, in the step V), the temperature of the deprotection reaction is 0-100 ℃.
24. The method of claim 23, wherein,
in step II), the molar ratio of the oxidant to the compound 10 is 0.5 to 8:0.8-1.2;
and/or, in the step II), the temperature of the allylic oxidation reaction is 15-50 ℃;
and/or, in the step II), the molar ratio of the oxidant for the allylic hydroxyl oxidation reaction to the compound 10 is 5-10:0.8-1.2;
and/or, in the step II), the temperature of the allylic hydroxyl oxidation reaction is 0-50 ℃;
and/or, in the step III), the temperature of the oxidation reaction is-15-25 ℃;
and/or, in step IV), the molar ratio of the oxidizing agent to the compound 12 is between 5 and 10:0.8-1.2;
and/or, in the step IV), the temperature of the oxidation reaction is-78-25 ℃.
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