CN115536496A - 选择性去羟基阿扑棉酚的合成方法 - Google Patents
选择性去羟基阿扑棉酚的合成方法 Download PDFInfo
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- CN115536496A CN115536496A CN202211181554.7A CN202211181554A CN115536496A CN 115536496 A CN115536496 A CN 115536496A CN 202211181554 A CN202211181554 A CN 202211181554A CN 115536496 A CN115536496 A CN 115536496A
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- apogossypol
- dehydroxy
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- PBJKWGWHZVXBGU-UHFFFAOYSA-N 3-methyl-5-propan-2-yl-2-(1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)naphthalene-1,6,7-triol Chemical compound CC(C)C1=C(O)C(O)=CC2=C(O)C(C=3C(O)=C4C=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 PBJKWGWHZVXBGU-UHFFFAOYSA-N 0.000 title claims abstract description 194
- 238000001308 synthesis method Methods 0.000 title claims abstract description 21
- -1 hydroxyl gossypol Chemical compound 0.000 claims abstract description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 17
- NIOHNDKHQHVLKA-UHFFFAOYSA-N acetic acid;7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde Chemical compound CC(O)=O.CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 NIOHNDKHQHVLKA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000543 intermediate Substances 0.000 claims description 247
- 238000006243 chemical reaction Methods 0.000 claims description 127
- 239000002243 precursor Substances 0.000 claims description 73
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 62
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 46
- 239000012043 crude product Substances 0.000 claims description 44
- 238000010438 heat treatment Methods 0.000 claims description 44
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 37
- 239000000047 product Substances 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 35
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 31
- 238000010791 quenching Methods 0.000 claims description 25
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 15
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 10
- 229940127204 compound 29 Drugs 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 10
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003172 aldehyde group Chemical group 0.000 claims description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 229940125851 compound 27 Drugs 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 230000001035 methylating effect Effects 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- QBKSWRVVCFFDOT-UHFFFAOYSA-N SJ000286711 Natural products CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 abstract description 23
- QHOPXUFELLHKAS-UHFFFAOYSA-N Thespesin Natural products CC(C)c1c(O)c(O)c2C(O)Oc3c(c(C)cc1c23)-c1c2OC(O)c3c(O)c(O)c(C(C)C)c(cc1C)c23 QHOPXUFELLHKAS-UHFFFAOYSA-N 0.000 abstract description 12
- 229930000755 gossypol Natural products 0.000 abstract description 12
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- 210000004881 tumor cell Anatomy 0.000 abstract description 7
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- 238000011160 research Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000005556 structure-activity relationship Methods 0.000 abstract description 3
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 238000002360 preparation method Methods 0.000 description 40
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 239000012074 organic phase Substances 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- 239000007787 solid Substances 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 235000013824 polyphenols Nutrition 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 13
- MSBVBOUOMVTWKE-UHFFFAOYSA-N 2-naphthalen-2-ylnaphthalene Chemical compound C1=CC=CC2=CC(C3=CC4=CC=CC=C4C=C3)=CC=C21 MSBVBOUOMVTWKE-UHFFFAOYSA-N 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 12
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- 210000004027 cell Anatomy 0.000 description 8
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 6
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 5
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- 102000004169 proteins and genes Human genes 0.000 description 4
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- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 3
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 3
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 3
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 3
- 238000002875 fluorescence polarization Methods 0.000 description 3
- 150000004548 gossypol derivatives Chemical class 0.000 description 3
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- QWDXLBMDVCKGJV-UHFFFAOYSA-N 7-methyl-6-(3-methyl-5-propan-2-ylnaphthalen-2-yl)-1-propan-2-ylnaphthalene Chemical compound C1=CC(C(C)C)=C2C=C(C)C(C=3C=C4C=CC=C(C4=CC=3C)C(C)C)=CC2=C1 QWDXLBMDVCKGJV-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
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- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 1
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- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
- C07C1/322—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom the hetero-atom being a sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了系列选择性去羟基阿扑棉酚的合成方法。本发明以醋酸棉酚1为起始原料通过合成路线的设计合成了9种不同位置的去羟基阿扑棉酚。所合成的产物均对肿瘤细胞有着抑制作用,并且抑制作用能力和机制上与阿扑棉酚相近。本发明所述方法提供了不同位置的羟基的去除方法,丰富了去除羟基棉酚的构效关系,具有较大的研究价值和参考意义。
Description
技术领域
本发明属于有机合成和药物领域,具体涉及选择性去羟基阿扑棉酚的合成方法。
背景技术
棉酚是一种黄色的多酚类化合物,具有抗肿瘤、抗疟、抗生育、抗病毒等多种生物活性,其单一手性异构体(-)-棉酚(AT-101)正处于临床Ⅱ期研究。基于棉酚的修饰改造工作具有较多困难,原因是棉酚首先有多个酚羟基,而且棉酚的8,8'-位醛基容易与羟基发生烯胺——亚胺式互变异构(8,8'-位醛基是毒性的来源,参考文献:Future Med.Chem.2017,9,1243-1275)。所以针对棉酚羟基的改造工作的仅有一篇文献报道,方法是通过全合成的方法得到1,1'-去氧棉酚(参考文献:J.Med.Chem.1995,38,2427-2432)。
专利CN112679319A公开了1,1'-去氧棉酚的合成方法,与报道的文献方法相比,原料为廉价易得天然产物棉酚,反应条件温和,合成工艺步骤少,且总产率高达45%,相比文献提高2.7倍。
通过生物活性研究结果表明1,1'-羟基去掉对棉酚的抗肿瘤活性影响较小,但是,其他位置的羟基对棉酚活性的影响还不得而知。因此,为了全面了解棉酚的构效关系,填补棉酚衍生物的空白,制备选择性去不同位置的羟基的棉酚衍生物是十分有必要的。
发明内容
针对上述技术问题,本发明提供选择性去羟基阿扑棉酚的合成方法。
本发明提供的技术方案如下:
选择性去羟基阿扑棉酚的合成方法,其特征在于,包括以下步骤:
路线一:6-去羟基阿扑棉酚7和6,6'-去羟基阿扑棉酚10的合成
合成路线如下:
合成方法包括以下步骤:
(1)在保护气体氛围下,以醋酸棉酚1为起始原料,加入碱液中反应,脱去醛基得到阿扑棉酚2;
(2)将阿扑棉酚2不完全甲基化得到五甲基化中间体3和四甲基化中间体4:将阿扑棉酚2溶于乙腈中,加入碳酸钾和硫酸二甲酯,回流反应至完全,经浓缩、分离得到五甲基化中间体3和四甲基化中间体4;
(3)将中间体3的剩余酚羟基用OTf保护得到中间体5:将中间体3溶于DCM中,加入TBD以及Tf2O,室温反应至完全,经浓缩、分离得到中间体5;
将中间体4的剩余酚羟基用OTf保护得到中间体8:将中间体4溶于DCM中,加入TBD以及Tf2O,室温反应至完全,经浓缩、分离得到中间体8;
(4)还原中间体5被保护的酚羟基得到6-去羟基阿扑棉酚前体6:将中间体5溶于DMF中,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到6-去羟基阿扑棉酚前体6;
还原中间体8被保护的酚羟基得到6,6'-去羟基阿扑棉酚前体9:将中间体8溶于DMF中,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到6,6'-去羟基阿扑棉酚前体9;
(5)脱除6-去羟基阿扑棉酚前体6的甲氧基得到目标产物6-去羟基阿扑棉酚7:将6-去羟基阿扑棉酚前体6溶于DCM中,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物6-去羟基阿扑棉酚7;
脱除6,6'-去羟基阿扑棉酚前体9的甲氧基得到目标产物6,6'-去羟基阿扑棉酚10:将6,6'-去羟基阿扑棉酚前体9溶于DCM中,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物6,6'-去羟基阿扑棉酚10;
路线二:1,1',6,6'-去羟基阿扑棉酚15和1,1',6,6',7,7'-去羟基阿扑棉酚17的合成
合成路线如下:
合成方法包括以下步骤:
(1)将阿扑棉酚2完全甲基化得到中间体11:将阿扑棉酚2用乙腈溶解,加入碳酸钾和硫酸二甲酯,回流反应至完全,经浓缩、分离得到中间体11;
(2)选择性脱去中间体11的1,1',6,6'-位的两组甲氧基得到中间体12:将中间体11溶于氯仿,惰性氛围下,加入碘化钾,进行反应,然后加入TMSI,升温反应至完全,经浓缩、分离得到中间体12;
(3)保护中间体12的酚羟基得到中间体13:将中间体12溶于DCM,加入DIPEA以及Tf2O,室温反应至完全,经浓缩、分离得到中间体13;
(4)还原中间体13被保护的酚羟基得到1,1',6,6'-去羟基阿扑棉酚前体14:将中间体13溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,6'-去羟基阿扑棉酚前体14;
(5)脱除1,1',6,6'-去羟基阿扑棉酚前体14的甲氧基得到目标产物1,1',6,6'-去羟基阿扑棉酚15:将1,1',6,6'-去羟基阿扑棉酚前体14溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物1,1',6,6'-去羟基阿扑棉酚15;
(6)1,1',6,6',7,7'-去羟基阿扑棉酚17的合成方法,步骤如下:
(6.1)将1,1',6,6'-去羟基阿扑棉酚15溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体16;
(6.2)将中间体16溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,6',7,7'-去羟基阿扑棉酚17;
路线三:7,7'-去羟基阿扑棉酚21的合成
合成路线如下:
合成方法包括以下步骤:
(1)选择性保护阿扑棉酚2的7,7'-羟基得到中间体18:将阿扑棉酚2溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体18;
(2)保护中间体18的1,1',6,6'-位酚羟基得到中间体19:将中间体18溶于DMF,加入碳酸钾进行反应,然后加入碘甲烷,室温反应至完全,经浓缩、分离得到中间体19;
(3)还原中间体19被保护的7,7'-位酚羟基得到7,7'-去羟基阿扑棉酚前体20:将中间体19溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到7,7'-去羟基阿扑棉酚前体20;
(4)脱除7,7'-去羟基阿扑棉酚前体20的甲氧基得到目标产物7,7'-去羟基阿扑棉酚21:将7,7'-去羟基阿扑棉酚前体20溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、分离得到产物7,7'-去羟基阿扑棉酚21;
路线四:1,6,6'-去羟基阿扑棉酚25的合成
合成路线如下:
合成方法包括以下步骤:
(1)选择性保护阿扑棉酚2的1',7,7'-羟基得到中间体22:将阿扑棉酚2溶于DMF,加入碳酸钠进行反应,然后加入碘甲烷,室温反应至完全,经浓缩、分离得到中间体22;
(2)保护中间体22的1,6,6'-位酚羟基得到中间体23:将中间体22溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体23;
(3)还原中间体23被保护的1,6,6'-位酚羟基得到1,6,6'-去羟基阿扑棉酚前体24:将中间体23溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,6,6'-去羟基阿扑棉酚前体24;
(4)脱除1,6,6'-去羟基阿扑棉酚前体24的甲氧基得到目标产物1,6,6'-去羟基阿扑棉酚25:将1,6,6'-去羟基阿扑棉酚前体24溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物1,6,6'-去羟基阿扑棉酚25;
路线五:1,1',7,7'-去羟基阿扑棉酚33和1,1',6,7,7'-去羟基阿扑棉酚37的合成
合成路线如下:
合成方法包括以下步骤:
(1)将阿扑棉酚2乙酰化得到乙酰化的阿扑棉酚26:将阿扑棉酚2用DCM溶解,加入DMAP以及Ac2O后,室温反应完全,经浓缩、分离得到乙酰化的阿扑棉酚26;
(2)选择性脱去乙酰化的阿扑棉酚26的6,6',7,7'-位乙酰基得到中间体27:将乙酰化的阿扑棉酚26溶于MeOH和DCM混合溶液,加入碳酸钾后,在惰性气氛下,加热至反应完全,经分离得到中间体27;
(3)用苄基化试剂选择性保护中间体27的6,6'-位羟基得到中间体28:将中间体27溶于DMF,加入碳酸钠进行反应,然后加入苄溴,室温反应至完全,经浓缩、分离得到中间体28;
(4)用甲基化试剂保护中间体28的剩余羟基得到中间体29:将中间体28溶于DMF,加入碳酸钾进行反应,然后加入碘甲烷,室温反应至完全,经浓缩、分离得到中间体29;
(5)选择性脱去中间体29的乙酰基和苄基得到中间体30:将化合物29溶于DCM,低温下加入三氯化硼,然后缓缓升温至室温反应至完全,经浓缩、分离得到中间体30;
选择性脱去中间体29的乙酰基和苄基和一个甲氧基得到中间体34:将化合物29溶于DCM,室温下加入三氯化硼,然后于室温反应至完全,经浓缩、分离得到中间体34;
(6)用Tf2O保护中间体30的1,1',7,7'-位酚羟基得到中间体31:将中间体30溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体31;
用Tf2O保护中间体34的1,1',6,7,7'-位酚羟基得到中间体35:将中间体34溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体35;
(7)还原中间体31被保护的1,1',7,7'-位酚羟基得到1,1',7,7'-去羟基阿扑棉酚前体32:将中间体31溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',7,7'-去羟基阿扑棉酚前体32;
还原中间体35被保护的1,1',6,7,7'-位酚羟基得到1,1',6,7,7'-去羟基阿扑棉酚前体36:将中间体35溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,7,7'-去羟基阿扑棉酚前体36;
(8)脱除1,1',7,7'-去羟基阿扑棉酚前体32的甲氧基得到目标产物1,1',7,7'-去羟基阿扑棉酚33:将1,1',7,7'-去羟基阿扑棉酚前体32溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经沉淀、水洗得到产物1,1',7,7'-去羟基阿扑棉酚33;
脱除1,1',6,7,7'-去羟基阿扑棉酚前体36的甲氧基得到目标产物1,1',6,7,7'-去羟基阿扑棉酚37:将1,1',6,7,7'-去羟基阿扑棉酚前体36溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经沉淀、水洗得到产物1,1',6,7,7'-去羟基阿扑棉酚37;
路线六:6,6',7,7'-去羟基阿扑棉酚40的合成
合成方法包括以下步骤:
(1)用Tf2O保护中间体27的6,6',7,7'-位酚羟基得到中间体38:将中间体27溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体38;
(2)还原中间体38被保护的6,6',7,7'-位酚羟基得到6,6',7,7'-去羟基阿扑棉酚前体39:将中间体38溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到6,6',7,7'-去羟基阿扑棉酚前体39;
(3)脱除6,6',7,7'-去羟基阿扑棉酚前体39的乙酰基得到目标产物6,6',7,7'-去羟基阿扑棉酚40:将6,6',7,7'-去羟基阿扑棉酚前体39溶于THF,降温,分批加入氢化铝锂,然后低温反应完全,经浓缩、分离6,6',7,7'-去羟基阿扑棉酚40。
进一步,所述路线一步骤(1)中,碱液为氢氧化钠溶液,反应后经淬灭、萃取,洗涤、干燥,再经过滤、减压浓缩获得粗产品。
进一步,所述路线一中,中间体3、TBD和Tf2O的摩尔用量分别为1.0eq、7.0eq和4.0eq;中间体4、TBD和Tf2O的摩尔用量分别为1.0eq、6.0eq和4.0eq;中间体5、Pd(OAc)2、dppp和Et3SiH的摩尔用量为1.0eq、0.2eq、0.2eq和8.0eq;中间体8、Pd(OAc)2、dppp和Et3SiH的摩尔用量为1.0eq、0.3eq、0.3eq和10.0eq;6-去羟基阿扑棉酚前体6和BBr3的摩尔用量为1.0eq和25.0eq;6,6'-去羟基阿扑棉酚前体9和BBr3的摩尔用量为1.0eq和25.0eq。
进一步,所述路线二中,中间体11、碘化钾的摩尔用量分别为1.0eq和0.6eq;中间体12、DIPEA、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体13、Pd(OAc)2、dppp、Et3SiH的摩尔用量比为1.0eq、0.2eq、0.2eq、10.0eq;1,1',6,6'-去羟基阿扑棉酚前体14、BBr3的摩尔用量为1.0eq、25.0eq。
进一步,所述路线二步骤(6)中,1,1',6,6'-去羟基阿扑棉酚15、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、8.0eq;中间体16、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、12.0eq。
进一步,所述路线三中,阿扑棉酚2、吡啶、Tf2O的摩尔用量为1.0eq、6.0eq、3.0eq;中间体18、碳酸钾、碘甲烷的摩尔用量为1.0eq、20.0eq、25.0eq;中间体19、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、12.0eq;7,7'-去羟基阿扑棉酚前体20、BBr3的摩尔用量为1.0eq、25.0eq。
进一步,所述路线四中,阿扑棉酚2、碳酸钠、碘甲烷的摩尔用量为1.0eq、8.0eq、50.0eq;中间体22、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体23、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、12.0eq;中间体24、BBr3的摩尔用量为1.0eq、25.0eq。
进一步,所述路线五中,化合物27、碳酸钠、苄溴的摩尔用量为1.0eq、5.0eq、10.0eq;化合物28、碳酸钾、碘甲烷的摩尔用量为1.0eq、25.0eq、25.0eq;化合物29、三氯化硼的摩尔用量为1.0eq、15.0eq;中间体30、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体31、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、20.0eq;中间体32、BBr3的摩尔用量为1.0eq、25.0eq。
进一步,所述路线五中,化合物29、三氯化硼的摩尔用量为1.0eq、20.0eq;中间体34、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体35、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、20.0eq;中间体36、BBr3的摩尔用量为1.0eq、25.0eq。
进一步,所述路线六中,中间体27、吡啶、Tf2O的摩尔用量为1.0eq、15.0eq、15.0eq;中间体38、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.5eq、0.5eq、10.0eq;中间体39、氢化锂铝的摩尔用量为1.0eq、20.0eq。
本发明的有益效果如下:
本发明以醋酸棉酚1为起始原料合成了9种去羟基阿扑棉酚。所合成的产物均对肿瘤细胞有着抑制作用,并且抑制作用与阿扑棉酚相近。本发明所述方法扩展了不同位置的羟基的去除方法,丰富了去除羟基棉酚的构效关系,具有较大的研究价值和参考意义。
具体实施方式
下面结合具体实施例对本发明进一步说明,本发明的内容完全不限于此。
1、阿扑棉酚2的制备
以醋酸棉酚1为起始原料,在氢氧化钠溶液的作用下脱去醛基得到阿扑棉酚2,无需纯化,直接用于下一步;所述醋酸棉酚和阿扑棉酚的结构为
2、5,5'-二异丙基-1,1',6',7,7'-五甲氧基-3,3'-二甲基-[2,2'-联二萘]-6-醇3和5,5'-二异丙基-1,1',7,7'-五甲氧基-3,3'-二甲基-[2,2'-联二萘]-6,6'-二醇4的制备
将醋酸棉酚1(1.0g,1.9mmol))加入10mL 40%NaOH中,加毕,用N2置换空气,加热至90℃,剧烈搅拌。2h后,将反应液缓缓倒入冰的硫酸溶液中淬灭,淬灭结束后,用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到粗产品阿扑棉酚2,无需纯化,直接用于下一步。粗产品用50mL乙腈溶解,加入碳酸钾(2.622g,19mmol),搅拌。10分钟后,加入硫酸二甲酯(2.394g,19mmol),加毕,用N2置换空气,加热至85℃,TLC、LC-MS监控。反应结束后,将反应液减压浓缩,得到粗产物用柱层析分离分别得到不完全甲基化的阿扑棉酚3和4,均为黄色固体,两步产率分别为21%和16%。
化合物3数据:1H NMR(600MHz,CDCl3)δ7.83(s,1H),7.77(s,1H),7.43(s,1H),7.40(s,1H),6.19(s,1H),4.02(s,3H),3.99–3.96(m,5H),3.93(s,3H),3.55(s,6H),2.20(s,3H),2.20(s,3H),1.56(t,J=6.6,12H).MS(ESI)calcd for C33H40O6:532.28,found m/z+=533.2,m/z-:not found.
化合物4数据:1H NMR(600MHz,CDCl3)δ7.78(s,2H),7.41(s,2H),6.19(s,2H),4.02(s,7H),3.93–3.89(m,2H),3.54(s,6H),2.21(s,6H),1.57(s,6H),1.55(s,6H).MS(ESI)calcd for C32H38O6:518.26,found m/z+=519.3,m/z-=517.4.
3、5,5'-二异丙基-1,1',6',7,7'-五甲氧基-3,3'-二甲基-[2,2'-联二萘]-6-三氟甲烷磺酸酯5的制备
将中间体3(260mg,0.49mmol,1.0eq)溶于干燥DCM(15mL)中,加入TBD(477mg,3.43mmol,7.0eq)。5分钟后,将Tf2O(553mg,1.96mmol,4.0eq)溶于干燥DCM(1mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体5,黄色固体136mg,产率42%。
1H NMR(600MHz,CDCl3)δ7.97(s,1H),7.86(s,1H),7.51(s,1H),7.42(s,1H),3.99(s,7H),3.96-3.93(m,4H),3.59(s,3H),3.57(s,3H),2.22(s,3H),2.21(s,3H),1.66(d,J=7.2,6H),1.57(d,J=6.6,6H).MS(ESI)calcd for C34H39F3O8S:664.23,not found.
4、5,5'-二异丙基-1,1',6',7,7'-五甲氧基-3,3'-二甲基-[2,2'-联二萘]6的制备
将中间体5(152mg,0.23mmol,1.0eq)加入封管中,加入DMF(8mL),N2保护下加入Pd(OAc)2(10mg,0.046mmol,0.2eq),dppp(19mg,0.046mmol,0.2eq)。5分钟后,加入Et3SiH(214mg,1.84mmol,8.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体6,黄色液体43mg,产率36%。
1H NMR(600MHz,CDCl3)δ7.85(s,1H),7.78(s,1H),7.44(s,1H),7.36(d,J=2.3,1H),7.13(d,J=2.4,1H),4.13(dd,J=14.3,7.2,1H),3.99(s,3H),3.95(s,6H),3.75(dd,J=13.6,6.8,1H),3.60(s,3H),3.58(s,3H),2.22(s,3H),2.21(s,3H),1.58(d,J=6.6,6H),1.44(dd,J=6.8,3.3,6H).MS(ESI)calcd for C33H40O5:516.28,not found.
二维核磁2D NMR NOE
5、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1',6',7,7'-五醇7的制备
将中间体6(43mg,0.083mmol,1.0eq)溶于干燥DCM(3mL),降温至-5℃,在N2氛围下滴加BBr3(522mg,2.08mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入冰水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用PE/DCM重结晶得到产物7,黄色固体19mg,产率51%。
HPLC purity:95.8%(20%H2O/CH3CN),tR=3.845min.1H NMR(600MHz,CDCl3)δ7.61(s,2H),7.44(s,1H),7.37(s,1H),7.10(s,1H),6.03(s,1H),5.26(s,2H),3.94–3.76(m,1H),3.74–3.63(m,1H),2.11(s,6H),1.53(s,6H),1.40(s,6H).13C NMR(150MHz,CDCl3)δ152.57,149.34,149.03,146.70,142.53,132.68,129.90,129.68,128.20,125.68,124.05,117.67,116.51,116.39,115.30,114.93,114.43,111.84,103.06,102.57,28.66,26.93,23.63,23.40,20.72,20.65.MS(ESI)calcd for C28H30O5:446.20,found:m/z+=not found,m/z-=445.2.
6、5,5'-二异丙基-1,1',7,7'-四甲氧基-3,3'-二甲基-[2,2'-联二萘]-6,6'-双三氟甲烷磺酸酯8的制备
将中间体4(165mg,0.32mmol,1.0eq)溶于干燥DCM(15mL)中,加入TBD(267mg,1.92mmol,6.0eq)。5分钟后,将Tf2O(361mg,1.28mmol,4.0eq)溶于干燥DCM(1mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体8,黄色固体38mg,产率15%。
1H NMR(600MHz,CDCl3)δ7.99(s,2H),7.49(s,2H),3.99(s,6H),3.97–3.91(m,2H),3.58(s,6H),2.22(s,6H),1.66(s,6H),1.65(s,6H).MS(ESI)calcd for C34H36F6O10S2:782.16,not found.
7、5,5'-二异丙基-1,1',7,7'-四甲氧基-3,3'-二甲基-[2,2'-联二萘]9的制备
将中间体8(38mg,0.049mmol,1.0eq)加入封管中,加入DMF(5mL),N2保护下加入Pd(OAc)2(3.3mg,0.0147mmol,0.3eq),dppp(6mg,0.0147mmol,0.3eq)。5分钟后,加入Et3SiH(57mg,0.49mmol,10.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体9,黄色液体20mg,产率83%。
1H NMR(600MHz,CDCl3)δ7.78(s,2H),7.355(s,1H),7.351(s,1H),7.123(s,1H),7.119(s,1H),3.94(s,6H),3.76–3.72(m,2H),3.59(s,6H),2.21(s,6H),1.44(d,J=3.2,6H),1.43(d,J=3.2,6H).MS(ESI)calcd for C32H38O4:486.27,not found.
8、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1',7,7'-四醇10的制备
将中间体9(26mg,0.053mmol,1.0eq)溶于干燥DCM(3mL),降温至-5℃,在N2氛围下滴加BBr3(336mg,1.34mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入冰水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用PE/DCM重结晶得到产物10,粉红色固体14mg,产率61%。
HPLC purity:95.7%(20%H2O/CH3CN),tR=3.845min.1H NMR(600MHz,CDCl3)δ7.61(s,2H),7.39(s,2H),7.12(s,2H),5.24(s,3H),3.71(dt,J=13.0,6.3,2H),2.13(s,6H),1.41(dd,J=8.8,7.3,12H).13C NMR(150MHz,CDCl3)δ152.65,149.23,146.70,132.34,128.24,124.05,116.49,114.97,114.12,102.53,28.66,26.90,23.64,23.38,20.58.MS(ESI)calcd for C28H30O4:430.21,found:m/z+=not found,m/z-=429.3.
9、5,5'-二异丙基-1,1',6,6',7,7'-六甲氧基-3,3'-二甲基-[2,2'-联二萘]11的制备
将醋酸棉酚1(1.0g,1.9mmol)加入10mL 40%NaOH中,加毕,用N2置换空气,加热至90℃,剧烈搅拌。2h后,将反应液缓缓倒入冰的硫酸溶液中淬灭,淬灭结束后,用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到粗产品阿扑棉酚2,无需纯化,直接用于下一步。粗产品用50mL乙腈溶解,加入碳酸钾(6.555g,47.5mmol),搅拌。10分钟后,加入硫酸二甲酯(5.98g,47.5mmol),加毕,用N2置换空气,加热至85℃,TLC、LC-MS监控。反应结束后,将反应液减压浓缩,得到粗产物用柱层析分离得到中间体11,黄色固体,两步产率93%。
1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.43(s,1H),3.98(s,3H),3.94(s,4H),3.57(s,3H),2.20(s,3H),1.57(d,J=7.0,6H).13C NMR(100MHz,CDCl3)δ152.76,151.88,135.09,132.81,128.72,126.47,124.72,100.58,61.14,60.54,55.46,22.27,21.01.MS(ESI)calcd for C34H42O6:546.29,found:m/z+=547.3,m/z-:not found.
10、5,5'-二异丙基-7,7'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,6'-四醇12的制备
将阿扑棉酚11(840mg,1.58mmol,1.0eq)溶于干燥氯仿(40mL)中,加入碘化钾(160mg,0.96mmol,0.6eq)。5分钟后,加入TMSI(2.5mL),加毕,用N2置换空气,加热至50℃,TLC、LC-MS监控。反应结束后,用饱和亚硫酸钠溶液淬灭,然后用EA萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体12,黄色固体542mg,产率72%。
1H NMR(600MHz,DMSO-d6)δ8.53(s,2H),8.03(s,2H),3.92(s,6H),3.90–3.82(m,2H),1.97(s,6H),1.45(d,J=6.3Hz,12H).MS(ESI)calcd for C30H34O6:490.23,found m/z+=491.2,m/z-=489.2.
11、5,5'-二异丙基-7,7'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,6'-四三氟甲烷磺酸酯13的制备
将中间体12(507mg,1.03mmol,1.0eq)溶于干燥DCM(25mL)中,加入DIPEA(2.66g,20.6mmol,20.0eq)。5分钟后,将Tf2O(2.9g,10.3mmol,10.0eq)溶于干燥DCM(5mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体13,黄色固体840mg,产率75%。
1H NMR(600MHz,CDCl3)δ8.27(s,2H),7.50(s,2H),4.02(s,6H),3.95–3.99(m,2H),2.33(s,6H),1.67(d,J=7.2,7H),1.63(d,J=7.2,7H).MS(ESI)calcd for C34H30F12O14S4:1018.03,not found.
12、5,5'-二异丙基-7,7'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,6'-四三氟甲烷磺酸酯14的制备
将中间体13(282mg,0.28mmol,1.0eq)加入封管中,加入DMF(10mL),N2保护下加入Pd(OAc)2(13mg,0.056mmol,0.2eq),dppp(23mg,0.056mmol,0.2eq)。5分钟后,加入Et3SiH(326mg,2.8mmol,10.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体14,黄色固体38mg,产率33%。
1H NMR(600MHz,CDCl3)δ7.94(s,2H),7.60(s,2H),7.118(s,1H),7.114(s,1H),6.980(s,1H),6.976(s,1H),3.93(s,6H),3.79–3.75(m,2H),2.25(s,6H),1.45(t,J=6.9,12H).MS(ESI)calcd for C30H34O2:426.25,not found.
二维核磁2D NMR NOE
13、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-7,7'-二醇15的制备
将中间体14(88mg,0.21mmol,1.0eq)溶于干燥DCM(6mL),降温至-5℃,在N2氛围下滴加BBr3(1.32g,5.25mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入冰水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用PE/EA重结晶得到产物15,黄色固体82mg,产率99%。
HPLC purity:95.4%(20%H2O/ACN),tR=4.213min.1H NMR(400MHz,DMSO-d6)δ9.51(s,2H),7.90(s,2H),7.44(s,2H),6.99(s,1H),6.99(s,1H),6.95(s,1H),6.94(s,1H),3.72(dt,J=13.5,6.8,2H),2.13(s,6H),1.34(t,J=6.6,12H).13C NMR(100MHz,DMSO-d6)δ155.06,145.88,140.37,134.21,130.62,127.25,125.58,123.50,114.96,107.26,28.16,24.13,23.79,20.76.MS(ESI)calcd for C28H30O2:398.2,m/z+=not found,m/z-=397.2.
14、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-7,7'-双三氟甲烷磺酸酯16的制备
将1,1',6,6'-去羟基阿扑棉酚15溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体16。优选的制备方法如下:将1,1',6,6'-去羟基阿扑棉酚15(50mg,0.125mmol,1.0eq)溶于干燥DCM(8mL)中,加入吡啶(198g,2.5mmol,20.0eq)。5分钟后,将Tf2O(282mg,1.0mmol,8.0eq)溶于干燥DCM(1mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体16,黄色固体45mg,产率54%。
MS(ESI)calcd for C30H28F6O6S2:662.12,not found.
15、5,5'-二异丙基-3,3'-二甲基-2,2'-联二萘17的制备
将中间体16溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,6',7,7'-去羟基阿扑棉酚17。优选的制备方法如下:将中间体16(45mg,0.068mmol,1.0eq)加入封管中,加入DMF(8mL),N2保护下加入Pd(OAc)2(6mg,0.0272mmol,0.4eq),dppp(11mg,0.0272mmol,0.4eq)。5分钟后,加入Et3SiH(95mg,0.816mmol,12.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到1,1',6,6',7,7'-去羟基阿扑棉酚17,白色固体20mg,产率80%。
HPLC purity:99.3%(20%H2O/ACN),tR=6.924min.1H NMR(600MHz,CDCl3)δ8.05(s,2H),7.69(dd,J=11.1,5.9,4H),7.44(dd,J=7.1,5.7,4H),3.83(dt,J=13.6,6.8,2H),2.29(s,6H),1.48(dd,J=9.0,7.0,12H).13C NMR(150MHz,CDCl3)δ143.92,139.81,134.41,132.40,130.91,128.98,125.98,125.20,123.32,121.68,28.53,23.80,23.56,21.08.MS(ESI)calcd for C28H30:366.23,not found.
16、1,1',6,6'-四羟基-5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-7,7'-双三氟甲烷磺酸酯18的制备
将阿扑棉酚2(924mg,1.0mmol,1.0eq)溶于干燥DCM(30mL)中,加入吡啶(475g,6.0mmol,6.0eq)。5分钟后,将Tf2O(847g,3.0mmol,3.0eq)溶于干燥DCM(5mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体18,黄色液体380mg,产率26%。
MS(ESI)calcd for C30H28F6O10S2:726.1,m/z+=not found,m/z-=725.1.
17、5,5'-二异丙基-1,1',6,6'-四甲氧基-3,3'-二甲基-[2,2'-联二萘]-7,7'-双三氟甲烷磺酸酯19的制备
将中间体18(440mg,0.51mmol,1.0eq)溶于DMF(20mL)中,加入碳酸钾(1.4g,10.26mmol,20.0eq),加毕,于室温搅拌。15分钟后,将碘甲烷(1.82mg,12.83mmol,25.0eq)溶于DMF(3mL)缓缓加到上述体系,加毕,室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用EA萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体19,白色固体389mg,产率82%。
1H NMR(400MHz,CDCl3)δ7.94(s,2H),7.92(s,2H),4.01(d,J=5.1,2H),3.95(s,6H),3.59(s,6H),2.21(s,6H),1.61(s,6H),1.59(s,6H).MS(ESI)calcd for C34H36F6O10S2:782.1,not found.
18、5,5'-二异丙基-1,1',6,6'-四甲氧基-3,3'-二甲基-[2,2'-联二萘]-7,7'-双三氟甲烷磺酸酯20的制备
将中间体19(75mg,0.096mmol,1.0eq)加入封管中,加入DMF(5mL),N2保护下加入Pd(OAc)2(9mg,0.0384mmol,0.4eq),dppp(16mg,0.0384mmol,0.4eq)。5分钟后,加入Et3SiH(134mg,1.152mmol,12.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体20,黄色固体38mg,产率36%。
1H NMR(600MHz,CDCl3)δ8.06(s,1H),8.05(s,1H),7.87(s,2H),7.27(s,1H),7.25(s,1H),3.96(s,8H),3.59(s,6H),2.20(s,6H),1.52(d,J=6.7,12H).MS(ESI)calcd forC32H38O4:486.2,not found.
二维核磁2D NMR NOE
19、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,6'-四醇21的制备
将中间体20(53mg,0.11mmol,1.0eq)溶于干燥DCM(5mL),降温至-5℃,在N2氛围下滴加BBr3(689mg,2.75mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入冰水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用制备板分离得到产物21,棕色固体38mg,产率81%。
HPLC purity:88%(20%H2O/ACN),tR=4.042min.1H NMR(600MHz,DMSO-d6)δ9.25(s,1H),7.88(d,J=9.0,2H),7.49(s,2H),6.98(d,J=8.9,2H),3.88–3.76(m,2H),1.96(s,6H),1.44(t,J=6.7,12H).13C NMR(150MHz,DMSO-d6)δ151.26,136.30,134.14,123.73,122.01,119.40,116.73,115.30,26.80,21.68,21.36,20.56.MS(ESI)calcd for C28H30O4:430.2,m/z+=not found,m/z-=429.2.
20、5,5'-二异丙基-1',7,7'-三甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,6,6'-三醇22的制备
将阿扑棉酚2(1g,2.16mmol,1.0eq)溶于DMF(10mL)中,加入碳酸钠(1.83g,17.28mmol,8.0eq),加毕,于室温搅拌。15分钟后,将碘甲烷(15.3g,108mmol,50.0eq)溶于DMF(5mL)缓缓加到上述体系,加毕,室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用EA萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体22,黄色固体287mg,产率26%。
1H NMR(600MHz,DMSO-d6)δ8.68(s,1H),8.56(s,1H),8.30(s,1H),7.74(s,1H),7.48–7.44(m,2H),7.28(s,1H),3.97–3.95(m,1H),3.94(s,3H),3.92(s,3H),3.89–3.86(m,1H),3.49(s,3H),2.03(s,3H),1.95(s,3H),1.46(dd,J=12.0,5.3,12H).MS(ESI)calcdfor C31H36O6:504.2,found m/z+=505.3,m/z-=503.3.
21、5,5'-二异丙基-1',7,7'-三甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,6,6'-三三氟甲烷磺酸酯23的制备
将中间体22(278mg,0.55mmol,1.0eq)溶于干燥DCM(30mL)中,加入吡啶(870mg,11.0mmol,20.0eq)。5分钟后,将Tf2O(1.552g,5.5mmol,10.0eq)溶于干燥DCM(5mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体23,黄色固体91mg,产率18%。
MS(ESI)calcd for C34H33F9O12S3:900.0,not found.
22、5,5'-二异丙基-1',7,7'-三甲氧基-3,3'-二甲基-[2,2'-联二萘]24的制备
将中间体23(91mg,0.1mmol,1.0eq)加入封管中,加入DMF(4mL),N2保护下加入Pd(OAc)2(9mg,0.0384mmol,0.4eq),dppp(16mg,0.0384mmol,0.4eq)。5分钟后,加入Et3SiH(141mg,1.2mmol,12.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体24,黄色液体47mg,产率99%。
1H NMR(600MHz,CDCl3)δ7.96(s,1H),7.75(s,1H),7.60(s,1H),7.32(d,J=2.0,1H),7.12(d,J=2.2,1H),7.10(d,J=2.2,1H),6.97(d,J=1.9,1H),3.94(s,3H),3.91(s,3H),3.79–3.71(m,2H),3.57(s,3H),2.23(s,3H),2.15(s,3H),1.43(dd,J=11.6,6.8,12H).MS(ESI)calcd for C31H36O3:456.2,not found.
二维核磁2D NMR NOE
23、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1',7,7'-三醇25的制备
将中间体24(66mg,0.14mmol,1.0eq)溶于干燥DCM(5mL),降温至-5℃,在N2氛围下滴加BBr3(877mg,3.5mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入冰水中淬灭,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用EA/PE重结晶得到产物25,灰色固体37mg,产率62%。
HPLC purity:92.1%(20%H2O/ACN),tR=4.063min.1H NMR(600MHz,DMSO-d6)δ7.92(s,1H),7.46(s,1H),7.40(s,1H),7.30(s,1H),6.99(s,1H),6.97(s,1H),6.94(s,1H),3.73(dt,J=13.5,6.7,1H),3.67(dd,J=16.7,10.0,1H),2.10(s,3H),1.99(s,3H),1.37–1.32(m,12H).13C NMR(150MHz,DMSO-d6)δ154.77,154.23,148.56,145.80,145.67,136.34,134.55,131.97,131.08,128.64,126.41,126.33,125.84,123.87,123.45,115.04,114.77,114.70,107.38,102.61,28.33,28.15,24.13,24.12,23.79,23.75,21.58,20.62.MS(ESI)calcd for C28H30O3:414.2,m/z+=not found,m/z-=413.2.
24、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,6',7,7'-六乙酸六酯26的制备
将醋酸棉酚1(1.0g,1.9mmol)加入10mL 40%NaOH中,加毕,用N2置换空气,加热至90℃,剧烈搅拌。2h后,将反应液缓缓倒入冰的硫酸溶液中淬灭,淬灭结束后,用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到粗产品阿扑棉酚2,无需纯化,直接用于下一步。粗产品用20mL DCM溶解,加入DMAP(24mg,0.20mmol)以及Ac2O(3.6mL,38.6mmol)后,室温反应,TLC、LC-MS监控。反应结束后,将反应液减压浓缩,得到的粗产物用柱层析分离得到乙酰化的阿扑棉酚26,黄色固体,两步产率92%。
1H NMR(600MHz,CDCl3)δ7.99(s,2H),7.45(s,2H),3.88–3.78(m,2H),2.40(s,6H),2.32(s,6H),2.19(s,6H),1.99(s,6H),1.52–1.45(m,12H).MS(ESI)calcd for C40H42O12:714.3,not found.
25、6,6',7,7'-四羟基-5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1'-二乙酸二酯27的制备
将乙酰化的阿扑棉酚26(0.97g,1.8mmol)溶于MeOH(40mL)和DCM(20mL)混合溶液,加入碳酸钾(2.4g,17.7mmol)后,用N2置换空气,加热至65℃,TLC、LC-MS监控。15h小时后,冷却至室温,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体27,黄色固体,产率85%。
1H NMR(400MHz,DMSO-d6)δ7.80(s,2H),6.88(s,2H),3.87(m,2H),2.03(s,6H),1.87(s,6H),1.46(dd,J=6.9,5.1Hz,12H).MS(ESI)calcd for C32H34O8:546.2,found m/z-=545.3.
26、7,7'-双苄氧基-6,6'-二羟基-5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1'-二乙酸二酯28的制备
将化合物27(1.3g,2.38mmol,1.0eq)溶于DMF(45mL)中,加入碳酸钠(1.26g,11.9mmol,5.0eq),加毕,于室温搅拌。15分钟后,将苄溴(4.07g,23.8mmol,10.0eq)溶于DMF(5mL)缓缓加到上述体系,加毕,室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用EA萃取(3*300mL),合并有机相,用饱和食盐水洗三次(3*150mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体28,棕色固体680mg,产率40%。
1H NMR(600MHz,CDCl3)δ7.86(s,1H),7.47–7.36(m,5H),6.95(s,1H),6.24(s,1H),5.21–5.15(m,2H),3.88(s,1H),2.17(s,3H),1.87(s,3H),1.53(dd,J=6.8,5.3,6H).MS(ESI)calcd for C46H46O8:726.3,found m/z+=not found,m/z-=725.3.
27、7,7'-双苄氧基-5,5'-二异丙基-6,6'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1'-二乙酸二酯29的制备
将化合物28(432mg,0.6mmol,1.0eq)溶于DMF(25mL)中,加入碳酸钾(2.07g,15.0mmol,25.0eq),加毕,于室温搅拌。15分钟后,将碘甲烷(2.13g,15.0mmol,25.0eq)溶于DMF(5mL)缓缓加到上述体系,加毕,室温反应,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用EA萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体29,黄色固体380mg,产率85%。
1H NMR(600MHz,CDCl3)δ7.91(s,1H),7.48(d,J=7.4,2H),7.40(t,J=7.5,2H),7.33(t,J=7.4,1H),6.96(s,1H),5.19(q,J=11.8,2H),3.95(s,4H),2.15(s,3H),1.88(s,3H),1.55(dd,J=13.7,7.7,6H).MS(ESI)calcd for C48H50O8:754.3,not found.
28、5,5'-二异丙基-6,6'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',7,7'-四醇30的制备
将化合物29(725mg,0.96mmol,1.0eq)溶于干燥DCM(2mL)中,0℃下加入三氯化硼(14.4mL,14.4mmol,15.0eq,1.0M in DCM),加毕,缓缓升至室温搅拌,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用EA萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体30,黄色固体380mg,产率81%。
MS(ESI)calcd for C30H34O6:490.2,found m/z+=not found,m/z-=489.2.
29、5,5'-二异丙基-6,6'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',7,7'-四三氟甲烷磺酸酯31的制备
将中间体30(380mg,0.78mmol,1.0eq)溶于干燥DCM(30mL)中,加入吡啶(1.23g,15.6mmol,20.0eq)。5分钟后,将Tf2O(2.2g,7.8mmol,10.0eq)溶于干燥DCM(5mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体31,黄色固体457mg,产率58%。
MS(ESI)calcd for C34H30F12O14S4:1018.0,not found.
30、5,5'-二异丙基-6,6'-二甲氧基-3,3'-二甲基-[2,2'-联二萘]32的制备
将中间体31(457mg,0.44mmol,1.0eq)加入封管中,加入DMF(8mL),N2保护下加入Pd(OAc)2(40mg,0.176mmol,0.4eq),dppp(72mg,0.176mmol,0.4eq)。5分钟后,加入Et3SiH(1023mg,8.8mmol,20.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*300mL),合并有机相,用饱和食盐水洗三次(3*150mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体32,黄色固体110mg,产率58%。
1H NMR(600MHz,CDCl3)δ8.06(s,2H),7.69(d,J=8.9,2H),7.63(s,2H),7.28(d,J=3.7,2H),4.06–3.99(m,2H),3.98(s,6H),2.28(s,6H),1.57–1.54(m,12H).MS(ESI)calcdfor C30H34O2:426.2,not found.
二维核磁2D NMR NOE
31、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-6,6'-二醇33的制备
将中间体32(20mg,0.047mmol,1.0eq)溶于干燥DCM(2mL),降温至-5℃,在N2氛围下滴加BBr3(294mg,1.175mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,加水析出沉淀,抽滤,滤渣用水洗,真空干燥,得到产物33,白色固体14mg,产率75%。
HPLC purity:95.3%(30%H2O/ACN),tR=6.918min.1H NMR(600MHz,DMSO-d6)δ9.38(s,1H),7.98(s,1H),7.56(d,J=8.5,1H),7.51(s,1H),7.09(d,J=8.4,1H),3.96–3.83(m,1H),2.17(s,3H),1.47(s,6H).13C NMR(150MHz,DMSO-d6)δ136.52,134.32,132.63,129.06,127.47,127.31,123.89,123.05,118.80,26.12,21.37,21.23.MS(ESI)calcd forC28H30O2:398.2,m/z+=not found,m/z-=397.2.
32、5,5'-二异丙基-6'-甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,7,7'-五醇34的制备
室温下,往化合物29(678mg,0.90mmol,1.0eq)中加入三氯化硼(18mL,18mmol,20.0eq,1.0M in DCM),加毕,于室温搅拌,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用EA萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体34,黄色固体197mg,产率46%。
MS(ESI)calcd for C29H32O6:476.2,found m/z+=not found,m/z-=475.2.
33、5,5'-二异丙基-6'-甲氧基-3,3'-二甲基-[2,2'-联二萘]-1,1',6,7,7'-五三氟甲烷磺酸酯35的制备
将中间体34(197mg,0.41mmol,1.0eq)溶于干燥DCM(10mL)中,加入吡啶(649mg,8.2mmol,20.0eq)。5分钟后,将Tf2O(1.156g,4.1mmol,10.0eq)溶于干燥DCM(3mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体35,黄色固体256mg,产率54%。
MS(ESI)calcd for C34H27F15O16S5:1135.9,not found.
34、5,5'-二异丙基-6-甲氧基-3,3'-二甲基-[2,2'-联二萘]36的制备
将中间体35(256mg,0.22mmol,1.0eq)加入封管中,加入DMF(5mL),N2保护下加入Pd(OAc)2(20mg,0.088mmol,0.4eq),dppp(36mg,0.088mmol,0.4eq)。5分钟后,加入Et3SiH(512mg,4.4mmol,20.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*300mL),合并有机相,用饱和食盐水洗三次(3*150mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体36,黄色固体40mg,产率42%。
1H NMR(400MHz,CDCl3)δ8.06(s,1H),8.04(s,1H),7.71–7.66(m,3H),7.62(s,1H),7.44(s,1H),7.43(d,J=1.1,1H),7.27(s,1H),4.05–3.98(m,1H),3.97(s,3H),3.83(dt,J=13.7,6.9,1H),2.29(s,3H),2.26(s,3H),1.54(dd,J=7.0,3.3,6H),1.47(t,J=6.4,6H).MS(ESI)calcd for C29H32O:396.2,not found.
35、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-6-醇37的制备
将中间体36(40mg,0.1mmol,1.0eq)溶于干燥DCM(2mL),降温至-5℃,在N2氛围下滴加BBr3(632mg,2.5mmol,25.0eq)。滴加完毕,缓缓升至室温反应,TLC、LC-MS监控。反应结束后,加水析出沉淀,抽滤,滤渣用水洗,真空干燥,得到产物37,黄色固体20mg,产率52%。
HPLC purity:84.9%(30%H2O/ACN),tR=9.717min.1H NMR(600MHz,DMSO-d6)δ9.42(s,1H),8.07(s,1H),8.00(s,1H),7.69(d,J=5.9,2H),7.57(d,J=1.8,2H),7.42(s,2H),7.11(s,1H),3.91(s,1H),3.80(s,1H),2.21(s,3H),2.17(s,3H),1.47(s,6H),1.38(s,6H).13C NMR(150MHz,DMSO-d6)δ143.90,140.00,136.26,134.60,134.02,132.73,132.50,130.76,129.18,128.90,127.45,127.37,126.30,125.60,123.92,123.50,122.06,118.90,28.25,24.17,23.88,21.37,21.13.MS(ESI)calcd for C28H30O:382.2,m/z+=not found,m/z-=381.2.
36、5,5'-二异丙基-3,3'-二甲基-6,6',7,7'-四(((三氟甲基)磺酰)氧基)-[2,2'-联二萘]-1,1'-双乙酸酯38的制备
将中间体27(382mg,0.7mmol,1.0eq)溶于干燥DCM(10mL)中,加入吡啶(819mg,10.5mmol,15.0eq)。5分钟后,将Tf2O(2.9g,10.5mmol,15.0eq)溶于干燥DCM(3mL)缓缓加到上述体系,TLC、LC-MS监控。反应结束后,将反应液缓缓倒入水中淬灭,用DCM萃取(3*200mL),合并有机相,用饱和食盐水洗三次(3*100mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到中间体38,黄色固体350mg,产率46%。
1H NMR(600MHz,CDCl3)δ8.23(s,2H),7.70(s,2H),3.99–3.95(m,2H),2.26(s,6H),2.05(s,6H),1.69(t,J=6.6,12H).MS(ESI)calcd for C36H30F12O16S4:1074.0,not found.
37、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1'-双乙酸酯39的制备
将中间体38(350mg,0.32mmol,1.0eq)加入封管中,加入DMF(5mL),N2保护下加入Pd(OAc)2(36mg,0.16mmol,0.5eq),dppp(66mg,0.16mmol,0.5eq)。5分钟后,加入Et3SiH(378mg,3.2mmol,10.0eq),封口,升温至85℃,TLC、LC-MS监控。24h后,将反应液缓缓倒入水中淬灭,然后用乙酸乙酯萃取(3*300mL),合并有机相,用饱和食盐水洗三次(3*150mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到6,6',7,7'-去羟基阿扑棉酚前体39,黄色固体58mg,产率38%。
1H NMR(600MHz,DMSO-d6)δ8.07(s,1H),7.66(d,J=7.0Hz,1H),7.55–7.47(m,2H),3.86-3.79(m,1H),2.14(s,3H),1.91(s,3H),1.39(dd,J=13.2,6.8Hz,6H).MS(ESI)calcdfor C32H34O4:482.2,m/z+=505.2,m/z-=not found.
38、5,5'-二异丙基-3,3'-二甲基-[2,2'-联二萘]-1,1'-二醇40的制备
将中间体39(58mg,0.12mmol,1.0eq)溶于THF(10mL),降温至0℃,分2批加入氢化锂铝(91mg,2.4mmol,20.0eq)。加毕,继续于0℃反应,TLC、LC-MS监控。反应结束后,用2M稀盐酸淬灭反应,然后用乙酸乙酯萃取(3*100mL),合并有机相,用饱和食盐水洗三次(3*50mL),然后用无水硫酸钠干燥。过滤,减压浓缩,得到的粗产品用柱层析分离得到6,6',7,7'-去羟基阿扑棉酚40,白色固体47mg,产率95%。
HPLC purity:95.5%(10%MeOH/H2O),tR=3.92min.,1H NMR(600MHz,DMSO-d6)δ8.09(d,J=8.0Hz,2H),7.62(s,2H),7.44–7.33(m,4H),3.78-3.73(m,2H),2.05(s,6H),1.38(t,J=6.6Hz,12H).13C NMR(150MHz,DMSO-d6)δ151.1,143.5,136.1,132.1,124.7,123.8,122.0,120.9,118.7,114.8,28.4,24.2,23.9,21.4.MS(ESI)calcd for:C28H30O2:398.2,m/z+=not found,m/z-=397.2.
39、本发明选择性去羟基阿扑棉酚体外抗肿瘤细胞系活性(CCK测试)
收集对数期细胞铺板(96孔平底板)将待测肿瘤细胞调密度至1000-10000孔(边缘孔用无菌PBS填充),待测肿瘤细胞分别选人肺癌细胞、人肝癌细胞L02。5%CO2 37℃孵育至细胞单层铺满孔底。加入浓度梯度的化合物,一般5-7个梯度,每孔100μL,设3-5个复孔。3.5%CO2 37℃孵育48小时。每孔加入10μL CCK溶液,继续培养4h。先离心后弃去培养液用PBS冲2-3遍后。终止培养,吸去孔内培养液。在酶标仪450nm处测量各孔的吸光值。肿瘤细胞抑制率(%)=[1-(加化合物细胞OD值/对照细胞OD值)]×100。以化合物浓度为横坐标,细胞抑制率为纵坐标作图,然后得到50%抑制率时候的化合物浓度,就是IC50,计算结果如表1所示。
表1.本发明选择性去羟基阿扑棉酚对肿瘤细胞和正常肝细胞活性
a:IC50值为三次实验结果的平均值。
b:选自本公司之前专利化合物(1,1’-去氧棉酚的合成方法,CN112679319A)
体外癌细胞抗增殖活性测试结果表明:
1)酚羟基对抗肿瘤活性有着重要作用,本发明的9个选择性去羟基阿扑棉酚除了无酚羟基的化合物17无生物活性外,其他化合物均对肿瘤细胞有着抑制作用,并且大部分化合物的抑制作用与阿扑棉酚相近。
2)酚羟基数量对抗肿瘤活性影响有限,最为典型的是只剩一个酚羟基的化合物37,仍然具有较强的抗肿瘤活性,这对我们后续设计棉酚衍生物和类似物非常关键。
3)酚羟基的位置比酚羟基的数量更为重要,1,1’-位羟基对抗肿瘤的作用贡献较小。
40、本发明选择性去羟基阿扑棉酚对Bcl-2和Mcl-1蛋白的抑制作用、相对结合力测试
在测试缓冲液(1×PBS)中加入40nM靶蛋白(靶蛋白通过大肠杆菌表达纯化得到,参考文献:2010,Journal of Molecular Biology,398,5,747–762)和不同浓度的待测化合物(0.1μM,0.2μM,1μM,5μM,10μΜ),混匀后室温避光孵育30min。再加入5nM FAM-Bid-BH3多肽(5-FAM-EDIIRNIARHLAQVGDSMDR,上海HD Biosenceces合成),使各溶液的总体积均为200μL,混匀后室温避光孵育20min。将上述溶液及校正溶液(1nM荧光黄,10mM NaOH)各取60μL转移至黑色384孔板中(平行三组),立即在酶标仪上进行荧光偏振的检测,以485nm为激发波长,535nm为发射波长,将校正溶液的荧光偏振值定为20mP,极化值测定结果取平均值。用GraphPad Prism软件处理数据和做图,得出化合物的IC50值。根据测量中所使用的蛋白总浓度、荧光多肽的总浓度、蛋白-多肽复合物的解离常数以及检测化合物的IC50值,使用下列文献中的计算方法得出化合物的竞争性抑制常数Ki(Nikolovska-Coleska,Z.;etal.Development and optimization ofa binding assay for the XIAP BIR3domainusing fluorescence polarization.Anal Biochem.2004,332,261-273)。优选化合物的IC50和Ki值见表2。
表2.本发明选择性去羟基阿扑棉酚对Bcl-2和Mcl-1蛋白抑制作用以及相对结合力测试结果
a:IC50值为三次实验结果的平均值。
对蛋白的相对结合力测试表明:与母体化合物阿扑棉酚相比,选择性去羟基以后的化合物对Bcl-2,Bcl-XL和Mcl-1系列蛋白基本无结合力,说明酚羟基对Bcl-2蛋白结合信号通路有着重要作用。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.选择性去羟基阿扑棉酚的合成方法,其特征在于,包括以下步骤:
路线一:6-去羟基阿扑棉酚7和6,6'-去羟基阿扑棉酚10的合成
合成路线如下:
合成方法包括以下步骤:
(1)在保护气体氛围下,以醋酸棉酚1为起始原料,加入碱液中反应,脱去醛基得到阿扑棉酚2;
(2)将阿扑棉酚2不完全甲基化得到五甲基化中间体3和四甲基化中间体4:将阿扑棉酚2溶于乙腈中,加入碳酸钾和硫酸二甲酯,回流反应至完全,经浓缩、分离得到五甲基化中间体3和四甲基化中间体4;
(3)将中间体3的剩余酚羟基用OTf保护得到中间体5:将中间体3溶于DCM中,加入TBD以及Tf2O,室温反应至完全,经浓缩、分离得到中间体5;
将中间体4的剩余酚羟基用OTf保护得到中间体8:将中间体4溶于DCM中,加入TBD以及Tf2O,室温反应至完全,经浓缩、分离得到中间体8;
(4)还原中间体5被保护的酚羟基得到6-去羟基阿扑棉酚前体6:将中间体5溶于DMF中,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到6-去羟基阿扑棉酚前体6;
还原中间体8被保护的酚羟基得到6,6'-去羟基阿扑棉酚前体9:将中间体8溶于DMF中,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到6,6'-去羟基阿扑棉酚前体9;
(5)脱除6-去羟基阿扑棉酚前体6的甲氧基得到目标产物6-去羟基阿扑棉酚7:将6-去羟基阿扑棉酚前体6溶于DCM中,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物6-去羟基阿扑棉酚7;
脱除6,6'-去羟基阿扑棉酚前体9的甲氧基得到目标产物6,6'-去羟基阿扑棉酚10:将6,6'-去羟基阿扑棉酚前体9溶于DCM中,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物6,6'-去羟基阿扑棉酚10;
路线二:1,1',6,6'-去羟基阿扑棉酚15和1,1',6,6',7,7'-去羟基阿扑棉酚17的合成
合成路线如下:
合成方法包括以下步骤:
(1)将阿扑棉酚2完全甲基化得到中间体11:将阿扑棉酚2用乙腈溶解,加入碳酸钾和硫酸二甲酯,回流反应至完全,经浓缩、分离得到中间体11;
(2)选择性脱去中间体11的1,1',6,6'-位的两组甲氧基得到中间体12:将中间体11溶于氯仿,惰性氛围下,加入碘化钾,进行反应,然后加入TMSI,升温反应至完全,经浓缩、分离得到中间体12;
(3)保护中间体12的酚羟基得到中间体13:将中间体12溶于DCM,加入DIPEA以及Tf2O,室温反应至完全,经浓缩、分离得到中间体13;
(4)还原中间体13被保护的酚羟基得到1,1',6,6'-去羟基阿扑棉酚前体14:将中间体13溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,6'-去羟基阿扑棉酚前体14;
(5)脱除1,1',6,6'-去羟基阿扑棉酚前体14的甲氧基得到目标产物1,1',6,6'-去羟基阿扑棉酚15:将1,1',6,6'-去羟基阿扑棉酚前体14溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物1,1',6,6'-去羟基阿扑棉酚15;
(6)1,1',6,6',7,7'-去羟基阿扑棉酚17的合成方法,步骤如下:
(6.1)将1,1',6,6'-去羟基阿扑棉酚15溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体16;
(6.2)将中间体16溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,6',7,7'-去羟基阿扑棉酚17;
路线三:7,7'-去羟基阿扑棉酚21的合成
合成路线如下:
合成方法包括以下步骤:
(1)选择性保护阿扑棉酚2的7,7'-羟基得到中间体18:将阿扑棉酚2溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体18;
(2)保护中间体18的1,1',6,6'-位酚羟基得到中间体19:将中间体18溶于DMF,加入碳酸钾进行反应,然后加入碘甲烷,室温反应至完全,经浓缩、分离得到中间体19;
(3)还原中间体19被保护的7,7'-位酚羟基得到7,7'-去羟基阿扑棉酚前体20:将中间体19溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到7,7'-去羟基阿扑棉酚前体20;
(4)脱除7,7'-去羟基阿扑棉酚前体20的甲氧基得到目标产物7,7'-去羟基阿扑棉酚21:将7,7'-去羟基阿扑棉酚前体20溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、分离得到产物7,7'-去羟基阿扑棉酚21;
路线四:1,6,6'-去羟基阿扑棉酚25的合成
合成路线如下:
合成方法包括以下步骤:
(1)选择性保护阿扑棉酚2的1',7,7'-羟基得到中间体22:将阿扑棉酚2溶于DMF,加入碳酸钠进行反应,然后加入碘甲烷,室温反应至完全,经浓缩、分离得到中间体22;
(2)保护中间体22的1,6,6'-位酚羟基得到中间体23:将中间体22溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体23;
(3)还原中间体23被保护的1,6,6'-位酚羟基得到1,6,6'-去羟基阿扑棉酚前体24:将中间体23溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,6,6'-去羟基阿扑棉酚前体24;
(4)脱除1,6,6'-去羟基阿扑棉酚前体24的甲氧基得到目标产物1,6,6'-去羟基阿扑棉酚25:将1,6,6'-去羟基阿扑棉酚前体24溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经浓缩、重结晶得到产物1,6,6'-去羟基阿扑棉酚25;
路线五:1,1',7,7'-去羟基阿扑棉酚33和1,1',6,7,7'-去羟基阿扑棉酚37的合成
合成路线如下:
合成方法包括以下步骤:
(1)将阿扑棉酚2乙酰化得到乙酰化的阿扑棉酚26:将阿扑棉酚2用DCM溶解,加入DMAP以及Ac2O后,室温反应完全,经浓缩、分离得到乙酰化的阿扑棉酚26;
(2)选择性脱去乙酰化的阿扑棉酚26的6,6',7,7'-位乙酰基得到中间体27:将乙酰化的阿扑棉酚26溶于MeOH和DCM混合溶液,加入碳酸钾后,在惰性气氛下,加热至反应完全,经分离得到中间体27;
(3)用苄基化试剂选择性保护中间体27的6,6'-位羟基得到中间体28:将中间体27溶于DMF,加入碳酸钠进行反应,然后加入苄溴,室温反应至完全,经浓缩、分离得到中间体28;
(4)用甲基化试剂保护中间体28的剩余羟基得到中间体29:将中间体28溶于DMF,加入碳酸钾进行反应,然后加入碘甲烷,室温反应至完全,经浓缩、分离得到中间体29;
(5)选择性脱去中间体29的乙酰基和苄基得到中间体30:将化合物29溶于DCM,低温下加入三氯化硼,然后缓缓升温至室温反应至完全,经浓缩、分离得到中间体30;
选择性脱去中间体29的乙酰基和苄基和一个甲氧基得到中间体34:将化合物29溶于DCM,室温下加入三氯化硼,然后于室温反应至完全,经浓缩、分离得到中间体34;
(6)用Tf2O保护中间体30的1,1',7,7'-位酚羟基得到中间体31:将中间体30溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体31;
用Tf2O保护中间体34的1,1',6,7,7'-位酚羟基得到中间体35:将中间体34溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体35;
(7)还原中间体31被保护的1,1',7,7'-位酚羟基得到1,1',7,7'-去羟基阿扑棉酚前体32:将中间体31溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',7,7'-去羟基阿扑棉酚前体32;
还原中间体35被保护的1,1',6,7,7'-位酚羟基得到1,1',6,7,7'-去羟基阿扑棉酚前体36:将中间体35溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到1,1',6,7,7'-去羟基阿扑棉酚前体36;
(8)脱除1,1',7,7'-去羟基阿扑棉酚前体32的甲氧基得到目标产物1,1',7,7'-去羟基阿扑棉酚33:将1,1',7,7'-去羟基阿扑棉酚前体32溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经沉淀、水洗得到产物1,1',7,7'-去羟基阿扑棉酚33;
脱除1,1',6,7,7'-去羟基阿扑棉酚前体36的甲氧基得到目标产物1,1',6,7,7'-去羟基阿扑棉酚37:将1,1',6,7,7'-去羟基阿扑棉酚前体36溶于DCM,降温,惰性氛围下,滴加BBr3,然后升温至反应完全,再经沉淀、水洗得到产物1,1',6,7,7'-去羟基阿扑棉酚37;
路线六:6,6',7,7'-去羟基阿扑棉酚40的合成
合成方法包括以下步骤:
(1)用Tf2O保护中间体27的6,6',7,7'-位酚羟基得到中间体38:将中间体27溶于DCM,加入吡啶以及Tf2O,室温反应至完全,经浓缩、分离得到中间体38;
(2)还原中间体38被保护的6,6',7,7'-位酚羟基得到6,6',7,7'-去羟基阿扑棉酚前体39:将中间体38溶于DMF,惰性氛围下,加入Pd(OAc)2和dppp,进行反应,然后加入Et3SiH,升温反应至完全,经浓缩、分离得到6,6',7,7'-去羟基阿扑棉酚前体39;
(3)脱除6,6',7,7'-去羟基阿扑棉酚前体39的乙酰基得到目标产物6,6',7,7'-去羟基阿扑棉酚40:将6,6',7,7'-去羟基阿扑棉酚前体39溶于THF,降温,分批加入氢化锂铝,然后低温反应完全,经浓缩、分离6,6',7,7'-去羟基阿扑棉酚40。
2.根据权利要求1所述的方法,其特征在于:所述路线一步骤(1)中,碱液为氢氧化钠溶液,反应后经淬灭、萃取,洗涤、干燥,再经过滤、减压浓缩获得粗产品。
3.根据权利要求1所述的方法,其特征在于:所述路线一中,中间体3、TBD和Tf2O的摩尔用量分别为1.0eq、7.0eq和4.0eq;中间体4、TBD和Tf2O的摩尔用量分别为1.0eq、6.0eq和4.0eq;中间体5、Pd(OAc)2、dppp和Et3SiH的摩尔用量为1.0eq、0.2eq、0.2eq和8.0eq;中间体8、Pd(OAc)2、dppp和Et3SiH的摩尔用量为1.0eq、0.3eq、0.3eq和10.0eq;6-去羟基阿扑棉酚前体6和BBr3的摩尔用量为1.0eq和25.0eq;6,6'-去羟基阿扑棉酚前体9和BBr3的摩尔用量为1.0eq和25.0eq。
4.根据权利要求1所述的方法,其特征在于:所述路线二中,中间体11、碘化钾的摩尔用量分别为1.0eq和0.6eq;中间体12、DIPEA、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体13、Pd(OAc)2、dppp、Et3SiH的摩尔用量比为1.0eq、0.2eq、0.2eq、10.0eq;1,1',6,6'-去羟基阿扑棉酚前体14、BBr3的摩尔用量为1.0eq、25.0eq。
5.根据权利要求1所述的方法,其特征在于:所述路线二步骤(6)中,1,1',6,6'-去羟基阿扑棉酚15、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、8.0eq;中间体16、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、12.0eq。
6.根据权利要求1所述的方法,其特征在于:所述路线三中,阿扑棉酚2、吡啶、Tf2O的摩尔用量为1.0eq、6.0eq、3.0eq;中间体18、碳酸钾、碘甲烷的摩尔用量为1.0eq、20.0eq、25.0eq;中间体19、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、12.0eq;7,7'-去羟基阿扑棉酚前体20、BBr3的摩尔用量为1.0eq、25.0eq。
7.根据权利要求1所述的方法,其特征在于:所述路线四中,阿扑棉酚2、碳酸钠、碘甲烷的摩尔用量为1.0eq、8.0eq、50.0eq;中间体22、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体23、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、12.0eq;中间体24、BBr3的摩尔用量为1.0eq、25.0eq。
8.根据权利要求1所述的方法,其特征在于:所述路线五中,化合物27、碳酸钠、苄溴的摩尔用量为1.0eq、5.0eq、10.0eq;化合物28、碳酸钾、碘甲烷的摩尔用量为1.0eq、25.0eq、25.0eq;化合物29、三氯化硼的摩尔用量为1.0eq、15.0eq;中间体30、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体31、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、20.0eq;中间体32、BBr3的摩尔用量为1.0eq、25.0eq。
9.根据权利要求1所述的方法,其特征在于:所述路线五中,化合物29、三氯化硼的摩尔用量为1.0eq、20.0eq;中间体34、吡啶、Tf2O的摩尔用量为1.0eq、20.0eq、10.0eq;中间体35、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.4eq、0.4eq、20.0eq;中间体36、BBr3的摩尔用量为1.0eq、25.0eq。
10.根据权利要求1所述的方法,其特征在于:所述路线六中,中间体27、吡啶、Tf2O的摩尔用量为1.0eq、15.0eq、15.0eq;中间体38、Pd(OAc)2、dppp、Et3SiH的摩尔用量为1.0eq、0.5eq、0.5eq、10.0eq;中间体39、氢化锂铝的摩尔用量为1.0eq、20.0eq。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101132783A (zh) * | 2004-11-02 | 2008-02-27 | 密执安州立大学董事会 | 阿朴棉子酚酮及其用途 |
CN105884634A (zh) * | 2015-01-05 | 2016-08-24 | 南开大学 | 棉酚衍生物和它们的制备,在农药上的应用及抗癌活性 |
CN111848374A (zh) * | 2019-04-30 | 2020-10-30 | 中国科学院上海有机化学研究所 | 一种棉酚、其衍生物的制备方法及其中间体 |
CN112679319A (zh) * | 2020-12-29 | 2021-04-20 | 江苏度未生物工程科技有限公司 | 1,1′-去氧棉酚的合成方法 |
-
2022
- 2022-09-27 CN CN202211181554.7A patent/CN115536496B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101132783A (zh) * | 2004-11-02 | 2008-02-27 | 密执安州立大学董事会 | 阿朴棉子酚酮及其用途 |
CN105884634A (zh) * | 2015-01-05 | 2016-08-24 | 南开大学 | 棉酚衍生物和它们的制备,在农药上的应用及抗癌活性 |
CN111848374A (zh) * | 2019-04-30 | 2020-10-30 | 中国科学院上海有机化学研究所 | 一种棉酚、其衍生物的制备方法及其中间体 |
CN112679319A (zh) * | 2020-12-29 | 2021-04-20 | 江苏度未生物工程科技有限公司 | 1,1′-去氧棉酚的合成方法 |
Non-Patent Citations (4)
Title |
---|
JUN WEI等: "Apogossypol Derivatives as Pan-Active Inhibitors of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 52, no. 14, pages 4511 - 4523, XP055019266, DOI: 10.1021/jm900472s * |
WANG WEI等: "Practical Strategy to 1, 1′-Dideoxygossypol Derivatives from Gossypol and Its Antitumor Activities", 《ACS OMEGA》, vol. 7, no. 26, pages 22938 - 22943 * |
ZHAN, YONGHUA等: "Design and Synthesis of a Gossypol Derivative with ImprovedAntitumor Activities", 《ARCHIV DER PHARMAZIE》, vol. 342, no. 4, pages 223 - 229, XP071647414, DOI: 10.1002/ardp.200800185 * |
郭争鸣等: "单醛棉酚及其类似物的合成", 《药学学报》, vol. 22, no. 8, pages 597 - 602 * |
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