CN100564370C - 异黄酮衍生物的制备 - Google Patents
异黄酮衍生物的制备 Download PDFInfo
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- CN100564370C CN100564370C CNB008038163A CN00803816A CN100564370C CN 100564370 C CN100564370 C CN 100564370C CN B008038163 A CNB008038163 A CN B008038163A CN 00803816 A CN00803816 A CN 00803816A CN 100564370 C CN100564370 C CN 100564370C
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- Prior art keywords
- alkene
- alcohol
- methyl
- diacetoxy
- different huang
- Prior art date
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- 150000002515 isoflavone derivatives Chemical class 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims description 46
- 229930012930 isoflavone derivative Natural products 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 73
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 34
- 150000002431 hydrogen Chemical group 0.000 claims description 32
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 28
- -1 halo (C1-C6) alkyl Chemical group 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 229910052763 palladium Inorganic materials 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 24
- 239000001301 oxygen Substances 0.000 claims description 24
- 150000002460 imidazoles Chemical class 0.000 claims description 23
- 229960004756 ethanol Drugs 0.000 claims description 20
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 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 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 12
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 4
- 230000007062 hydrolysis Effects 0.000 claims 2
- 238000006460 hydrolysis reaction Methods 0.000 claims 2
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 abstract description 82
- 235000008696 isoflavones Nutrition 0.000 abstract description 82
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 80
- 239000000203 mixture Substances 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 description 42
- 239000000047 product Substances 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 235000019441 ethanol Nutrition 0.000 description 29
- 235000019126 equol Nutrition 0.000 description 27
- ADFCQWZHKCXPAJ-UHFFFAOYSA-N indofine Natural products C1=CC(O)=CC=C1C1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-UHFFFAOYSA-N 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- ADFCQWZHKCXPAJ-GFCCVEGCSA-N equol Chemical compound C1=CC(O)=CC=C1[C@@H]1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-GFCCVEGCSA-N 0.000 description 24
- 235000007240 daidzein Nutrition 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 19
- 238000006356 dehydrogenation reaction Methods 0.000 description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 18
- 239000002585 base Substances 0.000 description 17
- 238000001819 mass spectrum Methods 0.000 description 16
- 238000001953 recrystallisation Methods 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 238000006722 reduction reaction Methods 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- NNQSGBRGJHSRFN-UHFFFAOYSA-N isoflavan Chemical compound C1OC2=CC=CC=C2CC1C1=CC=CC=C1 NNQSGBRGJHSRFN-UHFFFAOYSA-N 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 13
- 235000002324 isoflavanes Nutrition 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 125000003118 aryl group Chemical group 0.000 description 12
- 238000004140 cleaning Methods 0.000 description 11
- 238000007738 vacuum evaporation Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 239000007789 gas Substances 0.000 description 10
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 9
- 125000003710 aryl alkyl group Chemical group 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 239000002207 metabolite Substances 0.000 description 7
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 235000006408 oxalic acid Nutrition 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910003446 platinum oxide Inorganic materials 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
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- 239000000843 powder Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WMKOZARWBMFKAS-UHFFFAOYSA-N 7-hydroxyisoflavone Chemical compound C=1C(O)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 WMKOZARWBMFKAS-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- OHNNFNBOPWLDFH-UHFFFAOYSA-N [4-(7-acetyloxy-4-oxochromen-3-yl)phenyl] acetate Chemical class C1=CC(OC(=O)C)=CC=C1C1=COC2=CC(OC(C)=O)=CC=C2C1=O OHNNFNBOPWLDFH-UHFFFAOYSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
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- BDDWSAASCFBVBK-UHFFFAOYSA-N rhodium;triphenylphosphane Chemical compound [Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BDDWSAASCFBVBK-UHFFFAOYSA-N 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
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- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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Abstract
本发明描述了异黄酮的氢化方法,其可提供可操作量的异黄烷-4-醇、异黄-3-烯以及异黄酮。当应用制药上可接受的试剂和溶剂时,可以几乎定量的产率获得高纯度的异黄酮衍生物。
Description
发明领域
本发明涉及异黄酮的氢化方法及其产品。本发明还涉及从异黄酮的氢化产物进行植物雌性激素异黄酮代谢产物及衍生物的合成。
发明背景
异黄酮代谢产物具有非常广泛的重要生物学性质,包括雌性激素作用(WO 98/08503)。从富含植物类异黄烷(例如大豆、小扁豆、豌豆和豆类)的人类志愿者的尿中可以分离得到异黄酮代谢产物。
尽管新近发现异黄酮代谢产物具有生物学活性,但到目前为止尚无适合于大规模合成这些代谢产物的方法。少数文献报道了利用相应异黄酮的催化氢化或氢转移还原合成这些代谢产物的方法。人们发现这些还原反应缺乏选择性、控制起来很困难并且可以导致不同产品混合物的出现。
已有报道,5,7-二羟基异黄羊盐的还原生成了异黄-2-烯、异黄-3-烯和异黄烷。单独的化合物很难分离并且产率很低。用硼氢化钠还原异黄酮是已知的,参见Adam Major等人,Liebigs Ann.Chem.(1988)555-558。然而,反应产率很低,一般不纯,并且基本异黄酮环结构上的取代基需要加以保护使之不受金属氢化物的影响。
通常需要层析来分离反应产物,并且所得到的异黄酮、异黄烷-4-醇、异黄烯和异黄烷的产率很低。层析过程非常乏味并且通常对于大规模反应来说是无法操作的。进一步地,改进产率和得自氢化反应产品纯度的尝试仅获得了有限的成功,正如公开的结果所显示的那样,其具有很大的矛盾性。
文献中所报道的在异黄酮氢化反应中所使用的溶剂包括N-甲基吡咯烷酮,参见Liepa,A.J.Aust.J.Chem.,1981,34,2647-55。然而,此溶剂不适合异黄酮代谢产物和衍生物的药物制备,原因是N-甲基吡咯烷酮对眼睛有很强的刺激作用并可能致癌。进一步地,溶剂的高熔点使之在还原后的去除时极其困难。
在异黄烯的合成中,异黄烷-4-醇是关键的中间体,因此需要更有效和可靠地合成异黄烷-4-醇,或至少要比已知的那些方法更能被人们所接受。也需要异黄酮氢化的合成方法,所利用的药用溶剂比那些先前报道过的溶剂更易为人们接受。因此,本发明的目标是克服或至少减轻一或多个前述方法中提及的缺点。本发明的另一个目标是合成新的异黄酮代谢产物和衍生物。
出人意料的是,本发明者发现了氢化反应的条件,这些条件能以极好的产率合成异黄酮衍生物。特别地,本发明者所发现的这些条件以极好的产率进行异黄酮的氢化并得到相对纯的四氢异黄烷-4-醇产品,其在氢化反应时无需使用不适药用的溶剂及花费较高的层析。
发明详述
因此本发明提供了氢化式I化合物制备式II化合物的方法:
其中R1,R2,R3,R4,R5,R6,R7和R8独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,烷基,卤代烷基,芳基,芳烷基,硫基,烷硫基,氨基,烷基氨基,二烷基氨基,硝基或卤素以及
R9为烷基,卤代烷基,芳基,芳烷基或烷芳基,
其中
R1,R2,R3,R4,R5,R6,R7,R8和R9的定义同上。
本发明还提供了使式II化合物脱水制备式III化合物的方法,该方法任意地包括脱保护或转化步骤:
其中
R1,R2,R3,R4,R5,R6,R7和R8独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,烷基,卤代烷基,芳基,芳烷基,硫代,烷硫基,氨基,烷基氨基,二烷基氨基,硝基或卤素以及
R9为烷基,卤代烷基,芳基,芳烷基或烷芳基。
本发明还提供了氢化式I化合物制备式IV化合物的方法:
其中
R1,R2,R3,R4,R5,R6,R7,R8和R9的定义同上。
本发明还提供了氢化式III化合物制备式V化合物的方法:
其中
R1,R2,R3,R4,R5,R6,R7,R8和R9的定义同上。
本发明还提供了用上述方法制备的式II、III、IV和V化合物以及含它们的组合物。
本发明还提供了新的式I、II、III、IV和V化合物以及含它们的组合物。
在本发明方法中,起始物质式I异黄酮、式II的氢化产品异黄烷-4-醇、式IV异黄烷-4-酮、式V异黄烷以及式III异黄-3-烯优选地具有下列取代基,其中
R1,R2,R3,R4,R5,R6,R7和R8独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,烷基,卤代烷基,芳基,芳烷基,硫基,烷硫基,溴,氯或氟,并且
R9为烷基,氟烷基或芳烷基;
更优选的具有下列取代基,其中
R1为羟基、OR9或OC(O)R9,
R2,R3,R4,R5,R6和R7独立为氢、羟基、OR9,OC(O)R9,烷基,芳基或芳烷基,
R8为氢,并且
R9为甲基,乙基,丙基,异丙基或三氟甲基;并且
最优选的具有下列取代基,其中
R1为羟基、OR9,OC(O)R9,
R2,R3,R4,R5和R7独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,烷基,芳基或芳烷基,
R6和R8为氢,并且
R9为甲基。
特别优选的式I化合物为4’,7-二乙酰氧基异黄酮(黄豆苷原二乙酸)以及7-乙酰氧基-4’-甲氧基异黄酮;
特别优选的式II化合物为4’,7-二乙酰氧基异黄烷-4-醇(四氢黄豆苷原二乙酸)以及7-乙酰氧基-4’-甲氧基异黄烷-4-醇;
特别优选的式III化合物为4’,7-二乙酰氧基异黄-3-烯(脱氢牛尿酚二乙酸),4’,7-二羟异黄-3-烯(脱氢牛尿酚),7-乙酰氧基-4’-甲氧基异黄-3-烯以及7-羟基-4’-甲氧基异黄-3-烯;
特别优选的式IV化合物为4’,7-二乙酰氧基异黄-4-酮(二乙酸二氢黄豆苷原)以及4’,7-二羟基异黄-4-酮(二氢黄豆苷原);以及
特别优选的式V化合物为4’,7-二乙酰氧基异黄烷(牛尿酚二乙酸)以及4’,7-二氢异黄烷(牛尿酚)。
新的式I、II、III、IV和V化合物优选具有下列取代基,其中
R1为羟基、OR9,OC(O)R9,硫基,烷硫基或卤素,
R2,R3,R4,R5,R6,R7和R8独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,烷基,芳基,硫基,烷硫基或卤素,并且
R9为烷基,氟烷基或芳烷基,
条件是:
R5,R6和R7至少一个不为氢,或者
当R5,R6和R7均为氢时,R3为羟基、OR9,OC(O)R9,OS(O)R9,烷基,芳基,硫基,烷硫基或卤素;并且
更优选的具有下列取代基,其中
R1为羟基、OR9或OC(O)R9,
R2和R3独立为氢、羟基、OR9或OC(O)R9,
R4,R5,R6和R8为氢,
R7为羟基,OR9,OC(O)R9,烷基,芳基或卤素,并且
R9为甲基,乙基,丙基,异丙基或三氟甲基或苄基;或
其中
R1为羟基、OR9,OC(O)R9,
R2和R3独立为氢、羟基、OR9或OC(O)R9,
R5为OR9,OC(O)R9,烷基,芳基或卤素,
R4,R6,R7和R8为氢,并且
R9为甲基,乙基,丙基,异丙基或三氟甲基或苄基。
最优选的新的式I、II和II化合物为:
4’,7,8-三乙酰氧基异黄酮
7,8-二乙酰氧基-4’-甲氧基异黄酮
4’,7-二乙酰氧基-8-甲基异黄酮
3’,7-二乙酰氧基-8-甲基异黄酮
7-乙酰氧基-4’-甲氧基-8-甲基异黄酮
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄酮
4’,5,7-三乙酰氧基异黄酮
4’,7,8-三乙酰氧基异黄烷-4醇
7,8-二乙酰氧基-4’-甲氧基异黄烷-4醇
4’,7-二乙酰氧基-8-甲基异黄烷-4醇
3’,7-二乙酰氧基-8-甲基异黄烷-4醇
7-乙酰氧基-4’-甲氧基-8-甲基异黄烷-4-醇
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄烷-4-醇
4’,5,7-三乙酰氧基异黄烷-4-醇
4’,7,8-三羟基异黄烷-4-醇
7,8-二羟基-4-甲氧基异黄烷-4-醇
4’,7-二羟基-8-甲基异黄烷-4-醇
3’,7-二羟基-8-甲基异黄烷-4-醇
7-羟基-4’-甲氧基-8-甲基异黄烷-4-醇
4’,7-二羟基-3’-甲氧基-8-甲基异黄烷-4-醇
4’,5,7-三羟基异黄烷-4-醇
4’,7,8-三乙酰氧基脱氢牛尿酚(4’,7,8-三乙酰氧基异黄-3-烯)
7,8-二乙酰氧基-4-甲氧基脱氢牛尿酚(7,8-二乙酰氧基-4-甲氧基异黄-3-烯)
4,,7-二乙酰氧基-8-甲基异黄-3-烯
3’,7-二乙酰氧基-8-甲基异黄-3-烯
7-乙酰氧基-4’-甲氧基-8-甲基异黄-3-烯
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄-3-烯
4’,5,7-三乙酰氧基异黄-3-烯
异黄-3-烯-4’,7,8-三醇
4’-甲氧基异黄-3-烯-7,8-二醇
8-甲基异黄-3-烯-4’,7-二醇
8-甲基异黄-3-烯-3’,7-二醇
4’-甲氧基-8-甲基异黄-3-烯-7-醇
3’-甲氧基-8-甲基异黄-3-烯-4’,7-二醇
异黄-3-烯-4’,5,7-三醇
4’,7-二羟基-8-甲基异黄烷-4-醇
7-羟基-4’-甲氧基-8-甲基异黄烷-4-醇
术语“烷基”代表直链或支链的烷基。例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。优选的烷基是含有1-6个碳原子的低级烷基。烷基可以任意地被一或多个氟、氯、溴、碘、羧基、C1-C4-烷氧羰基、C1-C4-烷氨羰基、二(C1-C4-烷基)氨基羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基羰氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基取代。
术语“芳基”包括苯基或萘基,它们可以任意地被一或多个C1-C4-烷基、羟基、C1-C4-烷氧基、羰基、C1-C4-烷氧羰基、C1-C4-烷羰氧基或卤素取代。
术语“卤素”代表一或多个选自氟、氯、溴、碘的卤素及其混合物,优选的是氟和氯,更优选的是氟。“卤代烷基”包括单卤代、双卤代以及上至全卤代的烷基。优选的全卤代基团为三氟甲基和五氟乙基。
本发明化合物包括所有的盐类,例如酸加成盐、阴离子盐以及两性离子盐,特别包括制药上可接受的盐类。
除非内容另有要求,在本说明书及所随后的权利要求中,“包含”一词及其变形形式将被理解为暗示包括所叙述的整体或步骤中的整体或步骤或基团,但不排除任何其它整体或步骤中的整体或步骤或基团。
理想地,氢化反应是在有还原催化剂和溶剂的存在下用氢气进行。优选地,反应是在1-20个大气压的氢气下进行,更优选的是1-5个大气压。反应在10-60℃下进行,典型的是在室温下进行。
反应时间为12-96小时或更多,典型的是约为55小时或更多。通常,随着反应时间的延长,可以获得更好的产率,同时反应更彻底。较好的情况是,根据化合物的性质以及氢化反应的进程对反应条件进行变化。
还原反应的催化剂选自非均相催化剂(其中的催化剂不溶于反应介质)或均相催化剂(其中的催化剂溶于反应介质)。非均相还原催化剂的实施例包括Raney镍、钯黑、氢氧化钯/碳、钯/活性炭(1%Pd-30%Pd)、钯/氧化铝粉、钯/各种钡盐、硼氢化钠还原镍、金属铂、铂黑、铂/活性炭(1%Pt-10%Pt)、氧化铂、铑盐及它们手性盐类以及氧化锌。优选的催化剂为钯/活性炭(1%Pd-10%Pd),更优选的为5%的钯/碳。对于用本发明方法制备以异黄烷-4-醇顺式异构体为主的产品来说,氧化铂(Adam’s催化剂)也是很有用的氢化催化剂。
均相还原催化剂的实施例包括氯代三(三苯基磷)铑,氯代(三苯基磷)氢化钌(II)以及五氰基钴盐(II)。
适合本发明的溶剂包括但不限于C1-C8醇和多元醇、乙酸烷基酯、四氢呋喃、醚、二噁烷以及C1-C3酸。优选的溶剂为C1-C6醇或C1-C6乙酸烷基酯,更优选的是甲醇、乙醇或乙酸乙酯以及丙醇、异丙醇、丁醇、异丁醇、仲丁醇、叔丁醇、甲酸甲酯、甲酸乙酯、乙酸甲酯。最优选的溶剂为无水甲醇、乙醇或乙酸乙酯。
本发明者发现,如果明智地选择催化剂、溶剂和选择性的保护基团,可以更彻底地还原异黄酮并以较高的产率得到相应的异黄醇。特别是当使用无水甲醇或乙醇作为溶剂并在5%Pd/活性炭上对异黄酮提供非常清洁的催化氢化时,可以得到很高定量的异黄烷醇。在此方法中如果采用10%的Pd/活性炭可以加速反应,并大约在12小时内完成反应。异黄烷-4-醇氢化产物顺式和反式异构体的比例随着所选择的催化剂及异黄酮替代物的性质而变化。改变本发明方法有可能影响还原反应中所获得的异构体的比例。
具有特别兴趣的是在4’-和7-位带有氧取代的异黄酮(或为氧取代的前体),原因是这些化合物的还原将导致产生具有重要生物学意义的脱氢牛尿酚或其前体。常规的起始原料为黄豆苷原,它可以很容易地通过已知的途径获得。
应该明白的是,在进行氢化反应之前,异黄酮环上的一些基团需要保护或进行衍生化。例如可以根据需要用乙酰氧基保护游离的羟基将有助于提高取代异黄酮的溶解度和/或它们对氢化反应的敏感性。保护基团可用本领域内已知的方法得到,例如在有机合成中的保护基团,T.W.Greene中所述的。
具体讲,本发明者发现在还原前,用乙酰氧基或甲氧基保护羟基使之以酯或醚的形式存在是最可取的。羟基化合物的酰化反应优选的是在羧酸酐和碱的溶剂混合物中进行。在氢化反应之前保护游离羟基可以使反应的产率提高并包括定量的产率。反应产物更纯,并且在氢化产物的纯化和分离中不需要层析步骤。
于是,令人惊奇地,对二乙酰氧基黄豆苷原的乙醇溶液持续进行催化氢化55小时,可以定量得到四氢黄豆苷原二乙酸酯(盐)。分光镜分析法揭示该产品为1∶1的顺式-和反式-异构体的混合物。令人愉快的是,即使继续进行更长时间的还原反应,也没有观察到四氢黄豆苷原进一步的还原。
以相似的方式同样令人惊奇地发现保护的异黄酮7-乙酰氧基-4’-甲氧基黄豆苷原在乙醇中可以温和并清洁地进行氢化,并定量地得到1∶1的7-乙酰氧基-4’-甲氧基异黄烷-4-醇的顺式-和反式-异构体的混合物。此反应看上去非常温和,并可在许多不同量的底物(例如上至1.5克或更多)上进行重复。
通过这一点,发明者发现了可以通过相应异黄酮化合物的氢化来大规模制备清洁并近乎定量产率异黄烷-4-醇化合物的条件。具体讲,现已发现,公斤级的二乙酰氧基黄豆苷原可进行温和且有效的还原反应从而生成异构的顺式-和反式-4’,7-二乙酰氧基异黄烷-4-醇。异构体的比例受钯在催化剂中所占百分比的影响。
顺式-/反式-异构体混合物无需分离可以脱水生成异黄-3-烯。然而,如果需要可用下述各种方法分离混合物。
用制备HPLC可以分离顺式-和反式-四氢黄豆苷原化合物的混合物。此种分离方式非常有限而且仅限于小量物质。由于可以制备合理量的二乙酰氧基异黄烷醇,因而可采用分步结晶方法来分离顺式-和反式-异构体。用乙醇对1∶1的混合物单次重结晶可以得到以反式为主的二乙酰氧基四氢黄豆苷原(产率:50%,纯度:73%)(顺式异构体27%)。随后的乙醇重结晶得到反式异构体纯品,总产率25%。
同样,7-乙酰氧基-4’-甲氧基异黄烷-4-醇也可以分步重结晶,得到反式异构体纯品,滤液中含有的顺式异构体的比例升高。
多数氢化反应产生1∶1的顺式-和反式-异黄烷-4-醇的混合物。然而,其中有一个衍生物例外,即7-羟基-4’-甲氧基-8-甲基异黄酮,它的氢化反应主要生成反式-异构体,并且产率极好。
在温和的条件下,优选的是在回流的乙醇溶液中,采用咪唑除去保护的乙酰氧基,合成四氢黄豆苷原及有关的衍生物。用乙醇水溶液重结晶后,分离四氢黄豆苷原的产率为80%。
异黄烷-4-醇脱水生成不饱和的异黄-3-烯。于是,Liepa在文献中报道了在100℃顺式-/反式-异黄烷-4-醇混合物与苯甲酰氯/二甲基甲酰胺反应生成所需的异黄-3-烯脱水产物的反应。然而,此反应仅可以很低的产率进行重复。用酸例如硫酸、盐酸、多磷酸、亚硫酰氯等处理也可以进行脱水。还研究了在回流的二氯甲烷中使用对甲苯磺酸或三氟甲酸进行脱水的其它方法,但这些方法所提供的异黄烯的产率很低。
发明者发现选择的脱水剂为五氧化二磷的二氯甲烷溶液,其可以60%以上的产率生成异黄烯。脱水反应可在氢化产物上直接进行,也可在其脱保护的衍生物上进行。
可以在如合成四氢黄豆苷原所述的温和条件下除去保护基乙酰氧基来合成脱氢牛尿酚,用标准的结晶溶剂混合物例如乙醇/水对脱氢牛尿酚进行纯化。用相似的方法可以制备其它异黄-3-烯衍生物。
在氢气氛下,用Adam’s催化剂(氧化铂(IV))于乙酸乙酯中进行的4’,7-二乙酰氧基黄豆苷原的氢还原可得到4’,7-二乙酰氧基四氢黄豆苷原。然而不同于在乙醇中以pd/活性炭为催化剂进行的还原反应,Adam’s催化剂给出的产品以4’,7-二乙酰氧基四氢黄豆苷原的顺式异构体为主。
在本发明的另一个实施方案中,在氢气氛下,在乙酸乙酯中用5%pd/活性炭所进行的4’,7-二乙酰氧基黄豆苷原的氢化反应以极好的产率(80%)得到了4’,7-二乙酰氧基二氢黄豆苷原。这些条件为以极好的产率从相应的异黄酮制备异黄烷-4-酮提供了途径。
制备异黄烷衍生物例如牛尿酚可以在氢气氛下、于乙酸乙酯中、优选的是采用pd/活性炭对异黄-3-烯进行氢化来实现。通过这些方法可以获得极好的产率(75%)以及更多的氢化产物。这些产物是清洁的并且容易重结晶。
本发明者得到的令人惊奇的结果与文献中所报道的其它异黄酮的氢化方法形成鲜明的对照。其中一个显著的优势是在氢化反应中使用了乙酸烷基酯或醇性溶剂,例如无水甲醇或乙醇。用本发明方法所制备的这些异黄烷醇具有典型的结晶,并且无需层析即可以很好的纯度分离。通过脱水可使异黄烷醇转变为异黄-3-烯。本领域技术人员根据需要可以对其进行进一步的脱保护和衍生化,得到天然的异黄烷-4-酮、异黄烷,其代谢产物和其新的衍生物。
下列实施例将进一步说明本发明,但不以任何任何方式限制本发明。
实施例
乙酰化反应
实施例1
4’,7-二乙酰氧基黄豆苷原
方法A
将黄豆苷原(1.0g,3.9mmol),乙酸酐(5ml)和吡啶(5ml)组成的混合物于室温下放置在暗处24小时。将混合物倾入水中(100ml),搅拌2小时,用二氯甲烷(3×50ml)提取。用水洗涤二氯甲烷层,无水硫酸钠干燥并蒸发。用甲醇结晶白色残余物,得到黄豆苷原二乙酸酯,其为白色棱柱状(1.1g,83%)。
1H NMR(CDCl3):δ2.32(s,3H,OCOCH3),2.36(s,3H,OCOCH3),7.18(d,2H,J 9.2Hz,ArH),7.19(d,1H,J 9.0Hz,H6),7.31(d,1H,J 2.0HzH8),7.59(d,2H,J 9.2Hz,ArH),8.00(s,1H,H2),8.33(d,2H,J 8.2Hz,ArH).
方法B
将黄豆苷原(2.0g,7.9mmol),乙酸酐(10ml)和吡啶(2ml)组成的混合物在105-110℃的油浴下加热1小时。将混合物冷却至室温后,再搅拌30分钟,在此期间有二乙酸酯(盐)结晶从溶液中析出。过滤产品,用水彻底洗涤,用甲醇重结晶得到黄豆苷原二乙酸酯(盐),其为无色棱柱状(2.4g,90%)。
实施例2
7-乙酰氧基-4’-甲氧基异黄酮
将7-羟基-4’-甲氧基异黄酮(2.0g,7.5mmol),乙酸酐(10ml)和吡啶(2ml)组成的混合物在105-110℃的油浴下加热1小时。将混合物冷却至室温后,将混合物倾入水中(100ml),搅拌2小时,用二氯甲烷(3×50ml)提取。用水洗涤二氯甲烷层,无水硫酸钠干燥并蒸发。用甲醇结晶白色残余物,得到7-乙酰氧基-4’-甲氧基异黄酮,其为无色棱柱状(2.1g,91%)。
1H NMR(CDCl3):δ2.36(s,3H,OCOCH3),3.84(s,3H,OCH3),6.98(d,2H,J 8.7Hz,ArH),7.16(dd,1H,J 1.9Hz 8.6Hz,H6),7.30(d,1H,J 1.9Hz H8),7.50(d,2H,J8.7Hz,ArH),8.00(s,1H,H2),g.32(d,1H,J 8.6Hz,H5).
实施例3
3’,7-二乙酰氧基异黄酮
如制备4’,7-二乙酰氧基黄豆苷原所述,从3’,7-二羟基异黄酮(0.98g,3.9mmol),乙酸酐(6ml)和吡啶(1.1ml)制备3’,7-二乙酰氧基异黄酮,产量:(1.0g,77%),
m.p.152℃.1H NMR(CDCl3):δ2.31 and 2.36(each s,3H,OCOCH3),7.14(m,1H,ArH),7.18(dd,1H,J 2.0Hz 8.6Hz,H6),7.31(d,1H,J 2.0Hz H8),7.37-7.45(m,3H,ArH),8.03(s,1H,H2),8.32(d,1H,J 8.6Hz,H5).
质谱:m/z 338(M,8%);296(53);254(100);253(60)。
实施例4
7-乙酰氧基-3’-甲氧基异黄酮
如制备4’,7-二乙酰氧基黄豆苷原所述,从7-羟基-3’-甲氧基异黄酮(1.7g,6.3mmol),乙酸酐(6ml)和吡啶(1.0ml)制备7-乙酰氧基-3’-甲氧基异黄酮,产量:(1.6g,81%),m.p.118℃。
1H NMR(CDCl3):δ2.36(s,3H,OCOCH3),3.85(s,3H,OMe),6.95(dd,1H,J 2.0Hz 8.3Hz,H6),6.70-7.40(m,5H,ArH),8.01(s,1H,H2),8.32(d,1H,J 8.7Hz,H5).
实施例5
4’,7-二乙酰氧基-3’-甲氧基异黄酮
如制备4’,7-二乙酰氧基黄豆苷原所述,从4’,7-二羟基-3’-甲氧基异黄酮(0.37g,1.3mmol),乙酸酐(2.5ml)和吡啶(0.4ml)制备4’,7-二乙酰氧基-3’-甲氧基异黄酮,产量:(0.36g,75%),m.p.197℃。
1H NMR(CDCl3):δ2.33,2.36(each s,3H,OCOCH3),3.88(s,3H,OMe),7.06-7.17(m,2H,ArH),7.19(dd,1H,J 2.3Hz 9.0Hz,ArH),7.32(dd,2H,J 2.3Hz 7.6Hz,ArH),8.03(s,1H,H2),8.32(d,1H,J 8.6Hz,H5).
实施例6
7-乙酰氧基异黄酮
按照与制备4’,7-二乙酰氧基黄豆苷原相同的方法,从7-羟基异黄酮(2.6g,10.9mmol),乙酸酐(16ml)和吡啶(3.0ml)制备7-乙酰氧基异黄酮,产量:(2.5g,82%),m.p.133℃。
1H NMR(CDCl3):δ2.36(s,3H,OCOCH3),7.18(dd,1H,J 2.2Hz 8.6Hz,H6),7.31(d,1H,J 2.2Hz H8),7.39-7.57(m,5H,ArH),8.00(s,1H,H2),8.33(d,1H,J 8.6Hz,H5).
质谱:m/z 280(M,28%);237(98);238(57)。
实施例7
4’,7,8-三乙酰氧基异黄酮
将4’,7,8-三羟基异黄酮(1.4g,5.2mmol),乙酸酐(8.4ml)和吡啶(2ml)组成的混合物在105-110℃的油浴下加热1小时。将混合物冷却至室温后,再搅拌30分钟,在此过程中有二乙酸酯结晶从溶液中析出。过滤产品,用水彻底洗涤,用乙酸乙酯重结晶得到4’,7,8-三乙酰氧基异黄酮,其为无色棱柱状(1.49g,73%)。
m.p.190-192℃.1H NMR(CDCl3):δ2.32,2.36,2.42(each s,3H,OCOCH3),7.18(d,2H,J 8.6Hz,ArH),7.28(d,1H,J 8.9Hz,H6),7.56(d,2H,J 8.6HzH8),7.98(s,1H,ArH),8.18(d,1H,J 8.9Hz,H5).
实施例8
7,8-二乙酰氧基-4’-甲氧基异黄酮
按照与制备4’,7,8-三乙酰氧基异黄酮相同的方法,从7,8-二羟基-4’-甲氧基异黄酮(0.82g,2.9mmol),乙酸酐(4.9ml)和吡啶(0.9ml)制备7,8-二乙酰氧基-4’-甲氧基异黄酮,产量:(0.9g,85%),
m.p.165℃.1H NMR(CDCl3):δ2.36,2.42(each s,3H,OCOCH3),3.84(s,3H,OCH3),6.98(d,2H,J 9.0Hz,ArH),7.25(d,1H,J 8.7Hz,H6),7.48(d,2H,J 9.0Hz H8),7.95(s,1H,H2),8.20(d,1H,J9.1Hz,H5).
质谱:m/z 368(M,20%);326(15);312(18);284(80)。
实施例9
4’,7-二乙酰氧基-8-甲基异黄酮
将4’,7-二羟基-8-甲基异黄酮(2.9g,10.8mmol),乙酸酐(18ml)和吡啶(3ml)组成的混合物在105-110℃的油浴下加热1小时。将混合物冷却至室温后,再搅拌30分钟,在此过程中有二乙酸酯结晶从溶液中析出。过滤产品,用水彻底洗涤,用乙酸乙酯重结晶得到4’,7-二乙酰氧基-8-甲基异黄酮,其为无色棱柱状(3.2g,84%)。
1H NMR(CDCl3):δ2.31(s,3H,CH3),2.32,2.39(each s,3H,OCOCH3),7.13(d,1H,J 9.0Hz,H6),7.17(d,2H,J 8.7Hz,ArH),7.59(d,2H,J 8.7Hz,ArH),8.07(s,1H,H2),8.19(d,1H,J 8.7Hz,H5).
实施例10
3’,7-二乙酰氧基-8-甲基异黄酮
按照与制备4’,7-二乙酰氧基-8-甲基异黄酮相同的方法,从3’,7-二羟基-8-甲基异黄酮(1.3g,4.8mmol),乙酸酐(8ml)和吡啶(1.5ml)制备3’,7-二乙酰氧基-8-甲基异黄酮,产量:(1.2g,70%),m.p.112℃。
1H NMR(CDCl3):δ2.31(s,3H,CH3),2.32,2.39(each s,3H,OCOCH3),7.13(m,2H,ArH),7.37-7.45(m,3H,ArH),8.1(s,1H,H2),8.18(d,1H,J 8.7Hz,H5).
质谱:m/z 352(M,6%);310(35);268(100);267(60)。
实施例11
7-乙酰氧基-4’-甲氧基-8-甲基异黄酮
按照与制备4’,7-二乙酰氧基-8-甲基异黄酮相同的方法,从7-羟基-4’-甲氧基-8-甲基异黄酮(3.0g,10.6mmol),乙酸酐(10ml)和吡啶(2.0ml)制备7-乙酰氧基-4’-甲氧基-8-甲基异黄酮,产量:(2.0g,58%),m.p.190-192℃.1HNMR(CDCl3):δ2.31(s,3H,CH3),2.38(s,3H,OCOCH3),3.84(s,3H,OMe),6.98(d,2H,J 8.7Hz,ArH),7.12(d,1H,J 8.6Hz,H6),7.52(d,2H,J 8.7Hz,ArH),8.03(s,1H,H2),8.18(d,1H,J 8.6Hz,H5).
质谱:m/z 325(M+1,13%);324(M,58%);282(100);281(42)。
实施例12
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄酮
按照与制备4’,7-二乙酰氧基-8-甲基异黄酮相同的方法,从4’,7-二羟基-3’-甲氧基-8-甲基异黄酮(0.42g,1.4mmol),乙酸酐(2.6ml)和吡啶(0.5ml)制备4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄酮,产量:(0.4g,74%),m.p.209℃.1HNMR(CDCl3):δ2.22(s,3H,CH3),2.32,2.39(each s,3H,OCOCH3),3.89(s,3H,OMe),7.07-7.11(m,2H,ArH),7.13(d,1H,J 8.6Hz,H6),7.32(d,1H,J 1.5Hz,ArH),8.09(s,1H,H2),8.18(d,1H,J 8.7Hz,H5).
氢化反应:异黄酮→异黄烷-4-醇
实施例13
4’,7-二乙酰氧基四氢黄豆苷原(4’,7-二乙酰氧基异黄烷-4-醇)
方法A
将钯/碳(5%,0.08g)加到4’,7-二乙酰氧基黄豆苷原(0.5g,1.5mmol)的无水乙醇(400ml)悬浮液中,混合物在室温并氢气下搅拌55小时。通过硅藻土滤除催化剂,真空蒸发滤液,定量得到4’,7-二乙酰氧基四氢黄豆苷原(0.51g,100%)。产品的核磁共振光谱显示其为清洁的1∶1顺-和反-式4’,7-二乙酰氧基四氢黄豆苷原的混合物。
通过分级重结晶可以分离得到顺-和反式异构体。将如上制备的1∶1顺-和反-式4’,7-二乙酰氧基四氢黄豆苷原(0.17g)混合物溶于过量的无水乙醇中,并在旋转蒸发器上浓缩。在第一次出现结晶迹象时,停止进一步浓缩乙醇,用冰浴冷却烧瓶。过滤生成的结晶,用小量的冷无水乙醇洗涤。产物(0.08g)的核磁共振光谱显示其为反式4’,7-二乙酰氧基四氢黄豆苷原(73%)和顺式4’,7-二乙酰氧基四氢黄豆苷原(27%)的混合物。用乙醇进一步重结晶,得到反式4’,7-二乙酰氧基四氢黄豆苷原纯品(0.04g,24%)。
滤液得到的产品以顺式异构体为主。核磁共振光谱分析显示其为顺式4’,7-二乙酰氧基四氢黄豆苷原(73%)和反式4’,7-二乙酰氧基四氢黄豆苷原(27%)的混合物。
对于反式4’,7-二乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),2.29(s,3H OCOCH3),3.14(ddd,1H,J 3.7Hz,7.9Hz,9.1Hz,H3),4.24(dd,1H,J 9.1Hz,11.3Hz,H2);4.35(dd,1H,J 3.7Hz,11.3Hz,H2),4.87(d,1H,J 7.9Hz,H4),6.61(d,1H,J 2.3Hz,H8),6.70(dd,1H,J 2.3Hz,8.4Hz,H6),7.06(d,2H,J 8.6Hz,ArH),7.23(d,2H,J 8.4Hz,ArH),7.44(dd,1H,J 0.8Hz,8.4Hz,H5).13C NMR(CDCl3):20.98(OCOCH3),46.18(C3),68.04(C2),69.01(C4),109.67(C8),114.26(C6),121.96,128.96(ArCH),129.40(C5).
对于顺式4’,7-二乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),2.29(s,3H,OCOCH3),3.30(dt,1H,J 3.4Hz,J 11.8Hz,H3),4.31(ddd,1H,J 1.4Hz,3.6Hz,10.5Hz,H2);4.56(dd,1H,J 10.5Hz,11.8Hz,H2),4.75(dd,1H,J 1.3Hz,3.2Hz,H4),6.66(dd,1H,J 2.3Hz,8.7Hz,H6),6.69(d,1H,J 2.3Hz,H8),7.08(d,2H,J 8.6Hz,ArH),7.26(d,1H,8.4Hz,H5),7.29(d,2H,J 8.6Hz ArH).13C NMR(CDCl3);20.98(OCOCH3),43.52(C3),64.10(C2),66.46(C4),110.08(C6),114.09(C8),121.82,129.40(ArCH),131.10(C5).
方法B
将钯/活性炭(5%,3.1g)加到4’,7-二乙酰氧基黄豆苷原(30.0g)的无水甲醇(3600ml)悬浮液中,混合物在室温并氢气下搅拌55小时。通过硅藻土滤除催化剂,真空蒸发滤液,得到4’,7-二乙酰氧基四氢黄豆苷原(29.5g,96%)。产品的核磁共振光谱显示其为清洁的2∶1顺-和反式4’,7-二乙酰氧基四氢黄豆苷原的混合物。
方法C
将钯/活性炭(10%,3.0g)加到4’,7-二乙酰氧基黄豆苷原(30.1g)的无水甲醇(3600ml)悬浮液中,混合物在室温并氢气下搅拌15小时。通过硅藻土滤除催化剂,真空蒸发滤液,得到4’,7-二乙酰氧基四氢黄豆苷原(28.5g,94%)。产品的核磁共振光谱显示其为清洁的1∶1顺-和反式4’,7-二乙酰氧基四氢黄豆苷原的混合物。
方法D
将钯/活性炭(5%,100g)加到4’,7-二乙酰氧基黄豆苷原(980g)的无水甲醇(100L)悬浮液中,混合物在室温并氢气下搅拌78小时。通过陶瓷烛过滤装置滤除催化剂,真空蒸发滤液,得到4’,7-二乙酰氧基四氢黄豆苷原(820g,83%)。产品的核磁共振光谱显示其为清洁的2∶1顺-和反式4’,7-二乙酰氧基四氢黄豆苷原的混合物。
实施例14
7-乙酰氧基-4’-甲氧基异黄烷-4-醇
将钯/活性炭(5%,0.08g)加到7-乙酰氧基-4’-甲氧基异黄酮(0.5g,1.6mmol)的无水乙醇(400ml)悬浮液中,混合物在室温并氢气下搅拌55小时。通过硅藻土滤除催化剂,真空蒸发滤液,定量得到7-乙酰氧基-4’-甲氧基异黄烷-4-醇(0.51g,100%)。产品的核磁共振光谱显示其为清洁的1∶1顺-和反-式7-乙酰氧基-4’-甲氧基异黄烷-4-醇的混合物。
通过分步(级)重结晶可以分离得到顺-和反式异构体。将如上制备的1∶1顺-和反-式4’,7-二乙酰氧基四氢黄豆苷原用乙醇三次重结晶,得到反式7-乙酰氧基-4’-甲氧基异黄烷-4-醇纯品。滤液中的产品以顺式为主。
对于反式7-乙酰氧基-4’-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.31(s,3H,OCOCH3),3.14(dt,1H,J 3.8Hz,8.6Hz,H3),3.82(s,3H,OCH3),4.25(dd,1H,J 9.4Hz,11.3Hz,H2);4.37(dd,1H,J 4.1Hz,11.3Hz,H2),4.93(d,1H,J 7.8Hz,H4),6.63(d,1H,J2.3Hz,H8),6.73(dd,1H,J 2.3Hz,8.3Hz,H6),6.93(d,2H,J 8.7Hz,ArH),7.19(d,2H,J8.7Hz,ArH),7.51(d,1H,J 7.9Hz,H5).
对于顺式7-乙酰氧基-4’-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.30(s,3H,OCOCH3),3.28(dt,1H,J 3.4Hz,J 12.1Hz,H3),3.84(s,3H,OCH3),4.36(ddd,1H,J 1.4Hz,3.8Hz,10.1Hz,H2);4.57(dd,1H,J 10.1Hz,11.3Hz,H2),4.75(bs,1H,H4),6.58(d,1H,J2.3Hz,H8),6.75(dd,1H,J 2.3Hz,8.3Hz,H6),6.96(d,2H,J 8.6Hz,ArH),7.25(d,2H,8.6Hz,ArH),7.34(d,1H,J 8.3Hz,H5).
实施例15
3’,7-二乙酰氧基异黄烷-4-醇
将钯/活性炭(5%,0.03g)加到3’,7-二乙酰氧基异黄酮(0.2g,0.6mmol)的无水甲醇(50ml)悬浮液中,混合物在室温并氢气下搅拌55小时。通过硅藻土滤除催化剂,真空蒸发滤液,定量得到3’,7-二乙酰氧基异黄烷-4-醇。产品的核磁共振光谱显示其为清洁的1∶1顺-和反-式3’,7-二乙酰氧基异黄烷-4-醇的混合物。
对于反式3’,7-二乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.31 and 2.32(each s,3H,OCOCH3),3.17(ddd,1H,J 3.6Hz,8.6Hz,11.2Hz,H3),4.26(dd,1H,J 9.2Hz,11.6Hz,H2);4.33(m,1H,H2),4.91(d,1H,J 7.9Hz,H4),6.60-6.73(m,ArH),6.97-7.16(m,ArH),7.25-7.48(m,ArH).
对于顺式3’,7-二乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.30 and 2.31(each s,3H,OCOCH3),3.31(dt,1H,J 3.3Hz,J 11.6Hz,H3),4.31(m,1H,H2);4.57(dd,1H,J 10.6Hz,11.9Hz,H2),4.79(bs,1H,H4),6.60-6.73(m,ArH),6.97-7.16(m,ArH),7.25-7.48(m,ArH).
实施例16
7-乙酰氧基-3’-甲氧基异黄烷-4-醇
按照上述方法,用钯/活性炭(5%,0.12g)可从7-乙酰氧基-3’-甲氧基异黄烷-4-醇(0.5g,1.6mmol)的甲醇(100ml)溶液制备顺式和反式7-乙酰氧基-3’-甲氧基异黄烷-4-醇。
对于反式7-乙酰氧基-3’-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),3.15(ddd,1H,J 3.8Hz,8.3Hz,12.0Hz,H3),3.80(s,3H,OMe),4.26(dd,1H,J 9.4Hz,11.3Hz,H2);4.32(m,1H,H2),4.95(d,1H,J 7.9Hz,H4),6.60-6.93(m,ArH),7.23-7.33(m,ArH),7.49(d,J 8.7Hz,ArH).
对于顺式7-乙酰氧基-3’-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),3.30(dt,1H,J 3.3Hz,J 11.7Hz,H3),4.31(m,1H,H2);4.58(dd,1H,J 10.5Hz,11.7Hz,H2),4.81(bs,1H,H4),6.60-6.93(m,ArH),7.23-7.33(m,ArH),7.49(d,J 8.7Hz,ArH).
实施例17
4’,7-二乙酰氧基-3’-甲氧基异黄烷-4-醇
按照上述方法,在甲醇(50ml)中,用钯/活性炭(5%,0.06g)可从4’,7-二乙酰氧基-3’-甲氧基异黄酮(0.25g,0.7mmol)制备顺式和反式4’,7-二乙酰氧基-3’-甲氧基异黄烷-4-醇。
对于反式4’,7-二乙酰氧基-3’-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.29,2.31(each s,3H,OCOCH3),3.17(ddd,1H,J 3.8Hz,8.7Hz,12.5Hz,H3),3.79(s,3H,OMe),4.26(dd,1H,J 9.4Hz,11.3Hz,H2);4.32(m,1H,H2),4.93(d,1H,J 7.9Hz,H4),6.62-6.73(m,ArH),6.81-6.91(m,ArH),6.99-7.05(m,ArH),7.30(d,J 8.3Hz,ArH),7.48(d,J 9.0Hz,ArH).
对于顺式4,7-二乙酰氧基-3’-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.31,2.32(each s,3H,OCOCH3),3.33(dt,1H,J 3.3Hz,J 11.3Hz,H3),3.83(s,3H,OMe),4.31(m,1H,H2);4.58(t,1H,J 10.5Hz,H2),4.82(bs,1H,H4),6.62-6.73(m,ArH),6.81-6.91(m,ArH),6.99-7.05(m,ArH),7.30(d,J 8.3Hz,ArH),7.48(d,J 9.0Hz,ArH).
实施例18
7-乙酰氧基异黄烷-4-醇
用钯/活性炭(5%,0.09g)可从7-乙酰氧基异黄酮(0.4g,1.4mmol)的无水甲醇(60ml)溶液制备顺式和反式7-乙酰氧基异黄烷-4-醇。m.p.90℃。质谱:m/z 284(M,10%);226(42);138(100);137(58)。
对于反式7-乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.29(s,3H,OCOCH3),3.17(m,1H,H3),4.27(t,1H,J 10.6Hz,H2);4.30(m,1H,H2),4.97(d,1H,J 8.3Hz,H4),6.60-6.73(m,ArH),7.08(d,J 8.7Hz,ArH),7.23-7.37(m,ArH),7.49(d,J 8.7Hz,ArH).
对于顺式7-乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.30(s,3H,OCOCH3),3.33(dt,1H,J 3.4Hz,J 11.7Hz,H3),4.36(m,1H,H2);4.62(t,1H,J 10.5Hz,H2),4.80(bs,1H,H4),6.60-6.73(m,ArH),7.08(d,J 8.7Hz,ArH),7.23-7.37(m,ArH),7.49(d,J 8.7Hz,ArH).
实施例19
4’,7,8-三乙酰氧基异黄烷-4-醇
将钯/活性炭(5%,0.07g)加到4’,7,8-三乙酰氧基异黄酮(0.5g,1.3mmol)的无水甲醇(100ml)悬浮液中,混合物在室温并氢气下搅拌55小时。通过硅藻土滤除催化剂,真空蒸发滤液,定量得到4’,7,8-三乙酰氧基异黄烷-4-醇。产物的核磁共振光谱显示其为清洁的1∶1顺-和反-式4’,7,8-三乙酰氧基异黄烷-4-醇的混合物。
对于反式4’,7,8-三乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.28,2.29.2.31(each s,3H,OCOCH3),3.20(m,1H,H3),4.27(dd,1H,H2);4.37(m,1H,H2),4.93(d,1H,J 7.9Hz,H4),6.78(d,1H,J 8.3Hz,H8),7.09(m,ArH),7.11-7.31(m,ArH),7.39(d,1H,J 8.7Hz,ArH).
对于顺式4’,7,8-三乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.30,2.31,2.32(each s,3H,OCOCH3),3.35(m,1H,H3),4.38(m,1H,H2);4.57(t,1H,J 10.6Hz,H2),4.75(bs,1H,H4),6.78(d,1H,J 8.3Hz,H8),7.09(m,ArH),7.11-7.31(m,ArH),7.39(d,1H,J 8.7Hz,ArH).
实施例20
7,8-二乙酰氧基-4-甲氧基异黄烷-4-醇
按照上述方法,用钯/活性炭(5%,0.08g)可从7,8-二羟基-4’-甲氧基异黄酮(0.4g,1.1mmol)的甲醇溶液(120ml)制备7,8-二乙酰氧基-4-甲氧基异黄烷-4-醇。
对于反式7,8-二乙酰氧基-4-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.29,2.30(each s,3H,OCOCH3),3.14(ddd,1H,J 3.9Hz,9.2Hz,12.5Hz,H3),3.79(s,3H,OCH3),4.24(dd,1H,J 9.6Hz,11.2Hz,H2);4.35(m,1H,H2),4.92(d,1H,J 7.8Hz,H4),6.78(d,1H,J 8.6Hz,H6),6.90(m,ArH),7.13-7.22(m,ArH),7.38(d,J 8.6Hz,ArH).
对于顺式7,8-二乙酰氧基-4-甲氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.30,2.31(each s,3H,OCOCH3),3.29(dt,1H,J 3.0Hz,J12.0Hz,H3),3.80(s,3H,OCH3),4.36(m,1H,H2);4.57(t,1H,J 10.6Hz,H2),4.75(bs,1H,H4),6.77(d,1H,J 8.6Hz,H6),6.90(m,ArH),7.13-7.22(m,ArH),7.38(d,J 8.6Hz,ArH).
实施例21
4’,7-二乙酰氧基-8-甲基异黄烷-4-醇
将钯/活性炭(5%,0.12g)加到4’,7-二乙酰氧基-8-甲基异黄酮(1.0g,2.8mmol)的甲醇(200ml)悬浮液中,混合物在室温并氢气下搅拌55小时。通过硅藻土滤除催化剂,真空蒸发滤液,定量得到4’,7-二乙酰氧基-8-甲基异黄烷-4-醇。m.p.135-137℃。产品的核磁共振光谱显示其为清洁的1∶1顺-和反-式4’,7-二乙酰氧基-8-甲基异黄烷-4-醇的混合物。质谱:m/z 356(M,53%);254(86);253(100);240(80);196(37)。
对于反式4’,7-二乙酰氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.02(s,3H,CH3),2.30,2.31(each s,3H,OCOCH3),3.15(ddd,1H,J 3.8Hz,8.6Hz,11.7,H3),4.27(dd,1H,J 9.4Hz,11.3Hz,H2);4.39(m,1H,H2),4.92(d,1H,J 7.5Hz,H4),6.64(d,1H,J 8.0Hz,H6),7.06-7.32(m,ArH).
对于顺式4’,7-二乙酰氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.02(s,3H,CH3),2.31,2.32(each s,3H,OCOCH3),3.28(dt,1H,J 3.4Hz,J 11.7Hz,H3),4.40(m,1H,H2);4.58(dd,1H,J 10.1Hz,11.7Hz,H2),4.78(bs,1H,H4),6.67(d,1H,J 8.0Hz,H6),7.06-7.32(m,ArH).
实施例22
3’,7-二乙酰氧基-8-甲基异黄烷-4-醇
按照上述方法,用钯/活性炭(5%,0.06g)可从3’,7-二乙酰氧基-8-甲基异黄酮(0.25g,0.7mmol)的甲醇溶液(40ml)制备3’,7-二乙酰氧基-8-甲基异黄烷-4-醇。
对于反式3’,7-二乙酰氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.03(s,3H,CH3),2.30,2.32(each s,3H,OCOCH3),3.18(ddd,1H,J 3.8Hz,8.3Hz,12.1Hz,H3),4.28(dd,1H,J 9.0Hz,10.9Hz,H2);4.39(m,1H,H2),4.94(d,1H,J 8.7Hz,H4),6.65(d,1H,J 7.9Hz,H6),6.98-7.39(m,ArH).
对于顺式3’,7-二乙酰氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.05(s,3H,CH3),2.30,2.32(each s,3H,OCOCH3),3.32(dt,1H,J 3.4Hz,J 12.0Hz,H3),4.39(m,1H,H2);4.59(dd,1H,J 10.5Hz,11.7Hz,H2),4.80(bs,1H,H4),6.68(d,1H,J 8.3Hz,H6),6.98-7.39(m,ArH).
实施例23
7-乙酰氧基-4’-甲氧基-8-甲基异黄烷-4-醇
按照上述方法,用钯/活性炭(5%,0.08g)可从7-羟基-4’-甲氧基-8-甲基异黄酮(0.25g,0.8mmol)的甲醇溶液(50ml)制备7-乙酰氧基-4’-甲氧基-8-甲基异黄烷-4-醇。
对于反式7-乙酰氧基-4’-甲氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.02(s,3H,CH3),2.32(s,3H,OCOCH3),3.11(ddd,1H,J 3.8Hz,9.4Hz,12.1Hz,H3),3.80(s,3H,OMe),4.25(dd,1H,J 9.4Hz,11.3Hz,H2);4.40(dd,1H,J 3.8Hz,12.6Hz,H2),4.92(bd,1H,H4),6.67(d,1H,J 8.3Hz,H6),6.89(d,2H,J 8.7Hz,ArH),7.16(d,2H,J 8.7Hz,ArH),7.34(d,1H,J 8.3Hz,H5).
实施例24
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄烷-4-醇
按照上述方法,用钯/活性炭(5%,0.07g)可从4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄酮(0.25g,0.7mmol)的甲醇溶液(50ml)制备4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄烷-4-醇。
对于反式4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.05(s,3H,CH3),2.30,2.32(each s,3H,OCOCH3),3.18(ddd,1H,J 3.8Hz,8.3Hz,11.4Hz,H3),3.79(s,3H,OMe),4.28(dd,1H,J 9.0Hz,11.3Hz,H2);4.41(m,1H,H2),4.93(d,1H,J7.9Hz,H4),6.64(d,1H,J 7.9Hz,H6),6.75-6.92(m,ArH),7.00(d,1H,J 7.9Hz,ArH),7.16(d,1H,J 8.3Hz,ArH).
对于顺式4’,7-二乙酰氧基-8-甲基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.05(s,3H,CH3),2.30,2.32(each s,3H,OCOCH3),3.29(dt,1H,J 3.4Hz,J 11.7Hz,H3),4.40(m,1H,H2);4.59(t,1H,J 10.5Hz,H2),4.81(bs,1H,H4),6.67(d,1H,J 7.9Hz,H6),6.75-6.92(m,ArH),7.03(d,1H,J 8.3Hz,ArH),7.33(d,1H,J 8.3Hz,ArH).
实施例25
4’,7-二乙酰氧基脱氢牛尿酚(4’,7-二乙酰氧基异黄-3-烯)
方法A
将蒸馏的三氟乙酸(0.1ml)加到顺式和反式4’,7-二乙酰氧基四氢黄豆苷原(0.1g)的干燥蒸馏二氯甲烷溶液(15ml)中,混合物在氩气下回流。用薄层层析监测反应的进展情况,再加入0.1ml三氟乙酸。回流4小时后,冷却反应混合物,依次用饱和碳酸氢钠溶液、水和盐水洗涤。干燥生成的有机相,浓缩,层析并结晶,得到4’,7-二乙酰氧基脱氢牛尿酚,其为无色棱柱状(0.034g,35%)。
1H NMR(CDCl3+d6-DMSO):δ2.29(s,3H,OCOCH3),2.31(s,3H,OCOCH3),5.15(s,2H,H2),6.62(bs,1H,H4),6.65(dd,1H,J 2.1Hz 8.2Hz,H6),6.75(bs,1H,H8),7.06(d,1H,J 8.2Hz H5),7.12(d,2H,J 8.2Hz,ArH),7.43(d,2H,J 8.2Hz,ArH).
方法B
将对甲苯磺酸(0.02g)加到顺式和反式4’,7-二乙酰氧基四氢黄豆苷原(0.1g)的干燥蒸馏二氯甲烷溶液(15ml)中,混合物在氩气下回流。用薄层层析监测反应的进展情况。回流4小时后,使反应混合物通过硅胶短柱,洗脱物用乙醇重结晶,得到4’,7-二乙酰氧基脱氢牛尿酚,其为无色棱柱状(0.025g,26%)。
方法C
搅拌下,将五氧化二磷(5g)加到顺式和反式4’,7-二乙酰氧基四氢黄豆苷原(1.0g)的无水二氯甲烷溶液(80ml)中,混合物在室温下搅拌2小时然后经硅藻土板过滤。浓缩二氯甲烷溶液,硅胶层析,得到4’,7-二乙酰氧基脱氢牛尿酚,其为无色棱柱状(0.64g,67%)。
实施例26
7-乙酰氧基-4’-甲氧基异黄-3-烯
搅拌下,将五氧化二磷(1.0g)加到顺式和反式7-乙酰氧基-4’-甲氧基异黄烷-4-醇(0.1g,0.3mmol)的干燥二氯甲烷溶液(20ml)中,混合物在室温下搅拌2小时,然后经硅藻土板过滤。浓缩有机相,硅胶层析,得到7-乙酰氧基-4’-甲氧基异黄-3-烯(0.04g,42%)。
1H NMR(CDCl3);δ2.28(s,3H,OCOCH3)3.83(s,3H,OCH3),5.14(s,2H,H2),6.61(dd,1H,J 2.3Hz 6.4Hz,H6),6.65(d,1H,J 2.3Hz,H8),6.69(bs,1H,H4),6.92(d,2H,J 9.0Hz ArH),7.04(d,1H,J 7.9Hz,H5),7.37(d,2H,J9.0Hz,ArH).
实施例27
3’,7-二乙酰氧基脱氢牛尿酚(3’,7-二乙酰氧基异黄-3-烯)
用五氧化二磷(2.0g)从顺式和反式3’,7-二乙酰氧基异黄烷-4-醇(0.2g,0.6mmol)的无水二氯甲烷溶液(50ml)制备3’,7-二乙酰氧基异黄-3-烯。产量:(0.09g,48%)。
1H NMR(CDCl3):δ2.29and 2.32(each s,3H,OCOCH3),5.14(s,2H,H2),6.61(d,1H,J 2.3Hz,H8),6.66(dd,1H,J 2.3Hz 7.9Hz,H6),6.79(bs,1H,H4),7.02-7.15ψφ(m,3H,ArH),7.25-7.44(m,2H,ArH).
实施例28
7-乙酰氧基-3’-甲氧基脱氢牛尿酚(7-乙酰氧基-3’-甲氧基异黄-3-烯)
用五氧化二磷(2.0g),从顺式和反式7-乙酰氧基-3’-甲氧基异黄烷-4-醇(0.25g,0.8mmol)的无水二氯甲烷溶液(20ml)制备7-乙酰氧基-3’-甲氧基异黄-3-烯。产量:(0.15g,63%)。
1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),3.85(s,3H,OMe),5.15(s,2H,H2),6.60-6.67(m,2H,ArH),6.78(bs,1H,H4),6.84-7.06(m,4H,ArH),7.35(t,1H,J 8.6Hz,ArH).
实施例29
4’,7-二乙酰氧基-3’-甲氧基异黄-3-烯
用五氧化二磷(2.0g),从顺式和反式4’,7-二乙酰氧基-3’-甲氧基异黄烷-4-醇(0.20g,0.5mmol)的无水二氯甲烷溶液(20ml)制备4’,7-二乙酰氧基-3’-甲氧基异黄-3-烯。产量:(0.11g,58%)。
实施例30
7-乙酰氧基异黄-3-烯
用五氧化二磷(5.0g),从顺式和反式7-乙酰氧基异黄烷-4-醇(0.4g,1.4mmol)的无水二氯甲烷溶液(60ml)制备7-乙酰氧基异黄-3-烯。产量:(0.2g,53%)。
1H NMR(CDCl3):δ2.29(s,3H,OCOCH3),5.18(s,2H,H2),6.61-6.67(m,2H,ArH),6.79(bs,1H,H4),7.07(d,1H,J 7.9Hz,H5),7.23-7.45(m,5H,ArH).
实施例31
4’,7,8-三乙酰氧基脱氢牛尿酚(4’,7,8-三乙酰氧基异黄-3-烯)
搅拌下,将五氧化二磷(5.0g)加到顺式和反式4’,7,8-三乙酰氧基异黄烷-4-醇(0.5g,1.3mmol)的干燥二氯甲烷溶液(50ml)中,混合物在室温下搅拌2小时,然后经硅藻土板过滤。浓缩生成的溶液,硅胶层析,得到4’,7,8-三乙酰氧基异黄-3-烯(0.3g,63%)。
1H NMR(CDCl3):δ2.29,2.31,2.32,(each s,3H,OCOCH3),5.15(s,2H,H2),6.72(d,1H,J 8.3Hz,H6),6.75(bs,1H,H4),6.97(d,1H,J 7.9Hz,H5),7.12(d,2H,J 8.7Hz ArH).7.41(d.2H.J 8.7Hz.ArH).
实施例32
7,8-二乙酰氧基-4-甲氧基脱氢牛尿酚(7,8-二乙酰氧基-4-甲氧基异黄-3-烯)
搅拌下,用五氧化二磷(5.0g),从顺式和反式7,8-二乙酰氧基-4-甲氧基异黄烷-4-醇(0.4g,1.1mmol)的无水二氯甲烷溶液(60ml)制备7,8-二乙酰氧基-4-甲氧基异黄-3-烯。产量:(0.18g,47%)。
1H NMR(CDCl3):δ2.29,2.32(each s,3H,OCOCH3),3.83(s,3H,OCH3),5.14(s,2H,H2),6.69(bs,1H,H4),6.71(d,1H,J 8.3Hz,H6),6.90(d,2H,J 8.6Hz ArH),6.95(d,1H,J 7.9Hz,H5),7.36(d,2H,J 8.6Hz,ArH).
实施例33
4’,7-二乙酰氧基-8-甲基异黄-3-烯
搅拌下,将五氧化二磷(3.0g)加到顺式和反式4’,7-二乙酰氧基-8-甲基异黄烷-4-醇(0.55g,1.5mmol)的干燥二氯甲烷溶液(25ml)中,混合物在室温下搅拌2小时,然后经硅藻土板过滤。浓缩生成的溶液,硅胶层析,得到4’,7-二乙酰氧基-8-甲基异黄-3-烯(0.25g,48%)。
m.p.140℃.1H NMR(CDCl3):δ2.04(s,3H,CH3),2.31,2.32(each s,3H,OCOCH3),5.16(s,2H,H2),6.61(d,1H,J 8.3Hz,H6),6.75(bs,1H,H4),6.94(d,1H,J 8.3Hz,H5),7.13(d,2H,J 8.7Hz,ArH),7.45(d,2H,J 8.7Hz,ArH).
质谱:m/z 339(M+1,6%);338(M,26);296(48);254(90);253(100)。
实施例34
3’,7-二乙酰氧基-8-甲基异黄-3-烯
采用五氧化二磷(2.0g),从顺式和反式3’,7-二乙酰氧基-8-甲基异黄烷-4-醇(0.25g,0.7mmol)的干燥二氯甲烷溶液(20ml)制备3’,7-二乙酰氧基-8-甲基异黄-3-烯。产率:(0.13g,54%)。
m.p.116℃.1H NMR(CDCl3):δ2.04(s,3H,CH3),2.31,2.32(each s,3H,OCOCH3),5.16(s,2H,H2),6.61(d,1H,J 8.3Hz,H6),6.79(bs,1H,H4),6.92(d,1H,J 8.3Hz,ArH),7.05(dd,1H,J 2.0Hz,8.0Hz,ArH),7.15(s,1H,ArH),7.26(d,1H,J 8.0Hz,ArH),7.37(t,1H,J 8.0Hz,ArH).
质谱:m/z 339(M+1,15%);338(M,22);296(54);254(30)。
实施例35
7-乙酰氧基-4’-甲氧基-8-甲基异黄-3-烯
采用五氧化二磷(2.0g),从顺式和反式7-乙酰氧基-4’-甲氧基-8-甲基异黄烷-4-醇(0.25g,0.7mmol)的干燥二氯甲烷溶液(20ml)制备7-乙酰氧基-4’-甲氧基-8-甲基异黄-3-烯。产量:(0.11g,46%)。
m.p.107℃.1H NMR(CDCl3):δ2.04(s,3H,CH3),2.31(s,3H,OCOCH3),3.83(s,3H,OMe),5.16(s,2H,H2),6.59(d,1H,J 8.3Hz,H6),6.6g(bs,1H,H4),6.90(d,1H,J 8.3Hz,H5),6.93(d,2H,J 9.0Hz,ArH),7.37(d,2H,J 9.0Hz,ArH).
质谱:m/z 311(M+1,13%);310(M,68);267(100);152(68);135(90)。
实施例36
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄-3-烯
采用五氧化二磷(2.0g),从顺式和反式4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄烷-4-醇(0.25g,0.6mmol)的干燥二氯甲烷(25ml)溶液制备4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄-3-烯。产量:(0.14g,58%)。
m.p.123℃.1H NMR(CDCl3):δ2.05(s,3H,CH3),2.31.2.32(each s,3H,OCOCH3),3.88(s,3H,OMe),5.16(s,2H,H2),6.61(d,1H,J 8.3Hz,H6),6.73(bs,1H,H4),6.94(d,1H,J 8.3Hz,H5),6.97(dd,1H,J 1.9Hz,8.3Hz,ArH),7.03(d,1H,J 1.9Hz,ArH),7.05(d,1H,J 7.9Hz,ArH).
脱保护反应
实施例37
脱氢牛尿酚(异黄-3-烯-4’,7-二醇)
将咪唑(0.09g)加到4’,7-二乙酰氧基脱氢牛尿酚(0.03g,0.09mmol)的无水乙醇(2.0ml)悬浮液中,混合物在氩气下回流45分钟。减压浓缩,加入蒸馏水(10ml)沉淀产品。使混合物在冰箱中放置过夜,过滤得到脱氢牛尿酚。加入苯,从甲醇中再次沉淀粗品,得到脱氢牛尿酚,其为蓬松的白色固体(0.012g,55%)。1H NMR(CDCl3+d6-DMSO):δ4.93(s,2H,H2),6.26(bs,1H,H4),6.29(dd,1H,J 2.0Hz,8.2Hz,H6),6.50(bs,1H,H8),6.73(d,2H,J 8.2Hz,ArH),6.76(d,2H,J 8.2Hz,H5),7.13(d,2H,J 8.2Hz,ArH).
实施例38
7-羟基-4’-甲氧基异黄-3-烯
将咪唑(0.18g)加到7-乙酰氧基-4’-甲氧基异黄-3-烯(0.06g,0.02mmol)的无水乙醇(5.0ml)悬浮液中,混合物在氩气下回流45分钟。减压浓缩,加入蒸馏水(10ml)沉淀产品。使混合物在冰箱中放置过夜,过滤得到异黄-3-烯。粗品用甲醇/苯中重结晶,得到7-乙酰氧基-4’-甲氧基异黄-3-烯(0.034g,66%)。1H NMR(CDCl3+d6-DMSO):δ3.74(s,3H,OCH3),4.99(s,2H,H2),6.21(d,1H,J 2.3Hz,H8),6.29(dd,1H,J 2.3Hz,8.3Hz,H6),6.67(bs,1H,H4),6.85(d,1H,J 8.3Hz,H5),6.86(d,2H,J 8.7Hz,ArH),7.33(d,2H,J 8.7Hz,ArH).
实施例39
异黄-3-烯-3’,7-二醇
按照制备异黄-3-烯-4’,7-二醇的方法,从3’,7-二乙酰氧基异黄-3-烯(0.09g,0.3mmol)及咪唑(0.3g)的乙醇(2.0ml)溶液可以制备得到异黄-3-烯-3’,7-二醇。产量:(0.04g,60%)。
1H NMR(CDCl3+d6-DMSO):δ4.94(s,2H,H2),6.21(d,1H,J 2.0Hz,H8),6.29(dd,1H,J 2.3Hz,8.3Hz,H6),6.62(m,1H,ArH),6.64(bs,1H,H4),6.75-6.82(m,3H,ArH),7.07(t,1H,J 7.9Hz,ArH),8.99-9.17(bs,2H,OH).
实施例40
3’-甲氧基异黄-3-烯-7-醇
按照制备异黄-3-烯-4’,7-二醇的方法,从7-乙酰氧基-3’-甲氧基异黄-3-烯(0.1g,0.3mmol)及咪唑(0.15g)的乙醇溶液(2.0ml)可以制备得到3’-甲氧基异黄-3-烯-7-醇。产量:(0.06g,70%)。
m.p.75℃.1H NMR(CDCl3):δ3.84(s,3H,OMe),5.12(s,2H,H2),6.38(d,1H,J 2.0Hz,H8),6.40(dd,1H,J 2.0Hz,8.3Hz,H6),6.76(bs,1H,H4),6.84(dd,1H,J 1.9Hz,8.3Hz,ArH),6.95(m,3H,ArH),7.29(t,1H,J 8.3Hz,ArH).
实施例41
3’-甲氧基异黄-3-烯-4’,7-二醇
按照制备异黄-3-烯-4’,7-二醇的方法,从4’,7-二乙酰氧基-3-甲氧基异黄-3-烯(0.11g,0.3mmol)及咪唑(0.3g)的乙醇(2.0ml)溶液可以制备得到3’-甲氧基异黄-3-烯-4’,7-二醇。产量:(0.06g,71%)。
1H NMR(d6-acetone):δ3.90(s,3H,OMe),5.07(s,2H,H2),6.31(d,1H,J 2.3Hz,H8),6.40(dd,1H,J 2.3Hz,8.3Hz,H6),6.78(bs,1H,H4),6.83(d,1H,J 8.3Hz,ArH),6.92(dd,2H,J 1.9Hz,8.3Hz,ArH),7.14(d,1H,J 1.9Hz,ArH),7.04,7.63(each s,1H,OH).
实施例42
异黄-3-烯-7-醇
按照制备异黄-3-烯-4’,7-二醇的方法,从7-乙酰氧基异黄-3-烯(0.2g,0.75mmol)及咪唑(0.24g)的乙醇溶液(3.5ml)可以制备得到异黄-3-烯-7-醇。产量:(0.11g,66%)。
m.p.120℃.1H NMR(d6-DMSO):δ5.07(s,2H,H2),6.24(d,1H,J 2.2Hz,H8),6.33(dd,1H,J 1.9Hz,7.9Hz,H6),6.96(d,1H,J 7.9Hz,H5),7.00(s,1H,H4),7.26-7.47(m,5H,ArH),9.65(bs,1H,OH).
质谱:m/z 224(m,74%);223(100);175(28);165(23);147(41)。
实施例43
异黄-3-烯-4’,7,8-三醇
将咪唑(0.6g)加到4’,7,8-三乙酰氧基异黄-3-烯(0.16g,0.4mmol)的无水乙醇悬浮液(5.0ml)中,混合物在氩气下回流45分钟。减压浓缩,加入蒸馏水(10ml)沉淀产品。使混合物在冰箱中放置过夜,过滤得到异黄-3-烯。粗品用甲醇/苯中重结晶,得到异黄-3-烯-4’,7,8-三醇(0.08g,75%)。
1H NMR(CDCl3+d6-DMSO):δ4.97(s,2H,H2),6.30(d,1H,J 8.2Hz,H6),6.36(d,1H,J 8.3Hz,H5),6.55(bs,1H,H4),6.72(d,1H,J 8.7Hz,ArH),7.17(d,2H,J 8.7Hz,ArH).
实施例44
4’-甲氧基异黄-3-烯-7,8-二醇
按照制备异黄-3-烯-4’,7,8-三醇的方法,从7,8-二乙酰氧基-4-甲氧基异黄-3-烯(0.15g,0.4mmol)及咪唑(0.4g)的乙醇(1.6ml)溶液可以制备得到4’-甲氧基异黄-3-烯-7,8-二醇。产量:(0.73g,61%)。
1H NMR(CDCl3+d6-DMSO):δ3.83(s,3H,OCH3),5.15(s,2H,H2),6.51(d,1H,J 8.3Hz,H6),6.58(d,1H,J 8.3 Hz,H5),6.68(bs,1H,H4),6.92(d,1H,J 8.7Hz,ArH),7.35(d,2H,J 8.7Hz,ArH).
质谱:m/z 270(M,5%);256(100);255(70);239(20);181(25)。
实施例45
8-甲基异黄-3-烯-4’,7-二醇
将咪唑(0.6g)加到4’,7-二乙酰氧基-8-甲基异黄-3-烯(0.25g,0.7mmol)的无水乙醇悬浮液(5.0ml)中,混合物在氩气下回流45分钟。减压浓缩,加入蒸馏水(10ml)沉淀产品。使混合物在冰箱中放置过夜,过滤得到异黄-3-烯。粗品用甲醇/苯中重结晶,得到8-甲基异黄-3-烯-4’,7-二醇(0.13g,68%)。
m.p.190-93℃1H NMR(CDCl3+d6-DMSO):δ1.94(s,3H,CH3),4.98(s,2H,H2),6.32(d,1H,J 7.9Hz,H6),6.58(bs,1H,H4),6.67(bd,1H,H5),6.72(d,2H,J 8.7Hz,ArH),7.21(bd,2H,ArH).
质谱:m/z 255(M+1,16%);254(M,79);253(100);161(32)。
实施例46
8-甲基异黄-3-烯-3’,7-二醇
按照制备8-甲基异黄-3-烯-4’,7-二醇的方法,从3’,7-二乙酰氧基-8-甲基异黄-3-烯(0.12g,0.4mmol)及咪唑(0.3g)的乙醇溶液(2.5ml)可以制备得到8-甲基异黄-3-烯-3’,7-二醇。产量:(0.07g,77%)。m.p.130℃。
1H NMR(CDCl3+d6-DMSO):δ1.95(s,3H,CH3),4.98(s,2H,H2),6.34(d,1H,J 8.0Hz,H6),6.61-6.94(m,5H,ArH),7.08(bt,1H,ArH).
质谱:m/z 254(M,100%);253(95);161(45)。
实施例47
4’-甲氧基-8-甲基异黄-3-烯-7-醇
按照制备8-甲基异黄-3-烯-4’,7-二醇的方法,从7-乙酰氧基-4’-甲氧基-8-甲基异黄-3-烯(0.11g,0.3mmol)及咪唑(0.14g)的乙醇溶液(1.5ml)可以制备得到4’-甲氧基-8-甲基异黄-3-烯-7-醇。产量:(0.05g,53%)。
m.p.103℃.1H NMR(d6-acetone):δ1.99(s,3H,CH3),3.81(s,3H,OMe),5.11(s,2H,H2),6.43(d,1H,J 8.3Hz,H6),6.77(bs,1H,H4),6.80(d,1H,J 8.3Hz,H5),6.95(d,2H,J 9.0Hz,ArH),7.44(d,2H,J 9.0Hz,ArH).
质谱:m/z 282(M,9%);267(100);268(95);134(52)。
实施例48
3’-甲氧基-8-甲基异黄-3-烯-4’,7-二醇
按照制备8-甲基异黄-3-烯-4’,7-二醇的方法,从4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄-3-烯(0.21g,0.6mmol)及咪唑(0.52g)的乙醇溶液(4ml)可以制备得到3’-甲氧基-8-甲基异黄-3-烯-4’,7-二醇。产量:(0.1g,63%)。
1H NMR(CDCl3):δ2.14(s,3H,CH3),3.94(s,3H,OMe),5.11(s,2H,H2),6.42(d,1H,J 8.3Hz,H6),6.64(bs,1H,ArH),6.80(d,1H,J 7.9Hz,ArH),6.94(m,2H,ArH),7.12(m,1H,ArH),7.26,7.70(each bs,1H,OH).
脱保护反应
顺式-和反式-四氢黄豆苷原
将咪唑(0.2g)加到4’,7-二乙酰氧基四氢黄豆苷原(0.10g,0.3mmol)的无水乙醇悬浮液(4.0ml)中,混合物在氩气下回流45分钟。减压浓缩,加入蒸馏水(10ml)沉淀产品。使混合物在冰箱中放置过夜,过滤结晶产品,得到顺式-和反式-四氢黄豆苷原(0.06g,80%)。
实施例50
反式-四氢黄豆苷原(反式-4’,7-二羟基异黄烷-4-醇)
按照制备顺式-和反式-四氢黄豆苷原的方法,从反式-4’,7-二羟基异黄烷-4-醇及咪唑的乙醇溶液可以制备得到反式-4’,7-二羟基异黄烷-4-醇。1H NMR(d6-acetone):δ2.99(ddd,1H,J 3.4Hz,6.8Hz,10.6Hz,H3),4.13(dd,1H,J 7.0Hz,10.9Hz,H2);4.24(dd,1H,J 3.8Hz,11.3Hz,H2),4.70(d,1H,J 6.4Hz,H4),6.20(d,1H,J 2.6Hz,H8),6.38(dd,1H,J 2.3Hz,8.3Hz,H6),6.71(d,2H,J 8.7Hz,ArH),7.04(d,2H,J 8.7Hz,ArH),7.18(d,1H,J 8.3Hz,H5).
实施例51
顺式-和反式-7-羟基-4,-甲氧基异黄烷-4-醇
将咪唑(0.4g)加到7-乙酰氧基-4’-甲氧基异黄烷-4-醇(0.20g,0.6mmol)的无水乙醇悬浮液(8.0ml)中,混合物在氩气下回流45分钟。减压浓缩,加入蒸馏水(10ml)。使混合物在冰箱中放置过夜,过滤结晶产品,得到顺式-和反式-7-羟基-4’-甲氧基异黄烷-4-醇(0.16g,79%)。
实施例52
顺式-和反式-7-羟基异黄烷-4-醇
按照制备顺式-和反式-四氢黄豆苷原的方法,从7-乙酰氧基异黄烷-4-醇(0.14g,0.5mmol)及咪唑(0.17g)的乙醇(3.0ml)溶液可以制备得到7-羟基异黄烷-4-醇。
对于反式-7-羟基异黄烷-4-醇而言:
1H NMR(d6-acetone):δ3.08(m,1H,H3),4.00(t,1H,J10.2Hz,H2);4.30(m,1H,H2),4.81(d,1H,J 7.2Hz,H4),6.25-6.43(m,ArH),6.89(d,J8.3Hz,ArH),7.07(d,J 8.3Hz,ArH),7.22-7.64(m,ArH).
对于顺式-7-乙酰氧基异黄烷-4-醇而言:
1H NMR(d6-acetone):δ3.20(m,1H,H3),4.36(m,1H,H2);4.57(dd,1H,J 10.2Hz,12.0Hz,H2),4.68(bs,1H,H4),6.25-6.43(m,ArH),6.89(d,J8.3Hz,ArH),7.07(d,J 8.3Hz,ArH),7.22-7.64(m,ArH).
实施例53
顺式-和反式-4’,7-二羟基-8-甲基异黄烷-4-醇
按照制备顺式-和反式-四氢黄豆苷原的方法,从4’,7-二乙酰氧基-8-甲基异黄烷-4-醇(0.4g,1.1mmol)及咪唑(1.0g)的乙醇溶液(7.0ml)可以制备得到4’,7-二羟基-8-甲基异黄烷-4-醇。
对于反式-4’,7-二羟基-8-甲基异黄烷-4-醇而言:
1H NMR(d6-acetone):δ1.98(s,3H,CH3),2.98(ddd,1H,J 3.8Hz,10.9Hz,12.0Hz,H3),4.18(m,1H,H2);4.27(m,1H,H2),4.75(d,1H,J 6.4Hz,H4),6.42(m,ArH),6.75(m,ArH),7.05-7.19(m,ArH),7.66(bs,OH).
对于顺式-4’,7-二羟基-8-甲基异黄烷-4-醇而言:
1H NMR(d6-acetone):δ1.99(s,3H,CH3),3.01(dt,1H,J 3.4Hz,12.0Hz,H3),4.31(m,1H,H2);4.52(dd,1H,J 10.2Hz,12.0Hz,H2),4.60(bs,1H,H4),6.42(m,ArH),6.75(m,ArH),7.05-7.19(m,ArH),7.66(bs,OH).
实施例54
反式-7-羟基-4’-甲氧基-8-甲基异黄烷-4-醇
按照制备顺式-和反式-四氢黄豆苷原的方法,从反式7-乙酰氧基-4’-甲氧基-8-甲基异黄烷-4-醇(0.23g,0.7mmol)及咪唑(0.28g)的乙醇溶液(2.1ml)可以制备得到反式-7-羟基-4’-甲氧基-8-甲基异黄烷-4-醇。m.p.162℃。
质谱:m/z 285(M,5%);268(10);151(20);135(20);134(100);119(20)。
1H NMR(d6-acetone):δ1.97(s,3H,CH3),3.00(ddd,1H,J 3.4Hz,7.2Hz,10.2Hz,H3),3.72(s,3H,OMe),4.20(dd,1H,J7.5Hz,10.9Hz,H2);4.27(m,1H,H2),4.73(d,1H,J 6.8Hz,H4),6.45(d,1H,J 8.3Hz,H6),6.85(d,2H,J 8.6Hz,ArH),7.10(d,1H,J 8.7Hz,H5),7.18(d,2H,J 8.6Hz,ArH).
氢化反应:异黄酮→顺式异黄烷-4-醇
实施例55
顺式-4’,7-二乙酰氧基异黄烷-4-醇
将氧化铂(IV)(Adam’s催化剂)(0.05g)加到4’,7-二乙酰氧基异黄酮(0.25g,0.7mmol)的乙酸乙酯溶液(40ml)中,混合物在室温并氢气下搅拌55小时。经硅藻土滤除催化剂,真空蒸发滤液,主要得到顺式-4’,7-二乙酰氧基异黄烷-4-醇。
对于顺式-4’,7-二乙酰氧基异黄烷-4-醇而言:
1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),2.29(s,3H,OCOCH3),3.30(dt,1H,J 3.4Hz,J 11.8Hz,H3),4.31(ddd,1H,J 1.4Hz,3.6Hz,10.5Hz,H2);4.56(dd,1H,J 10.5Hz,11.8Hz,H2),4.75(dd,1H,J 1.3Hz,3.2Hz,H4),6.66(dd,1H,J 2.3Hz,8.7Hz,H6),6.69(d,1H,J 2.3Hz,H8),7.08(d,2H,J 8.6Hz,ArH),7.26(d,1H,8.4Hz,H5),7.29(d,2H,J 8.6Hz,ArH).13C NMR(CDCl3):δ20.98(OCOCH3),43.52(C3),64.10(C2),66.46(C4),110.08(C6),114.09(C8),121.82,129.40(ArCH),131.10(C5).
氢化反应:-异黄酮→异黄烷-4-酮
实施例56
4’,7-二乙酰氧基二氢黄豆苷原(4’,7-二乙酰氧基异黄烷-4-酮)
将Pd/活性炭(5%,0.02g)加到4’,7-二乙酰氧基黄豆苷原(0.50g,1.5mmol)的乙酸乙酯溶液(80ml)中,混合物在室温并氢气下搅拌72小时。经硅藻土滤除催化剂,真空蒸发滤液,残余物用乙醇重结晶,得到4’,7-二乙酰氧基二氢黄豆苷原(0.40g,80%),其为无色板状物。
1H NMR(CDCl3):δ2.29(s,3H,OCOCH3),2.23(s,3H,OCOCH3),3.98(dd,1H,J 6.2Hz,8.2Hz,H3),4.69(m,2H,H2),6.78-6.82(m,2H,ArH),7.08(d,2H,J 9.2Hz,ArH),7.30(d,2H,J 8.2Hz,ArH),7.98(d,1H,J 9.2Hz H5).
氢化反应:异黄烷-3-烯→异黄烷
实施例57
O,O-二乙酰基牛尿酚
将Pd/活性炭(5%,0.02g)加到4’,7-二乙酰氧基异黄-3-烯(0.20g,0.06ml)的乙酸乙酯(60ml)溶液中,混合物在室温并氢气下搅拌24小时。经硅藻土滤除催化剂,真空蒸发滤液,残余物用二氯甲烷/轻石油醚重结晶,得到O,O-二乙酰基牛尿酚(0.15g,75%)。1H NMR(CDCl3):δ2.29(s,3H,OCOCH3),2.31(s,3H,OCOCH3),3.00(d,2H,J 8.3Hz,H4),3.25(m,1H,H3),4.00(t,1H,H2),4.34(dd,1H,J 3.4Hz,10.9Hz,H2),6.61(d,J 7.5Hz,1H,ArH),6.60(s,1H,ArH),7.06(bd,3H,J 8.3Hz,ArH),7.24(d,3H,J 8.3Hz,ArH).
脱保护反应
实施例58
二氢黄豆苷原(4’,7-二羟基异黄烷-4-酮)
将咪唑(0.63g)加到4’,7-二乙酰氧基二氢黄豆苷原(0.26g,0.08mmol)的无水乙醇悬浮液(5.0ml)中,混合物在氩气下回流45分钟。减压浓缩,向残余物中加入蒸馏水(10ml)。使混合物在冰箱中放置过夜,过滤沉淀,用乙酸乙酯/二氯甲烷对粗品进行重结晶,得到4’,7-二羟基异黄烷-4-酮(0.14g,71%),其为白色粉末。
1H NMR(d6-acetone):δ3.83(t,1H,J 7.2Hz,H3),4.60(d,2H,J 6.2Hz,H2),6.39(d,1H,J 2.0Hz,H8),6.55(dd,1H,J 8.2,J 2.0Hz,ArH),6.80(d,2H,J 8.2Hz,ArH),7.10(d,1H,J 8.2Hz,ArH),7.74(d,1H,J 8.2Hz,H5).
实施例59
牛尿酚(4’,7-二羟基异黄烷)
将咪唑(0.5g)加到O,O-二乙酰基牛尿酚(0.15g,0.08mmol)的无水乙醇悬浮液(5.0ml)中,混合物在氩气下回流45分钟。减压浓缩,向残余物中加入蒸馏水(10ml)。使混合物在冰箱中放置过夜,过滤产品,得到牛尿酚(0.09g,80%),其为白色粉末。
1H NMR(d6-DMSO):δ2.70(d,2H,J 9.2Hz,H4),2.92(m,1H,H3),3.73(t,1H,J 1G.3Hz,H2),4.06(dd,1H,J 3.0Hz,11.2Hz,H2),6.16(bs,1H,ArH),6.21(bd,J 8.2Hz,1H,ArH),6.63(d,2H,J 8.2Hz,ArH),6.69(d,1H,J 8.2Hz,ArH),6.87(d,2H,J 8.2Hz,ArH)
本领域技术人员将明白这里所描述的发明除了上述特定的描述之外,还可以进行各种变化和修饰,并且本发明包括所有的变化和修饰。本发明还包括所有的步骤、特征、组合及在专利说明书中涉及或指出的单一或集合化合物,以及任意两个或多个所述步骤或特征的任意和全部组合。
Claims (13)
1.制备式II异黄烷-4-醇化合物的方法,
其中R1,R2,R3,R4,R5,R6,R7和R8独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,(C1-C6)烷基,卤代(C1-C6)烷基,苯基,苯基(C1-C6)烷基,(C1-C6)烷基硫基,氨基,(C1-C6)烷基氨基,二(C1-C6)烷基氨基,硝基或卤素
R9为(C1-C6)烷基,卤代(C1-C6)烷基,苯基,苯基(C1-C6)烷基或(C1-C6)烷基苯基,且R1,R2,R3,R4,R5,R6和R7中至少一个是羟基,
该方法包括
(a)保护式I异黄酮化合物的自由羟基,
其中R1,R2,R3,R4,R5,R6,R7和R8的定义同上且R1,R2,R3,R4,R5,R6和R7中至少一个为自由羟基,以制备保护的异黄酮化合物,其中R1,R2,R3,R4,R5,R6和R7的至少一个自由羟基被保护为乙酰氧基;
(b)氢化步骤(a)中保护的异黄酮化合物以制备保护的异黄烷-4-醇化合物,
且其中氢化步骤在还原催化剂存在下用氢气进行,还原催化剂选自钯/活性炭,且溶剂选自甲醇或乙醇;并且
(c)在回流的乙醇溶液中用咪唑水解乙酰氧基保护基而将来自步骤(b)中保护的异黄烷-4-醇去保护以制备式II的化合物,其中R1,R2,R3,R4,R5,R6和R7中至少一个是羟基。
2.权利要求1中所述的方法,其中的还原催化剂为钯/活性炭,钯从1%到10%。
3.权利要求1中所述的方法,其中的溶剂为无水甲醇或无水乙醇。
4.权利要求1中所述的方法,其中式II化合物具有下列取代基:
R1是羟基;
R2,R3,R4,R5,R6和R7独立为氢、羟基、OR9、OC(O)R9、(C1-C6)烷基、苯基或苯基(C1-C6)烷基,
R8是氢,及
R9是甲基、乙基、丙基、异丙基或三氟甲基。
5.权利要求4中所述的方法,其中式II化合物具有下列取代基:
R1是羟基;
R2,R3,R4,R5,和R7独立为氢、羟基、OR9、OC(O)R9、(C1-C6)烷基、苯基或苯基(C1-C6)烷基,
R8和R6是氢,及
R9是甲基。
6.权利要求5中所述的方法,其中式II化合物是4’,7-二羟基异黄烷-4-醇或7-羟基-4’-甲氧基异黄烷-4-醇。
7.制备式III异黄-3-烯化合物的方法,
其中R1,R2,R3,R4,R5,R6,R7和R8独立为氢、羟基、OR9,OC(O)R9,OS(O)R9,(C1-C6)烷基,卤代(C1-C6)烷基,苯基,苯基(C1-C6)烷基,(C1-C6)烷基硫基,氨基,(C1-C6)烷基氨基,二(C1-C6)烷基氨基,硝基或卤素
R9为(C1-C6)烷基,卤代(C1-C6)烷基,苯基,苯基(C1-C6)烷基或(C1-C6)烷基苯基,且R1,R2,R3,R4,R5,R6和R7中至少一个是羟基,
该方法包括以下步骤:
(a)保护式I的异黄酮化合物的自由羟基,
其中R1,R2,R3,R4,R5,R6,R7和R8的定义同上,且R1,R2,R3,R4,R5,R6和R7中至少一个是自由羟基,以制备保护的异黄酮化合物,其中R1,R2,R3,R4,R5,R6和R7中至少一个自由羟基被保护为乙酰氧基;
(b)氢化步骤(a)中保护的异黄酮化合物以制备保护的异黄烷-4-醇化合物,
其中氢化步骤在还原催化剂存在下用氢气进行,还原催化剂选自钯/活性炭,且溶剂选自甲醇或乙醇;并且
(c)脱水步骤(b)中保护的异黄烷-4-醇化合物来制备保护的异黄-3-烯化合物;以及
(d)在回流的乙醇溶液中用咪唑水解乙酰氧基保护基而将来自步骤(c)中保护的异黄-3-烯化合物去保护以制备式III的化合物,其中R1,R2,R3,R4,R5,R6和R7中至少一个是羟基。
8.权利要求7的方法,其中通过用三氟乙酸、对甲苯磺酸或五氧化二磷进行处理,使步骤(c)中保护的异黄烷-4-醇化合物4’,7-二乙酰氧基四氢黄豆苷原脱水以提供4’,7-二乙酰氧基异黄-3-烯。
9.权利要求7的方法,其中式III化合物具有下列取代基:
R1为羟基,
R2,R3,R4,R5,R6和R7独立为氢、羟基、OR9、OC(O)R9、(C1-C6)烷基、苯基或苯基(C1-C6)烷基,
R8为氢,并且
R9为甲基、乙基、丙基、异丙基或三氟甲基。
10.权利要求9中所述的方法,其中III化合物具有下列取代基:
R1为羟基,
R2,R3,R4,R5和R7独立为氢、羟基、OR9、OC(O)R9、(C1-C6)烷基、苯基或苯基(C1-C6)烷基,
R6和R8为氢,并且
R9为甲基。
11.权利要求10的方法,其中的式III化合物为4’,7-二羟基异黄-3-烯,7-羟基-4’-甲氧基异黄-3-烯,3’,7-二羟基异黄-3-烯或7-羟基-3’-甲氧基异黄-3-烯。
12.化合物,选自:
4’,7,8-三乙酰氧基异黄-4醇
7,8-二乙酰氧基-4’-甲氧基异黄-4醇
4’,7-二乙酰氧基-8-甲基异黄-4醇
3’,7-二乙酰氧基-8-甲基异黄-4醇
7-乙酰氧基-4’-甲氧基-8-甲基异黄-4醇
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄-4醇
4’,7-二羟基-8-甲基异黄-4醇
7-羟基-4’-甲氧基-8-甲基异黄-4醇。
13.化合物,选自:
4’,7,8-三乙酰氧基异黄-3-烯
7,8-二乙酰氧基-4′-甲氧基异黄-3-烯
4’,7-二乙酰氧基-8-甲基异黄-3-烯
3’,7-二乙酰氧基-8-甲基异黄-3-烯
7-乙酰氧基-4’-甲氧基-8-甲基异黄-3-烯
4’,7-二乙酰氧基-3’-甲氧基-8-甲基异黄-3-烯
3’,7-二乙酰氧基异黄-3-烯
7-乙酰氧基-3’-甲氧异黄-3-烯
异黄-3-烯-4’,7,8-三醇
4’-甲氧基异黄-3-烯-7,8-二醇
8-甲基异黄-3-烯-4’,7-二醇
8-甲基异黄-3-烯-3’,7-二醇
4’-甲氧基-8-甲基异黄-3-烯-7-醇
3’-甲氧基-8-甲基异黄-3-烯-4’,7-二醇
3’,7-二羟基异黄-3-烯
7-羟基-3’-甲氧基异黄-3-烯。
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IL144008A0 (en) | 2002-04-21 |
CN1340048A (zh) | 2002-03-13 |
US7906660B2 (en) | 2011-03-15 |
HK1041883B (zh) | 2010-04-23 |
HUP0105218A1 (hu) | 2002-07-29 |
AU2651000A (en) | 2000-09-04 |
NO20013945D0 (no) | 2001-08-14 |
AUPP868599A0 (en) | 1999-03-11 |
NO20013945L (no) | 2001-08-14 |
JP2002537295A (ja) | 2002-11-05 |
EP1153020A1 (en) | 2001-11-14 |
IL144008A (en) | 2011-03-31 |
CA2362819A1 (en) | 2000-08-24 |
HK1041883A1 (en) | 2002-07-26 |
US20050143588A1 (en) | 2005-06-30 |
BR0008222A (pt) | 2001-10-30 |
ZA200106502B (en) | 2005-05-09 |
CZ20012920A3 (cs) | 2001-11-14 |
NO327749B1 (no) | 2009-09-14 |
HUP0105218A3 (en) | 2002-10-28 |
EP1153020A4 (en) | 2002-08-21 |
TR200102367T2 (tr) | 2001-11-21 |
US20060217564A1 (en) | 2006-09-28 |
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