CN103275126A - 一种立体选择性合成3-位膦酰化吲哚的方法 - Google Patents
一种立体选择性合成3-位膦酰化吲哚的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title claims abstract 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 5
- 230000026731 phosphorylation Effects 0.000 title abstract 4
- 238000006366 phosphorylation reaction Methods 0.000 title abstract 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 13
- 239000012074 organic phase Substances 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004440 column chromatography Methods 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- RUUXACGTBRUUGB-UHFFFAOYSA-N 1h-indol-2-ylphosphonic acid Chemical class C1=CC=C2NC(P(O)(=O)O)=CC2=C1 RUUXACGTBRUUGB-UHFFFAOYSA-N 0.000 claims description 18
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 14
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 14
- 239000012071 phase Substances 0.000 claims description 12
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- -1 alkoxy aryl phosphinate Chemical compound 0.000 claims description 7
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 150000002390 heteroarenes Chemical class 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000010572 single replacement reaction Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 13
- 125000005843 halogen group Chemical group 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 150000001879 copper Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000010791 quenching Methods 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000012153 distilled water Substances 0.000 description 10
- 238000003810 ethyl acetate extraction Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 238000010189 synthetic method Methods 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- AZMUHUYPUWGKJR-IWEFOYFVSA-N CC(C)C[C@@H](C(NN(C[C@H](CCN1)C1=O)C([C@H](F)Cl)=O)=O)NC(C(NC1=CC=C2)=CC1=C2F)=O Chemical compound CC(C)C[C@@H](C(NN(C[C@H](CCN1)C1=O)C([C@H](F)Cl)=O)=O)NC(C(NC1=CC=C2)=CC1=C2F)=O AZMUHUYPUWGKJR-IWEFOYFVSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种立体选择性合成3-位膦酰化吲哚的方法,以化合物a和b为原料,以乙腈反应介质,在50-90℃下与铜盐反应20-30h,加入水淬灭反应,然后用二氯甲烷萃取,合并有机相,干燥、除去溶剂、柱层析得到白色固体,即为3-位膦酰化吲哚。本发明提供的立体选择性合成3-位膦酰化吲哚的方法,环境友好、操作简单;反应步骤少;反应条件温和;溶剂不需要进一步处理。有效地解决了现有合成路线中存在的步骤长、操作过程繁琐,大量卤代盐废物产生给后处理带来麻烦的问题。
Description
技术领域
本发明涉及3-位膦酰化吲哚的合成方法,属有机合成领域。
背景技术
近年来,吲哚衍生物的一些反应及其合成是有机化学领域研究的热点,由于很多药物和具有生物活性的天然产物是在吲哚的骨架上衍生出来的,它已成为有机化学重要的前沿研究方向。各种具有取代基的3-位膦酰化吲哚及其衍生物具有很好的生理活性和药用价值。
传统的合成方法,如F. R. Alexandre 报道的方法需要通过卤代吲哚和膦酰基金属盐进行反应,不仅合成步骤长,操作过程也比较繁琐,需要在严格无水的条件下进行操作,这给进行工业生产带来了很大的限制。另外,从经济和环境保护的角度,传统工艺中大量生成的卤代盐废物,不仅给后期处理带来了困难,也增加了生产成本。本专利申请的新方法很好地解决了传统工艺中存在的合成步骤长,操作繁琐及大量卤代盐废物产生的问题。
发明内容
本发明要解决的技术问题是克服现有的缺陷,提供了一种合成路线短、操作简单,后处理简单的立体选择性合成3-位膦酰化吲哚的方法。
本发明的目的通过以下技术方案来具体实现:
一种立体选择性合成3-位膦酰化吲哚的方法,以化合物a和b为原料,以乙腈为反应介质,在50-90℃下与铜盐反应20-30h,加入水淬灭反应,然后用二氯甲烷萃取,合并有机相,干燥、除去溶剂、柱层析得到白色固体,即为3-位膦酰化吲哚,其中,
所述化合物a的名称为N-R1-2-R2-吲哚,结构式如下,
R为在4、5、6、7位的取代基,为Me、 CH3(CH2)n、OCH3、F、Cl、Br、I或SH,
R1为在氮保护基,为H、Me、CH3(CH2)n、Boc、Ts、CH3CO、Ph或PhCH2,
R2为在2-位取代基,为COOH、COOMe、COOEt、CHO、CN、CONHOMe、CONHMe、CONH2或CONMe2,其中最优的为COOEt或CONHOMe;
所述化合物b的名称为芳基烷氧基亚膦酸酯,结构式如下,
R3为Me、Et、(1R,2S,5R)-(−)-Menthol或(1R,3R,4S)-(-)-Menthol;
Ar为芳香取代基,包括各种单取代或多取代的芳香烃或杂环芳烃;
所述化合物a、化合物b与铜盐的摩尔比为1:1-3:0.02-0.1;
所述乙腈的体积与化合物a的质量比为3-6
mL:150-300 mg。
其中R3为Me、Et的化合物可以从化学试剂公司买到,R3为 (1R,2S,5R)-(−)-Menthol或(1R,3R,4S)-(-)-Menthol的化合物可以根据现有方法(J. Am. Chem. Soc. 2008, 130,
12648-12655;J. Am. Chem. Soc. 2001, 123,
510-511;J. Organomet. Chem. 2002, 643-644,
154-163; Tetrahedron Lett. 2003, 781-783; J. Am. Chem. Soc. 1967,
90, 3459-3465)进行制备。
优选的,
所述化合物a、化合物b与铜盐的摩尔比为1:2:0.05;
所述乙腈的体积与化合物a的质量比为3
mL:150 mg;
所述化合物a中的取代基R为5-Cl 或 5-F;
所述化合物a中的取代基R1为Bn或Me。;
所述化合物a中的取代基R2为COOEt或CONHOMe;
所述化合物b中的R3为(1R,2S,5R)-(−)-Menthol或(1R,3R,4S)-(-)-Menthol;
所述化合物b中的Ar为苯、取代苯或吡啶的芳香杂环化合物,其中最佳的为5-Cl 或 5-F取代苯基;
所述铜盐为CuCl、CuBr、 CuI、CuCl2、CuBr2或
Cu(OAc)2、其中最佳的铜盐为CuCl。
所述反应温度优选50-90℃,在氮气保护下反应24h;所述干燥剂为无水Na2SO4;所述柱层析时使用流动相为石油醚与乙酸乙酯,两者体积比是1:1。
本发明的有益效果:
本发明提供的立体选择性合成3-位膦酰化吲哚的方法,环境友好、操作简单;反应步骤少;反应条件温和;溶剂不需要进一步处理。有效地解决了现有合成路线中存在的步骤长、操作过程繁琐,大量卤代盐废物产生给后处理带来麻烦的问题。尤其是,当反应物b为手性芳基烷氧基亚磷酸脂时,通过本发明的合成方法,可以实现现有技术中未曾开发出的分子中磷原子手性中心的构建和立体选择性合成。
具体实施方式
以下对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例
1
:
常温下,把0.5毫摩尔化合物1a,1毫摩尔化合物1b溶在3.0毫升乙腈溶液中,加入0.05毫摩尔CuCl在油浴中加热至50度, 连续搅拌24个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 =
1:1淋洗分离,得到白色固体1c,产率为50%, Slight yellow thick oil。 1 H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.0 Hz, 1H), 7.86-7.80 (m, 2H),
7.50-7.36 (m, 5H), 7.30-7.28 (m, 1H), 4.26(q, J = 6.8 Hz, 2H), 3.94 (s,
3H), 3.75 (d, J = 11.6 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ
161.5, 138.0 (d, J C-P = 13 Hz), 137 (d, J C-P
= 21 Hz), 132.9 (d, J C-P = 147 Hz), 132.0 (d, J C-P
= 2 Hz), 131.6 (d, J C-P = 3 Hz), 130.7 (d, J C-P
= 11 Hz), 128.4 (d, J C-P = 12 Hz), 124.8, 122.8, 122.5,
110.4, 105.6 (d, J C-P = 158 Hz), 61.9, 51.2 (d, J C-P
= 6 Hz), 31.8, 13.6. 31P NMR (162 MHz, CDCl3): δ 31.84.
实施例
2
:
常温下,把0.5毫摩尔化合物2a,1毫摩尔化合物2b溶在3.0毫升乙腈溶液中,加入0.08毫摩尔CuCl在油浴中加热至80度, 连续搅拌22个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体2c,产率为88%,dr.≥20/1, Slight
yellow thick oil。 1 H NMR
(400 MHz, CDCl3): δ 8.35
(d, J = 8.4 Hz, 1H), 7.84-7.78 (m, 2H), 7.46-7.35 (m, 5H), 7.28-7.23 (m,
1H), 4.44-4.40 (m, 1H), 4.25-4.09(m, 2H), 3.96 (s, 3H), 2.13-2.08 (m, 1H), 1.92
(d, J = 12 Hz, 1H), 1.66-1.61 (m, 2H), 1.49-1.42 (t, J = 11.2 Hz,
1H), 1.37-1.31 (m, 1H), 1.24-1.14 (m, 4H), 1.00-0.83 (m, 2H), 0.81 (d, J
= 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.51 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ
161.6, 138.1(d, J C-P = 48 Hz), 136.5, 135.1, 134.6 (d, J C-P
= 80 Hz), 131.1 (d, J C-P = 12), 130.6 (d, J C-P
= 44 Hz), 128.6 (d, J C-P = 32 Hz), 127.9 (d, J C-P
= 52 Hz), 124.7, 123.8, 122.0, 110.1, 108.9, 107.3, 76.3 (d, J C-P =
28 Hz), 61,5, 49.0 (d, J C-P = 20 Hz), 43.4, 34.1, 31.8, 31.5,
25.2, 22.7, 22.0, 21.1, 15.3, 13.7. 31P NMR (162 Hz, CDCl3):
δ 28.14.
实施例
3
:
常温下,把1.0毫摩尔化合物3a,2毫摩尔化合物2b溶在4.5毫升乙腈溶液中,加入0.10毫摩尔CuCl在油浴中加热至75度, 连续搅拌26个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体3c,产率为82%, dr.=18/1, Slight yellow thick oil。 1H NMR (400 MHz,
CDCl3): δ 10.86 (s, 1H), 7.68 ( d, J = 8.4 Hz, 1H),
7.88-7.82 (m, 2H), 7.49-7.38 (m, 5H), 7.24-7.20 (m, 1H), 4.47-4.37 (m, 1H),
4.14 (s, 3H), 2.10-1.97 (m, 2H), 1.64 (d, J = 10.8 Hz, 2H), 1.53-1.47
(m, 1H), 1.36-1.25 (m, 2H), 1.02-0.92 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H),
0.85 (d, J = 6.0 Hz, 3H), 0.76 (d, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 186.6(d, J C-P
= 72 Hz), 139.4 (d, J C-P = 48 Hz), 138.2 (d, J C-P
= 88 Hz), 135.6, 134.1, 131.9, 130.7 (d, J C-P = 44 Hz), 128.4
(d, J C-P = 42 Hz), 127.6 (d, J C-P = 36 Hz),
126.9, 123.6, 122.4, 116.4, 114.9, 110.6, 77.5, 49.0 (d, J C-P
= 20 Hz), 43.6, 34.0, 32.5, 31.6, 25.5, 22.7, 22.0, 21.0, 15.2. 31P
NMR (162 Hz, CDCl3): δ
25.95.
实施例
4
:
常温下,把1.0毫摩尔化合物4a,2毫摩尔化合物2b溶在4.0毫升乙腈溶液中,加入0.05毫摩尔CuCl在油浴中加热至80度, 连续搅拌24个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体4c,产率为79%, dr.≥20/1, Slight
yellow thick oil。 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8 Hz, 1H), 7.97-7.91 ( m, 2H),
7.53-7.48 (m, 1H), 7.46-7.40 (m, 3H), 7.37-7.34 (m, 1H), 7.25-7.22 (m, 1H),
4.46-4.37 (m, 1H), 3.95 (s, 3H), 2.30-2.20 (m, 1H), 1.97-1.93 (m, 1H),
1.70-1.53 (m, 3H), 1.35-1.27 (m, 2H), 1.04-0.94 (m, 2H), 0.88 (d, J =
7.2 Hz, 3H), 0.82 (d, J = 5.6 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ
139.0 (d, J C-P = 4 Hz), 134.4, 132.9, 132.1, 132.0, 131.4 (d,
J C-P = 40 Hz), 128.0 (d, J C-P = 52 Hz),
127.4 (d, J C-P = 40 Hz), 126.3, 122.9 (d, J C-P
= 52 Hz), 116.2, 114.7 (d, J C-P = 16 Hz), 114.5, 112.2,
110.2, 77.7 (d, J C-P = 28 Hz), 48.5 (d, J C-P
= 20 Hz), 43.2, 33.9, 31.9, 31.6, 25.5, 22.7, 21.9, 21.0, 15.4. 31P
NMR (162 Hz, CDCl3): δ
21.75.
实施例
5
:
常温下,把0.5毫摩尔化合物5a,1毫摩尔化合物2b溶在3.5毫升乙腈溶液中,加入0.15毫摩尔CuCl在油浴中加热至80度, 连续搅拌28个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体5c,产率为82%, dr.≥20/1, Slight
yellow thick oil。 1H NMR (400 MHz, CDCl3): δ 7.89-7.83 ( m, 2H), 7.80 (d, J = 8 Hz, 1H),
7.49-7.44 (m, 1H), 7.43-7.29 (m, 4H), 7.20-7.15 (m, 1H), 4.34-4.24 (m, 1H),
3.74 (s, 3H), 2.80 (s, 3H), 2.05-1.97 (m, 2H), 1.61 (d, J = 10 Hz, 2H),
1.45-1.39 (m, 1H), 1.35-1.20 (m, 2H), 0.99-0.82 (m, 2H), 0.80 (d, J =
2.8 Hz, 3H), 0.74 (d, J = 7.2 Hz, 3H), 0.45 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ
198.4, 144.5 (d, J C-P = 88 Hz), 137.5 (d, J C-P
= 44 Hz), 135.3, 133.9, 131.6 (d, J C-P = 12 Hz), 131.0 (d, J C-P
= 44 Hz), 128.2 (d, J C-P = 42 Hz), 127.5 (d, J C-P
= 40 Hz), 124.1, 122.4, 121.9, 110.2, 105.1, 103.5, 77.0, 49.0 (d, J C-P
= 24 Hz), 43.4, 34.0, 33.4, 31.5, 31.3, 25.5, 22.7, 22.0, 21.0, 15.1. 31P
NMR (162 Hz, CDCl3): δ
26.08.
实施例
6
:
常温下,把0.5毫摩尔化合物6a,1毫摩尔化合物2b溶在3.5毫升乙腈溶液中,加入0.10毫摩尔CuCl在油浴中加热至80度, 连续搅拌24个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体6c,产率为73%, dr.≥20/1, White
solid。 1H
NMR (400 MHz, CDCl3): δ 14.32 (br, 1H), 11.23 (br, 1H), 7.82-7.77 ( dd, J
= 13.6 Hz, 7.2 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.52-7.47 (m, 1H),
7.44-7.37 (m, 3H), 7.30-7.25 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H),
4.30-4.21 (m, 1H), 3.98 (s, 3H), 2.35-2.31 (m, 1H), 1.88-1.80 (m, 1H),
1.65-1.59 (m, 2H), 1.50-1.41 (m, 3H), 0.92-0.86 (m, 5H), 0.68 (d, J =
6.8 Hz, 3H), 0.19 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 158.3, 135.5 (d, J C-P
= 48 Hz), 135.1, 134.9, 134.0, 132.5, 132.2 (d, J C-P = 8 Hz),
130.7 (d, J C-P = 44 Hz), 129.0 (d, J C-P =
40 Hz), 128.5 (d, J C-P = 52 Hz), 124.8, 121.9 (d, J C-P
= 40 Hz), 112.6, 102.5, 101.0, 78.7 (d, J C-P = 24 Hz), 64.1
(d, J C-P = 20 Hz), 48.7 (d, J C-P = 28 Hz),
43.8, 33.9, 31.7, 25.2, 22.6, 22.0, 20.9, 14.8. 31P NMR (162 Hz,
CDCl3): δ 30.67.
实施例7:
常温下,把1.0毫摩尔化合物7a,2毫摩尔化合物2b溶在6.0毫升乙腈溶液中,加入0.25毫摩尔CuBr在油浴中加热至90度, 连续搅拌30个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体7c,产率为78%, dr.≥20/1, Slight
yellow thick oil。 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.82-7.76 (m, 2H), 7.48-7.40 (m, 1H),
7.40-7.37 (m, 2H), 7.34 (s, 2H), 4.49-4.39 (m, 1H), 4.24-4.07 (m, 2H), 3.96 (s,
3H), 2.14-2.07 (m, 1H), 1.85 (d, J = 12 Hz, 1H), 1.68-1.61 (m, 2H),
1.51-1.45 (t, J = 11.2 Hz, 1H), 1.37-1.32 (m, 1H), 1.21-1.11 (m, 4H),
1.05-0.85 (m, 2H), 0.83 (d, J = 7.2 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H),
0.55 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.2, 136.6, 136.4 (d, J C-P
= 72 Hz), 135.4 (d, J C-P = 84 Hz), 134.9, 131.3 (d, J C-P
= 8), 130.6 (d, J C-P = 44 Hz), 129.4 (d, J C-P
= 32 Hz), 128.1 (d, J C-P = 56 Hz), 128.0, 125.4, 123.2 111.3,
108.9, 107.3, 76.6 (d, J C-P = 28 Hz), 61,7, 49.0 (d, J C-P
= 20 Hz), 43.4, 34.1, 33.2, 31.5, 25.4, 22.7, 22.0, 21.1, 15.4, 13.8. 31P
NMR (162 Hz, CDCl3): δ
27.75.
实施例8:
常温下,把0.5毫摩尔化合物8a,1毫摩尔化合物2b溶在3.5毫升乙腈溶液中,加入0.15毫摩尔CuCl2在油浴中加热至90度, 连续搅拌24个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体8c,产率为76%, dr.=17/1, Slight yellow thick oil。 1H NMR (400 MHz,
CDCl3): δ 10.78 (s, 1H), 8.03 ( d, J = 1.2 Hz, 1H),
7.88-7.80 (m, 2H), 7.52-7.47 (m, 1H), 7.45-7.34 (m, 4H), 4.50-4.41 (m, 1H),
4.11 (s, 3H), 2.10-2.00 (m, 2H), 1.70-1.65 (m, 2H), 1.57-1.50 (m, 1H),
1.42-1.23 (m, 2H), 1.05-0.87 (m, 2H), 0.86-0.80 (m, 6H), 0.85 (d, J = 6.0 Hz,
3H), 0.76 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 186.2, 138.7 (d, J C-P
= 84 Hz), 137.8 (d, J C-P = 48 Hz), 135.3, 133.9, 132.1 (d, J C-P
= 8 Hz), 130.7 (d, J C-P = 44 Hz), 128.7, 128.5, 128.4, 127.5,
122.8, 116.0, 114.5, 111.9, 78.0 (d, J C-P = 28 Hz), 49.0 (d, J C-P
= 24 Hz), 43.6, 34.0, 32.8, 31.6, 25.7, 22.8, 21.9, 21.0, 15.3. 31P
NMR (162 Hz, CDCl3): δ
25.44.
实施例9:
常温下,把1.0毫摩尔化合物9a,1毫摩尔化合物2b溶在6.0毫升乙腈溶液中,加入0.20毫摩尔Cu(OAc)2在油浴中加热至80度, 连续搅拌26个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体9c,产率为68%, dr.≥20/1, White
solid, 1H NMR (400 MHz, CDCl3): δ 14.24 (br, 1H), 11.15(br, 1H), 7.81-7.74 ( m, 2H),
7.56-7.51 (m, 2H), 7.48-7.41 (m, 3H), 7.25-7.24 (m, 1H), 4.31-4.22 (m, 1H),
3.97 (s, 3H), 2.30-2.26 (m, 1H), 1.92-1.83 (m, 1H), 1.66-1.62 (m, 2H),
1.54-1.51 (m, 1H), 1.49-1.37 (m, 2H), 0.98-0.85 (m, 5H), 0.75 (d, J = 6.8 Hz,
3H), 0.28 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 157.9, 136.0 (d, J C-P
= 80 Hz), 133.8 (d, J C-P = 48 Hz), 133.6, 132.5 (d, J C-P
= 12 Hz), 132.1, 130.6 (d, J C-P = 48 Hz), 129.9 (d, J C-P
= 44 Hz), 128.7 (d, J C-P = 52 Hz), 127.8, 125.5, 121.3,
113.8, 102.7, 101.2, 79.2 (d, J C-P = 28 Hz), 64.2, 48.7 (d, J C-P
= 28 Hz), 43.7, 33.9, 31.7, 25.5, 22.7, 22.0, 20.9, 14.9. 31P NMR
(162 Hz, CDCl3): δ
29.95.
实施例10:
常温下,把0.5毫摩尔化合物2a,1毫摩尔化合物3b溶在3.0毫升乙腈溶液中,加入0.10毫摩尔CuCl在油浴中加热至90度, 连续搅拌24个小时,然后停止加热,待反应物温度降至室温后,加入10毫升蒸馏水淬灭反应,用20毫升乙酸乙酯萃取3次。合并有机相,无水Na2SO4干燥,旋出溶剂,在硅胶柱子上用流动相石油醚:乙酸乙酯 = 1:1淋洗分离,得到白色固体10c,产率为46%, White solid。 1 H NMR
(400 MHz, CDCl3): δ 8.21
(d, J = 8.4 Hz, 1H), 7.87-7.84 (m, 2H), 7.76 (d, J = 13.2 Hz,
1H), 7.47-7.40 (m, 2H), 7.34-7.29 (m, 1H), 7.07 (d, J = 12 Hz, 1H), 5.44(d,
J = 12 Hz, 1H), 4.34-4.28 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 3.79
(d, J = 11.2 Hz, 3H), 2.41 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ
161.6, 147.8, 139.0, 138.9, 138.2, 133.7, 133.6, 133.5, 133.4, 131.7, 129.4,
129.3, 128.2 (d, J C-P = 40 Hz), 125.0, 123.0, 122.7, 116.9,
110.5, 96.0, 62.1, 51.4 (d, J C-P = 24 Hz), 32.0, 21.3, 13.7. 31P
NMR (162 Hz, CDCl3): δ
30.25.
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种立体选择性合成3-位膦酰化吲哚的方法,其特征在于:以化合物a和b为原料,以乙腈为反应介质,在惰性气氛、50-90℃下与铜盐反应20-30h,加入水淬灭反应,然后用二氯甲烷萃取,合并有机相,干燥、除去溶剂、柱层析得到白色固体,即为3-位膦酰化吲哚,其中,
所述化合物a的名称为N-R1-2-R2-吲哚,结构式如下,
R为在苯环4、5、6、7位的取代基,为Me、 CH3(CH2)n、OCH3、F、Cl、Br、I或SH,
R1为在氮保护基,为H、Me、CH3(CH2)n、Boc、Ts、CH3CO、Ph或PhCH2;
R2为在2-位取代基,为COOH、COOMe、COOEt、CHO、CN、CONHOMe、CONHMe、CONH2或CONMe2;
所述化合物b的名称为芳基烷氧基亚膦酸酯,结构式如下,
R3为Me、Et、(1R,2S,5R)-(-)-Menthol或(1R,3R,4S)-(-)-Menthol;
Ar为各种芳香取代基,包括各种单取代或多取代的芳香烃或杂环芳烃;
所述化合物a、化合物b与铜盐的摩尔比为1:1-3:0.02-0.1;
所述乙腈的体积与化合物a的质量比为3-6 mL:150-300
mg。
2.根据权利要求1所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述化合物a、化合物b与铜盐的摩尔比为1:2:0.05。
3.根据权利要求1所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述乙腈的体积与化合物a的质量比为3 mL:150 mg。
4.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述化合物a中的取代基R为5-Cl 或 5-F。
5.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述化合物a中的取代基R1为Bn或Me。
6.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述化合物a中的取代基R2为COOEt或CONHOMe。
7.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述化合物b中的R3为
(1R,2S,5R)-(−)-Menthol或(1R,3R,4S)-(-)-Menthol。
8.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述化合物b中的Ar为苯、取代苯或吡啶的芳香杂环化合物,其中最佳的为5-Cl 或 5-F取代苯基。
9.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述铜盐为 CuCl、CuBr、CuI、CuCl2、CuBr2或Cu(OAc)2,其中最佳的铜盐为CuCl。
10.根据权利要求1至3任一项所述的立体选择性合成3-位膦酰化吲哚的方法,其特征在于:所述反应温度为50-90℃,在氮气保护下反应24h;所述干燥剂为无水Na2SO4;所述柱层析时使用流动相为石油醚与乙酸乙酯,两者体积比是1:1。
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CN112724171B (zh) * | 2021-01-06 | 2022-02-08 | 南京林业大学 | 一种2-膦酰基-3-氟代乙烯基吲哚化合物及其制备方法 |
CN112920220A (zh) * | 2021-02-03 | 2021-06-08 | 南京林业大学 | 一种水相合成含三氟甲基c-2膦酰基吲哚的方法 |
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