CN107056676B - 一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法 - Google Patents
一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 29
- WVDMAYQJYOOQOE-UHFFFAOYSA-N 3-(aminomethyl)-3-fluoro-1h-indol-2-one Chemical compound C1=CC=C2C(CN)(F)C(=O)NC2=C1 WVDMAYQJYOOQOE-UHFFFAOYSA-N 0.000 title claims abstract description 20
- UJSHYNUSRWUTAS-UHFFFAOYSA-N 3-fluoroindol-2-one Chemical compound C1=CC=CC2=NC(=O)C(F)=C21 UJSHYNUSRWUTAS-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000002466 imines Chemical class 0.000 claims abstract description 27
- -1 tert-butylsulfinyl Chemical group 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims 2
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000012827 research and development Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000012512 characterization method Methods 0.000 description 15
- 238000004293 19F NMR spectroscopy Methods 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- ULYONBAOIMCNEH-HNNXBMFYSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1h-indol-2-one Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-HNNXBMFYSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- ULYONBAOIMCNEH-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1h-indol-2-one Chemical compound COC1=CC=C(Cl)C=C1C1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-UHFFFAOYSA-N 0.000 description 1
- MXIRBQGJHHAAIX-UHFFFAOYSA-N 3-fluoro-1,3-dihydroindol-2-one Chemical compound C1=CC=C2C(F)C(=O)NC2=C1 MXIRBQGJHHAAIX-UHFFFAOYSA-N 0.000 description 1
- NNWGOUJBCKZULC-UHFFFAOYSA-N 5-methyl-5-(5-methylthiophen-3-yl)-4-oxofuran-2-carboxylic acid Chemical compound S1C(C)=CC(C2(C)C(C=C(O2)C(O)=O)=O)=C1 NNWGOUJBCKZULC-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical class CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明涉及一种制备手性3‑(胺甲基)‑3‑氟‑2‑吲哚酮的方法,在有机溶剂中,手性(R)‑N‑(叔丁基亚磺酰)亚胺、3‑氟‑2‑吲哚酮以及碱在‑80℃~0℃温度下,反应0.5~6小时,得到手性3‑(胺甲基)‑3‑氟‑2‑吲哚酮。与现有技术相比,本发明采用易于制备的3‑氟‑2‑吲哚酮以及(R)‑N‑(叔丁基亚磺酰)亚胺作为起始原料。这种方法简洁高效,普适性强。本发明用到的原料经济易得,制备的工艺条件温和,方法高效。本发明制备得到的手性3‑(胺甲基)‑3‑氟‑2‑吲哚酮,为一种潜在的活性分子合成砌块,有望在不对称合成以及医药研发领域得到应用。
Description
技术领域
本发明属于有机物合成技术领域,尤其是涉及一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法。
背景技术
3-氟-2-吲哚酮结构是生物活性分子的重要结构单元。比如,化合物3-(5-氯-2-甲氧基苯基)-3-氟-6-三氟甲基-2-吲哚酮(BMS-204352)已被发现能够开启Maxi-K钾离子通道(P.Hewawasam,V.K.Gribkoff,Y.Pendri,S.I.Dworetzky,N.A.Meanwell,E.Martinez,C.G.Boissard,D.J.Post-Munson,J.T.Trojnacki,K.Yeleswaram,L.M.Pajor,J.Knipe,Q.Gao,R.Perrone,J.E.Starrett,Bioorg.Med.Chem.Lett.2002,12,1023–1026)。因此,发展高效的合成3-氟-2-吲哚酮衍生物的方法,对于药物研发有着重要的意义。
目前,合成3-(胺甲基)-3-氟-2-吲哚酮的方法非常少,仅有报道利用3-氟-3-(2,2,2-三氟-1,1-二羟基乙基)-2-吲哚酮与亚胺的加成反应进行制备((a)C.Xie,L.Zhang,W.Sha,V.A.Soloshonok,J.Han,Y.Pan,Org.Lett.2016,18,3270–3273;(b)C.Xie,L.Zhang,H.Mei,J.Han,V.A.Soloshonok,Y.Pan,ChemistrySelect 2016,1,4435–4439)。但这种方法由于需要活化的3-氟-2-吲哚酮,制备不方便,从其限制了其实用性。另外,适用的亚胺仅为多氟烷基醛亚胺。
考虑到3-(胺甲基)-3-氟-2-吲哚酮的重要性以及目前方法的局限性,发展简洁高效的合成方法具有重要的意义。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种手性3-(胺甲基)-3-氟-2-吲哚酮的制备方法。该方法用到的原料易于制备,反应易于操作且方法高效,制备得到的3-(胺甲基)-3-氟-2-吲哚酮的光学纯度高。
本发明的目的可以通过以下技术方案来实现:
一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法,在有机溶剂中,手性(R)-N-(叔丁基亚磺酰)亚胺、3-氟-2-吲哚酮以及碱在-80℃~0℃温度下,反应0.5~6个小时,得到手性3-(胺甲基)-3-氟-2-吲哚酮;
其中,手性(R)-N-(叔丁基亚磺酰)亚胺具有如下结构式:
其中,R为C1-12的烷基、C2-12的烯基、苯基、取代苯基、萘基、或杂芳基;
所述的取代苯基为C1-6的烷基取代的苯基、C1-8的烷氧基取代的苯基、硝基取代的苯基或腈基取代的苯基;
所述的杂芳基为呋喃基或吡啶基。
所述的手性(R)-N-(叔丁基亚磺酰)亚胺优选采用如下结构式:
所述的3-氟-2-吲哚酮具有如下结构式:
其中R1为C1-C10的烷基、或含有炔丙基或烯丙基结构的取代基;
R2为氢原子、C1-C8的烷基或卤素原子。
所述的碱为叔丁醇钠、叔丁醇钾、双(三甲基硅基)氨基锂、双(三甲基)硅基氨基钠、双(三甲基)硅基氨基钾或二(异丙基)胺基锂。
手性(R)-N-(叔丁基亚磺酰)亚胺、3-氟-2-吲哚酮以及碱的摩尔比为1:(1~3):(1~3)。
所述的有机溶剂为乙醚、四氢呋喃、甲苯、二氯甲烷或N,N-二甲基甲酰胺。
所述的手性3-(胺甲基)-3-氟-2-吲哚酮结构式如下:
其中,R1为C1-C10的烷基、或含有炔丙基或烯丙基结构的取代基;
R2为氢原子、C1-C8的烷基或卤素原子;
R为C1-12的烷基、C2-12的烯基、苯基、取代苯基、萘基、或杂芳基;所述的取代苯基为C1-6的烷基取代的苯基、C1-8的烷氧基取代的苯基、硝基取代的苯基或腈基取代的苯基;所述的杂芳基为呋喃基或吡啶基。
典型反应如下:
上述式(1)中(R)-N-(叔丁基亚磺酰)亚胺可利用相应的醛酮与商品化的叔丁基亚磺酰胺缩合制备(Liu,G.;Cogan,D.A.;Owens,T.D.;Tang,T.P.;Ellman,J.A.J.Org.Chem.1999,64,1278)。
上述式(2)中3-氟-2-吲哚酮可利用2-吲哚酮的氟化反应制备(Y.Jin,M.Chen,S.Ge,J.F.Hartwig,Org.Lett.2017,DOI:10.1021/acs.orglett.7b00294)。
与现有技术相比,本发明采用3-氟-2-吲哚酮作为起始原料,通过与手性Ellman亚胺发生加成反应,得到手性3-(胺甲基)-3-氟-2-吲哚酮。这种方法简洁高效,普适性高。
本发明制备的手性3-(胺甲基)-3-氟-2-吲哚酮的方法,制备用到的原料经济易得,制备的工艺条件温和、方法高效且制备得到的3-(胺甲基)-3-氟-2-吲哚酮光学纯度高。本发明制备得到的手性3-(胺甲基)-3-氟-2-吲哚酮,为一种潜在的生物活性分子合成砌块,有望在不对称合成以及医药研发领域得到应用。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
以下实施例中,反应的产率指的是分离收率;dr指的是反应的非对映异构体比例。
实施例1
在-80℃下,LiHMDS(1.0mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(165毫克,1.0mmol)、式(4a)所示的亚胺(209毫克,1mmol)、以及3ml无水THF的反应瓶中,反应体系氮气保护。滴加完毕后,继续低温反应0.5小时。反应结束后,低温下加入4ml氯化铵水溶液淬灭反应。将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5aa,产率为92%(344毫克),dr为99:1。
化合物5aa的表征数据:
白色固体,m.p.147-149℃. 1H NMR(400MHz,CDCl3)δ7.40(d,J=7.4Hz,1H),7.28(t,J=7.8Hz,1H),7.18–7.02(m,6H),6.54(d,J=7.8Hz,1H),5.21(dd,J=7.2,4.3Hz,1H),4.85(d,J=3.3Hz,1H),2.97(s,3H),1.26(s,9H).19F NMR(376MHz,CDCl3)δ-161.96(d,J=6.7Hz).13C NMR(101MHz,CDCl3)δ171.06(d,J=22.2Hz),144.06(d,J=5.2Hz),134.51(d,J=5.2Hz),131.61(d,J=2.6Hz),128.65(s),128.29(s),127.73(s),124.99(s),123.42(d,J=18.5Hz),123.03(d,J=2.3Hz),108.50(s),92.73(d,J=199.6Hz),62.94(d,J=26.4Hz),56.35(s),25.86(s),22.58(s).IR(cm-1):2924,1718,1617,1471,1379,1907,1072,756,700.MS(ESI)m/z:375.2[M+H]+.HRMS(ESI)m/z:calcd for C20H24FN2O2S+[M+H]+,375.1543,found:375.1548.
实施例2
在-70℃下,LiHMDS(1.4mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(232毫克,1.4mmol)、式(4b)所示的亚胺(223毫克,1mmol)以及3ml乙醚的反应瓶中,反应体系氮气保护。滴加完毕后,继续低温反应0.5小时。反应结束后,低温下加入4ml氯化铵水溶液淬灭反应。将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5ab,产率为92%(357毫克),dr为99:1。
化合物5ab的表征数据:
白色固体,m.p.138-140℃;1H NMR(400MHz,CDCl3)δ7.39(d,J=7.4Hz,1H),7.31–7.26(m,1H),7.08(t,J=7.5Hz,1H),6.94(q,J=8.3Hz,4H),6.57(d,J=7.9Hz,1H),5.18(dd,J=7.2,4.3Hz,1H),4.81(d,J=3.2Hz,1H),2.99(s,3H),2.23(s,3H),1.25(s,9H).19FNMR(376MHz,CDCl3)δ-161.37(s).13C NMR(101MHz,CDCl3)δ171.15(d,J=22.1Hz),144.07(d,J=5.2Hz),138.08(s),131.60(d,J=2.8Hz),131.26(s),131.20(s),128.55(d,J=1.3Hz),125.00(s),123.44(d,J=18.3Hz),123.05(d,J=2.7Hz),108.60(s),92.78(d,J=199.0Hz),62.57(d,J=26.3Hz),56.36(s),25.93(s),22.61(s),21.11(s).IR(cm-1):3293,1716,1619,1490,1465,1380,1076,1055,822,756.MS(ESI)m/z:389.2[M+H]+.HRMS(ESI)m/z:calcd for C21H26FN2O2S+[M+H]+389.1694,found 389.1694.
实施例3
在-20℃下,NaHMDS(2.5mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(330毫克,2.0mmol)、式(4c)所示的亚胺(239毫克,1mmol)以及3ml二氯甲烷的反应瓶中,反应体系用氮气保护。滴加完毕后,继续低温反应0.5小时,加入4ml氯化铵水溶液淬灭反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5ac,产率为91%(368毫克),dr为99:1。
化合物5ac的表征数据
白色固体,m.p.109-111℃;1H NMR(500MHz,CDCl3)δ7.38(d,J=7.4Hz,1H),7.30–7.23(m,1H),7.07(t,J=7.5Hz,1H),6.98(d,J=8.7Hz,2H),6.64(d,J=8.7Hz,2H),6.56(d,J=7.8Hz,1H),5.17(dd,J=7.0,4.1Hz,1H),4.87(d,J=2.7Hz,1H),3.70(s,3H),2.98(s,3H),1.25(s,9H).19F NMR(471MHz,CDCl3)δ-161.55(s).13C NMR(126MHz,CDCl3)δ171.15(d,J=22.6Hz),159.42(s),144.05(d,J=5.4Hz),131.58(d,J=2.6Hz),129.88(s),126.10(d,J=5.4Hz),124.96(s),123.50(d,J=18.3Hz),123.06(d,J=2.0Hz),113.21(s),108.61(s),92.85(d,J=199.6Hz),62.19(d,J=26.4Hz),56.37(s),55.10(s),25.92(s),22.59(s).IR(cm-1):2950,1723,1614,1515,1471,1249,1066,836,759,730.MS(ESI)m/z:405.2[M+H]+.HRMS(ESI)m/z:calcd for C21H26FN2O3S+[M+H]+405.1642,found 405.1643.
实施例4
在10℃下,tBuONa(1.0mmol,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(231毫克,1.4mmol)、式(4d)所示的亚胺(234毫克,1mmol)以及3ml无水THF的反应瓶中,反应体系用氮气保护。滴加完毕后,继续低温反应0.5小时,加入4ml氯化铵水溶液淬灭反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5ad,产率为90%(359毫克),dr为96:4。
化合物5ad的表征数据
白色固体,m.p.158-160℃;1H NMR(500MHz,CDCl3)δ7.43(t,J=7.8Hz,3H),7.34(t,J=7.8Hz,1H),7.21(d,J=8.2Hz,2H),7.13(t,J=7.6Hz,1H),6.61(d,J=7.9Hz,1H),5.27(dd,J=7.1,4.2Hz,1H),4.92(d,J=3.4Hz,1H),2.99(s,3H),1.27(s,9H).19F NMR(471MHz,CDCl3)δ-161.73(s).13C NMR(126MHz,CDCl3)δ170.50(d,J=21.8Hz),143.89(d,J=5.2Hz),140.20(d,J=5.3Hz),132.21(d,J=2.7Hz),131.57(s),129.47(s),124.96(s),123.44(d,J=2.6Hz),122.66(d,J=19.0Hz),118.19(s),112.43(s),108.94(s),92.15(d,J=201.3Hz),62.54(d,J=27.1Hz),56.62(s),26.00(s),22.55(s).IR(cm-1):2950,1718,1613,1490,1464,1079,1052,1014,854,756.MS(ESI)m/z:400.1[M+H]+.HRMS(ESI)m/z:calcd for C21H23FN3O2S+[M+H]+400.1491,found 400.1490.
实施例5
在-40℃下,KHMDS(1.4mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(231毫克,1.4mmol)、式(4e)所示的亚胺(254毫克,1mmol)以及3ml无水DMF的反应瓶中,反应体系用氮气保护。滴加完毕后,继续低温反应0.5小时,加入4ml氯化铵水溶液淬灭反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5ae,产率为86%(360毫克),dr为99:1。
化合物5ae的表征数据
白色固体,m.p.160-161℃;1H NMR(500MHz,CDCl3)δ8.00(d,J=8.7Hz,2H),7.44(d,J=7.4Hz,1H),7.34(t,J=7.8Hz,1H),7.31–7.24(m,2H),7.14(t,J=7.6Hz,1H),6.61(d,J=7.8Hz,1H),5.34(dd,J=7.1,4.2Hz,1H),4.96(d,J=3.1Hz,1H),3.00(s,3H),1.27(s,9H).19F NMR(471MHz,CDCl3)δ-161.28(s).13C NMR(126MHz,CDCl3)δ170.49(d,J=21.8Hz),147.79(s),143.90(d,J=5.0Hz),142.20(d,J=5.4Hz),132.30(d,J=2.6Hz),129.71(s),124.98(s),123.50(d,J=2.5Hz),122.97(s),122.58(d,J=18.7Hz),109.02(s),92.06(d,J=200.9Hz),62.35(d,J=27.4Hz),56.66(s),26.05(s),22.55(s).IR(cm-1):2970,1718,1616,1522,1472,1347,1076,858,754,696.MS(ESI)m/z:420.1[M+H]+.HRMS(ESI)m/z:calcd for C20H23FN3O4S+[M+H]+420.1387,found 420.1388.
实施例6
在30℃下,tBuOK(1.4mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(231毫克,1.4mmol)、式(4f)所示的亚胺(259毫克,1mmol)以及3ml无水THF的反应瓶中,反应体系用氮气保护。滴加完毕后,继续低温反应0.5小时,加入4ml氯化铵水溶液淬灭反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5fb,产率为84%(356mg),dr为84:8:6:2。
化合物5af的表征数据
类白色至白色结晶固体,m.p.85-87℃;1H NMR(500MHz,CDCl3)δ8.25(d,J=7.2Hz,1H),7.73(d,J=8.1Hz,2H),7.55–7.37(m,4H),7.29(d,J=7.0Hz,1H),7.10(t,J=7.7Hz,1H),6.83(t,J=7.4Hz,1H),6.50(d,J=6.7Hz,1H),6.22(s,1H),4.72(s,1H),3.09(s,3H),1.16(s,9H).19F NMR(471MHz,CDCl3)δ-158.23(s).13C NMR(101MHz,CDCl3)δ171.78(d,J=23.3Hz),144.18(d,J=6.1Hz),133.42(s),131.66(s),131.56(d,J=2.1Hz),129.21(s),128.53(s),126.17(s),125.67(s),125.51(s),124.33(s),122.61(d,J=2.2Hz),108.43(s),93.26(d,J=199.3Hz),56.33(s),26.09(s),22.43(s).IR(cm-1):2954,1718,1615,1472,1375,1070,908,730.MS(ESI)m/z:425.2[M+H]+.HRMS(ESI)m/z:calcd forC24H26FN2O2S+[M+H]+425.1692,found 425.1694.
实施例7
在-70℃下,LiHMDS(1.4mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(231毫克,1.4mmol)、式(4g)所示的亚胺(210毫克,1mmol)以及3ml无水THF的反应瓶中,反应体系用氮气保护。滴加完毕后,继续低温反应0.5小时,加入4ml氯化铵水溶液淬灭反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5ag,产率为92%(345mg),dr为99:1。
化合物5ag的表征数据
白色固体,m.p.118-120℃;1H NMR(400MHz,CDCl3)δ8.40(d,J=5.4Hz,2H),7.41(d,J=7.4Hz,1H),7.33(tt,J=7.8,1.4Hz,1H),7.12(t,J=7.6Hz,1H),7.01(d,J=5.9Hz,1H),6.60(d,J=7.9Hz,1H),5.20(dd,J=7.0,4.8Hz,1H),4.92(d,J=4.4Hz,1H),2.99(s,3H),1.26(s,9H).19F NMR(376MHz,CDCl3)δ-161.34(s).13C NMR(101MHz,CDCl3)δ170.54(d,J=22.0Hz),149.45(s),144.06(dd,J=8.8,5.2Hz),132.23(d,J=2.8Hz),125.00(s),123.44(d,J=2.1Hz),122.52(d,J=18.3Hz),109.00(s),91.90(d,J=201.1Hz),62.12(d,J=27.3Hz),56.67(s),25.99(s),22.55(s).IR(cm-1):2954,1712,1618,1472,1381,1102,1073,847,752,701.MS(ESI)m/z:376.1[M+H]+.HRMS(ESI)m/z:calcd for C19H23FN3O2S+[M+H]+376.1490,found 376.1490.
实施例8
在-70℃下,LiHMDS(1.4mL,1.0M溶于THF中)逐滴加入含有式(3a)所示氟代吲哚酮(231毫克,1.4mmol)、式(4h)所示的亚胺(199毫克,1mmol)以及3ml无水THF的反应瓶中,反应体系用氮气保护。滴加完毕后,继续低温反应0.5小时,加入4ml氯化铵水溶液淬灭反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(10ml×3)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:2)快速柱层析,得到产品5ah,产率为91%(331mg),dr为99:1。
化合物5ah的表征数据
白色固体,m.p.138-140℃;1H NMR(400MHz,CDCl3)δ7.40–7.33(m,1H),7.27(d,J=1.0Hz,1H),7.23(d,J=7.5Hz,1H),7.08(t,J=7.6Hz,1H),6.77(d,J=7.9Hz,1H),6.27(dd,J=3.2,1.8Hz,1H),6.23(d,J=3.2Hz,1H),5.29(t,J=6.8Hz,1H),4.52(d,J=7.1Hz,1H),3.18(s,3H),1.17(s,9H).19F NMR(376MHz,CDCl3)δ-158.87(d,J=6.3Hz).13C NMR(101MHz,CDCl3)δ171.21(d,J=21.5Hz),148.99(d,J=4.9Hz),144.82(d,J=5.0Hz),142.57(s),131.84(d,J=2.8Hz),125.41(s),123.15(d,J=2.5Hz),122.69(d,J=18.3Hz),110.60(s),109.54(d,J=1.9Hz),108.76(s),91.31(d,J=198.2Hz),57.29(d,J=31.3Hz),56.65(s),26.25(s),22.32(s).IR(cm-1):2951,1720,1617,1472,1379,1072,754,738,705.MS(ESI)m/z:365.1[M+H]+.HRMS(ESI)m/z:calcd for C18H22FN2O3S+[M+H]+365.1332,found 365.1330.
实施例9
采用与实施例1相同的方法,其中:
采用的氟代吲哚酮为3a,采用的亚胺为4i:产率为92%,dr为99:1。
化合物5ai的表征数据
白色固体,m.p.186-187℃;1H NMR(500MHz,CDCl3)δ7.45(d,J=7.4Hz,1H),7.42(t,J=7.8Hz,1H),7.33–7.24(m,5H),7.13(t,J=7.5Hz,1H),6.84(d,J=7.8Hz,1H),6.60(d,J=15.9Hz,1H),6.02(dd,J=15.8,6.6Hz,1H),4.84(q,J=6.3Hz,1H),4.10(d,J=6.3Hz,1H),3.20(s,3H),1.24(s,9H).19F NMR(471MHz,CDCl3)δ-160.05(s).13C NMR(126MHz,CDCl3)δ171.28(d,J=21.8Hz),144.86(d,J=5.1Hz),135.97(s),135.45(d,J=1.2Hz),131.95(d,J=2.7Hz),128.64(s),128.25(s),126.64(s),125.16(s),123.33(d,J=2.6Hz),123.16(d,J=18.4Hz),122.65(d,J=4.3Hz),108.99(s),92.11(d,J=198.0Hz),60.63(d,J=28.2Hz),56.50(s),26.31(s),22.58(s).IR(cm-1):3291,1718,1614,1471,1360,1072,1013,974,757,689.MS(ESI)m/z:401.2[M+H]+.HRMS(ESI)m/z:calcd for C22H26FN2O2S+[M+H]+401.1695,found 401.1694.
实施例10
采用与实施例3相同的方法,其中:
采用的氟代吲哚酮为3a,采用的亚胺为4j:产率为86%,dr为98:2。
化合物5aj的表征数据
白色固体,m.p.171-173℃;1H NMR(400MHz,CDCl3)δ7.46–7.38(m,2H),7.16(t,J=7.6Hz,1H),6.90(d,J=7.8Hz,1H),5.41(d,J=7.3Hz,1H),4.01(ddd,J=12.9,7.3,2.2Hz,1H),3.19(s,3H),1.34(s,9H),0.88(d,J=6.8Hz,3H),0.63(d,J=6.7Hz,3H).19F NMR(376MHz,CDCl3)δ-152.02(s).13C NMR(101MHz,CDCl3)δ172.74(d,J=22.0Hz),144.27(d,J=4.9Hz),131.68(d,J=3.1Hz),124.75(d,J=1.4Hz),124.56(d,J=17.6Hz),123.81(d,J=2.7Hz),109.23(d,J=1.1Hz),90.63(d,J=190.1Hz),65.14(d,J=24.9Hz),57.04(s),29.26(d,J=4.6Hz),26.18(s),23.26(s),21.91(s),15.89(s).IR(cm-1):2970,1716,1613,1471,1376,1079,842,747,701,676.MS(ESI)m/z:341.2[M+H]+.HRMS(ESI)m/z:calcd forC17H26FN2O2S+[M+H]+341.1694,found 341.1694.
实施例11
采用与实施例5相同的方法,其中:
采用的氟代吲哚酮为3b,采用的亚胺为4a:产率为80%,dr为90:10。
化合物5ba的表征数据
白色固体,m.p.172-174℃;1H NMR(500MHz,CDCl3)δ7.19–7.13(m,3H),7.10(d,J=6.8Hz,2H),7.01(t,J=2.1Hz,1H),6.83–6.76(m,1H),6.47(d,J=8.5Hz,1H),5.19(dd,J=7.1,4.6Hz,1H),4.90(d,J=4.0Hz,1H),3.81(s,3H),2.95(s,3H),1.26(s,9H).19F NMR(471MHz,CDCl3)δ-161.72(s).13C NMR(126MHz,CDCl3)δ170.84(d,J=22.0Hz),156.19(d,J=2.7Hz),137.29(s),134.46(s),128.63(s),128.34(s),127.80(s),124.37(d,J=18.2Hz),116.44(d,J=2.7Hz),111.79(s),109.18(s),92.94(d,J=200.6Hz),62.94(d,J=26.3Hz),56.42(s),55.94(s),25.96(s),22.61(s).IR(cm-1):3301,1716,1599,1496,1473,1289,1078,1042,818,707.MS(ESI)m/z:405.2[M+H]+.HRMS(ESI)m/z:calcd forC21H26FN2O3S+[M+H]+405.1644,found 405.1643.
实施例12
采用与实施例6相同的方法,其中:
采用的氟代吲哚酮为3c,采用的亚胺为4a:产率为75%,dr为86:8:6。
化合物5ca的表征数据
白色固体,m.p.177-179℃;1H NMR(400MHz,CDCl3)δ7.37(t,J=1.8Hz,1H),7.29–7.24(m,1H),7.22–7.14(m,3H),7.09(dd,J=7.6,1.6Hz,1H),6.49(dd,J=8.4,0.8Hz,1H),5.18(dd,J=7.3,4.6Hz,1H),4.77(d,J=3.9Hz,1H),2.97(s,3H),1.26(s,9H).19F NMR(376MHz,CDCl3)δ-162.07(d,J=6.3Hz).13C NMR(101MHz,CDCl3)δ170.61(d,J=22.0Hz),142.60(d,J=5.1Hz),134.07(d,J=5.0Hz),131.49(d,J=2.4Hz),128.57(d,J=3.9Hz),127.96(s),125.49(s),124.96(d,J=18.5Hz),109.54(s),92.46(d,J=201.5Hz),62.89(d,J=26.3Hz),56.45(s),26.01(s),22.55(s).IR(cm-1):3304,1719,1612,1491,1362,1107,1085,821,717,705.MS(ESI)m/z:409.1[M+H]+.HRMS(ESI)m/z:calcd forC20H23FClN2O2S+[M+H]+409.1148,found 409.1147.
实施例13
采用与实施例6相同的方法,其中:
采用的氟代吲哚酮为3d,采用的亚胺为4a:产率为92%,dr为99:1。
化合物5da的表征数据
白色固体,m.p.113-115℃;1H NMR(400MHz,CDCl3)δ7.57–7.53(m,1H),7.24–7.10(m,10H),6.81(dd,J=7.7,1.7Hz,2H),6.39(d,J=7.8Hz,1H),5.32(dd,J=6.8,3.9Hz,1H),5.09(dd,J=3.5,1.6Hz,1H),4.86(d,J=16.0Hz,1H),4.55(d,J=16.0Hz,1H),1.31(s,9H).19F NMR(376MHz,CDCl3)δ-157.61(s).13C NMR(101MHz,CDCl3)δ171.14(d,J=22.3Hz),143.55(d,J=5.2Hz),134.39(d,J=2.6Hz),134.32(s),131.65(d,J=2.8Hz),129.04(s),128.69(s),128.26(s),128.07(s),127.58(s),126.83(s),125.13(s),123.61(d,J=18.2Hz),123.17(d,J=2.6Hz),109.86(s),92.55(d,J=198.1Hz),62.67(d,J=26.1Hz),56.39(s),43.79(s),22.67(s).IR(cm-1):2953,1717,1616,1489,1471,1368,1181,1070,990,751,700.MS(ESI)m/z:451.2[M+H]+.HRMS(ESI)m/z:calcd forC26H28FN2O2S+[M+H]+451.1849,found 451.1850.
实施例14
采用与实施例6相同的方法,其中:
采用的氟代吲哚酮为3e,采用的亚胺为4a:产率为77%,dr为89:7:4。
化合物5ea的表征数据
淡黄色液体;1H NMR(400MHz,CDCl3)δ7.44(d,J=7.4Hz,1H),7.34–7.26(m,1H),7.18–7.03(m,6H),6.77(d,J=7.8Hz,1H),5.23(dd,J=7.4,3.9Hz,1H),4.82(d,J=2.3Hz,1H),4.29(qd,J=17.8,2.4Hz,2H),2.13(t,J=2.4Hz,1H),1.27(s,9H).19F NMR(376MHz,CDCl3)δ-161.33(d,J=5.7Hz).13C NMR(101MHz,CDCl3)δ170.05(d,J=22.4Hz),142.18(d,J=5.2Hz),134.07(d,J=5.3Hz),131.61(d,J=2.5Hz),128.73(s),128.34(s),127.94(s),125.11(s),123.41(d,J=2.3Hz),123.26(s),109.54(s),92.81(d,J=200.2Hz),75.50(s),72.57(s),62.98(d,J=26.3Hz),56.39(s),29.12(s),22.60(s).IR(cm-1):2962,1733,1616,1489,1470,1366,1183,1067,995,751.MS(ESI)m/z:399.2[M+H]+.HRMS(ESI)m/z:calcd for C22H24FN2O2S+[M+H]+399.1537,found 399.1537.
实施例15
采用与实施例6相同的方法,其中:
采用的氟代吲哚酮为3f,采用的亚胺为4a:产率为82%,dr为91:7:2。
化合物5fa的表征数据
淡黄色液体;1H NMR(400MHz,CDCl3)δ7.51(d,J=7.4Hz,1H),7.35–7.21(m,7H),7.15–7.08(m,6H),6.62(d,J=7.8Hz,1H),6.29(d,J=16.0Hz,1H),5.77(dt,J=15.9,5.9Hz,1H),5.28(dd,J=6.8,3.9Hz,1H),5.06(d,J=2.1Hz,1H),4.49(ddd,J=16.2,5.5,1.2Hz,1H),1.30(s,9H).19F NMR(376MHz,CDCl3)δ-160.71(s).13C NMR(101MHz,CDCl3)δ170.77(d,J=22.1Hz),143.39(d,J=5.2Hz),136.00(s),134.29(d,J=5.4Hz),133.18(s),131.66(d,J=2.5Hz),128.98(s),128.52(s),128.37(s),127.97(s),127.92(s),126.46(s),125.12(s),123.61(d,J=18.5Hz),123.15(d,J=2.5Hz),121.85(s),109.56(s),92.62(d,J=199.4Hz),62.86(d,J=26.1Hz),56.41(s),41.89(s),22.66(s).IR(cm-1):2920,1717,1616,1470,1364,1180,1069,909,732,700.MS(ESI)m/z:477.2[M+H]+.HRMS(ESI)m/z:calcd for C28H30FN2O2S+[M+H]+477.2001,found 477.2007.
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (6)
1.一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法,其特征在于,在有机溶剂中,手性(R)-N-(叔丁基亚磺酰)亚胺、3-氟-2-吲哚酮以及碱反应,得到手性3-(胺甲基)-3-氟-2-吲哚酮;
所述的手性(R)-N-(叔丁基亚磺酰)亚胺具有如下结构式:
所述的3-氟-2-吲哚酮具有如下结构式:
所述的手性3-(胺甲基)-3-氟-2-吲哚酮结构式如下:
其中,R为C1-12的烷基、C2-12的烯基、苯基、取代苯基、萘基或杂芳基;
所述的取代苯基为C1-6的烷基取代的苯基、C1-8的烷氧基取代的苯基、硝基取代的苯基或腈基取代的苯基;
所述的杂芳基为呋喃基或吡啶基;
R1为C1-C10的烷基、炔丙基的取代基或烯丙基苯基;
R2为氢原子、C1-C8的烷基或卤素原子;
所述的碱为叔丁醇钠、叔丁醇钾、双(三甲基硅基)氨基锂、双(三甲基)硅基氨基钠、双(三甲基)硅基氨基钾或二(异丙基)胺基锂。
4.根据权利要求1所述的一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法,其特征在于,手性(R)-N-(叔丁基亚磺酰)亚胺、3-氟-2-吲哚酮以及碱的摩尔比为1:(1~3):(1~3)。
5.根据权利要求1所述的一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法,其特征在于,所述的有机溶剂为乙醚、四氢呋喃、甲苯、二氯甲烷或N,N-二甲基甲酰胺。
6.根据权利要求1所述的一种制备手性3-(胺甲基)-3-氟-2-吲哚酮的方法,其特征在于,反应条件为:-80℃~0℃下,反应0.5~6个小时。
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CN104098501A (zh) * | 2014-06-23 | 2014-10-15 | 华东师范大学 | 3-二氟烷基取代的全碳季碳氧化吲哚衍生物及其合成方法 |
CN104693092A (zh) * | 2015-02-16 | 2015-06-10 | 华东师范大学 | 手性3,3-二取代氧化吲哚衍生物及其合成方法和应用 |
CN104689849A (zh) * | 2015-02-11 | 2015-06-10 | 华东师范大学 | 一类磷酰胺-(伯)二级胺双功能催化剂及其合成方法 |
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CN104689849A (zh) * | 2015-02-11 | 2015-06-10 | 华东师范大学 | 一类磷酰胺-(伯)二级胺双功能催化剂及其合成方法 |
CN104693092A (zh) * | 2015-02-16 | 2015-06-10 | 华东师范大学 | 手性3,3-二取代氧化吲哚衍生物及其合成方法和应用 |
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