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Preparation method of 3-oxoindoline compounds

A technology of indoline and compounds, which is applied in pharmaceutical and chemical intermediates and related chemical fields, can solve the problems of poor functional group compatibility, heavy metal waste residue, poor reaction selectivity, etc., and achieve fewer reaction steps, short synthetic routes, and mild reaction conditions. Effect

Inactive Publication Date: 2015-04-08
DALIAN UNIV OF TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, this type of method has the following disadvantages: using noble metal oxides or peroxyacids as oxidants; producing heavy metal waste residue; poor reaction selectivity; poor functional group compatibility, etc.
Although several other indoline ring synthesis methods have been developed [see: (a) Kawasaki, T.; Nonaka, Y.; Matsumura, K. et al. b) Colandrea, V.J.; Rajaraman, S.; Jimenez, L.S.Org. Lett. 2003, 5, 785–787. (c) Kiraz, C.I.A.; Emge, T.J., Jimenez, L.S.J.Org.Chem. (d) Ratnikov, M.O.; Farkas, L.E.; McLaughlin, E.C. et al.J.Org.Chem.2011,76,2585–2593.], but these methods require special compounds as raw materials, poor reaction selectivity, atom economy Therefore, it is of great research significance to develop a synthesis method of 3-oxoindoline ring with mild reaction conditions, high atom economy and high yield.

Method used

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  • Preparation method of 3-oxoindoline compounds
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  • Preparation method of 3-oxoindoline compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Synthesis of tert-Butyl 2-methyl-3-oxoindoline-1-carboxylate (2a)

[0037]

[0038] Accurately weigh N-Boc-2-methylindole (57.8mg, 0.25mmol), RuCl 2 (PPh 3 ) 3 (14.4mg, 0.015mmol), sodium periodate (80.0mg, 0.38mmol), and sequentially added to a 25mL Schlenk bottle, added tetrahydrofuran (2.0mL), placed in an oil bath at 40°C, and reacted for 24h. After the reaction, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent, and silica gel column separation was performed. The yield of N-Boc-2-methyl-3-oxoindoline 2a was 92%. 1 H NMR (400MHz, CDCl 3 ): δ1.54–1.61(m,12H),4.22–4.24(m,1H),7.13(dd,J=7.6Hz,8.5Hz,1H),7.61–7.72(m,1H),7.71(d, J=7.6Hz,1H),8.17(br,1H); 13 C NMR (100MHz, CDCl 3 ): δ17.0, 28.3, 61.7, 116.9, 123.0, 124.0, 137.1, 150.9, 199.6; -1 ; HRMS (EI) Calcd for C 14 h 17 NO 3 :247.1208[M] + ;found: 247.1198.

Embodiment 2

[0039] Example 2: Synthesis of tert-butyl 2-hexyl-3-oxoindoline-1-carboxylate (2b)

[0040]

[0041]Accurately weigh N-Boc-2-cyclohexylindole (74.8mg, 0.25mmol), [RuCl 2 (p-cymene)] 2 (4.6mg, 0.0075mmol), sodium periodate (160.0mg, 0.75mmol), and sequentially added to a 25mL Schlenk bottle, added ethyl acetate (4.0mL), placed in an oil bath at 60°C, and reacted for 24h. After the reaction, the solvent was removed under reduced pressure, and petroleum ether / ethyl acetate was used as the eluent, and silica gel column separation was performed. The yield of N-Boc-2-n-hexyl-3-oxoindoline 2b was 89%. 1 H NMR (400MHz, CDCl 3 ):δ0.83(t,J=6.7Hz,3H),1.08–1.26(m,8H),1.60(s,9H),2.06–2.12(m,2H),4.25(d,J=2.4Hz, 1H), 7.12(t, J=7.5Hz, 1H), 7.60–7.64(m, 1H), 7.70(d, J=7.6Hz, 1H), 8.16(brs, 1H); 13 C NMR (100MHz, CDCl 3 ): δ14.0, 22.5, 22.9, 28.3, 29.2, 31.5, 65.5, 82.3, 116.8, 122.9, 123.6, 124.2, 136.9, 151.0, 199.7; IR (neat) 2958, 2928, 2859, 1713, 1606, 1468, 1379,1283,1257,1155,1...

Embodiment 3

[0042] Example 3: Synthesis of tert-butyl 2,5-dimethyl-3-oxoindoline-1-carboxylate (2c)

[0043]

[0044] Accurately weigh N-Boc-2,5-dimethylindole (61.3mg, 0.25mmol), ruthenium trichloride (13.1mg, 0.05mmol), and sequentially add to a 25mL Schlenk bottle, sodium periodate (160.0mg, 0.75mmol), and sequentially added to a 25mL Schlenk bottle, added acetone (10.0mL), placed in an oil bath at 70°C, and reacted for 24h. After the reaction, the solvent was removed under reduced pressure, using petroleum ether / ethyl acetate as the eluent, and separated on a silica gel column, the yield of N-Boc-2,5-dimethyl-3-oxoindoline 2c was 85% . 1 H NMR (400MHz, CDCl 3 ): δ1.54(d, J=7.0Hz, 3H), 1.60(s, 9H), 2.36(s, 3H), 4.21(d, J=6.5Hz, 1H), 7.45(dd, J=8.5Hz ,1.5Hz,1H),7.50(d,J=0.7Hz,1H),8.03(d,J=8.6Hz,1H); 13 C NMR (100MHz, CDCl 3 ): δ17.0, 20.6, 28.4, 61.9, 82.1, 116.6, 123.3, 123.7, 132.8, 138.3, 150.9, 199.7; 1097,1067,849,765cm -1 ; HRMS (ESI) Calcd for C 15 h 20 NO 3 :262.144...

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Abstract

The invention belongs to the field of medical and chemical intermediates and related chemical technology, and relates to a preparation method of 3-oxoindoline compounds, which is a method for synthesizing 3-oxoindoline compounds based on N-Boc indole. In the method, N-Boc indole is used as a raw material, the oxidation-dearomatization reaction of N-Boc indole is catalyzed by a ruthenium catalyst, the oxidation reaction of N-Boc indole is realized, and the aromaticity of an indole ring on the N-Boc indole is broken to obtain the 3-oxoindoline compounds. The method provided by the invention has the advantages of mild reaction conditions, good compatibility of functional groups, wide substrate range and environmental friendliness; and prepared 3-oxoindoline is an important organic synthesis intermediate which is widely used in the fields of organic synthesis and pharmacy.

Description

technical field [0001] The invention relates to the field of pharmaceutical and chemical intermediates and related chemical technologies, and relates to a preparation method of 3-oxoindoline compounds based on N-Boc indole as a raw material. Background technique [0002] 3-Oxoindoline compounds are a class of important biologically active molecules or intermediates in organic synthesis, and have a very wide range of applications in many fields. 3-Oxoindoline compounds are particularly useful in the synthesis of medicines and pesticides. Therefore, the synthesis of such compounds is one of the current research hotspots. The classic method for the synthesis of 3-oxoindolines is the oxidation of indoles [cf.: Desarbre, E.; Savelon, L.; Cornec, O. et al. Tetrahydron 1996, 52, 2983–2994.]. However, this type of method has the following disadvantages: using noble metal oxides or peroxyacids as oxidants; generating heavy metal waste residue; poor reaction selectivity; poor functio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/36
CPCC07D209/36
Inventor 冯秀娟包明于晓强陈霞周晓玉
Owner DALIAN UNIV OF TECH
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