Carbon Dioxide → 2-(5-Bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

HRID 1991569

反応式

HRID 1991569 の反応式
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([OH:19])(=O)[CH2:14]C(O)=O.[N:20]1[CH:25]=CC=C[CH:21]=1.BrN1C2C(=CC=CC=2)C(=O)C1=O.C(=O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O.Cl>C(OCC)(=O)C.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][C:13]([N:20]([CH3:25])[CH3:21])=[O:19])[OH:12]

参加物

12

反応物 8

HCID 280Carbon Dioxide2 回HCID 313Hydrochloric AcidHCID 867Malonic AcidHCID 1049PyridineHCID 6598Dimethylcarbamoyl ChlorideHCID 68895-BromoisatinHCID 8471TriethylamineHCID 53957429Bromo isatin

生成物 1

HCID 591297542-(5-Bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒HCID 8857Ethyl Acetate溶媒2 回

反応条件

温度
50 °C

実験手順

A 2 L flask fitted with an inner thermometer, mechanical stirrer, and reflux condenser is charged with 5-bromo-isatin (100 g, 0.442 mol), malonic acid (55.2 g, 053 mol), pyridine (100.6 g, 1.274 mol), dimethyl formamide (80 g), and ethyl acetate (100 g). When the temperature of the mixture reaches 60° C., the bromo isatin starts to dissolve, and a deep red mixture forms. Carbon dioxide starts to evolve, and after about 45 minutes the precipitation of the intermediate pyridinium (5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-ylacetate starts. The reaction mixture is kept at 80° C. for another 3 hours. Then triethyl amine (49.2 g, 0.486 mol) iss added, and the pyridinium salt dissolves to give a deep brown solution. This solution is allowed to cool to 50° C., and then a solution of dimethyl carbamoyl chloride (48 g, 0.442 mol, CAUTION: carcinogen) in 40 g of ethyl acetate is added dropwise during 30 minutes. Carbon dioxide evolves, and the temperature rises to 60° C. After about 45 minutes, the product starts to precipitate from the reaction mixture. The mixture is kept at 60° C. for another hour, and then water (500 mL) and 36% HCl (250 mL, 4 mol) are added in that order during 10 minutes. The product is filtered off, and reslurried in an mixture of acetone/water (500 mL, 1:1, v:v). The slurry is filtered again, and the product is finally dried to give the title compound as a gray powder which is of suitable purity for direct use in the further steps. Yield: 75.2 g (54.2%). An analytically pure sample is obtained by recrystallization from methanol, mp=245-246° C., dec. 1H-NMR (DMSO-D6, 300 MHz): δ 2.64 (s, 3, CH3), 2.93 (s, 3, CH3), 2.93, 3.27 (AB, 2, 2J=16.5 Hz, CH2), 6.01 (br s, 1, OH), 6.73 (d, 1, 3J=8.2 Hz, H-7), 7.30 (dd, 1, 3J=2.0 Hz, H-6), 7.42 (d, 1, H-4), 10.18 (br s, 1, NH). 13C-NMR (DMSO-D6, 75 MHz) δ 35.04, 37.45 (N(CH3)2), 40.78 (CH2), 73.90 (C-3), 111.85 (C-7), 113.29 (C-5), 127.03 (C-4), 131.83 (C-6), 135.78 (C-9), 143.18 (C-8), 168.93 (CONMe2), 178.68 (C-2).

後処理

  1. customA 2 L flask fitted with an inner thermometer, mechanical stirrer
  2. temperaturereflux condenser
  3. customreaches 60° C.
  4. dissolutionto dissolve
  5. customafter about 45 minutes the precipitation of the intermediate pyridinium (5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-ylacetate
  6. customto give a deep brown solution
  7. customrises to 60° C
  8. waitAfter about 45 minutes
  9. customto precipitate from the reaction mixture
  10. waitThe mixture is kept at 60° C. for another hour
  11. filtrationThe product is filtered off
  12. additionreslurried in an mixture of acetone/water (500 mL, 1:1, v:v)
  13. filtrationThe slurry is filtered again
  14. customthe product is finally dried

出典と根拠

ORDレコード
ord-57b493f6f04e441e9e884fa7b7b2bc48
出典データセット
uspto-grants-2010_01
特許番号
US07645886B2

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