1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(6-Acetoxy-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-3-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide

HRID 1967475Notes

Reaction equation

HRID 1967475 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.CN(C)CCCN=C=NCC.[C:33]([O:36][CH:37]1[C:41]2=[N:42][C:43]3[C:44](=[N:45][CH:46]=[C:47]([NH2:49])[CH:48]=3)[N:40]2[CH2:39][CH2:38]1)(=[O:35])[CH3:34]>CN(C)C=O>[C:33]([O:36][CH:37]1[C:41]2=[N:42][C:43]3[C:44](=[N:45][CH:46]=[C:47]([NH:49][C:19]([C:6]4[N:7]([CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=5)[C:8]5[C:4]([CH:5]=4)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:20])[CH:48]=3)[N:40]2[CH2:39][CH2:38]1)(=[O:35])[CH3:34]

Participants

5

Reactant 3

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 574315135-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acidHCID 594026426-acetoxy-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-3-amine

Product 1

HCID 66905274N-(6-Acetoxy-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-3-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamideYield 61.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
20 °C

Procedure

A solution of 0.25 g (0.87 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid, prepared in step 1.1, 0.166 g (0.87 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and 0.117 g (0.87 mmol) of N-1-hydroxybenzotriazole in 3 ml of dimethylformamide is stirred at 20° C. for 15 minutes. The reaction mixture is subsequently admixed with 0.245 g (1.04 mmol) of 6-acetoxy-7,8-dihydro-6H-pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridin-3-amine (compound IV-b), in solution in 3 ml of dimethylformamide. The reaction mixture is subsequently stirred at 20° C. for 16 hours and then concentrated under reduced pressure, poured into 50 ml of water and extracted with three times 50 ml of ethyl acetate. The organic phases are combined, then washed with twice 20 ml of saturated sodium hydrogen carbonate solution, once with 20 ml of water and then once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. The product thus purified is finally triturated in hot diisopropyl ether and filtered while hot to give 0.27 g of the expected product.

Workup

  1. stirringThe reaction mixture is subsequently stirred at 20° C. for 16 hours
  2. concentrationconcentrated under reduced pressure
  3. additionpoured into 50 ml of water
  4. extractionextracted with three times 50 ml of ethyl acetate
  5. washwashed with twice 20 ml of saturated sodium hydrogen carbonate solution, once with 20 ml of water
  6. dry with materialonce with 50 ml of saturated sodium chloride solution, dried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe product obtained
  9. customis purified by chromatography on a silica column
  10. washeluting with a mixture of dichloromethane and methanol
  11. customThe product thus purified
  12. customis finally triturated in hot diisopropyl ether
  13. filtrationfiltered while hot

Sources & evidence

ORD record
ord-a8ceaf79141c4441906c76fef84e5465
Source dataset
uspto-grants-2013_04
Patent number
US08420817B2

Reaction notes

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