1-Hydroxybenzotriazole → N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-6-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide

HRID 1948781Notes

Reaction equation

HRID 1948781 reaction equation
Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:23][Si:24]([CH3:46])([CH3:45])[C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:42](O)=[O:43])[N:31]2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:27][CH:26]=1.[NH2:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[CH2:57][CH:56]([OH:58])[CH2:55]2)=[CH:52][CH:53]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:58][CH:56]1[CH2:57][N:54]([C:51]2[N:50]=[CH:49][C:48]([NH:47][C:42]([C:30]3[N:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)[C:32]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[C:25]([Si:24]([CH3:23])([CH3:46])[CH3:45])[CH:33]=4)=[O:43])=[CH:53][CH:52]=2)[CH2:55]1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 574315251-(5-Aminopyridin-2-yl)azetidin-3-olHCID 581009486-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid

Product 1

HCID 44194379N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-6-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamideYield 60.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

114 mg (0.59 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 81 mg (0.59 mmol) of 1-hydroxybenzotriazole (HOBT) are added to a solution, stirred at 20° C. under an inert atmosphere, of 0.2 g (0.59 mmol) of 6-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in stage 1.4, in 5 ml of DMF. The reaction mixture is stirred at ambient temperature for 15 minutes. 145 mg (0.88 mmol) of 3-amino-6-(3-hydroxyazetidin-1-yl)pyridine, prepared in stage 2.2, are subsequently added to the reaction mixture. After stirring at 20° C. for 20 hours, the reaction mixture is poured into a mixture of 30 ml of a saturated aqueous solution of NaHCO3 and 30 ml of ethyl acetate. The resulting mixture is separated by settling out and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. The solid obtained after evaporation of the solvent under reduced pressure is recrystallized from isopropyl ether. 175 mg of the expected product are thus isolated.

Workup

  1. additionare subsequently added to the reaction mixture
  2. stirringAfter stirring at 20° C. for 20 hours
  3. customThe resulting mixture is separated
  4. extractionthe aqueous phase is extracted with 20 ml of ethyl acetate
  5. washThe combined organic phases are washed three times with 30 ml of water
  6. dry with materialdried over sodium sulphate
  7. concentrationconcentrated under reduced pressure
  8. customThe product obtained
  9. customis purified by silica column chromatography, elution
  10. additionbeing carried out with a mixture of dichloromethane and methanol
  11. customThe solid obtained
  12. customafter evaporation of the solvent under reduced pressure
  13. customis recrystallized from isopropyl ether

Sources & evidence

ORD record
ord-f986392e72ec4b539b9df9a1fb102853
Source dataset
uspto-grants-2013_03
Patent number
US08399491B2

Reaction notes

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