1-Hydroxybenzotriazole hydrate → (+/-)-cis-N1-[(5-Chloroindol-2-yl) carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclobutanediamine hydrochloride

HRID 546499Notes

Reaction equation

HRID 546499 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:4]=2[CH2:3]1.[Li+].O.ON1C2C=CC=CC=2N=N1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([NH:38][C@@H:39]1[CH2:42][CH2:41][C@@H:40]1[NH2:43])=[O:37])=[CH:30]2>CN(C)C=O>[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([NH:38][C@@H:39]1[CH2:42][CH2:41][C@@H:40]1[NH:43][C:11]([C:9]1[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=1)=[O:13])=[O:37])=[CH:30]2

Participants

5

Reactant 3

HCID 27960291-Hydroxybenzotriazole hydrateHCID 18442846(+/-)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclobutanediamineHCID 23704331Lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

Product 1

HCID 68908268(+/-)-cis-N1-[(5-Chloroindol-2-yl) carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclobutanediamine hydrochlorideYield 52.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate (136 mg), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (255 mg) and 1-hydroxybenzotriazole monohydrate (90 mg) were added to a solution with (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclobutanediamine (117 mg) dissolved in N,N-dimethylformamide (5 ml), and the mixture was stirred overnight at room temperature. The solvent was then distilled off under reduced pressure using a vacuum pump, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct liquid separation. The resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (methanol:dichloromethane=7:93). After ethyl acetate and a 1N ethanol solution of hydrochloric acid were added to the thus-obtained compound to acidify it, and the solvent was distilled off under reduced pressure. Ethyl acetate was added again, and precipitate formed was collected by filtration and dried to obtain the title compound (56 mg) as a colorless powder.

Workup

  1. distillationThe solvent was then distilled off under reduced pressure
  2. additiona saturated aqueous solution of sodium hydrogencarbonate were added to the residue
  3. customliquid separation
  4. washThe resultant organic layer was washed with saturated saline
  5. dry with materialdried over anhydrous sodium sulfate
  6. distillationthe solvent was distilled off under reduced pressure
  7. customthe residue was purified by flash column chromatography on silica gel (methanol:dichloromethane=7:93)
  8. additionAfter ethyl acetate and a 1N ethanol solution of hydrochloric acid were added to the thus-obtained compound
  9. distillationthe solvent was distilled off under reduced pressure
  10. additionEthyl acetate was added again
  11. customprecipitate formed
  12. filtrationwas collected by filtration
  13. customdried

Sources & evidence

ORD record
ord-572c5eecbccc42a6b4676ebc7996efb0
Source dataset
uspto-grants-2011_05
Patent number
US07935824B2

Reaction notes

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