Diisopropylamine → Telaprevir, (alpha-ketoamide bond reduced)-

HRID 391493Notes

Reaction equation

HRID 391493 reaction equation
[NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].CCN=C=NCCCN(C)C.ON1C(=O)CCC1=O.[CH:33]1([C@H:39]([NH:61][C:62]([C:64]2[CH:69]=[N:68][CH:67]=[CH:66][N:65]=2)=[O:63])[C:40]([NH:42][C@@H:43]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:44]([N:46]2[CH2:50][C@@H:49]3[CH2:51][CH2:52][CH2:53][C@@H:48]3[C@H:47]2[C:54](O)=[O:55])=[O:45])=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.N[C@@H](CCC)C(O)C(NC1CC1)=O>CN(C=O)C.C(OCC)(=O)C>[CH:33]1([C@H:39]([NH:61][C:62]([C:64]2[CH:69]=[N:68][CH:67]=[CH:66][N:65]=2)=[O:63])[C:40]([NH:42][C@@H:43]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:44]([N:46]2[CH2:50][C@@H:49]3[CH2:51][CH2:52][CH2:53][C@@H:48]3[C@H:47]2[C:54]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]2[CH2:8][CH2:9]2)=[O:5])=[O:55])=[O:45])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1

Participants

10

Reactant 7

HCID 7912DiisopropylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide2×HCID 80170N-HydroxysuccinimideHCID 27960291-Hydroxybenzotriazole hydrateHCID 23634852(1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta(c)pyrrole-1-carboxylic acidHCID 23634853(3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamideHCID 66656935Hexanamide, 3-amino-N-cyclopropyl-2-hydroxy-, hydrochloride (1:1), (3S)-

Product 1

HCID 23634854Telaprevir, (alpha-ketoamide bond reduced)-

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

The title compound is prepared from the hydroxy-amino amide product of Step g by condensation with the appropriate acid in the presence of a coupling reagent such as, e.g., EDCI and HOSu. Specifically, in a flask containing 1.2 eq. of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1.59 g) in 20 mL of DMF, is added 2.5 eq. of diisopropylamine (980 uL), 1.2 eq. N-hydroxybenzotriazole hydrate (411 mg) and 1.3 eq. of EDCI (558 mg). After 15 minutes of stirring at the room temperature, 1.0 eq. of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (500 mg) is added to the mixture. After another 24 hours, the reaction mixture is diluted into 400 mL of ethyl acetate. The organic phase of the mixture is washed with HCl (1N), water, saturated sodium bicarbonate solution, brine, and then dried over MgSO4. The crude product is purified by chromatography on silica (ethyl acetate 70-100% in Hexanes) to give the tile compound.

Workup

  1. additionis added to the mixture
  2. washThe organic phase of the mixture is washed with HCl (1N), water, saturated sodium bicarbonate solution, brine
  3. dry with materialdried over MgSO4
  4. customThe crude product is purified by chromatography on silica (ethyl acetate 70-100% in Hexanes)
  5. customto give the tile compound

Sources & evidence

ORD record
ord-14f30c26ba11478ba8b90b3dbf48510c
Source dataset
uspto-grants-2013_02
Patent number
US08383858B2

Reaction notes

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