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Diisopropylethylamine → Daclatasvir metabolite 4

HRID 237930
Notes
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Reaction equation

HRID 237930 reaction equation
[CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.[NH:44](C(OCC1C=CC=CC=1)=O)[C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO.[Pd]>[NH2:44][C@@H:45]([CH:46]([CH3:48])[CH3:47])[C:49]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]1[NH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[NH:11][C:10]([C@@H:6]5[CH2:7][CH2:8][CH2:9][N:5]5[C:4](=[O:37])[C@@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:2]([CH3:43])[CH3:1])=[N:14][CH:13]=4)=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[CH:28][N:29]=1)=[O:50]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 726987N-Carbobenzoxy-L-valineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59668805Monodes(N-carboxymethyl)valine Daclatasvir

Product 1

HCID 24897982
Daclatasvir metabolite 4
Yield 77.5%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-12) (1.16 g, 1.99 mmol), Z-Val-OH (0.712 g, 2.83 mmol) and iPr2NEt (0.70 mL, 5.42 mmol) in DMF (40 mL) was added HATU (1.10 g, 2.89 mmol) portionwise. The mixture was allowed to stir at room temperature for 1 h and was then poured into ice-water (400 mL) and allowed to stand for 20 min. The mixture was filtered and the solid washed with cold water and allowed to air dry overnight to give the Z-protected intermediate. LCMS: Anal. Calcd. for C46H54N8O6: 814. found: 815 (M+H)+. The obtained solid was dissolved in MeOH (80 mL), 10% Pd—C (1.0 g) was added and the mixture was hydrogenated at room temperature and atmospheric pressure for 3 h. The mixture was then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2/5-20% MeOH—CH2Cl2) to afford the title compound (1.05 g, 77%) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.75-7.79 (m, 3H), 7.61-7.67 (m, 5H), 7.49 (s, 1H), 7.26-7.28 (m, 1H), 5.05-5.09 (m, 2H), 4.03-4.09 (m, 2H), 3.77-3.80 (m, 1H), 3.66-3.70 (m, 1H), 3.52 (s, 3H), 3.40-3.47 (m, 2H), 2.21-2.26 (m, 1H), 2.10-2.17 (m, 3H), 1.81-2.02 (m, 6H), 0.77-0.92 (m, 12H). LCMS: Anal. Calcd. for C38H48N8O4: 680. found: 681 (M+H)+.

Workup

  1. waitto stand for 20 min
  2. filtrationThe mixture was filtered
  3. washthe solid washed with cold water
  4. customto air dry overnight
  5. customto give the Z-protected intermediate
  6. customwas hydrogenated at room temperature
  7. waitatmospheric pressure for 3 h
  8. filtrationThe mixture was then filtered
  9. concentrationthe filtrate concentrated in vacuo
  10. customThe resulting residue was purified by flash chromatography (SiO2/5-20% MeOH—CH2Cl2)

Sources & evidence

ORD record
ord-9d3ff749d089405b8ce300fa95211997
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08642025B2

Reaction notes

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