HOAt → N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3 aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide

HRID 2040733Notes

Reaction equation

HRID 2040733 reaction equation
[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:24]2)[O:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[F:67][C:68]([F:79])([F:78])[O:69][C:70]1[CH:71]=[C:72]([NH2:77])[C:73]([NH2:76])=[CH:74][CH:75]=1>C(Cl)Cl>[NH2:77][C:72]1[CH:71]=[C:70]([O:69][C:68]([F:67])([F:78])[F:79])[CH:75]=[CH:74][C:73]=1[NH:76][C:29](=[O:31])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1

Participants

6

Reactant 4

HCID 181649HOAtHCID 27739594-(Trifluoromethoxy)benzene-1,2-diamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 677751233-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid

Product 1

HCID 67777193N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3 aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamideYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.2 g, 2.91 mmol), HATU (2.17 g, 5.83 mmol) and HOAT (0.91 g, 5.83 mmol) in DCM (17 mL) were added 4-(trifluoromethoxy)benzene-1,2-diamine (1.1 g, 5.83 mmol) and TEA (2.05 mL, 14.56 mmol). The mixture was stirred at rt overnight. The mixture was diluted with DCM (50 mL) and washed with water (15 mL×3) and brine (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (40 g silica gel, start EA:DCM MeOH=10:10:0 to 10:10:8 by gradient, 40 mL/min, 50 min, 2.0 L total solvent volume) to afford the desired compound (1.0 g, yield: 60%) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.29 (s, 1H), 8.25-8.24 (m, 1H), 7.20-7.13 (m, 1H), 6.95-6.85 (m, 0.4H), 6.73 (brs, 0.8H), 6.54 (d, J=7.5 Hz, 0.8H), 6.22 (d, J=2.0 Hz, 1H), 5.60-5.55 (m, 1H), 5.03-5.00 (m, 1H), 4.40-4.35 (m, 1H), 3.40-3.35 (m, 0.3H), 3.00-2.92 (m, 0.7H), 2.70-2.47 (m, 3H), 2.36-2.28 (m, 2H), 2.20-1.80 (m, 6H), 1.76-1.66 (m, 2H), 1.60 (s, 3H), 1.40 (s, 3H), 1.26-1.16 (m, 1H) ppm; ESI-MS (m/z): 621.3 [M+1]+.

Workup

  1. washwashed with water (15 mL×3) and brine (30 mL)
  2. dry with materialThe organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by Combi-Flash (40 g silica gel, start EA:DCM MeOH=10:10:0 to 10:10:8 by gradient, 40 mL/min, 50 min, 2.0 L total solvent volume)

Sources & evidence

ORD record
ord-374637d7643247c496bfa1c5955b9b9d
Source dataset
uspto-grants-2013_11
Patent number
US08580762B2

Reaction notes

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