HOAt → N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanamide

HRID 511688Notes

Reaction equation

HRID 511688 reaction equation
[CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.FC(F)(F)O[C:49]1[CH:50]=[C:51]([NH2:56])[C:52]([NH2:55])=[CH:53][CH:54]=1.CN(C(ON1N=NC2[CH:70]=[CH:71][CH:72]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:83]1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:56][C:51]1[CH:50]=[C:49]([C:71]([CH3:70])([CH3:72])[CH3:83])[CH:54]=[CH:53][C:52]=1[NH:55][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH:37]([CH3:39])[CH3:38])[CH2:31]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 677769633-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid

Product 1

HCID 67775308N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanamideYield 67%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (2.7 g, 4.33 mmol), 4-(trifluoromethoxy)benzene-1,2-diamine (1.23 g, 6.49 mmol), HATU (2.5 g, 6.49 mmol) and HOAT (0.88 g, 6.49 mmol) in DCM (30 mL) was added TEA (1.8 mL, 12.99 mmol). The mixture was stirred at rt for 2 h. The mixture was added DCM (70 mL) and washed with water (20 mL×2) and brine (50 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (80 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:2 by gradient, 60 mL/min, 40 min, 2.4 L total solvent volume) to afford to afford the desired compound (2.2 g, yield: 67% (two steps) as a brown solid. 1H NMR (500 MHz, MeOD): δH 8.21 (s, 1H), 7.28-7.12 (m, 3H), 6.73 (brs, 1H), 6.69 (brs, 1H), 6.56-6.52 (m, 2H), 6.42 (dd, J=8.0 and 2.5 Hz, 1H), 6.26 (d, J=1.5 Hz, 1H), 5.48 (d, J=6.0 Hz, 1H), 5.20-5.16 (m, 1H), 4.66 (s, 2H), 4.46-4.42 (m, 1H), 4.08-3.98 (m, 0.5H), 3.84 (s, 3H), 3.76 (s, 3H), 3.75-3.69 (m, 0.5H), 3.60-3.38 (m, 2H), 2.60-2.30 (m, 3H), 1.92-1.86 (m, 1H), 1.80-1.70 (m, 1H), 1.59 (d, J=3.5 Hz, 3H), 1.40 (s, 3H), 1.25 (t, J=7.5 Hz, 3H),), 1.00-0.80 (m, 2H) ppm; ESI-MS (m/z): 798.3 [M+1]+.

Workup

  1. washwashed with water (20 mL×2) and brine (50 mL)
  2. dry with materialThe organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by Combi-Flash (80 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:2 by gradient, 60 mL/min, 40 min, 2.4 L total solvent volume)
  6. customto afford

Sources & evidence

ORD record
ord-ebe947f4c3b9499db432f144d8b611de
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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