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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 2040732
Notes
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Reaction equation

HRID 2040732 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.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.[C:80]([C:84]1[CH:85]=[C:86]([NH2:91])[C:87]([NH2:90])=[CH:88][CH:89]=1)([CH3:83])([CH3:82])[CH3:81]>C(Cl)Cl>[NH2:91][C:86]1[CH:85]=[C:84]([C:80]([CH3:83])([CH3:81])[CH3:82])[CH:89]=[CH:88][C:87]=1[NH:90][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][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]([CH3:38])[CH3:39])[CH2:29]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 181649HOAtHCID 4327084-Tert-butylbenzene-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 67775308
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
Yield 50.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

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 (1.1 g, 1.76 mmol), HATU (1 g, 2.64 mmol), HOAT (359 mg, 2.64 mmol) in DCM (30 mL) was added a solution of 4-tert-butylbenzene-1,2-diamine (433 mg, 2.64 mmol) and TEA (533 mg, 5.28 mmol) in DCM (10 mL) dropwise, then the resultant reaction mixture was stirred at rt overnight. After diluted with DCM (50 mL), the mixture was washed water (30 mL×3), dried and concentrated. The crude was purified by SGC (DCM:MeOH=100:1 to 40:1) to afford the desired compound (680 mg, yield: 50%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.16 (s, 1H), 7.19 (d, J=3.5 Hz, 1H), 7.14-7.10 (m, 1.7H),6.99-6.97 (m, 0.6H), 6.92 (s, 0.6H), 6.77 (dd, J=8.0, 2.0 Hz, 1H), 6.66-6.65 (m, 1H), 6.54-6.53 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.20 (d, J=2.0 Hz, 1H), 5.36-5.35 (m, 1H), 4.96-4.95 (m, 1H), 4.65 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.17-2.73 (m, 4H), 2.33-1.71 (m, 8H), 1.58 (s, 3H), 1.53-1.50 (m, 1H), 1.38 (s, 3H), 1.28 (s, 9H), 1.0 (d, J=5.5 Hz, 3H), 0.84 (d, J=5.0 Hz, 3H) ppm; LC-MS (m/z): 770.0 [M+1]+.

Workup

  1. customthe resultant reaction mixture
  2. washthe mixture was washed water (30 mL×3)
  3. customdried
  4. concentrationconcentrated
  5. customThe crude was purified by SGC (DCM:MeOH=100:1 to 40:1)

Sources & evidence

ORD record
ord-933058f7fb5e446e8e49460dd8c4650f
Source dataset
uspto-grants-2013_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08580762B2

Reaction notes

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