Isopropyl iodide → benzyl 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)propanoate

HRID 511686Notes

Reaction equation

HRID 511686 reaction equation
[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][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][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.I[CH:51]([CH3:53])[CH3:52].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][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:51]([CH3:53])[CH3:52])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1

Participants

5

Reactant 3

HCID 6362Isopropyl iodideHCID 11430Potassium CarbonateHCID 67776180benzyl 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)amino)cyclobutyl)propanoate

Product 1

HCID 67776124benzyl 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)propanoateYield 71%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of benzyl 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)amino)cyclobutyl)propanoate (4 g, 5.95 mmol), 2-iodopropane (6 g, 35.72 mmol) and K2CO3 (2.5 g, 17.86 mmol) in CH3CN (50 mL) was stirred at reflux for 2 days. The mixture was cooled to rt, filtered and the filtered cake was washed with CH3CN (20 mL). The filtrate was concentrated and the residue was purified by Combi-Flash (80 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:1 by gradient, 60 mL/min, 40 min, 2.4 L total solvent volume) to afford the desired compound (3 g, yield: 71%) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.15 (s, 1H), 7.38-7.29 (m, 5H), 7.19 (d, J=4.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.65 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 6.41 (dd, J=8.5 and 2.0 Hz, 1H), 6.20 (d, J=2.5 Hz, 1H), 5.36-5.32 (m, 1H), 5.09 (s, 1H), 5.07 (s, 1H), 4.94-4.89 (m, 3H), 4.65 (s, 2H), 4.17-4.14 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.41-3.35 (m, 0.5H), 3.04-2.95 (m, 0.5H), 2.94-2.86 (m, 1H), 2.72-2.52 (m, 2H), 2.25 (t, J=7.5 Hz, 1H), 2.21 (t, J=8.0 Hz, 1H), 2.05-1.90 (m, 2H), 1.90-1.82 (m, 0.5H), 1.76-1.70 (m, 0.5H), 1.65-1.55 (m, 5H), 1.42-1.34 (m, 4H), 0.95 (d, J=6.5 Hz, 3H), 0.83-0.80 (m, 3H) ppm; ESI-MS (m/z): 714.4 [M+1]+.

Workup

  1. temperatureat reflux for 2 days
  2. filtrationfiltered
  3. washthe filtered cake was washed with CH3CN (20 mL)
  4. concentrationThe filtrate was concentrated
  5. customthe residue was purified by Combi-Flash (80 g silica gel, start EA:DCM:MeOH=10:10:0 to 10:10:1 by gradient, 60 mL/min, 40 min, 2.4 L total solvent volume)

Sources & evidence

ORD record
ord-debe70c8bdbf42f3945070420bc62dff
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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