Acetic Acid → 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

HRID 511685Notes

Reaction equation

HRID 511685 reaction equation
[NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:36]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CO.C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[O:42])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 677747277-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineHCID 67774851Benzyl 3-(3-oxocyclobutyl)propanoate

Product 1

HCID 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)propanoateYield 71.2%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
30 °C

Procedure

A solution of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 g, 43.91 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (12.2 g, 52.69 mmol) and HOAc (15 mL) in DCE (200 mL) was stirred at 30° C. for 3 h. NaBH(OAc)3 (18.6 g, 87.81 mmol) was added and the reaction mixture was stirred at 30° C. for another 1 h. The mixture was washed with water (100 mL×2) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using EA:DCM:MeOH=10:10:1 as eluent to afford the desired compound (21 g, yield: 65%, cis/trans=52/47) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.16 (brs, 1H), 7.36-7.29 (m, 5H), 7.22 (d, J=3.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.66 (brs, 1H), 6.54 (d, J=2.0 Hz, 1H), 6.43 (dd, J=8.5 and 2.0 Hz, 1H), 6.20 (brs, 1H), 5.41-5.39 (m, 1H), 5.08 (d, J=3.0 Hz, 1H), 4.99-4.95 (m, 1H), 4.66 (s, 2H), 4.30-4.25 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.38-3.35 (m, 0.5H), 3.11-3.06 (m, 0.5H), 2.92-2.82 (m, 2H), 2.29-2.18 (m, 3H), 2.12-2.05 (m, 0.5H), 1.90-1.68 (m, 4H), 1.63-1.61 (m, 1H), 1.60 (s, 3H), 1.38 (s, 3H), 1.35-1.28 (m, 0.5H), 1.25 (t, J=6.5 Hz, 2H), 1.15-1.12 (m, 0.5H) ppm; ESI-MS (negative mode, m/z): 670.3 [M−1]+.

Workup

  1. washThe mixture was washed with water (100 mL×2) and brine (100 mL)
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-766c44e8f5a54c4fb4ff885faf5499b9
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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