Diisopropylethylamine → (3RS,4R)-4-{9-Isopropyl-6-[(pyridin-3-ylmethyl)-amino]-9H-purin-2-ylamino}-2,2-dimethyl-hexan-3-ol

HRID 81450Notes

Reaction equation

HRID 81450 reaction equation
F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 115220602-fluoro-9-isopropyl-N-(pyridin-3-ylmethyl)-9H-purin-6-amineHCID 57714163(3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol

Product 1

HCID 12111413(3RS,4R)-4-{9-Isopropyl-6-[(pyridin-3-ylmethyl)-amino]-9H-purin-2-ylamino}-2,2-dimethyl-hexan-3-ol

Reagents, catalysts & solvents 1

HCID 20476217n-BuOH DMSOSolvent

Procedure

To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (52 mg, 3.41 eq, 0.36 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 7.3 mg (17%). (55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.99-1.03 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56 & 1.58 (2×d, 6H, J=6.63 & 6.79 Hz, —CH(CH3)2), 1.69-1.91 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.55 (d, 1H, J=1.74 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.76-3.87 (m, 1H, —NHCH(CH2CH3)CH(C (CH3)3)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.80-4.89 (m, 2H, —HNCH2-Pyr), 5.22-5.35 & 6.07-6.23 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.24-7.36 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (s, 1H, Pyr-H), 7.74 (d, 1H, J=7.58 Hz, Pyr-H), 8.50-8.74 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (80). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.

Workup

  1. customThe reaction mixture was placed in a preheated oil bath at 140° C.
  2. customthe solvent was evaporated in vacuo
  3. customThe residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL)
  4. extractionthe aqueous phase was extracted with more EtOAc (2×25 mL)
  5. washthe combined organic phase was washed with brine (50 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated in vacuo
  8. customThe residue was purified by gradient column chromatography on silica gel
  9. washeluted with CHCl3:MeOH (100:0→98:2)

Sources & evidence

ORD record
ord-33779ccac30e45d887b4c71ec6d2af42
Source dataset
uspto-grants-2014_09
Patent number
US08846696B2

Reaction notes

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