Methanol → [8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl]methanol

HRID 928602

Reaction equation

HRID 928602 reaction equation
[Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([CH2:20][OH:21])[CH2:13]2.C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C.ClCCl>[Br:1][C:2]1[C:10]2[C:9]([N:19]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([CH2:20][OH:21])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 454802995-Bromo-4-chlorothieno[2,3-d]pyrimidineHCID 457926978-Azabicyclo[3.2.1]octan-3-ylmethanol

Product 1

HCID 117739109[8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl]methanolYield 91.5%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

5-Bromo-4-chloro-thieno[2,3-d]pyrimidine (1.0 g, 4.0 mmol) in acetonitrile (25 mL) was treated with 8-azabicyclo[3.2.1]octan-3-ylmethanol (705 mg, 16 mmol) and potassium carbonate (2.208 g, 16 mmol) at reflux for 4 h. The reaction was then concentrated in vacuum to a gum and partitioned between ethyl acetate (100 mL) and water (50 mL). The ethyl acetate was separated, dried over sodium sulphate and concentrated in vacuum to give a yellow gum. The gum was columned on silica in a gradient of 2-8% methanol in dichloromethane on a 100 g column. The main first fraction was collected and concentrated in vacuum to a gum. The gum was triturated with diethyl ether (20 mL) and crystallized on standing for a few minutes. The diethyl ether was decanted off and the crystals dried in vacuum to yield 3 [8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl]methanol (1.297 g, 3.66 mmol, 91%). 1H NMR (CDCl3) δ: 1.42 (2H, dd, J=12 Hz, J′=4 Hz), 1.67 (2H, d, J=4 Hz), 1.82 (1H, br s), 1.98 (3H, br m), 2.48 (2H, quintet, J=4 Hz), 3.64 (2H, d, J=4 Hz), 4.7 (2H, br s), 7.32 (1H, s), 8.45 (1H, s).

Workup

  1. temperatureat reflux for 4 h
  2. concentrationThe reaction was then concentrated in vacuum to a gum
  3. custompartitioned between ethyl acetate (100 mL) and water (50 mL)
  4. customThe ethyl acetate was separated
  5. dry with materialdried over sodium sulphate
  6. concentrationconcentrated in vacuum
  7. customto give a yellow gum
  8. customThe main first fraction was collected
  9. concentrationconcentrated in vacuum to a gum
  10. customThe gum was triturated with diethyl ether (20 mL)
  11. customcrystallized
  12. waiton standing for a few minutes
  13. customThe diethyl ether was decanted off
  14. customthe crystals dried in vacuum

Sources & evidence

ORD record
ord-6a7de14c51f94896976921ed3ca4f657
Source dataset
uspto-grants-2016_03
Patent number
US09290511B2

Linked notes

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