Azetidine → HCID 178508591, compound

HRID 422672Notes

Reaction equation

HRID 422672 reaction equation
[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:30][C@H:29]([CH2:31]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:43]1[CH2:46][CH2:45][CH2:44]1>C1COCC1>[N:43]1([CH2:31][C@H:29]2[CH2:30][C@H:27]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)=[CH:9]3)[CH2:28]2)[CH2:46][CH2:45][CH2:44]1

Participants

4

Reactant 2

HCID 10422Azetidine2×HCID 178427767HCID 178427767, compound

Product 1

HCID 178508591HCID 178508591, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of toluene-4-sulfonic acid trans-3-[4-amino-5-(2-phenylquinolin-7-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester and azetidine (0.30 mL, 254 mg, 4.5 mmol) in THF (4 mL) was heated in a sealed tube to 50° C. overnight. More azetidine (0.30 mL, 254 mg, 4.5 mmol) was added, and heating was continued overnight. THF was evaporated, water and saturated NaHCO3 solution were added, the mixture was extracted with CH2Cl2 (5×20 mL), and the combined CH2Cl2 extracts were washed with water and brine and dried over MgSO4. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-9)→5% MeOH in CH2Cl2 (10-31)→6.6% MeOH in CH2Cl2 (32-55)→6.6% MeOH in CH2Cl2+NH3 (0.05 M) (56-86)], yielding the title compound as a highly viscous yellow oil. This oil was dissolved in CDCl3 (0.7 mL), tBuOMe was added, and the off-white precipitate was filtered off and dried in vacuo yielding the desired product. 1H NMR (CDCl3, 400 MHz) δ 2.15 (quint, J=7.2 Hz, 2H), 2.33-2.54 (m, 4H), 2.57-2.70 (m, 3H), 2.73 (d, J=7.4 Hz, 2H), 3.33 (t, J=7.2 Hz, 4H), 5.26 (brs, 2H), 5.44 (quint, J=8.1 Hz, 1H), 7.37 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.7, 8.3 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.28-8.31 (m, 1H), 8.35 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 17.73 (−), 27.06 (+), 33.60 (2C, −), 46.72 (+), 55.51 (2C, −), 63.99 (−), 101.05 (Cquart), 116.12 (Cquart), 118.85 (+), 120.57 (+), 125.86 (Cquart), 127.29 (+), 127.45 (2C, +), 128.18 (+), 128.34 (+), 128.76 (2C, +), 129.41 (+), 136.31 (Cquart), 136.46 (+), 139.30 (Cquart), 148.38 (Cquart), 150.73 (Cquart), 151.83 (+), 157.07 (Cquart), 157.95 (Cquart). MS (ES+): m/z 461.2 (11) [MH+], 338.2 (14) [MH+−C4H5CH2azetidine]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).

Workup

  1. temperatureheating
  2. customTHF was evaporated
  3. additionwater and saturated NaHCO3 solution were added
  4. extractionthe mixture was extracted with CH2Cl2 (5×20 mL)
  5. washthe combined CH2Cl2 extracts were washed with water and brine
  6. dry with materialdried over MgSO4
  7. customThe crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge
  8. washeluting with CH2Cl2 (1-9)

Sources & evidence

ORD record
ord-aea6b52c4bc94f6a81ed1587dd3633af
Source dataset
uspto-grants-2012_01
Patent number
US08101613B2

Reaction notes

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