Thionyl Chloride → Methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate

HRID 525425Notes

Reaction equation

HRID 525425 reaction equation
C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)[N:7]=[CH:6]2.B(Br)(Br)Br.O=S(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)[N:7]=[CH:6]2

Participants

7

Reactant 4

HCID 24386Thionyl ChlorideHCID 25134Boron tribromideHCID 516892Sodium BicarbonateHCID 68279459Methyl 1-((6-methoxyquinazolin-2-yl)methyl)piperidine-4-carboxylate

Product 1

HCID 68279500Methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylateYield 77%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of methyl 1-((6-methoxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (3.0 g, 9.5 mmol) in DCM (15 mL) was added BBr3 (9.5 mmol, 1.0 eq) at 0° C. under N2. The reaction was stirred at room temperature for 16 h. After the removal of solvent, SOCl2 (2.8 g, 0.238 mol, 1.5 eq) and MeOH (20 mL) was added at 0° C. The mixture was refluxed at 80° C. for 3 h, poured into the NaHCO3 aqueous solution and extracted with DCM (100 mL*3). The combined extracts were dried over anhydrous Na2SO4 and evaporated to dryness in vacuum. The crude product was purified by chromatography (eluting with DCM/MeOH=25/1) to give methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (1.7 g, yield: 77%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ: 10.36 (s, 1H), 9.35 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.51 (dd, J=9.2, 2.4 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 3.74 (s, 2H), 3.57 (s, 3H), 2.86˜2.84 (m, 2H), 2.27 (m, 1H), 2.16 (m, 2H), 1.77 (m, 2H), 1.56 (m, 2H); ESI-MS: m/z 302.1 ([M+1]+).

Workup

  1. additionwas added at 0° C
  2. temperatureThe mixture was refluxed at 80° C. for 3 h
  3. extractionextracted with DCM (100 mL*3)
  4. dry with materialThe combined extracts were dried over anhydrous Na2SO4
  5. customevaporated to dryness in vacuum
  6. customThe crude product was purified by chromatography (eluting with DCM/MeOH=25/1)

Sources & evidence

ORD record
ord-c52a7a55200140fd910b19c11e8e66ba
Source dataset
uspto-grants-2016_05
Patent number
US09340527B2

Reaction notes

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