3-Amino-1-propanol → 4-[7-(3-Methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 657240Notes

Reaction equation

HRID 657240 reaction equation
[NH2:1][CH2:2][CH2:3][CH2:4][OH:5].CC([O-])(C)C.[K+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31](F)=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl.C(Cl)Cl.CC(C)=O.COCCOC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]

Participants

9

Reactant 5

HCID 90863-Amino-1-propanolHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 23665647Potassium tert-butoxideHCID 595517364-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 595516844-[7-(3-Methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl esterYield 79.3%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolventHCID 21584124Propan-2-one--dichloromethane (1/1)Solvent

Procedure

A mixture of 3-amino-propan-1-ol (37.9 mg, 505 μmol), t-BuOK (63.1 mg, 563 μmol), and DME (505 μL) was stirred for 5 min at rt until a homogeneous yellow solution resulted. Solid 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (170.7 mg, 516 μmol), as prepared in the previous step, was added in one portion under air at “rt” (vial spontaneously warmed), and the resulting homogeneous amber solution was stirred at rt 1 h. The reaction was then diluted with DCM (1.0 mL) and stirred at 0° C. for 5 min before adding MsCl (48 μL, 620 μmol) dropwise with stirring at 0° C. over 1 min. After 1 min additional stirring at 0° C., the ice bath was removed and the hazy yellow solution was stirred at “rt” for 5 min. DIEA (94 μL, 568 μmol) was then added dropwise, and the reaction was stirred rt 2 days. The crude reaction was then loaded directly onto a flash silica column (4:3 DCM/acetone eluent) to provide the title compound as an off-white foam (186 mg, 79%). 1H-NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.06 (d, 1H), 7.32 (d, 1H), 7.24 (m, 1H), 4.47 (br t, 1H), 4.32 (br s, 2H), 4.26 (t, 2H), 3.61 (m, 1H), 3.43 (q, 2H), 2.99-2.89 (m, 2H), 2.98 (s, 3H), 2.17 (pentet, 1H), 2.10-1.94 (m, 2H), 1.92-1.83 (m, 2H), 1.49 (s, 9H). LC/MS (ESI): calcd mass 464.2, found 465.2 (MH)+.

Workup

  1. customresulted
  2. additionwas added in one portion under air at “rt” (vial
  3. temperaturespontaneously warmed), and the resulting homogeneous amber solution
  4. stirringwas stirred at rt 1 h
  5. stirringstirred at 0° C. for 5 min
  6. stirringwith stirring at 0° C. over 1 min
  7. stirringAfter 1 min additional stirring at 0° C.
  8. customthe ice bath was removed
  9. stirringthe hazy yellow solution was stirred at “rt” for 5 min
  10. stirringthe reaction was stirred rt 2 days
  11. customThe crude reaction

Sources & evidence

ORD record
ord-758e0f074ea24426972370e02be6f04d
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

Loading…