4-(2-Chloroethyl)morpholine → HCID 46893003, compound

HRID 1801926Notes

Reaction equation

HRID 1801926 reaction equation
ClCCN1CCOCC1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([OH:67])[C:36]2[N:45]=[C:44]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[C:43]3[C:38](=[CH:39][C:40]([O:53][CH:54]4[CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56][CH2:55]4)=[CH:41][CH:42]=3)[N:37]=2)=[CH:31][CH:30]=1.Cl.O1CCOCC1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]([C:36]2[N:45]=[C:44]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[C:43]3[C:38](=[CH:39][C:40]([O:53][CH:54]4[CH2:55][CH2:56][NH:57][CH2:58][CH2:59]4)=[CH:41][CH:42]=3)[N:37]=2)[OH:67])=[CH:33][CH:34]=1

Participants

5

Reactant 4

HCID 767274-(2-Chloroethyl)morpholineHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidineHCID 204431481,4-Dioxane hydrochlorideHCID 66617266HCID 66617266, compound

Product 1

HCID 46893003HCID 46893003, compoundYield 21%

Procedure

Intermediate compound (R,S)-tert-butyl 4424(4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate was obtained (105 mg) following the procedure described in Example 38 for the synthesis of (R,S)-(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholinoethoxy)quinazolin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 with tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate. To the crude tert-butyl 4-(2-((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate (100 mg, 18.2 mmol) in a flask at 0° C. was added 4N HCl/dioxane (5 mL). After stirring for 20 h, the solvent was removed and the residue was shaken with DCM and aq sodium bicarbonate. The solvents were removed, and the remaining residue was extracted with MeOH/DCM. The extracts were concentrated and the residue was chromatographed on reverse phase HPLC to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(piperidin-4-yloxy)quinazolin-2-yl)methanol as a white solid (32 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 2 H) 1.89 (s, 13 H) 1.89 (s., 3 H) 1.98 (m, 2 H) 2.68 (m, 2 H) 2.99 (m, 2 H) 4.66 (m, 4 H) 5.62 (s, 1 H) 5.76 (s, 1 H) 6.36 (b., 1 H) 7.08-7.18 (m, 4 H) 7.52 (m, 2 H) 8.45 (m., 1H), 10.29 (bs, 1H). LC-MS (ESI) m/z 449 (M+H)+.

Workup

  1. customthe solvent was removed
  2. stirringthe residue was shaken with DCM and aq sodium bicarbonate
  3. customThe solvents were removed
  4. extractionthe remaining residue was extracted with MeOH/DCM
  5. concentrationThe extracts were concentrated
  6. customthe residue was chromatographed on reverse phase HPLC

Sources & evidence

ORD record
ord-b0778aa2dcfd4b0299eaf8442cc10cd9
Source dataset
uspto-grants-2013_01
Patent number
US08349851B2

Reaction notes

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