Tris(hydroxymethyl)aminomethane → 5-[1-(3,4-Difluorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine

HRID 1015336Notes

Reaction equation

HRID 1015336 reaction equation
[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br.C(O)C(N)(CO)CO>CN(C)C=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 79724-MethylmorpholineHCID 5814364-(Bromomethyl)-1,2-difluorobenzeneHCID 575765655-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine

Product 1

HCID 250077855-[1-(3,4-Difluorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamineYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at 60° C. in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzyl bromide (77 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield 5-[1-(3,4-difluorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine (30 mg; 42% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.61 (m, 2H), 7.34 (m, 2H), 7.14 (m, 2H), 6.76 (m, 1H), 6.52 (m, 1H), 5.94 (br s, 2H), 3.99 (d, J=6.0 Hz, 2H), 3.46 (s, 3H), 3.12 (m, 1H), 2.82 (br d, J=10.8 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 2H), 1.73 (br d, J=11.2 Hz, 1H), 1.34 (m, 1H). MS m/z (ESI) 400 (M+H)+.

Workup

  1. filtrationResins were filtered off
  2. washrinsed with methanol
  3. concentrationFiltrate was concentrated at reduced pressure, and residue
  4. customwas triturated with 2 mL 1 N NaOH and ethanol (1:1)
  5. filtrationSolids were collected by filtration

Sources & evidence

ORD record
ord-663fc5c7605d4ef899db475baada6a83
Source dataset
uspto-grants-2011_07
Patent number
US07985755B2

Reaction notes

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