Triethylamine → (5)-1-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(oxetan-3-yl)urea

HRID 72190Notes

Reaction equation

HRID 72190 reaction equation
[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]2[N:25]([CH3:26])[N:24]=[CH:23][C:10]=2[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:13]=1.C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[O:47]1[CH2:50][CH:49]([NH2:51])[CH2:48]1>ClCCCl.CCOC(C)=O>[CH3:26][N:25]1[C:9]2[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])=[N:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:35]([NH:51][CH:49]4[CH2:50][O:47][CH2:48]4)=[O:37])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:23]=[N:24]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 23062080Oxetan-3-amine hydrochlorideHCID 58222489(S)-3-methyl-4-(1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)morpholine

Product 1

HCID 51355347(5)-1-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(oxetan-3-yl)ureaYield 75.6%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of (S)-3-methyl-4-(1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)morpholine (50.0 mg, 0.154 mmol) in anhydrous 1,2-dichoroethane (5.0 mL) was added triethylamine (0.071 mL, 0.51 mmol, 3.3 eq.). The reaction was cooled to 0° C. and triphosgene (45.7 mg, 0.154 mmol, 1.0 eq) was added in one portion. After stirring at 0° C. under N2 for 5 minutes, the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to RT, and 3-oxetanamine hydrochloride (84.4 mg, 0.77 mmol, 5.0 eq.) was then added. The reaction mixture was stirred at RT under N2 for 16 h and then diluted with EtOAc (25 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by column chromotagraphy (Si-PPC, gradient 50 to 100% EtOAc in heptane, followed by 0 to 30% methanol in dichloromethane). Trituration from methanol afforded the title compound (49.3 mg, 75.5%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.76 (s, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.97 (d, J=6.7 Hz, 1H), 4.85 to 4.69 (m, 3H), 4.44 (t, J=6.0 Hz, 2H), 4.23 to 4.12 (m, 4H), 3.96 to 3.81 (m, 2H), 3.72 (dd, J=14.7 Hz, 5.8 Hz, 1H), 3.69 to 3.58 (m, 2H), 3.50 (d, J=13.3 Hz, 1H), 1.26 (d, J=6.5 Hz, 3H); LC-MS m/z (method C1)=424.2 [M+H]+, RT=3.12 min.

Workup

  1. stirringthe reaction mixture was stirred at 70° C. for 1 h
  2. temperatureThe reaction mixture was cooled to RT
  3. stirringThe reaction mixture was stirred at RT under N2 for 16 h
  4. washThe organic layer was washed with water and brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude was purified by column chromotagraphy (Si-PPC, gradient 50 to 100% EtOAc in heptane, followed by 0 to 30% methanol in dichloromethane)

Sources & evidence

ORD record
ord-c3413a6d73644ad6805a0f4fcc8e642a
Source dataset
uspto-grants-2014_09
Patent number
US08828990B2

Reaction notes

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