4-Methylmorpholine → HCID 89906211, compound

HRID 1482780Notes

Reaction equation

HRID 1482780 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C@H:20]([CH3:25])[CH2:21][C:22](O)=[O:23])=[C:18]([I:26])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:40][NH:41][O:42][CH3:43].CN1CCOCC1.[Cl-].[NH4+]>O1CCCC1.O>[I:26][C:18]1[N:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[C:19]=1[C@@H:20]([CH2:21][C:22]([N:41]([O:42][CH3:43])[CH3:40])=[O:23])[CH3:25]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 25517Ammonium ChlorideHCID 682631,1'-CarbonyldiimidazoleHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 118077991HCID 118077991, compound

Product 1

HCID 89906211HCID 89906211, compoundYield 99%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

Into a solution of (R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodopyrimidin-5-yl)butanoic acid (100 g, 210 mmol) in tetrahydrofuran (700 mL) was added 1,1′-carbonyldiimidazole (40.9 g, 252 mmol) in portions. The reaction mixture was stirred at 20° C. for 1 h and cooled to 5° C. N,O-dimethylhydroxyamine hydrochloride (41.0 g, 420 mmol) was added in portions followed by N-methylmorpholine (6.94 mL, 63.0 mmol). The mixture was stirred at 5° C. for about 1 h, slowly warmed up to room temperature, and stirred for 24 h. Saturated aqueous ammonium chloride (500 mL) and water (150 mL) were added to get a clear phase separation. The organic layer was washed with saturated aqueous ammonium chloride (500 mL) and brine (200 mL). The residual water was azeotroped off to less than 500 ppm by co-evaporation with tetrahydrofuran. The product, as a solution in tetrahydrofuran was used for the next step without further purification or isolation (weight assay yield: >99%. 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 3.84 (ddq, J=9.0, 7.2, 5.1 Hz, 1H), 3.72 (s, 3H), 3.61-3.57 (m, 4H), 3.42 (dd, J=16.5, 9.0 Hz, 1H), 3.25-3.21 (m, 4H), 3.17 (s, 3H), 2.76 (dd, J=16.5, 5.1 Hz, 1H), 1.47 (s, 9H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C19H31IN5O4 [M+H]+: 520.1415. found 520.1413.

Workup

  1. temperaturecooled to 5° C
  2. stirringThe mixture was stirred at 5° C. for about 1 h
  3. temperatureslowly warmed up to room temperature
  4. stirringstirred for 24 h
  5. customto get
  6. customa clear phase separation
  7. washThe organic layer was washed with saturated aqueous ammonium chloride (500 mL) and brine (200 mL)
  8. customThe residual water was azeotroped off to less than 500 ppm by co-evaporation with tetrahydrofuran
  9. customThe product, as a solution in tetrahydrofuran was used for the next step without further purification or isolation (weight assay yield: >99%

Sources & evidence

ORD record
ord-0e57d86d30c4452fb5c6343e5c786f3f
Source dataset
uspto-grants-2016_08
Patent number
US09416110B2

Reaction notes

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