Hydrochloric Acid → HCID 118436372, compound

HRID 1775467Notes

Reaction equation

HRID 1775467 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C@:23]4([CH3:35])[CH2:27][CH2:26][N:25]([C:28](OC(C)(C)C)=[O:29])[CH2:24]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)=[CH:4][N:3]=1.Cl.O1CCOCC1.C[CH2:44][N:45](C(C)C)C(C)C.CN=C=O.C([O-])(O)=O.[Na+]>CO.C1(C)C=CC=CC=1.CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C@:23]4([CH3:35])[CH2:27][CH2:26][N:25]([C:28]([NH:45][CH3:44])=[O:29])[CH2:24]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)=[CH:6][N:7]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 12228Methyl Isocyanate2×HCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 118436652HCID 118436652, compound

Product 1

HCID 118436372HCID 118436372, compoundYield 68%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 1140TolueneSolvent

Procedure

To a solution of tert-butyl(3R)-3-[4-(2-aminopyrimidin-5-yl)-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (150 mg, 0.311 mmol) in MeOH (1.5 mL) was added 4 N HCl in dioxane (1.5 mL, 6 mmol), and the mixture was stirred at room temperature for 45 min. The mixture was diluted with toluene and concentrated under reduced pressure. The residue was triturated again with toluene to give a yellow foam. To a solution of this residue in DMSO (3 mL) was added DIPEA (0.25 mL, 1.43 mmol) and methyl isocyanate (0.021 mL, 0.342 mmol), and the mixture was stirred for 45 min. Another portion of methylisocyanate (0.005 mL) was added and the mixture was stirred at room temperature for 18 h. The mixture was dropped into 50% saturated NaHCO3 (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% (MeOH with 10% NH4OH)/(EtOAC/DCM, 1:1) as eluent. The desired fractions were concentrated to a minimum volume and the residue was taken up in MeOH/water and lyophilized to give 93 mg (68%) of the title compound as a white solid. 1H NMR (600 MHz, 80° C., DMSO-d6) δ 8.72 (s, 2 H), 6.59 (br s, 2 H), 5.72 (br d, J=3.7 Hz, 1 H), 3.75 (d, J=10.6 Hz, 1 H), 3.71-3.50 (m, 11 H), 3.41-3.24 (m, 2 H), 3.08 (t, J=8.2 Hz, 2H), 2.60 (d, J=4.5 Hz, 3 H), 2.48-2.43 (m, 1H, partially overlapped with DMSO), 2.14-2.05 (m, 1 H), 1.34 (s, 3 H). m/z (APCI+) for C21H29N9O2 440.2 (M+H)+.

Workup

  1. concentrationconcentrated under reduced pressure
  2. customThe residue was triturated again with toluene
  3. customto give a yellow foam
  4. stirringthe mixture was stirred for 45 min
  5. stirringthe mixture was stirred at room temperature for 18 h
  6. extractionextracted with EtOAc (3×)
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel chromatography
  10. concentrationThe desired fractions were concentrated to a minimum volume

Sources & evidence

ORD record
ord-436a4240f86c409e9cc9f70c46dcf439
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

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