Methanol → Osimertinib

HRID 1842639Notes

Reaction equation

HRID 1842639 reaction equation
[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[C:7]([NH2:31])=[CH:8][C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[C:10]([O:12][CH3:13])[CH:11]=1.Cl[CH2:35][CH2:36][C:37](Cl)=[O:38].[OH-].[Na+].CO>C1COCC1.O>[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:8][C:7]=1[NH:31][C:37](=[O:38])[CH:36]=[CH2:35]

Participants

7

Reactant 4

HCID 887MethanolHCID 14798Sodium HydroxideHCID 693643-Chloropropionyl chlorideHCID 78358313Mutated EGFR-IN-12×

Product 1

HCID 71496458OsimertinibYield 94%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0° C. was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65° C. for 10 h. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50° C. for 12 h to give the title compound (7.0 g, 94%) as a solid form identified herein as polymorphic Form D. 1H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d) 6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d) 8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES+ MH+ 500.26.

Workup

  1. temperatureThe resulting mixture was heated to 65° C. for 10 h
  2. temperatureThe mixture was then cooled to r.t.
  3. stirringThe resulting mixture was stirred overnight
  4. filtrationThe resulting solid was collected by filtration
  5. washwashed with water (25 mL)
  6. customdried at 50° C. for 12 h

Sources & evidence

ORD record
ord-2504213e11234d95a280e4429db7acf4
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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