Diisopropylethylamine → N-[7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 77583

Reaction equation

HRID 77583 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:16][NH:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.[F:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]23[CH2:16][N:15]([C:31]4[N:32]=[CH:33][C:28]([F:27])=[CH:29][N:30]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 5834662-Chloro-5-fluoropyrimidineHCID 86762766N-[7a-(5-Amino-2-fluoro-phenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762771N-[7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamideYield 66.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of N-[7a-(5-amino-2-fluoro-phenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (705 mg, 1.90 mmol), 5-fluoro-2-chloropyrimidine (1.01 g, 7.61 mmol), and diisopropylethylamine (1.66 mL, 9.52 mmol) are heated in 1,4-dioxane (20 mL) to reflux for 4 hours under nitrogen. The reaction is cooled, diluted with water, and extracted with ethyl acetate (3×). The organic layers are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo to give crude product. The crude product is purified over silica gel with a 25 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (590 mg, 66%). ES/MS (m/e): 467 (M+H).

Workup

  1. temperatureto reflux for 4 hours under nitrogen
  2. temperatureThe reaction is cooled
  3. extractionextracted with ethyl acetate (3×)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. customthe solvent removed in vacuo
  7. customto give crude product
  8. customThe crude product is purified over silica gel with a 25 minute 5% to 100% ethyl acetate in hexanes gradient

Sources & evidence

ORD record
ord-bdf06a1452104d8aba101250f7b63b2c
Source dataset
uspto-grants-2014_09
Patent number
US08841293B1

Linked notes

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