Diisopropylethylamine → HCID 89832315, compound

HRID 338140Notes

Reaction equation

HRID 338140 reaction equation
[C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19](OCC3C=CC=CC=3)=O)[CH2:16][C:14]2([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:52]=[N:53]C(Cl)=[N:55][CH:56]=1>C(#N)C>[Br:35][C:31]1[CH:30]=[C:29]([C:14]23[CH2:16][N:17]([C:19]4[N:53]=[CH:52][C:51]([F:50])=[CH:56][N:55]=4)[CH2:18][CH:13]2[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:15]3)[CH:34]=[CH:33][CH:32]=1

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 85247Trimethylsilyl iodideHCID 5834662-Chloro-5-fluoropyrimidineHCID 89832292HCID 89832292, compound

Product 1

HCID 89832315HCID 89832315, compoundYield 74%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of racemic benzyl 2-benzamido-7a-(3-bromophenyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.6 g, 2.9 mmol) in acetonitrile (60 mL) is added iodotrimethylsilane (1.3 mL, 9.1 mmol). The resultant solution is stirred at ambient temperature for 3 hours and concentrated to dryness. The residue is purified by ion exchange chromatography (first elute with MeOH/CH2Cl2 (¼, 50 mL), followed by 7 N NH3 in MeOH/CH2Cl2 (¼, 50 mL)) to give after evaporation of the solvent 1.7 g of intermediate, N-[7a-(3-bromophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide. This is then dissolved in 1,4-dioxane (30 mL) and diisopropylethylamine (2.0 mL, 11 mmol) and 5-fluoro-2-chloropyrimidine (850 μL, 8.90 mmol) are added sequentially. The resulting solution is heated at 110° C. for 1 hour before additional diisopropylethylamine (1.0 mL, 5.7 mmol) is added and heating is continued for another 17 hours before it is cooled to room temperature and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with gradient of ethyl acetate/dichloromethane (0% to 30%) to give the title compound (1.1 g, 73%). ES/MS (m/z): (79Br/81Br) 512/514 (M+H).

Workup

  1. concentrationconcentrated to dryness
  2. customThe residue is purified by ion exchange chromatography (first elute with MeOH/CH2Cl2 (¼, 50 mL), followed by 7 N NH3 in MeOH/CH2Cl2 (¼, 50 mL))
  3. customto give
  4. customafter evaporation of the solvent 1.7 g of intermediate, N-[7a-(3-bromophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide
  5. dissolutionThis is then dissolved in 1,4-dioxane (30 mL)
  6. additionis added
  7. temperatureheating
  8. concentrationconcentrated to dryness
  9. customThe residue is purified by silica gel flash chromatography
  10. washeluting with gradient of ethyl acetate/dichloromethane (0% to 30%)

Sources & evidence

ORD record
ord-e859674b270044dca6fb850e011a7c8f
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

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