L-Alanine → 2-{{2-Chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-phenyl}imino}-alpha-methyl-4-oxo-3-thiazolidineacetic acid

HRID 380794Notes

Reaction equation

HRID 380794 reaction equation
[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C1C=C2[CH:13]([CH2:20][O:21]C(NCC=O)=O)C3C(C2=CC=1)=CC=CC=3.N1CCCCC1.[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([N:42]2[C:47](=[O:48])[CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[N:44]([CH3:53])[C:43]2=[O:54])=[CH:37][C:36]=1[N:55]=[C:56]=[S:57].BrCC(OC)=O.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)Cl.CO>[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([N:42]2[C:47](=[O:48])[CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[N:44]([CH3:53])[C:43]2=[O:54])=[CH:37][C:36]=1[N:55]=[C:56]1[N:1]([CH:2]([CH3:3])[C:4]([OH:6])=[O:5])[C:20](=[O:21])[CH2:13][S:57]1

Participants

10

Reactant 6

HCID 5950L-AlanineHCID 8082PiperidineHCID 60984Methyl bromoacetateHCID 81531DiisopropylethylamineHCID 10858926(9H-Fluoren-9-yl)methyl 2-oxoethylcarbamateHCID 183659632-Chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-phenyl isothiocyanate

Product 1

HCID 183659022-{{2-Chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-phenyl}imino}-alpha-methyl-4-oxo-3-thiazolidineacetic acid

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

An alanine substituted resin (1.0 mmol) which is N-protected with Fmoc and supported on polystyrene (commercially available as Fmoc-gly-Wang resin from Midwest Bio-tech Inc., Fishers, Ind.) is treated with a 20% piperdine in N,N-dimethylformamide solution to remove the Fmoc protecting group. The solvents are removed and the resin is washed with N,N-dimethylformamide, methanol and methylene chloride, treated with a solution of 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl isothiocyanate (0.57 g, 1.5 mmol) in methylene chloride, and stirred at room temperature for 6 hours. The solvents are removed and the resin is washed with N,N-dimethylformamide, methanol and methylene chloride, diluted with N,N-dimethylformamide, treated with methyl bromoacetate (0.46 g, 3 mmol) and N,N-diisopropylethylamine (1 ml), and stirred overnight at room temperature. The solvents are removed and the resultant resin is washed sequentially with N,N-dimethylformamide, methanol and methylene chloride, air-dried, and cleaved with trifluoroacetic acid. Column chromatography of the resultant reaction mixture using silica gel and a 15% methanol in methylene chloride solution gives the title product (0.55 g) which is identified by 1H and 13C NMR spectral analyses.

Workup

  1. customto remove the Fmoc protecting group
  2. customThe solvents are removed
  3. washthe resin is washed with N,N-dimethylformamide, methanol and methylene chloride
  4. customThe solvents are removed
  5. washthe resin is washed with N,N-dimethylformamide, methanol and methylene chloride
  6. additiondiluted with N,N-dimethylformamide
  7. stirringstirred overnight at room temperature
  8. customThe solvents are removed
  9. washthe resultant resin is washed sequentially with N,N-dimethylformamide, methanol and methylene chloride
  10. customair-dried
  11. customColumn chromatography of the resultant reaction mixture

Sources & evidence

ORD record
ord-8d6562bffd874d7884e285893fa48952
Source dataset
uspto-grants-2001_10
Patent number
US06303783B1

Reaction notes

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