Triethylamine → N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamide

HRID 1040112Notes

Reaction equation

HRID 1040112 reaction equation
[NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:7][C:8]1[CH:9]=[C:10]([C:25]2[S:29][C:28]([C:30](O)=[O:31])=[N:27][CH:26]=2)[CH:11]=[C:12]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O.O>[OH:6][C@@H:3]([CH2:4][OH:5])[CH2:2][NH:1][C:30]([C:28]1[S:29][C:25]([C:10]2[CH:11]=[C:12]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][N:16]=3)[CH:13]=[C:8]([CH3:7])[CH:9]=2)=[CH:26][N:27]=1)=[O:31]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 2724699PyBOPHCID 6994409(2R)-3-aminopropane-1,2-diolHCID 584562975-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxylic acid

Product 1

HCID 58456310N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamideYield 82%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (2R)-3-aminopropane-1,2-diol (132 mg, L446 mmol), 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxylic acid (500 mg, 1.315 mmol), and triethylamine (0.403 mL, 2.89 mmol) in N,N-dimethylformamide (8 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (821 mg, 1.578 mmol). After 45 minutes, water (32 mL) was added to the reaction mixture and the resulting yellow solid was collected by filtration; the solid was then purified by trituration using a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration and drying in vacuo. The mother liquor from the trituration was concentrated and additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol). The combined material afforded in N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamide (487 mg 82% yield) as a yellow solid. MS ESI: [M+H]+ m/z 454.0. 1H NMR (500 MHz, d6-DMSO): δ 10.31 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.53 (t, J=5.9 Hz, 1H); 8.29 (s, 1H); 8.11 (s, 1H); 7.51 (s, 1H); 7.31 (s, 1H); 7.30 (d, J=4.9 Hz, 1H); 4.90 (d, J=5.1 Hz, 1H); 4.64 (t, J=5.7 Hz, 1H); 3.63 (m, 1H); 3.42 (m, 1H); 3.35 (m, 2H); 3.23 (m, 1H); 2.34 (s, 3H). rhSYK activity=+++

Workup

  1. filtrationthe resulting yellow solid was collected by filtration
  2. customthe solid was then purified by trituration
  3. additiona mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL)
  4. filtrationfollowed by filtration
  5. customdrying in vacuo
  6. concentrationThe mother liquor from the trituration was concentrated
  7. customadditional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol)

Sources & evidence

ORD record
ord-712d5720dfb3423dab1bad1bbc202830
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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