Diisopropylethylamine → Trifluoroacetic acid

HRID 410587Notes

Reaction equation

HRID 410587 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:10][CH:9]=2)[CH:7]=1.[N:30]1(C(OC(C)(C)C)=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25]([C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:16])([F:17])[F:15])=[N:10][CH:9]=2)[CH:7]=1.[C:13]([OH:19])([C:14]([F:17])([F:16])[F:15])=[O:37]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 143452tert-Butyl piperazine-1-carboxylateHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 58456124HCID 58456124, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 58456264[2-({3-Methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)-pyrimidin-4-yl](piperazin-1-yl)methanone

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To 2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)-pyrimidine-4-carboxylic acid (Example 68, 68.9 mg, 0.162 mmol) in a scintillation vial was added DMF (812 μL), tert-butyl piperazine-1-carboxylate (33.4 mg, 0.179 mmol), DIPEA (85 μL, 0.487 mmol) and BOP (108 mg, 0.244 mmol). The reaction was stirred at room temperature for 1 hour before being diluted with water and dichloromethane. The organic was dried over sodium sulfate, filtered and concentrated to dryness. The resultant residue was purified by normal phase chromatography (10% MeOH in DCM: hexanes, 10-100%, linear gradient). Boc deprotection was carried out on the isolated material with 1:1 TFA:dichloromethane (1 mL) at room temperature. Upon completion the reaction was concentrated to dryness and was directly purified by reverse phase chromatography (10-80% MeCN in water, linear gradient) to yield [2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)-pyrimidin-4-yl](piperazin-1-yl)methanone as a TFA salt. MS ESI: [M+H]+ m/z 493.1. 1H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.87 (s, 2H), 8.67 (d, J=4.8, 1H), 8.08 (s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.00 (s, 1H), 3.82 (s, 2H), 3.67 (s, 2H), 3.21 (s, 2H), 3.08 (s, 2H), 2.33 (s, 3H), 1.76 (s, 3H). rhSYK activity=+++

Workup

  1. dry with materialThe organic was dried over sodium sulfate
  2. filtrationfiltered
  3. concentrationconcentrated to dryness
  4. customThe resultant residue was purified by normal phase chromatography (10% MeOH in DCM: hexanes, 10-100%, linear gradient)
  5. customat room temperature
  6. concentrationUpon completion the reaction was concentrated to dryness
  7. customwas directly purified by reverse phase chromatography (10-80% MeCN in water, linear gradient)

Sources & evidence

ORD record
ord-6e74ab23ae5041258fa1925256b88285
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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