Trifluoroacetic acid → (S)-1-(4-(2-(5-((4-(2-amino-3-methylbutanoyl)piperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylurea

HRID 1400816Notes

Reaction equation

HRID 1400816 reaction equation
[CH:1]1([NH:4][C:5](=[O:51])[NH:6][C:7]2[CH:49]=[CH:48][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([C:34](=[O:47])[C@@H:35]([NH:39]C(=O)OC(C)(C)C)[CH:36]([CH3:38])[CH3:37])[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:50])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[OH-:11].[NH4+:4].[NH2:39][C@@H:35]([CH:36]([CH3:38])[CH3:37])[C:34]([N:31]1[CH2:30][CH2:29][N:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:13]4[C:14](=[N:15][CH:16]=[CH:17][C:12]=4[O:11][C:10]4[CH:48]=[CH:49][C:7]([NH:6][C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)=[O:51])=[CH:8][C:9]=4[F:50])[CH:18]=3)=[N:26][CH:25]=2)[CH2:33][CH2:32]1)=[O:47]

Participants

6

Reactant 2

HCID 6422Trifluoroacetic acidHCID 67442183(S)-tert-butyl 1-(4-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)piperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Product 2

HCID 14923Ammonium HydroxideYield 2%HCID 68224013(S)-1-(4-(2-(5-((4-(2-amino-3-methylbutanoyl)piperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylureaYield 149.6%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of 75 (171 mg, 0.238 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at RT for 2 h. The TFA was removed by co-evaporation with DCM, diluted with a minimum of water, and the pH was adjusted to around 10 with a saturated aqueous solution of sodium bicarbonate and a few drops of 1N NaOH at the end. The resultant suspension was sonicated for 15 min. The solid was collected by filtration, rinsed with water and dried under high vacuum. The crude product was purified by Biotage (SiliaFlash 12 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 5/95 to 15/85 over 20 CV, then 15/85 to 20/80 over 10 CV), to afford the title compound 76 (110 mg, 0.178 mmol, 74% yield) as a white sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.52 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.88 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.21 (bd, J=8.8 Hz, 1H), 6.65 (d, J=5.3 Hz, 1H), 6.61 (bd, J=2.5 Hz, 1H), 3.59 (s, 2H), 3.54-3.42 (m, 5H), 2.59-2.51 (m, 1H), 2.48-2.28 (m, 4H), 2.20-1.80 (m, 2H), 1.74-1.62 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H), 0.73-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 519.6 and 618.7 (M+H).

Workup

  1. customThe TFA was removed by co-evaporation with DCM
  2. additiondiluted with a minimum of water
  3. customThe resultant suspension was sonicated for 15 min
  4. filtrationThe solid was collected by filtration
  5. washrinsed with water
  6. customdried under high vacuum
  7. customThe crude product was purified by Biotage (SiliaFlash 12 g cartridge

Sources & evidence

ORD record
ord-1cbad35ed8bc4bbbaf9092eaba463a4c
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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