Methanol → Trifluoroacetic acid

HRID 1471161Notes

Reaction equation

HRID 1471161 reaction equation
CN([C:4]([O:8]N1N=NC2C=CC=NC1=2)=[N+:5](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26].[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]1[NH:41][C:40]2[CH:42]=[C:43]([C:46]3[CH:55]=[CH:54][C:53]4[C:48](=[CH:49][CH:50]=[C:51]([C:56]5[NH:60][C:59]([C@@H:61]6[CH2:65][CH2:64][CH2:63][NH:62]6)=[N:58][CH:57]=5)[CH:52]=4)[CH:47]=3)[CH:44]=[CH:45][C:39]=2[N:38]=1.C(N([CH:72]([CH3:74])[CH3:73])CC)(C)C.[CH3:75][O:76][C:77]([NH:79][C@@H:80]([CH:84]([CH3:86])[CH3:85])[C:81](O)=[O:82])=[O:78].[CH3:87][OH:88]>CN(C=O)C.O>[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26].[CH3:87][O:88][C:4](=[O:8])[NH:5][C@H:27]([C:25]([N:62]1[CH2:63][CH2:64][CH2:65][C@H:61]1[C:59]1[NH:58][CH:57]=[C:56]([C:51]2[CH:50]=[CH:49][C:48]3[C:53](=[CH:54][CH:55]=[C:46]([C:43]4[CH:44]=[CH:45][C:39]5[NH:38][C:37]([C@@H:33]6[CH2:34][CH2:35][CH2:36][N:32]6[C:81](=[O:82])[C@@H:80]([NH:79][C:77]([O:76][CH3:75])=[O:78])[CH:84]([CH3:86])[CH3:85])=[N:41][C:40]=5[CH:42]=4)[CH:47]=3)[CH:52]=2)[N:60]=1)=[O:26])[CH:72]([CH3:73])[CH3:74]

Participants

10

Reactant 6

HCID 887MethanolHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 58315880HCID 58315880, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 178502350HCID 178502350, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

HATU (40 mg, 0.11 mmol) was added to a mixture of a TFA salt of 2-((S)-pyrrolidin-2-yl)-6-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazole (32 mg), diisopropylethylamine (62 μL, 0.35 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19 mg, 0.106 mmol) in DMF (2 mL) and the resulting mixture was stirred at ambient conditions for 9 hours. The reaction mixture was diluted with methanol (2 mL) and water (2 mL). The volatile component was removed in vacuo and the residue was purified by reverse phase HPLC (once with water/acetonitrile 10 mM ammonium acetate and twice with water/acetonitrile 0.1% TFA) to provide a TFA salt of methyl((1S)-1-(((2S)-2-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (21 mg) as white solid. LC-MS retention time 1.17 min; Calcd. for C42H50N8O6 762.39 Found m/z 763.34 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. 1H NMR (500 MHz, MeOD) δ ppm 8.30 (s, 1H), 8.27 (s, 1H), 8.15 (d, J=8.9 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H), 8.07 (s, 1H), 7.94-8.01 (m, 3H), 7.82-7.89 (m, 2H), 5.38 (t, J=7.2 Hz, 1H), 5.31 (t, J=7.6 Hz, 1H), 4.28 (dd, J=14.5, 7.2 Hz, 2H), 4.15 (br s, 2H), 3.86-4.01 (m, 2H), 3.69 (s, 6H), 2.55-2.69 (m, 2H), 2.19-2.39 (m, 6H), 2.04-2.15 (m, 2H), 0.86-1.05 (m, 12H).

Workup

  1. customThe volatile component was removed in vacuo
  2. customthe residue was purified by reverse phase HPLC (once with water/acetonitrile 10 mM ammonium acetate

Sources & evidence

ORD record
ord-8edde340aee845f695f0016a7e1bcd44
Source dataset
uspto-grants-2015_04
Patent number
US09006455B2

Reaction notes

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