Methanol → Trifluoroacetic acid

HRID 625658Notes

Reaction equation

HRID 625658 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][C:50]([C:56]5[N:57]=[C:58]([C@@H:61]6[CH2:65][CH2:64][CH2:63][NH:62]6)[NH:59][CH:60]=5)=[CH:51][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]([OH:83])=O)=[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].[CH3:75][O:76][C:77]([NH:79][C@@H:80]([CH:84]([CH3:86])[CH3:85])[C:81]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]1[NH:38][C:39]2[CH:45]=[CH:44][C:43]([C:46]3[CH:47]=[C:48]4[C:53]([CH:52]=[CH:51][C:50]([C:56]5[N:57]=[C:58]([C@@H:61]6[CH2:65][CH2:64][CH2:63][N:62]6[C:25]([C@@H:27]([NH:5][C:4](=[O:8])[O:88][CH3:87])[CH:72]([CH3:73])[CH3:74])=[O:31])[NH:59][CH:60]=5)=[CH:49]4)=[CH:54][CH:55]=3)=[CH:42][C:40]=2[N:41]=1)=[O:83])=[O:78]

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 178419817HCID 178419817, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 178502352HCID 178502352, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

HATU (20 mg, 0.053 mmol) was added to a mixture of a TFA salt of 2-((S)-pyrrolidin-2-yl)-6-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazole (16 mg), diisopropylethylamine (31 μL, 0.18 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (9.3 mg, 0.053 mmol) in DMF (2 mL) and the resulting mixture was stirred at ambient 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 a reverse phase HPLC (water/acetonitrile 0.1% TFA) to provide a TFA salt of methyl ((1S)-1-(((2S)-2-(4-(7-(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 (7.9 mg) as white solid. LC-MS retention time 1.20 min; calcd. for C42H50N8O6 762.39. found m/z 763.35 [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 8.35 (s, 1H), 8.25 (s, 1H), 8.09 (dd, J=8.4, 3.2 Hz, 2H), 8.04 (s, 1H), 7.89-8.00 (m, 3H), 7.77-7.87 (m, 2H), 5.37 (t, J=7.0 Hz, 1H), 5.30 (t, J=7.3 Hz, 1H), 4.28 (dd, J=15.4, 7.2 Hz, 2H), 4.08-4.20 (m, 2H), 3.86-4.01 (m, 2H), 3.69 (s, 6H), 2.56-2.68 (m, 3H), 2.39-2.02 (m, 7H), 0.87-1.04 (m, 12H).

Workup

  1. customThe volatile component was removed in vacuo
  2. customthe residue was purified by a reverse phase HPLC (water/acetonitrile 0.1% TFA)

Sources & evidence

ORD record
ord-36341282617249df85f481bdcd69cd5c
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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