Methanol → Trifluoroacetic acid

HRID 625659Notes

Reaction equation

HRID 625659 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:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:57]=[CH:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([C:58]5[NH:62][C:61]([C@@H:63]6[CH2:67][CH2:66][CH2:65][NH:64]6)=[N:60][CH:59]=5)[CH:54]=4)[CH:49]=3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1.C(N([CH:74]([CH3:76])[CH3:75])CC)(C)C.[CH3:77][O:78][C:79]([NH:81][C@@H:82]([CH:86]([CH3:88])[CH3:87])[C:83]([OH:85])=O)=[O:80].[CH3:89][OH:90]>CN(C=O)C.O>[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26].[CH3:77][O:78][C:79]([NH:81][C@@H:82]([CH:86]([CH3:88])[CH3:87])[C:83]([N:64]1[CH2:65][CH2:66][CH2:67][C@H:63]1[C:61]1[NH:60][CH:59]=[C:58]([C:53]2[CH:54]=[C:55]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([C:45]2[CH:46]=[CH:47][C:42]([C:39]4[N:38]=[C:37]([C@@H:33]5[CH2:34][CH2:35][CH2:36][N:32]5[C:25]([C@@H:27]([NH:5][C:4](=[O:8])[O:90][CH3:89])[CH:74]([CH3:75])[CH3:76])=[O:31])[NH:41][CH:40]=4)=[CH:43][CH:44]=2)[CH:57]=[CH:56]3)[N:62]=1)=[O:85])=[O:80]

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 57462071HCID 57462071, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 178502356HCID 178502356, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

HATU (57.6 mg, 0.152 mmol) was added to a stirred solution of a TFA salt of 2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole (47 mg), diisopropylethylamine (88 μL, 0.51 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26.5 mg, 0.152 mmol) in DMF (4 mL) and the resulting mixture was stirred at ambient conditions for 2 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/methanol/TFA), repurified by a reverse phase HPLC (water/acetonitrile/ammonium acetate) and finally repurified by a reverse phase HPLC (water/methanol/TFA) to provide a TFA salt of methyl ((1S)-1-(((2S)-2-(4-(4-(6-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (33.3 mg) as yellow solid. LC-MS retention time 1.237 min; m/z 789.29 (MH+). 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. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.29 (d, J=8.9 Hz, 2H), 8.15 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.95-8.03 (m, 4H), 7.93 (s, 1H), 7.84-7.91 (m, 3H), 5.69-5.72 (m, 0.2H), 5.24-5.35 (m, 1.8H), 4.27 (dd, J=7.2, 2.6 Hz, 2H), 4.09-4.19 (m, 2H), 3.85-3.97 (m, 2H), 3.67-3.76 (m, 6H), 2.55-2.68 (m, 2H), 2.27-2.38 (m, 2H), 2.14-2.27 (m, 4H), 2.02-2.14 (m, 2H), 0.86-1.06 (m, 12H).

Workup

  1. customThe volatile component was removed in vacuo
  2. customthe residue was purified by a reverse phase HPLC (water/methanol/TFA)
  3. customrepurified by a reverse phase HPLC (water/acetonitrile/ammonium acetate)
  4. customfinally repurified by a reverse phase HPLC (water/methanol/TFA)

Sources & evidence

ORD record
ord-a7e31c8e30de4b3dbfde29479a8e23de
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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