Diisopropylethylamine → HCID 178502483, compound

HRID 1471201Notes

Reaction equation

HRID 1471201 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C@@H:25]12[CH2:30][C@@H:29]1[CH2:28][CH:27]([C:31]1[NH:32][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]4[CH:43]=[C:44]5[C:49](=[CH:50][CH:51]=4)[CH:48]=[C:47]([C:52]4[NH:56][C:55]([C@@H:57]6[CH2:62][C@@H:61]7[C@@H:59]([CH2:60]7)[N:58]6[C:63](=[O:73])[C@@H:64]([NH:68][C:69](=[O:72])[O:70][CH3:71])[CH:65]([CH3:67])[CH3:66])=[N:54][CH:53]=4)[CH:46]=[CH:45]5)=[CH:38][CH:37]=3)=[CH:34][N:35]=1)[NH:26]2.[CH3:74][O:75][C:76]([NH:78][C@@H:79]([CH:83]1[CH2:88][CH2:87][O:86][CH2:85][CH2:84]1)[C:80](O)=[O:81])=[O:77].CCN(C(C)C)C(C)C>CO.CN(C=O)C>[CH3:71][O:70][C:69]([NH:68][C@@H:64]([CH:65]([CH3:67])[CH3:66])[C:63]([N:58]1[C@H:57]([C:55]2[NH:54][CH:53]=[C:52]([C:47]3[CH:48]=[C:49]4[C:44](=[CH:45][CH:46]=3)[CH:43]=[C:42]([C:39]3[CH:38]=[CH:37][C:36]([C:33]5[N:32]=[C:31]([CH:27]6[CH2:28][C@@H:29]7[C@@H:25]([CH2:30]7)[N:26]6[C:80](=[O:81])[C@@H:79]([NH:78][C:76](=[O:77])[O:75][CH3:74])[CH:83]6[CH2:88][CH2:87][O:86][CH2:85][CH2:84]6)[NH:35][CH:34]=5)=[CH:41][CH:40]=3)[CH:51]=[CH:50]4)[N:56]=2)[CH2:62][C@@H:61]2[C@H:59]1[CH2:60]2)=[O:73])=[O:72]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59264488(S)-2-(Methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidHCID 123329634methyl(2S)-1-((1R,3S,5R)-3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate2×

Product 1

HCID 178502483HCID 178502483, compoundYield 6.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

HATU (27.8 mg, 0.073 mmol) was added to a solution of methyl(2S)-1-((1R,3S,5R)-3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Intermediate 131) (40 mg, 0.061 mmol) and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (15.90 mg, 0.073 mmol) were dissolved into DMF (0.5 mL) and DIPEA (0.053 mL, 0.31 mmol) and the reaction was stirred at rt for 2 h. The reaction was diluted with methanol and purified by preparative HPLC (MeOH/water with an ammonium acetate buffer) to yield methyl ((1S)-2-((1R,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (3.5 mg) as a light yellow solid. LC-MS retention time 2.785 min; m/z 855.74 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 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 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.17 (s, 1 H), 8.10 (s, 1 H), 7.93 (dd, J=8.5, 3.0 Hz, 2H), 7.77-7.86 (m, 6 H), 7.44 (s, 1 H), 7.35 (s, 1 H), 5.20 (dd, J=8.9, 4.6 Hz, 1 H), 5.15 (dd, J=8.8, 5.0 Hz, 1 H), 4.66 (d, J=7.8 Hz, 1 H), 4.61 (d, J=6.8 Hz, 1 H), 3.90-3.99 (m, 2 H), 3.68 (s, 6 H), 3.64-3.76 (m, 3 H), 3.34-3.43 (m, 3 H), 2.39-2.61 (m, 4 H), 2.12-2.23 (m, 1 H), 1.99-2.10 (m, 2 H), 1.52-1.67 (m, 2 H), 1.41-1.51 (m, 1 H), 1.08-1.18 (m, 2 H), 1.02 (d, J=6.8 Hz, 3 H), 0.94 (d, J=6.8 Hz, 3 H), 0.76-0.84 (m, 2 H).

Workup

  1. custompurified by preparative HPLC (MeOH/water with an ammonium acetate buffer)

Sources & evidence

ORD record
ord-7fc382939c0e4f47b06306c64b6d3b05
Source dataset
uspto-grants-2015_04
Patent number
US09006455B2

Reaction notes

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