Trifluoroacetic acid → methyl (S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1471153Notes

Reaction equation

HRID 1471153 reaction equation
C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:59]([CH3:61])[CH3:60])[C:14]([N:16]1[C@H:21]([C:22]2[NH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]3[CH:38]=[CH:39][C:40]5[N:44]=[C:43]([C@@H:45]6[CH2:50][C@@H:49]7[C@@H:47]([CH2:48]7)[N:46]6C(OC(C)(C)C)=O)[NH:42][C:41]=5[CH:58]=3)[CH:31]=[CH:30]4)=[CH:25][N:26]=2)[CH2:20][C@@H:19]2[C@H:17]1[CH2:18]2)=[O:15])=[O:11]>C(Cl)Cl>[C@@H:47]12[CH2:48][C@@H:49]1[CH2:50][C@@H:45]([C:43]1[NH:42][C:41]3[CH:58]=[C:37]([C:32]4[CH:33]=[C:34]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:24]4[NH:23][C:22]([C@@H:21]6[CH2:20][C@@H:19]7[C@@H:17]([CH2:18]7)[N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[CH:59]([CH3:61])[CH3:60])=[N:26][CH:25]=4)[CH:36]=[CH:35]5)[CH:38]=[CH:39][C:40]=3[N:44]=1)[NH:46]2

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 58498984(1R,3S,5R)-tert-butyl 3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

Product 1

HCID 86659019methyl (S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamateYield 67.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

TFA (2 mL) was added to a solution of (1R,3S,5R)-tert-butyl 3-(6-(6-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (226 mg, 0.310 mmol) in DCM (5 mL) and the reaction was stirred for 2 h at room temperature. The solution was concentrated under vacuum and the residue was taken in MeOH (10 mL) and filtered through a Strata XC MCX cartridge and washed with methanol (25 mL). The compound was released from the cartridge by washing the column with a solution of 2M of ammonia/methanol (10 mL) and concentrated under reduced pressure to give a methyl(S)-1-((1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (131 mg, 0.208 mmol) as tan solid. LC-MS retention time 1.235 min; m/z 630.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 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 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.16 (s, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.3, 6.3 Hz, 2H), 7.87 (s, 1H), 7.78-7.85 (m, 2H), 7.60-7.69 (m, 2H), 7.44 (s, 1H), 5.20 (dd, J=8.8, 4.8 Hz, 1H), 4.62 (d, J=6.8 Hz, 1H), 4.28 (dd, J=9.8, 7.8

Workup

  1. concentrationThe solution was concentrated under vacuum
  2. filtrationfiltered through a Strata XC MCX cartridge
  3. washwashed with methanol (25 mL)
  4. washby washing the column with a solution of 2M of ammonia/methanol (10 mL)
  5. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-086eaa9e74c340c8bbd8bb1eec6a2c31
Source dataset
uspto-grants-2015_04
Patent number
US09006455B2

Reaction notes

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