Trifluoroacetic acid → Carbamate

HRID 1471200Notes

Reaction equation

ClC1NC=CN=1.C(O)(C(F)(F)F)=O.Cl[C:15]1[N:16]=[C:17]([C@@H:59]2[CH2:64][C@@H:63]3[C@@H:61]([CH2:62]3)[N:60]2[C:65](=[O:78])[C@@H:66]([NH:73][C:74](=[O:77])[O:75][CH3:76])[CH:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[NH:18][C:19]=1[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:46][C@@H:45]6[C@@H:43]([CH2:44]6)[N:42]5[C:47](=[O:57])[C@@H:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][C:37]=4[Cl:58])=[CH:32][CH:31]=3)[CH:26]=2)[CH:21]=1>>[C:53](=[O:54])([O-:55])[NH2:52].[Cl:58][C:37]1[N:38]=[C:39]([C@@H:41]2[CH2:46][C@@H:45]3[C@@H:43]([CH2:44]3)[N:42]2[C:47]([C@@H:48]([NH:52][C:53](=[O:54])[O:55][CH3:56])[CH:49]([CH3:50])[CH3:51])=[O:57])[NH:40][C:36]=1[C:33]1[CH:34]=[CH:35][C:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([C:19]4[N:18]=[C:17]([C@@H:59]5[CH2:64][C@@H:63]6[C@@H:61]([CH2:62]6)[N:60]5[C:65](=[O:78])[C@@H:66]([NH:73][C:74]([O:75][CH3:76])=[O:77])[CH:67]5[CH2:68][CH2:69][O:70][CH2:71][CH2:72]5)[NH:16][CH:15]=4)[CH:21]=3)[CH:26]=2)=[CH:31][CH:32]=1

Participants

Reactant 3

HCID 6422Trifluoroacetic acid2×

HCID 27733282-chloro-1H-imidazole

HCID 178502490HCID 178502490, compound

Product 2

HCID 276Carbamate

HCID 178502489HCID 178502489, compound

Procedure

A mixture of two chloroimidazole regioisomers as TFA salts (Examples 68 and 69) (21.4 mg) was isolated from the same reaction that prepared a TFA salt of methyl ((1S)-2-((1R,3S,5R)-3-(4-chloro-5-(6-(4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (Example 64). The two regioisomeric compounds were separated in multiple injections using SCF chromatography (2-ethylpyridine SCF column (4.6×250 mm, 5 μm) and 80% CO2-20% EtOH/0.1% DEA). The absolute regiochemistry of the separated materials was determined by HMBC correlation. The reaction yielded methyl((1S)-1-(1R,3S,5R)-3-(4-(4-(6-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate (7.4 mg) and methyl ((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(4-(6-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-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)carbonyl)-2-methylpropyl)carbamate (4.5 mg), each as an off-white solid. For Example 68: LC-MS retention time 2.683 min; m/z 889.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 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 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 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. For Example 69: LC-MS retention time 2.695 min; m/z 889.22 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 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 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 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.

Workup

customwas isolated from the same reaction that
customThe two regioisomeric compounds were separated in multiple injections

Sources & evidence

ORD record: ord-a782d4f5033747bfb123df3089813a76
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09006455B2

Reaction notes

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