Hydrochloric Acid → HCID 178502488, 화합물

4M HCl (0.3 mL, 1.3 mmol) in dioxane was added to mixture of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-(6-((2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 158) (60 mg, 0.064 mmol) in dioxane (0.5 mL) and the reaction was stirred vigorously for 4 h. The reaction was concentrated to dryness. Then (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid (Cap-177a) (18.2 mg, 0.084 mmol), DMF (0.5 mL), DIPEA (0.067 mL, 0.39 mmol) and finally HATU (32 mg, 0.084 mmol) was added to the crude material and the reaction was stirred at rt for 1 h. The reaction was partially concentrated, diluted with MeOH, filtered and purified by preparative HPLC (MeOH/water with a TFA buffer) and repurified in one injection by Prep HPLC (MeOH/water with an ammonium acetate buffer) to yield methyl ((1S)-2-((1R,3S,5R)-3-(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)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-((3S)-tetrahydro-2H-pyran-3-yl)ethyl)carbamate (30.5 mg) as a white solid. LC-MS retention time 3.376 min; m/z 803.66 (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 8.14 (s, 1H), 7.94 (s, 1H), 7.78-7.86 (m, 3H), 7.49 (dd, J=8.5, 1.5 Hz, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 5.15 (ddd, J=12.9, 8.7, 4.5 Hz, 2H), 4.57 (d, J=6.8 Hz, 1H), 3.70-3.86 (m, 3H), 3.67 (br. s., 3H), 3.66 (br. s., 3H), 3.58-3.64 (m, 1H), 3.53 (t, J=8.3 Hz, 1H), 3.45 (dd, J=11.4, 8.2 Hz, 1H), 2.31-2.57 (m, 4H), 1.93-2.17 (m, 5H), 1.67-1.84 (m, 2H), 1.50-1.63 (m, 2H), 1.08-1.17 (m, 2H), 0.98 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H), 0.78 (br. s., 2H).

1. concentrationThe reaction was concentrated to dryness
2. stirringthe reaction was stirred at rt for 1 h
3. concentrationThe reaction was partially concentrated
4. additiondiluted with MeOH
5. filtrationfiltered
6. custompurified by preparative HPLC (MeOH/water with a TFA buffer) and
7. customrepurified in one injection by Prep HPLC (MeOH/water with an ammonium acetate buffer)

ORD 기록

ord-bf5c57f8eb004574a5e61376dddee0de

출처 데이터셋

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09303007B2