Trifluoroacetic acid → HCID 89682762, compound

Temperature

0 °C

A round bottom flask was charged with triphosgene (18 mg, 0.061 mmol), CH2Cl2 (1 mL), and 1,1,1,3,3,3-hexafluoropropan-2-ol (30 mg, 0.202 mmol). DIPEA (104 μL, 0.606 mmol) was added to this solution dropwise and the chloroformate was allowed to form at room temperature for 2 h. A separate flask was charged with (R)-tert-butyl 4-(2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (100 mg, 0.202 mmol) and CH2Cl2 (3 mL) and cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise over 1 minute. The reaction was stirred at 0° C. for 15 min. The reaction was allowed to warm to room temperature. After 60 min, the reaction was concentrated under reduced pressure. Methanol was added and the solution was concentrated yielding crude diamine. The crude diamine was dissolved in CH2Cl2 (3 mL) and cooled to 4° C. DIPEA (150 μL, 0.876 mmol) was added followed by the chloroformate solution over 5 minutes. After stirring for 2 h at 0° C. the reaction was quenched by addition of sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 10% 2M NH3 in MeOH) and yielded (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (28 mg, 28%): 1H NMR 400 MHz (CDCl3) δ 7.29-7.22 (m, 1H), 6.92-6.76 (m, 2H), 5.82-5.66 (m, J=6.4 Hz, 1H), 3.54 (tddd, J=37.8, 22.2, 11.8, 6.2 Hz, 9H), 3.21 (ddd, J=15.3, 10.0, 5.8 Hz, 1H), 3.11-3.04 (m, 1H), 2.49-2.34 (m, 4H), 2.22 (ddd, J=19.5, 13.0, 6.6 Hz, 1H), 1.80 (dt, J=12.7, 6.4 Hz, 1H). LCMS (ESI, m/z): 489 [M+H]+.

1. customto form at room temperature for 2 h
2. temperatureto warm to room temperature
3. waitAfter 60 min
4. concentrationthe reaction was concentrated under reduced pressure
5. additionMethanol was added
6. concentrationthe solution was concentrated
7. customyielding crude diamine
8. temperaturecooled to 4° C
9. stirringAfter stirring for 2 h at 0° C. the reaction
10. customwas quenched by addition of sat Na2CO3
11. extractionextracted with CH2Cl2 (3×)
12. dry with materialThe organics were dried (Na2SO4)
13. filtrationfiltered
14. concentrationconcentrated
15. customThe residue was chromatographed on a silica gel column (100% CH2Cl2 to 10% 2M NH3 in MeOH)

ORD record

ord-e24847d183554d85894cd051a39cdf3d

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133148B2