Hydrochloric Acid → (2S)-1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-hydroxy-3-methylbutan-1-one

(S)-2-hydroxy-3-methylbutyric acid (13.5 mg, 0.11 mmol) and PyBOP (60 mg, 0.12 mmol) were combined in THF (0.4 mL) and stirred for 10 minutes. To this mixture was added {3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (20 mg, 0.05 mmol) and DIEA (31 mg, 0.24 mmol). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 10% Na2CO3 (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (1:4 ethyl acetate/hexanes) to provide Boc-protected diastereomer A (less polar, 2.0 mg) and Boc-protected diastereomer B (more polar, 4.2 mg). To the Boc-protected diastereomer A was added HCl (1 mL, 4M in dioxane) at 0° C. After warming to room temperature and stirring for 1 hour, the mixture was concentrated under a stream of N2. The residue was dissolved in an ether/dioxane mixture and precipitated with hexanes. The solid was filtered and washed with hexanes to provide the final product as yellow solid. MS ESI (+) m/z 416 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 8.4 (br s, 3H), 7.5 (m, 2H), 7.43-7.28 (m, 4H), 7.24-7.11 (m, 3H), 4.66 (br s, 1H), 3.30 (br s, 1H), 3.15-2.92 (m, 2H), 2.73 (m, 1H), 2.30 (m, 1H), 2.18 (m, 1H), 1.81-1.49 (m, 2H), 1.10 (br m, 3H), 0.9 (br m, 3H).

1. stirringAfter stirring at room temperature for 24 hours
2. extractionextracted with ethyl acetate (3×20 mL)
3. dry with materialThe combined organics were dried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe residue was chromatographed (1:4 ethyl acetate/hexanes)
7. customto provide Boc-
8. stirringstirring for 1 hour
9. concentrationthe mixture was concentrated under a stream of N2
10. dissolutionThe residue was dissolved in an ether/dioxane mixture
11. customprecipitated with hexanes
12. filtrationThe solid was filtered
13. washwashed with hexanes

ORD record

ord-e31ad8c32b7f4a86b952a0c4c268d190

Source dataset

uspto-grants-2008_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07449486B2