Trifluoroacetic acid → Methyl 3-benzyloxy-5-[3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]carbonylamino]piperidin-1-yl]benzoate

Temperature

0 °C

Methyl 3-benzyloxy-5-(3-tert-butoxycarbonylaminopiperidin-1-yl)benzoate (23.0 mg, 0.0522 mmol) was dissolved in anhydrous dichloromethane (0.5 mL). While this solution is chilled in an ice bath and stirred, trifluoroacetic acid (80 μL, 6.82 mmol) was added and the reaction mixture was stirred for 2 hours. Subsequently, the mixture was concentrated and a 10% hydrochloric acid/methanol solution (1.5 mL) was added to the residue. The mixture was then stirred at room temperature for 1 hour and was concentrated. The same process was repeated 3 times and the resulting solid were washed with ethyl acetate. This gave 20.9 mg of a blown powder. This product (19.8 mg) was dissolved in N,N-dimethylformamide (1 mL). While the solution was chilled to 0° C. and stirred, 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid (15.5 mg, 0.0611 mmol), 1-hydroxybenzotriazole monohydrate (8.8 mg, 0.0575 mmol), N-methylmorpholine (17 μL, 0.155 mmol) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (11.7 mg, 0.0610 mmol) were added and the mixture was stirred for 20 min. The reaction mixture was further stirred at room temperature for the subsequent 6 hours. Subsequently, the mixture was diluted with ethyl acetate and the organic layer washed sequentially with 5% aqueous citric acid, a saturated aqueous sodium bicarbonate solution, water and brine. The washed product was then dried over anhydrous sodium sulfate and was concentrated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=4:1) gave 22.8 mg (75%) of the desired compound as a colorless powder.

1. temperatureWhile this solution is chilled in an ice bath
2. stirringthe reaction mixture was stirred for 2 hours
3. concentrationSubsequently, the mixture was concentrated
4. additiona 10% hydrochloric acid/methanol solution (1.5 mL) was added to the residue
5. stirringThe mixture was then stirred at room temperature for 1 hour
6. concentrationwas concentrated
7. washthe resulting solid were washed with ethyl acetate
8. dissolutionThis product (19.8 mg) was dissolved in N,N-dimethylformamide (1 mL)
9. stirringstirred
10. stirringthe mixture was stirred for 20 min
11. stirringThe reaction mixture was further stirred at room temperature for the subsequent 6 hours
12. washthe organic layer washed sequentially with 5% aqueous citric acid
13. dry with materialThe washed product was then dried over anhydrous sodium sulfate
14. concentrationwas concentrated
15. customPurification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=4:1)

ORD record

ord-376fa7834c564599a70875fc0154303c

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07902367B2