Triethylamine → HCID 11291100, compound

To a stirred solution of (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (2.6 g, 15.18 mmol), triethylamine (4.2 mL, 30.38 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (4.8 g, 18.22 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (150 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (6.1 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-6 as eluent. This produced the title compound 5-chloro-N-[(1S, 2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white amorphous solid (5.15 g, 96.4%). The product contained impurities. The white amorphous solid was further purified by recrystallization from 1:4 EtOAc-heptane. The mixture of solvents was added to 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution, allowed to cool to 25° C. for 3 h and then stored at 0° C. for 19 hours. A crystalline white solid precipitated, was filtered and washed with ice-cold heptane to obtain a white crystalline solid (2.7 g, 40.9%). The recrystallized material still contained impurities. The white solid (2.7 g) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-I-PrOH (1 mL/min)] to obtain 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white crystalline solid, mp 132-133° C. (0.93 g, 14.1%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 350 (M−H)−.

1. customthe ice bath was removed
2. waitto attain 25° C. overnight
3. customThe reaction was quenched
4. additionby pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (150 mL)
5. customThe organic phase was separated
6. washwashed sequentially with 1N HCl solution, H2O, brine
7. dry with materialdried over MgSO4
8. filtrationThe organic phase was filtered
9. customevaporated
10. customto produce a crude oil (6.1 g) that
11. customwas purified by flash chromatography

ORD record

ord-b6b5bf35489a4963b323dbfc5854b7da

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07858658B2