Reacción #45306

Ecuación de reacción

5-chloro-thiophene-2-sulfonyl chloride

(2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-ol HCl

1-methylmorpholine

Me3SiCl

→

5-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide

Rendimiento 100.4%

Disolventes

CH2Cl2

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONwas added with
2. 2
   Lavadoa wash of 200 mL CH2Cl2
3. 3
   Temperaturacooled to 15-20° C
4. 4
   Lavadowashed with 190 mL CH2Cl2
5. 5
   workup.WAITThe temperature rose to 31.5° C. over 30 minutes with the reactor in a bath at 30° C
6. 6
   workup.STIRRINGThe mixture was stirred for 16 hours
7. 7
   OtroThe solvent was removed by distillation under vacuum at 90 mm Hg in a bath at 20-30° C
8. 8
   workup.ADDITION3.65 L isopropyl acetate and 2 N H2SO4 (2 L) were added
9. 9
   workup.STIRRINGthe mixture was stirred for 20 minutes
10. 10
    Otrothe layers separated
11. 11
    ExtracciónThe aqueous layer was back extracted with 0.5 L isopropyl acetate
12. 12
    FiltraciónThe layers were clarified by filtration through 0.2 μM
13. 13
    Filtraciónfilter
14. 14
    OtroThe isopropyl acetate was removed under vacuum (40 to <10 mm Hg) to dryness

Procedimiento

(2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-ol HCl (10) (385.5 g, 1.99 moles) was stirred with 3.8 L CH2Cl2 and 1007 g (9.96 mole, equivalents) 1-methylmorpholine was added with a wash of 200 mL CH2Cl2. At 20-30° C., Me3SiCl (443 g, 4.08 mole, 2.05 equivalents) was over 15-30 minutes. The solution was stirred for 1 h at 20-30° C., then cooled to 15-20° C. 454 g (2.09 moles, 1.05 equivalents) of 5-chloro-thiophene-2-sulfonyl chloride was added over 10-15 minutes at 18 to 24° C. and washed with 190 mL CH2Cl2. The temperature rose to 31.5° C. over 30 minutes with the reactor in a bath at 30° C. The mixture was stirred for 16 hours and tested by HPLC to assure that excess (1-10%) 5-chloro-thiophene-2-sulfonyl chloride remains. 22 mL 1-methylpiperazine (0.199 mole, 0.1 equivalents) was added. The solvent was removed by distillation under vacuum at 90 mm Hg in a bath at 20-30° C. 3.65 L isopropyl acetate and 2 N H2SO4 (2 L) were added, the mixture was stirred for 20 minutes and the layers separated. The aqueous layer was back extracted with 0.5 L isopropyl acetate. 2 L 2 N H2SO4, 2 L ½ saturated NaHCO3 and 2 L water were used as a wash. The layers were clarified by filtration through 0.2 μM filter. The isopropyl acetate was removed under vacuum (40 to <10 mm Hg) to dryness giving 675 g of crude 5-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide. The product was recrystallized from 10 volumes of 1:4 EtOAc/Heptanes giving 499 g after drying at 55° C. for 16 hours. A second crop of 49 g may be obtained from the mother liquors for a total yield of 548 g, 81%.

Fuente