1,4-Dibromobenzene → (S)-2-[[(S)-alpha-(Trifluoromethyl)-4-bromobenzyl]amino]-4-methyl-1-pentanol

Temperature

0 °C

n-BuLi (2.5 M in hexanes, 42 mL) was added to a −70° C. THF (400 mL) solution of 1,4-dibromobenzene (25.8 g) and the mixture was stirred for 25 minutes. A THF (30 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (31 g) was then added dropwise and the mixture was stirred for 1.5 hour. It was then poured slowly into a mixture of ethyl acetate (500 mL), water (2 L), ice (300 g) and ammonium chloride (100 g) under vigorous stirring. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue, which was used as such. The residue from above was dissolved in THF (250 mL) and the solution was cooled to 0° C. A 1 M THF solution of t-butylammonium fluoride (110 mL) was added dropwise and the mixture was reacted for 4 hours. It was poured into ethyl acetate (300 mL), water (2 L) and ammonium chloride (100 g) under vigorous stirring. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified on SiO2 using a gradient of ethyl acetate and hexanes (1:5 to 1:4) as eluant to yield the title compound.

1. customThe organic layer was separated
2. extractionthe aqueous further extracted with ethyl acetate (2×500 mL)
3. washThe combined organic layers were washed with brine
4. dry with materialdried with magnesium sulfate
5. customthe solvent was removed in vacuo
6. customto yield a residue, which
7. customthe mixture was reacted for 4 hours
8. customThe organic layer was separated
9. extractionthe aqueous further extracted with ethyl acetate (2×100 mL)
10. washThe combined organic layers were washed with brine
11. dry with materialdried with magnesium sulfate
12. customthe solvent was removed in vacuo
13. customto yield a residue which
14. customwas purified on SiO2 using a gradient of ethyl acetate and hexanes (1:5 to 1:4) as eluant

ORD record

ord-4bcd4b6c09454b5a8f0f636f34481741

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08772336B2