Hexamethyldisilazane → HCID 21051854, compound

Temperature

-7 °C

A solution of 1,1,1,3,3,3-hexamethyldisilazane (3.18 mL, 15.05 mmol) in tetrahydrofuran (20 mL) cooled to −20° C. was treated with a 2.5M solution of n-butyllithium in hexanes (5.8 mL, 14.5 meq) over 10 min at such a rate as to keep the temperature below −15° C. The mixture was stirred for an additional 5 min. The cold reaction mixture was then treated with a solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-N-(2(R)-hydroxy-1 (R)-methyl-2-phenyl-ethyl)-N-methylacetamide (prepared as in Example 30, 2.77 g, 7.61 mmol) in tetrahydrofliran (22 mL) via syringe over 8 min, at such a rate as to keep the temperature below -15° C. The reaction was then slowly allowed to warm to −7° C. over 20 min and then a solution of 7(R)-iodomethyl-2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]nonane (2.42 g, 5.76 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.7 mL, 14.1 mmol) in tetrahydrofuran (10 mL) was added over 6 min. An exotherm increased the temperature to −4° C. during the addition. The reaction was allowed to warm to 0° C., where it was stirred for an additional 3 h. At this time, the reaction was poured into a mixture of toluene (70 mL) and a 20% aqueous ammonium chloride solution (50 mL, 187 mmol) and was then stirred vigorously. The organic layer was separated and re-washed with a 20% aqueous ammonium chloride solution (50 mL, 187 mmol). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(2(S),3 (S)-diphenyl-1,4-dioxa-spiro [4.4]non-7(S)-yl)-N-(2(R)-hydroxy-1(R)-methyl-2-phenyl-ethyl)-N-methyl-propionamide (3.86 g) as an overweight brown semi-solid. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]non-7(S)-yl)-N-(2(R)-hydroxy-1(R)-methyl-2-phenyl-ethyl)-N-methylpropionamide as a yellow foam (2.28 g, 60.4%).

1. customthe temperature below −15° C
2. customThe cold reaction mixture
3. customthe temperature below -15° C
4. temperatureAn exotherm increased the temperature to −4° C.
5. additionduring the addition
6. temperatureto warm to 0° C.
7. stirringwhere it was stirred for an additional 3 h
8. customThe organic layer was separated
9. dry with materialThe organic layer was dried over anhydrous sodium sulfate
10. concentrationconcentrated in vacuo

ORD record

ord-4483f2629890468182ad619678e3aa22

Source dataset

uspto-grants-2007_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07259166B2