Dichloromethane → (2S)-neopentyl 2-(chloro-(naphthalene-1-yl)phosphorylamino)-propanoate

Naphthalene-1-yl phosphorodichloridate (1219 g, 4.67 mol) and (S)-neopentyl 2-aminopropanoate p-toluenesulfonic acid (1547 g, 4.67 mol) were suspended in anhydrous dichloromethane (15 L) in a 22 L 3-neck flask equipped with a mechanical stirrer, an internal thermocouple, a cooling bath of dry/acetone, an additional funnel and a nitrogen inlet. Anhydrous triethylamine (1.3 L, 9.34 mmol, ≧99.5% grade, Product No 471283, Aldrich) was slowly added at −25° C. for one h. Later the reaction mixture was warmed to room temperature and stirred for overnight and monitored by 31P NMR. After completion, the solvent was removed under reduced pressure and the resulting crude residue that was triturated with a 1:1 mixture of ethyl acetate (2 L)/hexanes (2 L) was filtered by short pad of silica gel (Silicycle, SiliaFlash® P60, 3 inch high, funnel: 3 L medium size) and eluted using a mixture of ethyl acetate/hexanes (3 L: 3 L) followed by rinse with a mixture of ethyl acetate/hexanes (1.5 L: 1.5 L). Upon concentration, the dark oil was diluted with 3 L THF and was concentrated again under reduced pressure to deliver 1700 g (94%) of product which was used without further purification.

1. customequipped with a mechanical stirrer
2. dry with materialan internal thermocouple, a cooling bath of dry/acetone, an additional funnel and a nitrogen inlet
3. customAfter completion, the solvent was removed under reduced pressure
4. customthe resulting crude residue that was triturated with a 1:1 mixture of ethyl acetate (2 L)/hexanes (2 L)
5. filtrationwas filtered by short pad of silica gel (Silicycle, SiliaFlash® P60, 3 inch high, funnel: 3 L medium size)
6. washeluted
7. additiona mixture of ethyl acetate/hexanes (3 L: 3 L)
8. washby rinse with a mixture of ethyl acetate/hexanes (1.5 L: 1.5 L)
9. concentrationUpon concentration
10. additionthe dark oil was diluted with 3 L THF
11. concentrationwas concentrated again under reduced pressure
12. customwas used without further purification

ORDレコード

ord-348316c6b0694afcb76dd1eb0ad3afc5

出典データセット

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08759318B2