반응 #50253

반응 방정식

Pivaloyl chloride

oxazolidinone

(R)-4-benzyl-2-oxazolidinone

butyl lithium

triethylamine

Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid

→

N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-(R)-4-benzyl-2-oxazolidinone

용매

tetrahydrofuran

hexane

tetrahydrofuran

반응 조건

후처리

1. 1
   온도the reaction is warmed to 0° C.
2. 2
   온도cooled down again to -78° C
3. 3
   온도cooled to -78° C.
4. 4
   workup.STIRRINGthe reaction is stirred at -78° C. for 30 minutes
5. 5
   workup.STIRRINGis stirred at -78° C. for an additional 1 hour
6. 6
   온도to warm up to room temperature
7. 7
   workup.STIRRINGstir overnight
8. 8
   기타The reaction is quenched with saturated ammonium chloride
9. 9
   기타all of the solvent is evaporated
10. 10
    기타The product is purified by an initial silica gel chromatography (50% ethyl acetate/hexane)

실험 절차

Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (2.90 g, 10.1 mmol) is dissolved in tetrahydrofuran (45.0 mL), triethylamine (1.48 mL, 10.2 mmol) is added, and the reaction is cooled to -78° C. Pivaloyl chloride (1.31 mL, 10.2 mmol) is added, the reaction is warmed to 0° C., stirred for 3 hours, and then cooled down again to -78° C. Meanwhile, in a separate flask, (R)-4-benzyl-2-oxazolidinone (1.88 g, 10.2 mmol) is dissolved in tetrahydrofuran (35 mL) and cooled to -78° C.; butyl lithium (6.63 mL of a 1.6M solution in hexane, 10.2 mmol) is added and the reaction is stirred at -78° C. for 30 minutes. This oxazolidinone anion is then cannulated into the first reaction flask, which is stirred at -78° C. for an additional 1 hour, and then allowed to warm up to room temperature and stir overnight. The reaction is quenched with saturated ammonium chloride, and all of the solvent is evaporated. The product is purified by an initial silica gel chromatography (50% ethyl acetate/hexane) to give N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-(R)-4-benzyl-2-oxazolidinone as a mixture of two chiral diastereomers. These diastereomers are then separated by another silica gel chromatography (15% ether/40% hexane/45% methylene chloride) to yield the less polar (minor) chiral isomer, and the more polar (major) chiral isomer, m.p. 65°-66° C., [α]D +10.97° (c=7.52 mg/ml, CH2Cl2) leading to the more active NEP inhibiting enantiomer.

출처