Réaction #50253

Équation de réaction

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

Solvants

tetrahydrofuran

hexane

tetrahydrofuran

Conditions de réaction

Traitement

1. 1
   Températurethe reaction is warmed to 0° C.
2. 2
   Températurecooled down again to -78° C
3. 3
   Températurecooled 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
   Températureto warm up to room temperature
7. 7
   workup.STIRRINGstir overnight
8. 8
   AutreThe reaction is quenched with saturated ammonium chloride
9. 9
   Autreall of the solvent is evaporated
10. 10
    AutreThe product is purified by an initial silica gel chromatography (50% ethyl acetate/hexane)

Mode opératoire

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.

Source