Reaction #44640

Reaction equation

4-chlorophenyl magnesium bromide

(R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester

THF

→

(R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester

Conditions

Workup

1. 1
   OtherThe resulting reaction solution
2. 2
   Otherquenched with a saturated ammonium chloride aqueous solution at −40° C
3. 3
   workup.ADDITIONTo this reaction solution, water was added
4. 4
   ExtractionThe resulting mixture was extracted with ethyl acetate
5. 5
   ExtractionThe obtained extract solution
6. 6
   Dryingwas dried over magnesium sulfate
7. 7
   Concentrationconcentrated under reduced pressure
8. 8
   OtherThe residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system)

Procedure

In nitrogen atmosphere, 4-chlorophenyl magnesium bromide (1.0 M, diethylether solution, 42 mL) was added to a THF solution (120 mL) of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS Register No. 183890-36-0, 9.00 g) over 20 min at −78° C. The resulting reaction solution was stirred at −78° C. to −40° C. for 1.5 hr and then quenched with a saturated ammonium chloride aqueous solution at −40° C. To this reaction solution, water was added. The resulting mixture was extracted with ethyl acetate. The obtained extract solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 9.53 g of (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester. To an ethyl acetate solution (90 mL) of the (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester (9.53 g), a 4 N hydrogen chloride-ethyl acetate solution (90 mL) was added at room temperature. The resulting reaction solution was stirred at room temperature for 12 hr and then concentrated under reduced pressure. A saturated sodium hydrogencarbonate aqueous solution was added to the residue for basification, and then chloroform was added thereto. The resulting reaction solution was stirred at room temperature for 2 hr. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. To a methanol solution (150 mL) of the residue, sodium cyano borohydride (3.29 g) and then acetic acid (4.27 mL) were added at 0° C. The resulting reaction solution was stirred at 0° C. for 1 hr and further at room temperature for 1 hr, and then a saturated sodium hydrogencarbonate aqueous solution was added thereto. The resulting mixture was extracted with chloroform. The obtained extract solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) and further solidified from a heptane-diisopropylether system to give 2.47 g of the title compound. The physical property values of this compound were as follows:

Source