Reaction #3852

Reaction equation

Oxalyl chloride

(±)-2-[(acetylthio)methyl]-3-phenylpropanoic acid

4-aminobutanoic acid, methyl ester, hydrochloride

diisopropylethylamine

→

(±)-4-[[2-[(Acetylthio)methyl]-1 oxo-3-phenylpropyl]amino]butanoic acid, methyl ester

Solvents

ethyl ether

methylene chloride

Conditions

Workup

1. 1
   ConcentrationAfter concentrating in vacuo
2. 2
   workup.ADDITIONthe residue is treated with tetrahydrofuran (10 ml.)
3. 3
   Concentrationagain concentrated
4. 4
   Otherto remove excess oxalyl chloride
5. 5
   workup.ADDITIONThe resulting residue is treated with methylene chloride (5 ml.)
6. 6
   Otherthe soluble portion is transferred to a dropping funnel
7. 7
   workup.ADDITIONThis soluton is added, dropwise over 10 minutes, to a cold (-5°)
8. 8
   workup.STIRRINGAfter stirring for 3 hours in the cold, the yellow solution
9. 9
   Concentrationis concentrated in vacuo
10. 10
    workup.ADDITIONThe residue is treated with ethyl acetate (60 ml.)
11. 11
    Filtrationfiltered
12. 12
    Otherto remove diisopropylethylamine hydrochloride
13. 13
    Washwashed sequentially with 10% potassium bisulfate, water, 50% saturated sodium bicarbonate, and 50% brine (30 ml
14. 14
    DryingThe organic layer is dried (Na2SO4)
15. 15
    Concentrationconcentrated to a light brown solid (1.34 g.)
16. 16
    Otherdried
17. 17
    WashElution with 5:2 hexane/acetone
18. 18
    Otheryields 1.09 g

Procedure

Oxalyl chloride (0.37 ml., 4.2 mmole) is added, under nitrogen, to a solution of (±)-2-[(acetylthio)methyl]-3-phenylpropanoic acid (0.95 g., 4.0 mmole) in ethyl ether (8 ml.). This mixture is cautiously treated with a catalytic amont of dimethylformamide (3 drops), and then stirred for one hour at room temperature. After concentrating in vacuo, the residue is treated with tetrahydrofuran (10 ml.) and again concentrated to remove excess oxalyl chloride. The resulting residue is treated with methylene chloride (5 ml.), and the soluble portion is transferred to a dropping funnel. This soluton is added, dropwise over 10 minutes, to a cold (-5°), stirred solution of 4-aminobutanoic acid, methyl ester, hydrochloride (0.68 g., 4.4 mmole) and diisopropylethylamine (1.6 ml., 9.0 mmole) in methylene chloride (10 ml.) under nitrogen. After stirring for 3 hours in the cold, the yellow solution is concentrated in vacuo. The residue is treated with ethyl acetate (60 ml.), filtered to remove diisopropylethylamine hydrochloride, and washed sequentially with 10% potassium bisulfate, water, 50% saturated sodium bicarbonate, and 50% brine (30 ml. each). The organic layer is dried (Na2SO4) and concentrated to a light brown solid (1.34 g.). This solid is adsorbed onto a small amount of silica gel (230- 400 mesh), dried, and applied to column of 80 g. of the same silica. Elution with 5:2 hexane/acetone yields 1.09 g. of (±)-4-[[2-[(acetylthio)methyl-1-oxo-3-phenylpropyl]amino]butanoic acid, methyl ester as a white solid; m.p. 81°-82°.

Source