Reaction #2271679

Reaction equation

fumaric acid

6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride

K2CO3

1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone

→

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]propoxy]-3-methylpheny]ethanone hemifumarate

Solvents

ethanol

ethanol

dimethylformamide

acetonitrile

Conditions

Workup

1. 1
   OtherAt the end of the reaction
2. 2
   Concentrationthe solvent was concentrated down to about 30 ml
3. 3
   Otherpartitioned between water (200 ml) and dichloromethane (300 ml)
4. 4
   OtherThe dichloromethane solution was separated
5. 5
   Washwashed with water and brine
6. 6
   Dryingdried over MgSO4
7. 7
   OtherThe crude product from the evaporated solution was purified by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% methanol in dichloromethane, 600 ml; 2% methanol in dichloromethane, 600 ml)
8. 8
   OtherThe material thus obtained

Procedure

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.0 g; 11.7 mmol). K2CO3 (3.0g), and 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone (3.19 g) in dimethylformamide (20 ml) and acetonitrile (50 ml) was heated at 95° C. for 4 hours. At the end of the reaction, the solvent was concentrated down to about 30 ml, then partitioned between water (200 ml) and dichloromethane (300 ml). The dichloromethane solution was separated and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% methanol in dichloromethane, 600 ml; 2% methanol in dichloromethane, 600 ml). The material thus obtained was a light yellow oil, weight: 2.07 g (43%). This oil was dissolved in ethanol and treated with a solution of fumaric acid (585 mg) in ethanol. The 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]propoxy]-3-methylpheny]ethanone hemifumarate crystals formed on cooling at 0° C. This was collected and weighed 1.5 g., m.p.=185°-187° C.

Source