4,4'-Dimethylbenzophenone → 4-[Bis(4-methylphenyl)methoxy]piperidine

25 g of 4,4′-dimethylbenzophenone was dissolved in ethanol-tetrahydrofuran (180 ml-60 ml); 2.23 g of sodium borohydride was added under ice cooling conditions, followed by stirring at room temperature for 24 hours. The mixture was concentrated under reduced pressure; ice water was added to the residue; the crystal precipitated was collected and dried; the crystal obtained (30.5 g) was dissolved in 800 ml of toluene; 11.9 g of 4-hydroxypiperidine and 24.9 g of p-toluenesulfonic acid monohydrate were added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; 100 ml of ice water and 140 ml of a 1 N aqueous solution of sodium hydroxide were added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90;10:1). The desired fraction was collected to yield 32.8 g of 4-[bis(4-methylphenyl)methoxy]piperidine as an oily substance. 16.4 g of 4-[bis(4-methylphenyl)methoxylpiperidine was dissolved in 100 ml of N,N-dimethylformamide; 14.2 g of N-(3-bromopropyl)phthalimide and 8.15 g of potassium carbonate were added, followed by stirring at room temperature for 16 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:2). The desired fraction was collected to yield 21.2 g of N-[3-[4-[bis(4-methylphenyl)methoxy]piperidino]propyl]phthalimide as an oily substance. 20.5 g of this oily substance was dissolved in 150 ml of ethanol; 2.18 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethanol was added to the residue; the crystal precipitated was collected, dissolved in 40 ml of a 1 N aqueous solution of sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure to yield 10.5 g of the title compound as an oily substance.

1. concentrationThe mixture was concentrated under reduced pressure
2. additionice water was added to the residue
3. customthe crystal precipitated
4. customwas collected
5. customdried
6. customthe crystal obtained (30.5 g)
7. customrefluxing for 3 hours
8. temperatureAfter cooling
9. concentrationthe mixture was concentrated under reduced pressure
10. addition100 ml of ice water and 140 ml of a 1 N aqueous solution of sodium hydroxide were added
11. extractionfollowed by extraction with ethyl acetate
12. washthe extract was washed with saline
13. dry with materialdried with sodium sulfate
14. concentrationThe dry product was concentrated under reduced pressure
15. washeluted with ethyl acetate-methanol-triethylamine (90;10:1)
16. customThe desired fraction was collected

ORD record

ord-626fa85e19774c49b5976a0e002635d1

Source dataset

uspto-grants-2001_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06248740B1