207290-72-0

5382-16-1

4701-17-1

207290-72-0

1. 5-bromothiophene-2-carbaldehyde (42.30 g) was placed in a reactor and an appropriate amount of water was added. 2. 4-hydroxypiperidine (67.30 g, 3 eq.) was added to the reactor and the mixture was stirred under reflux conditions for tens of minutes until overnight. 3. Immediately after completion of the reaction, the reaction mixture was filtered through filter paper, and the filtrate was cooled with water for tens of minutes, followed by chilling with ice for several hours. 4. The precipitated crystals are collected by diafiltration and washed with cold water. 5. 5. The crystals are dried and dissolved in chloroform and the chloroform solution is dried with anhydrous sodium sulfate. 6. The dried solution is filtered through a pad of silica gel and washed with chloroform until the filtrate becomes pale in color. 7. Concentrate the filtrate under pressure until it begins to crystallize, add n-hexane and stir overnight at room temperature. 8. The crystals formed were collected by filtration, washed with hexane and dried under reduced pressure to give 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carbaldehyde (33.00 g, 71%). 9. 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carboxaldehyde (10.56 g) was subjected to a condensation reaction with 3,4-dimethoxybenzyl cyanide (8.86 g) to give (Z)-2-(3,4-dimethoxyphenyl)-3-[5-(4-hydroxypiperidin-1-yl)-thiophen-2-yl]-acrylonitrile (13.50 g, 73%). 10. (Z)-2-(3,4-dimethoxyphenyl)-3-[5-(4-hydroxypiperidin-1-yl)-thiophen-2-yl]-acrylonitrile (20.00 g) was dissolved in chloroform (650 mL), and pyridine (6.41 g) and bromoacetyl bromide (14.13 g) were added and reacted to give bromoacetic acid 1-[5-[(Z)-2-cyano-2-(3,4-di (Z)-2-cyano-2-(3,4-dimethoxyphenyl)-vinyl]-thiophen-2-yl]-piperidin-4-yl ester (23.00 g, 87%). 11. 1-[5-[(Z)-2-cyano-2-(3,4-dimethoxyphenyl)-vinyl]-thiophen-2-yl]-piperidin-4-yl ester of bromoacetic acid (2.30 g) was dissolved in chloroform (100 mL), and piperidine (533 mg) and triethylamine (658 mg) were added and reacted to give 5-(4-hydroxypiperidinyl)-2-thiophenecarboxaldehyde (1.40 g. 60%).