Hydrochloric Acid → Methyl 7-methoxy-2,3-dihydro-1-benzothiepine-4-carboxylate

A suspension of 7-methoxy-3,4-dihydro-1-benzothiepin-5(2H)-one (3.87 g) and sodium methoxide (5.0 g) in dimethyl carbonate (50 ml) was heated at reflux for 4 hours. The reaction mixture was mixed with 1 N hydrochloric acid (100 ml) and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain a yellow oily substance (4.96 g). Into a mixture of the thus-obtained oily substance, sodium borohydride (0.7 g) and THF (50 ml) was added dropwise at −40° C. methanol (5 ml), and the resulting mixture was stirred at −10° C. to −20° C. for one hour. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain a yellow oily substance (4.80 g). Into a solution of the thus-obtained oily substance and triethylamine (7.5 ml) in THF (50 ml) was added at 0° C. methanesulfonyl chloride (2.09 ml), and the resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for one hour. To this reaction mixture was added 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (4.0 ml), and the resulting mixture was stirred for 2.5 hours. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:5) to obtain methyl 7-methoxy-2,3-dihydro-1-benzothiepine-4-carboxylate (3.00 g) as a yellow oily substance.

1. temperaturewas heated
2. temperatureat reflux for 4 hours
3. extractionwas then extracted with ethyl acetate
4. washThe organic layer was washed with an aqueous saturated solution of sodium chloride
5. dry with materialwas dried with magnesium sulfate
6. concentrationThe resulting organic layer was concentrated under reduced pressure
7. customto obtain a yellow oily substance (4.96 g)
8. extractionwas then extracted with ethyl acetate
9. washThe organic layer was washed with an aqueous saturated solution of sodium chloride
10. dry with materialwas dried with magnesium sulfate
11. concentrationThe resulting organic layer was concentrated under reduced pressure
12. customto obtain a yellow oily substance (4.80 g)
13. stirringthe resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for one hour
14. stirringthe resulting mixture was stirred for 2.5 hours
15. extractionwas then extracted with ethyl acetate
16. washThe organic layer was washed with an aqueous saturated solution of sodium chloride
17. dry with materialwas dried with magnesium sulfate
18. concentrationAfter concentration under reduced pressure
19. customthe residue was subjected to separation and purification

ORD record

ord-8f59b303cbce4d7689f0cb2179e264dd

Source dataset

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06627651B1