Dichloromethane → 4-Methoxyphenylacetyl chloride

Temperature

-75 °C

8-Ethano-1-(p-hydroxybenzyl)-2-methyl- 1,2,3,4,5,6,7,8-octahydroisoquinoline (10). A 100 mL three-necked flask was dried for 24 h at 210° C. While cooling under a stream of dry nitrogen, the flask was immersed in an ethanol/dry ice bath and cooled to -75° C. Boron tribromide (300 μl, 3.16 mmole) was introduced, followed by 10 ml of dry dichloromethane. Purified 9 (224 mg, 0.754 mmole), as the base, in 30 ml of dry dichloromethane was added in a dropwise fashion. Thirty minutes after the addition of 9, the stirring was stopped, the nitrogen was replaced by a calcium sulfate drying tube, and the mixture was left in the cold for 12 h. After refluxing for 1 h, the reaction mixture was recooled in an ice bath and 3.5 ml of 10% ammonium hydroxide was slowly added and a flocculent precipitate formed. After stirring for 15 min, the cold bath was removed and 50 ml of water was added. The subsequent isolation of the product was conducted in the dark to minimize photooxidation. The phases were separated, the dichloromethane was removed in vacuo and the residue was dissolved in ethyl ether. The aqueous phase (pH 8.4) was adjusted to pH 9.1 with 10% ammonium hydroxide and extracted eight times with 20 ml portions of ether. All ether phases were combined, dried (Na2SO4), and concentrated to give a yellow oil. An attempt was made to purify this base by methansulfonate salt formation, but this salt form resisted crystallization. The hydrochloride salt was made and recrystallized from acetone/ethanol/ethyl ether in 29% yield. There was evidence of additional product in the mother liquor but it resisted crystallization: mp (sealed tube) 218°-220° C. sublime; 1H NMR (base in CDCl3) δ 6.67 (AA'BB', 4 H aromatic), 4.58 (s, 1 H, OH), 2.87-3.30 (m, 1 H, 1-H), 2.43-2.87 (m, 4 H, 1-CH2, 3-H2), 2.33 (s, 3 H, NCH3), 1.90-2.27 (m, 4 H, 4-H2, 5-H, 8-H), 0.93-1.72 (m, 8 H, remaining protons); IR (base, neat) 3300 (OH stretch) cm -1 ; mass spectrum, m/z 283 (M+), 176 (M+ -p-hydroxybenzyl, base), 148 (retro-Diels-Alder), 107 (p-hydroxybenzyl+), 106 (p-hydroxybenzyl-1+), 42 (CH2 =N=CH2+).

1. customA 100 mL three-necked flask was dried for 24 h at 210° C
2. temperatureWhile cooling under a stream of dry nitrogen
3. customthe flask was immersed in an ethanol/dry ice bath
4. additionThirty minutes after the addition of 9
5. customthe nitrogen was replaced by a calcium sulfate drying tube
6. temperatureAfter refluxing for 1 h
7. customthe reaction mixture was recooled in an ice bath
8. customa flocculent precipitate formed
9. customthe cold bath was removed
10. addition50 ml of water was added
11. customThe phases were separated
12. customthe dichloromethane was removed in vacuo
13. dissolutionthe residue was dissolved in ethyl ether
14. extractionextracted eight times with 20 ml portions of ether
15. dry with materialdried (Na2SO4)
16. concentrationconcentrated
17. customto give a yellow oil
18. customto purify this base by methansulfonate salt formation
19. customcrystallization
20. customrecrystallized from acetone/ethanol/ethyl ether in 29% yield
21. customcrystallization
22. custommp (sealed tube) 218°-220° C. sublime

ORD record

ord-e0be67bb7e6f40f6a7ca7cf23823ec96

Source dataset

uspto-grants-1996_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05512577