Hydrogen Bromide → Biotin

A mixture of 3.0 g of (3aS,4S,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-pentanoic acid and 24 ml of 48% hydrobromic acid was refluxed at 110° C. to 120° C. for 48 hours. Hot extraction with 10 ml of toluene was carried out four times to remove benzyl bromide. The aqueous layer was concentrated, 15 ml of water and 11.5 ml of 6M aqueous sodium hydroxide solution were added to the residue, subsequently 3.36 g of ethoxycarbonyl chloride was added dropwise, and the reaction was carried out while maintaining pH to 8 to 10, at room temperature for 3 hours. Thereafter, a temperature of the reaction mixture was raised to 70° C. to 80° C., and the reaction was carried out for 20 hours (during the reaction, pH was maintained to 12 by adding 6M aqueous sodium hydroxide solution). pH was adjusted to 7.4 to 7.8 with 7 ml of 16% hydrochloric acid, and filtration was carried out at 90° C. to 95° C. by using 1.0 g of activated charcoal. The filtrate was heated to 80° C. to 85° C., pH thereof was adjusted to 1.8 to 2.2 by using 6 ml of 16% hydrochloric acid, and neutralization crystallization was carried out. After cooling, crystal was collected by filtration and washed with water, and dried by blowing air at 50° C. to give 1.38 g of (+)-biotin as colorless crystal.

1. temperaturewas refluxed at 110° C. to 120° C. for 48 hours
2. extractionHot extraction with 10 ml of toluene
3. customto remove benzyl bromide
4. concentrationThe aqueous layer was concentrated
5. addition15 ml of water and 11.5 ml of 6M aqueous sodium hydroxide solution were added to the residue, subsequently 3.36 g of ethoxycarbonyl chloride
6. additionwas added dropwise
7. temperaturewhile maintaining pH to 8 to 10
8. temperatureThereafter, a temperature of the reaction mixture was raised to 70° C. to 80° C.
9. waitthe reaction was carried out for 20 hours
10. custom(during the reaction
11. temperaturepH was maintained to 12
12. filtrationpH was adjusted to 7.4 to 7.8 with 7 ml of 16% hydrochloric acid, and filtration
13. customwas carried out at 90° C. to 95° C.
14. temperatureThe filtrate was heated to 80° C. to 85° C.
15. custom6 ml of 16% hydrochloric acid, and neutralization crystallization
16. temperatureAfter cooling
17. filtrationcrystal was collected by filtration
18. washwashed with water
19. customdried
20. customat 50° C.

ORD record

ord-313d4762a86d4cdab75973baa8c441a2

Source dataset

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07799929B2