Hydrastine

Hydrastine is an alkaloid which was discovered in 1851 by Alfred P. Durand.[1] Hydrolysis of hydrastine yields hydrastinine, which was patented by Bayer as a haemostatic drug[2] during the 1910s. It is present in Hydrastis canadensis (thus the name) and other plants of the family Ranunculaceae.

Hydrastine
Clinical data
ATC code
  • none
Pharmacokinetic data
MetabolismHepatic
ExcretionRenal
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.003.849
Chemical and physical data
FormulaC21H21NO6
Molar mass383.400 g·mol−1
3D model (JSmol)
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Total synthesis

The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers[3] in 1931. Following studies[4][5] where the synthesis of the key lactonic amide intermediate (structure 4 in figure) was the most troublesome, the major breakthrough was achieved in 1981 when J. R. Falck and co-workers[6] reported a four-step total synthesis of hydrastine from simple starting materials. The key step in the Flack synthesis was using a Passerini reaction to construct the lactonic amide intermediate 4.

Starting from a simple phenylbromide variant 1, alkylation reaction with lithium methylisocyanide gives the isocyanide intermediate 2. Reacting isocyanide intermediate 2 with opianic acid 3 initiated the intramolecular Passerini reaction to give the key lactonic amide intermediate 4. The tetrahydro-isoquinolin ring was formed by first a ring-closure reaction under dehydration conditions using POCl3 and then a catalyzed hydrogenation using PtO2 as the catalyst. Finally, hydrastine was synthesized by installing the N-methyl group via reductive amination reaction with formaldehyde.

See also

References
  1. Pharmaceutical Journal;: A Weekly Record of Pharmacy and Allied Sciences. J. Churchill. 1862. pp. 547–.
  2. Römpp CD, Georg Thieme Verlag, 2006
  3. Hope, Edward; Pyman, Frank Lee; Remfry, Frederick George Percy; Robinson, Robert (1931). "XXXI.—A synthesis of hydrastine. Part I". J. Chem. Soc. 0 (0): 236–247. doi:10.1039/JR9310000236. ISSN 0368-1769.
  4. Haworth, R. D.; Pinder, A. R.; Robinson, R. (1950). "Synthesis of Hydrastine". Nature. 165 (4196): 529–529. doi:10.1038/165529a0. ISSN 0028-0836.
  5. Haworth, Robert D.; Pinder, A. Reginald (1950). "360. A new route to the phthalide-isoquinoline bases, and a synthesis of (–)-hydrastine". J. Chem. Soc. 0 (0): 1776–1780. doi:10.1039/JR9500001776. ISSN 0368-1769.
  6. Falck, J.R.; Manna, Sukumar (1981). "An intramolecular passerini reaction: Synthesis of hydrastine". Tetrahedron Letters. 22 (7): 619–620. doi:10.1016/S0040-4039(01)92504-3. ISSN 0040-4039.
  • Chisholm, Hugh, ed. (1911). "Hydrastine" . Encyclopædia Britannica. 14 (11th ed.). Cambridge University Press. p. 34.
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