Hydrastine

Hydrastine
Clinical data
ATC code
  • none
Pharmacokinetic data
MetabolismHepatic
ExcretionRenal
Identifiers
  • 6,7-Dimethoxy-3-(6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-2-benzofuran-1(3H)-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.003.849 Edit this at Wikidata
Chemical and physical data
FormulaC21H21NO6
Molar mass383.400 g·mol−1
3D model (JSmol)
Melting point132 °C (270 °F)
  • O=C2O[C@@H](c1ccc(OC)c(OC)c12)[C@@H]5N(C)CCc4c5cc3OCOc3c4
  • InChI=1S/C21H21NO6/c1-22-7-6-11-8-15-16(27-10-26-15)9-13(11)18(22)19-12-4-5-14(24-2)20(25-3)17(12)21(23)28-19/h4-5,8-9,18-19H,6-7,10H2,1-3H3/t18-,19+/m1/s1 checkY
  • Key:JZUTXVTYJDCMDU-MOPGFXCFSA-N checkY
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Hydrastine is an isoquinoline 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.

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 Falck synthesis was using a Passerini reaction to construct the lactonic amide intermediate 4.

Falck’s total synthesis of hydrastine, the mechanism of the Passerini reaction for synthesis of the key intermediate is also illustrated

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. ^ Perrins JD (July 1862). "On Hydrastine, an Alkaloid Occurring in Hydrastis Canadensis". Pharmaceutical Journal: A Weekly Record of Pharmacy and Allied Sciences. J. Churchill: 547–.{cite journal}: CS1 maint: date and year (link)
  2. ^ Römpp CD, Georg Thieme Verlag, 2006
  3. ^ Hope E, Pyman FL, Remfry FG, Robinson R (1931). "XXXI.—A synthesis of hydrastine. Part I". J. Chem. Soc.: 236–247. doi:10.1039/JR9310000236. ISSN 0368-1769.
  4. ^ Haworth RD, Pinder AR, Robinson R (1950). "Synthesis of Hydrastine". Nature. 165 (4196): 529. Bibcode:1950Natur.165..529H. doi:10.1038/165529a0. ISSN 0028-0836. S2CID 4198366.
  5. ^ Haworth RD, Pinder AR (1950). "360. A new route to the phthalide-isoquinoline bases, and a synthesis of (–)-hydrastine". J. Chem. Soc.: 1776–1780. doi:10.1039/JR9500001776. ISSN 0368-1769.
  6. ^ Falck JR, Manna S (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.