Hydrastine

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Hydrastine
Hydrastine.svg
Systematic (IUPAC) name
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
Pharmacokinetic data
Metabolism Hepatic
Excretion Renal
Identifiers
CAS Number 118-08-1 YesY
ATC code none
PubChem CID: 197835
ChemSpider 171234 YesY
UNII 8890V3217X YesY
ChEMBL CHEMBL497942 N
Chemical data
Formula C21H21NO6
Molecular mass 383.395 g/mol
  • 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 YesY
  • Key:JZUTXVTYJDCMDU-MOPGFXCFSA-N YesY
 NYesY (what is this?)  (verify)

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 Ranunculaceae family.

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] which were mostly troublesome for the synthesis of the key lactonic amide intermediate (structure 4 in Figure). 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.

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.

References

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  1. ↑ Lua error in package.lua at line 80: module 'strict' not found..
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Hope, E.; Pyman, F. L.; Remfry, F. G. P.; Robinson, R., J. Chem. Soc. 1931, 236.
  4. ↑ Haworth, R. D.; Pinder, A. R.; Robinson, R., Nature 1950, 165, 529.
  5. ↑ Haworth, R. D.; Pinder, A. R., J. Chem. Soc. 1950, 1776.
  6. ↑ Falck, J. R.; Manna, S., Tetrahedron Lett. 1981, 22, 619.
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