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Hydrastine
Clinical data
ATC code	none;
Pharmacokinetic data
Metabolism	Hepatic
Excretion	Renal
Identifiers
	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;
CAS Number	118-08-1 ;
PubChem CID	197835;
ChemSpider	171234 ;
UNII	8890V3217X;
ChEMBL	ChEMBL497942 ;
CompTox Dashboard (EPA)	DTXSID9025409 ;
ECHA InfoCard	100.003.849
Chemical and physical data
Formula	C21H21NO6
Molar mass	383.400 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	132 °C (270 °F)
	SMILES O=C2O[C@@H](c1ccc(OC)c(OC)c12)[C@@H]5N(C)CCc4c5cc3OCOc3c4;
	InChI 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 ; Key:JZUTXVTYJDCMDU-MOPGFXCFSA-N ;
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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.

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

^ 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)
^ Römpp CD, Georg Thieme Verlag, 2006
^ 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.
^ 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.
^ 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.
^ 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.