Halostachine (also known as N-methylphenylethanolamine) is a natural product, an alkaloid first isolated from the Asian shrub Halostachys caspica (synonym Halostachys belangeriana), and structurally a β-hydroxy-phenethylamine (a phenylethanolamine) related to its better-known "parent" biogenic amine, phenylethanolamine, to the adrenergic drug synephrine, and to the alkaloid ephedrine. The pharmacological properties of halostachine have some similarity to those of these structurally-related compounds, and Halostachys caspica extracts have been included as a constituent of certain OTC dietary supplements, but halostachine has never been developed as a prescription drug. Although it is found in nature as a single stereoisomer, halostachine is more commonly available as a synthetic product in the form of its racemate (see below). In appearance it is a colorless solid.
Occurrence
Naturally-occurring halostachine was first discovered by Syrneva in the halophytic plant Halostachys caspica (now classed as Halostachys belangeriana) (family Amaranthaceae). The erroneous structure originally proposed for this compound was subsequently corrected by Menshikov and Rubinstein.
Halostachine has also been isolated from perennial ryegrass, Lolium perenne and from tall fescue, Festuca arundinacea.
The presence of N-methylphenylethanolamine in rat brain was implied by the experiments described by Saavedra and Axelrod.
Chemistry
Synthesis
Several syntheses of racemic N-methylphenylethanolamine have been published over the years. A synthesis using "classical" methodology was reported by Durden and co-workers, starting from acetophenone. The methyl group of acetophenone was brominated with bromine to give α-bromoacetophenone, which was then reacted with N-methylbenzylamine to give an amino-ketone. The amino-ketone was reduced with lithium aluminium hydride to the corresponding amino-alcohol, and the N-benzyl group finally removed by catalytic hydrogenation using a palladium on charcoal catalyst.
Another synthesis, due to Nordlander and co-workers, began with the Friedel-Crafts acylation of benzene by N-(trifluoroacetyl)glycyl chloride in the presence of aluminum chloride. The resulting N-(trifluoroacetyl)-α-aminoacetophenone was then N-methylated with methyl iodide and potassium carbonate, and the product finally converted to racemic N-methylphenylethanolamine by means of sodium borohydride in ethanol.
An efficient, stereospecific synthesis of halostachine was reported by Zandbergen and co-workers: (R)-(+)-α-hydroxybenzeneacetonitrile was first O-protected using 2-methoxypropene. The product was then treated with DIBAL, and the unisolated imine then treated sequentially with ammonium bromide and methylamine to effect "transimination". The resulting N-methylimine was converted to (R)-(−)-α-[(methylamino)methyl]benzenemethanol (i.e. (R)-(−)-halostachine) with sodium borohydride.
Properties
Chemically, N-methylphenyethanolamine is an aromatic compound, an amine, and an alcohol. The amino-group makes this compound a weak base, capable of reacting with acids to form salts.
One common salt of N-methylphenylethanolamine is the (racemic) hydrochloride, C9H13NO.HCl, m.p. 103-104 °C.
The pKa of N-methylphenylethanolamine hydrochloride, at 25 °C and at a concentration of 10 mM, is 9.29.
The presence of the hydroxy-group on the benzylic C of the N-methylphenylethanolamine molecule creates a chiral center, so the compound exists in the form of two enantiomers, d- and l-N-methylphenylethanolamine, or as the racemic mixture, d,l- N-methylphenylethanolamine. The dextrorotatory isomer corresponds to the S-configuration, and the levorotatory isomer to the R-configuration.
The N-methylphenylethanolamine isolated from Halostachys caspica, and given the alkaloid name "halostachine", was found to be the levorotatory enantiomer.
Halostachine has a melting point of 43-45 °C and [α]D = - 47.03°; the hydrochloride salt of this enantiomer has m.p. 113-114 °C, and [α]D = - 52.21°. The resolution of racemic N-methylphenylethanolamine, by means of its tartrate salts, yielded enantiomers with specific rotations of [α]D = - 52.46° and + 52.78°.