Atropine was first synthesised by Richard Willstatter in 1901.
.This was quite a feat at the time given the complexity of the atropine molecule. It is a tropinone-based compound made up of forty-five atoms. It has a cycloheptane ring with a methylamine bridge and an ester group incorporated into the molecule.
Atropine exists naturally in the plant Atropa belladonna, also known as Deadly Nightshade. It is an intensely poisonous chemical with a structure analogous to cocaine, whose synthesis was also devised by Willstatter. His work in organic chemistry was an enormous boost to chemical synthesis, not just in terms of originality but also the degree to which he improved already existing synthetic pathways. His labours achieved just recognition in 1915 by the award of the Nobel Prize in Chemistry.
The original synthesis of tropinone (from which atropine can be made) involved so many steps that the total yield barely scraped 1%. This meant that only tiny amounts of the target compound could be made at any one time and large quantities of starting chemicals were needed. The greatest single improvement in this regard was made by Robert Robinson who devised a one-pot synthesis for tropinone dicarboxylate. This decomposes upon thermal acidification to yield tropinone. This meant that tropinone could be made by reacting succindialdehyde, methylamine and a salt of propanedicarboxylic acid in one step rather than in fifteen steps. This resulted in the yield increasing to levels in the region of 90%. The tropinone can then be reduced to tropine by treating with zinc in hydroiodic acid.
The synthesis of tropic acid was devised by Ward and MacKenzie. Treating acetophenone with potassium cyanide and acidifying in situ creates 2-hydroxy-2-phenylpropanoic acid. Further controlled heating, acidification with hydrochloric acid and treatment with potassium carbonate. An alternative synthesis of tropic acid involves reacting phenylethanoic acid with 2-propylmagnesium chloride in anhydrous conditions and bubbling methanal through the solution. So long as the apparatus is kept dry and air is kept away from the reaction, the net yield should be much higher, but it’s more expensive this way.
Atropine is made by heating tropic acid and tropine together, followed by standard isolation. A catalyst of a small quantity of hydrochloric acid is necessary to initiate the reaction. Atropine is effectively an ester of tropine and tropic acid.
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