Current Projects for Schistosomiasis

Published by MatTodd on 29 January 2006 - 12:35pm

Comments

Dear Matt,

I thought I would act on your suggestion of up-dating "the synaptic leap" about an idea I had regarding your goal of making enantio pure praziquantel for under 24c/gram.

For the readers Matt and I made up part of an Australian delegation to the Shanghai Institute for Organic Chemistry at which all participants presented a short lecture on their current research activities. Matt presented an excellent lecture on his goal to synthesise praziquantel for under 24c/gram for the purpose of curing the 400 million people in the third world suffering from the most serious disease schistosomiasis.

When Matt was giving his talk he detailed his exhaustive efforts to synthesise enantio pure praziquantel. In typical organic chemist style I looked at the target molecule and looked for viable disconnections (retrosynthesis). I wasn't surprised, I couldn't find any that Matt hadn't already thought of. Then I had a good hard look at commercial praziquantel (racemic) and the target enantio pure praziquantel at which moment I recognised the only difference was the chiral centre (that sounds simplistic I know but was considered at a higher level). This suggested to me that if the chiral (racemic) centre could be destroyed and then re-established using a chiral format Matt would have a good chance of solving his problem (which later dawned on me that his problem solved meant another 40 million people could be treated with Gates funding). I then put up my hand and suggested commercial praziqunatel could be oxidised at the
stereogenic centre (racemic) to give a double bond which could then be reduced enantio selectively giving enantio pure praziquantel in two steps most likely under 24c/gram.

Matt, I hope that this suggestion benefits your efforts to help the
many suffers of this disease.

I wish you much success in this regard.

Regards,

Craig

MatTodd's picture

This is a new project idea for the synthesis of (R)-PZQ, so I'll start a new page here. And now

here

.

In connection with your idea of oxidation rac praziquantel to an analog with double bound you should see the publication

Arch. Pharm. (Weinheim) 322,795-799 (1989) where appropriate procedure for oxidation PZQ is described:

The mixture of 0.312 g (1 mmol) of 2 and 0.032 g (1 mmol) of sulphur was melted under N2 at 180°C for 2 h. The obtained dark oil was purifiedby cc (15 g) using CHCl3 : AcOEt (1:l) as a developing system. Fractions 6-8 were evaporated, recrystallized (diethyl ether, hexane) to afford 0.1 18 g of 6 (38%), M.P. 128-132OC. Rf l(0.80). 11 (0.56), 111 (0.66).- ClgH22N202(310.4) Calcd. C 73.5 H 7.15 N 9.0 found C 73.3 H 7.23 N 8.9.- IR: 3450;2960; 2880 1680; 1650 1425; 1315; 770 cm-'.- 'H-NMR (MeOD + CDCl3): 1.10-1.90(m; 10H.cyclohexyl); 2.64-2.72 (m; lH, H-13); 2.85 (1; (m; 4H, Ar-H); 7.44-7.58 (m; IH, H-l).- EI-MS: 310(M+', 24), 199(100). 171(98), 144(38). 130(26), 115(66), 103(20), 83(99), 55(99).J=8 Hz, 2H, H-7); 3.80 (ti J=8 Hz, 2H. H-6); 4.74 (s; 2H, H-3); 7.10-7.30.

Have a nice reading

Piotr Roszkowski

MatTodd's picture

Thanks, Piotr. Yes, we have this paper, and we've been having a go at the reaction - it's not the world's best procedure, it has to be said. Though sulfur does fit the bill as an inexpensive reagent. Any ideas for another reagent that might do this transformation? We've tried a few standard lab oxidising agents without much luck - we'll report on these fully in a short while.

Mat