Starting from the Racemate

Published by MatTodd on 29 November 2007 - 12:15pm
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There are two general ways to generate enantioenriched PZQ starting from the racemate - either by destroying the stereocentre, or not.
1. Destroying the stereocentre, then reinstating it (a "stereoablative" approach). Craig Williams suggested this interesting possibility: take rac-PZQ and oxidize to the enediamide 2. This allows a catalytic, asymmetric hydrogenation to give (R)-PZQ. This is attractive because asymmetric hydrogenations are efficient, and both enantiomers of rac-PZQ can be taken through to the enantiopure material.
Craig's Suggestion
Craig's Suggestion
This is a great suggestion. According to the original review of PZQ by Peter Andrews et al., a similar idea is contained in the original patent literature on PZQ. The reference is "J. Seubert, German Pat. Appl. 2,418,111". I tracked down this patent, and it's unsurprisingly in German. While I can order a beer in German and ask the way to the cinema, I can't translate this. Does anyone with some German have some time to extract relevant information from this patent and give the conditions that were used for the generation of the enediamide, and whether this was done on PZQ or an analog? I'll post it below. [update - translation now shown below]
We have started to look at the oxidation reaction to the enediamide, but need help with this reaction. [update - this approach has now been given its own page here]. The review has no experimental details - but the reaction has been published in...[need reference]
2. Resolution
According to the same review above, intermediates in the synthesis of PZQ (3 and 4 below) could be resolved. (PZQ itself presumably cannot, unless anyone has any bright ideas). Obviously this is a less attractive approach than a catalytic, asymmetric synthesis of such intermediates. However, the unwanted enantiomer, after conversion to (S)-PZQ, can be transformed to the enediamide 2 and hydrogenated to rac-PZQ. This therefore converts the inactive enantiomer of PZQ to rac-PZQ, giving another 25% yield of the desired enantiomer.
Resolvable intermediates
Resolvable intermediates
The review describes this process without specifiying what R is (where for PZQ it's cyclohexanoyl).
For the resolution via 4 to be effective, this molecule either needs to be synthesised from scratch, or it can be made from PZQ. For an industrial approach, it is probably best to simply make this molecule from scratch, as in the current industrial synthesis, but either way can easily be used to generate quantities of 4. What is needed now is a robust method for the resolution of amine 4. This idea now has its own page here.

Comments

Hi Mat,

 

I am currently working at the University of Queensland as a post-doc with Craig Williams. He asked me if I wouldn't mind translating the Seubert patent posted on this site. Since there is a large amount of information (although not very detailed) scattered throughout the whole document, I decided to provide a literal translation covering the full document.

 

While I worked to the best of my ability, I am not a professional translator and cannot take responsibility for any mistakes I might have made.

 

I hope this will help in your endavours.

Kind regards,

Heiko

--- cut here ---

 

2-Benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline

This inventions regards the new
2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]­isoquinoline.

This compound shows important
pharmacological properties, e.g. it can positively influence the circulation
and the psyche. Furthermore, it is an important intermediate in the production
of the antihelminthic agent 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]­isoquinoline and the
two optical antipodes thereof, which are important in the treatment of Bandworm
and Schistosomiasis.

The aim of this invention was to
find a new substance, which can be used as a drug. A further task was to find a
new procedure to produce the pharmacologically active
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline
and its (–)-antipode, respectively.

It was found, that the
2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline,
while being very biocompatible, showed valuable pharmacological properties. For
instance, it acts positively onto the heart and the circulation [this can be
detected by the method of Lochner and Oswald (Pflügers Archiv der gesamten
Physiologie, Band 281, pp 305–308,
1964)], but shows also psychotropic activity. Furthermore it was found, that
the 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline
is perfectly suited as an intermediate in a two step procedure for producing
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline.
This procedure relies on the observation that the optical anti­podes of
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline
with respect to their pharmacological properties; namely, the antipode rotating
the light to the left displays higher activity than the racemate, whereas the
other antipode is less active. It was therefore highly desirable to find a
method through which the (+)-antipode of
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline
could be transformed into the more active racemate or even better into the
highly active (–)-antipode of 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline.
According to the present invention, this problem can be solved by converting
the (+)-antipode of 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline with
sulfur or another dehydrogenating agent into
2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline
and then transform this optically inactive intermediated via hydrogenation
under usual conditions into the more active racemic form or via asymmetrical
hydrogenation into the desired (–)-antipode. Of course, it is possible to
transform the already active racemic form of
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline
via the two-step procedure of dehydrogenation and subsequent asymmetrical
hydrogenation into the particularly active (–)-antipode of 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]isoquinoline, as well.

Thus, the
2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline
can be used as a drug by itself or as an intermediate in the production of
other drugs.

The subject of this invention is
accordingly 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline and a procedure for its production,
which is to react the (+)-antipode or the racemate of
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline
with an dehydrogenating agent e.g. sulfur.

Another important aspect of this
invention is the utilisation of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline in the
production of the racemic form or the (–)-antipode of
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline
via conventional or asymmetric hydrogenation, respectively. Furthermore a
two-step procedure is of importance, in which the (+)-antipode or the racemate
of 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline
is dehydrogenated and the resulting 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline is subsequently
subjected to a conven­tio­nal or asymmetric dehydrogenation.

According to the procedure described
in this invention, it is possible to selectively dehydrogenate
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline
or its antipodes to obtain 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline, without
observing dehydrogenations on other parts of the ring system. This unambiguous
course of reaction was not to be expected and therefore represents another
important aspect of this invention.

Sulfur is preferably used as the
dehydrogenating agents according to this invention, although also selenium,
platinum-, palladium-, nickel- or cobalt-catalyst (either in their metallic
form or on the surface of carriers like charcoal, calcium carbonate or
strontium carbonate), or selenium dioxide, manganese dioxide, dialkyl
disulfides, e.g. diisoamyl disulfide, quinones, e.g. benzoquinone,
tetrachloro-1,2-benzoquinone, tetrachloro-1,4-benzoquinone or other mildly
working oxidizing agents, e.g. iron trichloride or nitrobenzene, could be used.
In addition, silver- and copper-catalysts, either on their own or as mixed
catalysts, cobalt-charcoal-catalysts, nickel-aluminium oxide-catalysts as well
as a multitude of other mixed catalysts, which have been described in
literature for dehydrogenation reactions, can be used as dehydrogenating
agents.

The dehydrogenations using sulfur or
selenium are preferably conducted with one equivalent of sulfur or selenium,
respectively, since side-reaction could interfere when using excesses of these
reagents. The reactions are performed between approx. 140 and 300 °C for about 1
to 100 hours. Usually the reaction is performed in the molten state, otherwise,
high-boiling solvents, e.g. mesitylene, p-cumene,
naphthaline, quinoline, acetanilide, dimethyl formamide or other high-boiling
aromatic compounds, are added. The usage of sulfur and dimethyl formamide
proved to be particularly effective.

The dehydrogenation with metal- or
metaloxide catalysts is performed in the molten state, as well. Reaction times
and –temperatures vary within wide margins, thus temperatures between 100 and
350 °C and reaction times between 5 and 100 hours may be necessary.

Dehydrogenations with quinones like chloranil
take place under milder conditions. Heating of the starting material in the
presence of one of the aforementioned quinones in inert solvents, e.g. benzene,
toluene, xylene or tert-butanol,
furnishes the desired product at temperatures between 70 and 150 °C.

The starting material, i.e. (+)-2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline, can be
obtained by e.g. exposing the known racemic (±)-2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline to a
methanolic solution of hydrogen chloride and subsequent heating furnishing
(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline.
This base should then be resolved in the usual way by reacting with an
optically active acid and finally the pure (+)-antipode benzoylated. Following
this procedure, the (–)-antipode of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline is also
obtained, which can be transformed into the pharmacologically highly active
(–)-2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline by benzoylation.

2-Benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline can be
formulated as mixtures with solid, liquid and/or semi-solid excipients for
human or veterinary use. Both organic and inorganic substances can be
considered, which need to be suitable for parenteral or enteral application and
not reacting with the active agent. Examples of these include water, vegetable
oils, polyethylene glycols, gelatin, lactic sugar, starch, magnesium stearate,
talc, vaseline, cholesterol and so on. For parenteral application, oily or
aqueous solutions or suspensions or emulsions may be used. Suitable for enteral
application are tablets, dragées, syrups or juices. The formulations can be
sterilised or mixed with stabilising or surface-active agents, osmotic salts,
buffers, colours, or flavour additives.

Usual doses of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline range
between 2 and 100 mg per unit. Depending on the weight of the patient and the
method of application, but also on the species and its individual response
towards the drug, or its method of application and the time and interval of
application this dosage may vary within wide ranges.

2-Benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline may also
be used as an intermediate during the production of the pharmacologically valuable
racemic
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline. This
transformation requires a reduction, preferably by catalytic hydrogenation.
Suitable catalysts include the known precious metal catalysts, but also
copper-chromium-oxide as well as nickel and cobalt catalysts. The precious
metal catalysts can be used on carriers (e.g. palladium on charcoal), as oxides
(e.g. platinum oxide) or as finely divided metals (e.g. platinum sponge).
Nickel and cobalt catalysts will be best used in form of their Raney-metals,
nickel also on diatomaceous earth or pumice as carrier substances. The
hydrogenation can be performed at atmospheric pressure and room temperature or
under higher pressure (up to about 200 atmos) and/or at elevated temperatures
(up to about 200 °C). Usually these hydrogenations are performed in the
presence of a solvent, preferably an alcohol, e.g. methanol, ethanol,
isopropanol or tert-butanol, ethyl
acetate, ethers, e.g. dioxane or tetrahydrofuran, water and/or aqueous alkali.
If desired, the hydrogenation can be performed in homogeneous phases. Suitable
catalysts for this method include among others complexes of heavy metals, e.g.
soluble rhodium complexes such as hydrido-carbonyl-tris(triphenylphosphine)
rhodium.

The reduction of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline may be
influenced by asymmetric hydrogenolysis so as to obtain only or mainly the
(–)-antipode of
2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline.
Suitable catalysts include Raney-nickel, which had been modified by asymmetric
reagents, the preparation of which is described e.g. in Angew. Chemie 1971, 83, 956–966. As modifying agents,
aqueous solutions of
a-hydroxy and a-amino acids have been used, e.g. solution of alanine, isoleucine,
lysine, phenylalanine, valine, leucine or the corresponding hydroxy compounds,
bearing a hydroxy function instead of an amino group, as well as optically
active tartaric acids, citric acids and derivatives thereof. The conditions for
the asymmetric hydrogenations with chirally modified Raney-nickel match the
given conditions for the normal hydrogenation, however, lower pressures (e.g. 1
to 3 atmospheres) and lower temperatures (e.g. 20 to 50 °C) are preferred.

Furthermore, heavy metals which have
been adsorbed onto naturally occurring or synthetically prepared polymers, e.g.
silk-palladium-catalysts or palladium or platinum catalysts on specially
prepared silicalgel or polyaminoacid carriers, which have been described in the
literature, can be used as heterogeneous catalysts in the asymmetric
hydrogenation.

It is also possible to perform the
asymmetric hydrogenation in homogenous phases. Soluble asymmetric complexes of
heavy metals, e.g. rhodium, can be used. An example for such a catalysts is the
complex formed from 0.5 moles chloro-bis(ethylene) rhodium(I) dimer and
1 mole (+)-2,3-isoproylidenedioxy-1,4-bis(diphenylphosphino)butane under
an inert atmo­sphere and exclusion of oxygen in an inert solvent as benzene.
The hydrogenation can be conducted at room temperature; reaction times between
10 minutes and 24 hours are necessary, most suitable are times between 30
minutes and 6 hours.

Example 1:

(+)-2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline {30.6 g;
prepared from racemic 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline by
exposing to methanolic hydrogen chloride solution and subsequent heating,
resolution of the resulting
(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline
into its antipodes with an optically active acid and finally benzoylation of
the (+)-antipode of this base in the usual manner} and sulfur (3.2 g) were
heated for 2 hours to 180 °C. The reaction mixture was purified by
chromatography on silica gel (eluting with chloroform) to give
2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline; m.p.
167–168 °C (from ethanol).

Example 2:

According to example 1, 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline (m.p.
167–168 °C) has been obtained from racemic 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline by
reaction with sulfur.

The following examples show the
usage of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline as an intermediate.

Example 3:

A solution of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline (304 mg)
in methanol (40 mL) was hydrogenated in the presence of platinum dioxide (300
mg) at atmospheric pressure and room temperature. Subsequently, the solvent was
evaporated to obtain racemic 2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline; m.p.
161 °C (from ethanol / diethyl ether).

Example 4:

A solution of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline (304 mg)
in methanol (40 mL) was hydrogenated in the presence of Raney-nickel (300 mg),
which had been modified with (–)-tartaric acid (see
Angew. Chemie 1971, 83, 956–966), at atmospheric pressure and room
temperature. Subsequently, the solvent was evaporated, the residue was taken up
in chloroform and the resulting solution was washed with diluted sodium
hydroxide solution and water. After evaporation of the solvent, (–)-2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline was
obtained; m.p. 159–160 °C (from ethanol / diethyl ether); [
α]D20 = –10°
(in ethanol).

CLAIMS

  1. 2-Benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline
    having the following constitution

(( see structure in the original document))

  1. A
    procedure for the preparation of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline,
    which is characterised by reacting the racemic form or the (+)-antipode of
    2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino­[2,1-a]­isoquinoline with a dehydrogenating agent.
  2. The
    procedure according to claim 2, which is characterised by the use of
    sulfur as dehydrogenating agent.
  3. Pharmaceuticals
    which contain 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline.
  4. Procedures
    for the production of pharmaceutical formulations, characterised by using
    an effective dose of 2-benzoyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino­[2,1-a]­isoquinoline and
    optionally one or more of a solid, liquid or semi-solid carrier or
    additive to obtain a suitable form for administration.

 

MatTodd's picture

Heiko,

Thanks - this is really useful. Buried in patents there's usually some useful preparative information. We'll take a look at some of this and report back on what we find. Anyone else should of course feel free to try out some of this chemistry it it's of interest. Our preliminary literature searching indicate that oxidations on similar ring systems are quite rare.

Thanks again for a wonderful effort, Heiko. Ausgezeichnet!

Mat

MatTodd's picture

We have been spending a little time on this idea of an oxidation-then-reduction of PZQ. The first step to give the dehydro-PZQ is not pleasant, but goes OK. The bizarre issue we are faced with now is the difficulty of the reduction. Achirally, this goes fine under regular hydrogenation conditions (Rh/C). As soon as we add in a chiral ligand, however, we get no reaction at all (good recovery of starting material). We have tried the usual suspects for this reaction (e.g. RuCl3/BINAP, RuCl[(p-cymene)(BINAP)]Cl). A check of the literature reveals no cases of an asymmetric reduction of a double bond between two amides like this.

There may well be good mechanistic reasons. My gut feeling is that the double bond is electron-rich and quite polarised, as well as being fairly hindered. But the rac reaction goes fine!

We are searching around for alternative catalysts. I hope soon to be able to announce an exciting contribution to this project from a major chemical supplier. In the meantime, my question for asymmetric hydrogenation experts out there (particularly from industry) is: what catalyst ought we to be trying for a double bond like this? Cheers, Mat