Practical asymmetric synthesis of (+)-erythro mefloquine hydrochloride

Article abstract of DOI:10.1021/op200354f

A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as the hydrogen source. T

Full text of DOI:10.1021/op200354f

Article
pubs.acs.org/OPRD
Practical Asymmetric Synthesis of (+)-erythro Mefloquine
Hydrochloride
William P. Hems,† William P. Jackson,† Peter Nightingale,‡ and Rob Bryant*
†Creative Chemistry, I-64 Building 1, Brunel Science Park, Kingston Lane, Uxbridge UB8 3PQ, U.K.
‡Development Chemicals Limited, UK Operations, 34 The Drive, Orpington, Kent BR6 9AP, U.K.
ABSTRACT: A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been
developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as
the hydrogen source. The ratio of formic acid to NEt3 was found to be very important to achieving a highly efficient process.
efloquine is a highly efficacious antimalaria drug that is
approved in its racemic form for both treatment (in
asymmetric hydrogenation of KI using (S)XylBinap-RuCl2-
(S)Daipen, which gave the chiral alcohol in 88% ee, 92% yield
using 1 mol % of catalyst.6 These two reports provided
evidence for the asymmetric reduction approach we favored,
but we were worried by the economic issues of using both these
expensive Rh and Ru catalysts. Another outstanding catalytic
asymmetric reduction technology has been developed in recent
years for the enantioselective reduction of ketones. Mono-
sulfonated diamine Ru arene complexes, which utilize hydrogen
donors such as 2-propanol or formic acid, have been used to
reduce ketones with excellent enantioselectivities.7 In light of
the Merck result, we investigated whether transfer hydro-
genation (TH) would yield an efficient enantioselective
reduction process.
The pyridyl ketone KI was synthesized using known
literature procedures.8 When standard catalytic asymmetric
transfer hydrogenation conditions, using [(S,S)TsDpen]Ru(p-
cymene)Cl as the catalyst precursor were applied, the ketone
was reduced to the chiral alcohol in full conversion and in 96%
ee (Scheme 2). It was extremely gratifying to achieve such high
enantioselectivity, and so we continued to investigate the scope
of the reaction.
Amazingly, a screen of different solvents and catalysts led to
virtually no change in the enantioselectivity of the reaction. It
was pleasing to note that the use of TsDACH ligand9 in place
of TsDPEN resulted in equally excellent ee (96%), as this
added a cost benefit in terms of lower catalyst cost contribution
to the process.10 The parameter which had the most impact on
the reaction was the ratio of formic acid to NEt3. The results of
using different ratios of formic acid/NEt3 are summarized in
Table 1. We found that a narrow window existed in which the
reaction proceeded with exceptionally high TOF11 and
enantioselectivity. The reaction appeared fastest when the
molar ratio of formic acid to NEt3 was 1. Increasing the ratio
led to a much reduced reaction rate, but maintenance of the
enantioselectivity. Lowering the ratio to below 1 resulted in not
only a lower rate but also a lowering in ee. The optimized
conditions (s/c 1000,11 formic acid/NEt3 1:1, DMF, rt, 20 h)
were reproduced on 2 × 11 g input of pyridyl ketone KI, and
M
combination with artesunate) and prophylaxis (as monother-
apy) of malaria.1 The molecule contains two contiguous chiral
centres, which means that it can exist in four possible
stereoisomers (Figure 1).2 Larium, the Roche branded
formulation, contains rac-( )-erythro mefloquine HCl with
undetectable levels of the rac-threo stereoisomers. Although
rac-erythro mefloquine is an attractive antimalaria therapy, its
clinical utility has been compromised by CNS side effects. It
has been felt on theoretical grounds that these side effects
might be mainly a byproduct of the (−)-erythro stereoisomer.
In June 2009, Treague Ltd., a small biotech company based in
Cambridge, U.K., and Medicine for Malaria Venture (MMV3),
a specialist malaria funding charity, initiated phase 1 stage
clinical development of the single enantiomer (R,S)-erythro
mefloquine HCl for the treatment of malaria.
As part of that program, Development Chemicals Ltd./
Creative Chemistry were invited to identify manufacturing
options and to develop a process to provide single enantiomer
active ingredient for further clinical trials. The perceived benefit
of (+)-erythro mefloquine would be the lowering of the CNS
side effects and, therefore, better compliance. A higher dose,
however, makes the development even more sensitive to cost of
goods in that it is not desirable for the single enantiomer to be
of greater cost than the racemate. With the fact that the API
would be destined for use in combination therapies to be
dispensed in predominantly disadvantaged regions of the world,
MMV and Treague set a very tough target of half the cost of the
current racemate! Therefore, it was extremely important that a
cost-effective asymmetric synthesis of (+)-erythro mefloquine
was developed. Although the resolution of the rac-erythro
mefloquine has been reported, this route was discounted as
inevitably the route that produced material of at least twice the
cost of the racemate.4 It was interesting to note, however, that
the synthesis of rac mefloquine went via pyridyl ketone KI
(Scheme 1).
Roche has reported the Rh(bisphosphine) hydrogenation of
pyridyl ketone KI. The product carbinol was typically in the
range 82−92% ee in 84−92% yield.5 After asymmetric
reduction of the carbonyl moiety, the pyridyl ring was
hydrogenated using a heterogeneous Pt catalyst without
isomerisation. More recently, Merck has also published the
Received: December 5, 2011
Published: February 21, 2012
© 2012 American Chemical Society
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dx.doi.org/10.1021/op200354f | Org. Process Res. Dev. 2012, 16, 461−463

Organic Process Research & Development
Article
Figure 1. Stereoisomers of mefloquine.
Scheme 1. Retrosynthesis of Racemic Mefloquine
Scheme 2. Preliminary Result for the Catalytic Asymmetric
Transfer Hydrogenation of Pyridyl Ketone KI
In summary, we have developed a highly enantioselective and
cost efficient process for the synthesis of (+)-erythro
mefloquine. The key step is the enantioselective reduction of
pyridyl ketone KI using transfer hydrogenation with formic acid
as the hydrogen source. The ratio of formic acid to NEt3 was
found to be very important to achieving a highly efficient
process. The improvement from 88% ee to 98% ee is also
commercially very significant, and the key improvement was
achieved using a substantially different catalyst, which also
promotes a faster reaction. An 88% ee product could never be
registered for sale as a pharmaceutical product.
EXPERIMENTAL SECTION
■
Transfer Hydrogenation of KI. Experimental Procedure:
In a 500 mL 3-N flask equipped with a thermometer and an N2
bubbler was added DMF (120 mL). Triethylamine (20.8 mL,
0.15 mol) was then added to the stirred solution. Formic acid
(5.6 mL, 0.15 mol) was added dropwise while maintaining the
temperature below 30 °C. N2 was then bubbled through the
resulting solution for 5 min before the addition of KI (11 g, 3 0
mmol). The solution was stirred with N2 bubbling through for
a total of 30 min. Then the catalyst (16 mg, 30 μmol) was
added to the reaction mixture, and this was stirred at room
temperature (24 °C) overnight. The reaction was quenched by
the dropwise addition of water whilst cooling the reaction to
between 10 and 15 °C. During the addition of water the
product precipitated (120 mL of water was added in total). The
solid was collected and dried in a vacuum oven to give the
chiral alcohol as a colourless solid (10.1 g, 91% yield, 98% ee).
HPLC analysis using a Chiralcel OD column (hexane/EtOH:
0.025% Et2NH, 90:10). mp 133−134 °C (lit.5 135−136).
5% Pt/C Reduction of Chiral Alcohol. The 5% Pt/C (3.4
g) catalyst was placed in a glass autoclave with MeOH (100
mL). The mixture was heated to 55 °C under 2 bar hydrogen
for 1 h. The flask was cooled, and a solution of chiral alcohol
(22.25 g) in MeOH (120 mL) and conc HCl (6.5 mL) was
added to the catalyst mixture. The mixture was stirred under
hydrogen (2 bar) for 24 h. The hydrogen was released and the
catalyst filtered. The amount of MeOH was reduced by
the rate and selectivity were maintained to give complete
conversion in 20 h. The product was simply obtained directly
from the reaction mixture by the addition of water in 91%
isolated yield and 98% ee.
The final step in the sequence was the diastereoselective
reduction of the pyridine ring. In the Roche approach, this was
carried out using PtO2 as catalyst. The major disadvantage in
this approach, however, is the use of PtO2, due to its cost and
availability. We therefore focused on whether a standard Pt/C
catalyst would also achieve the same chemo- and diaster-
eoselectivity. A standard 5% Pt/C catalyst was taken and
preactivated under H2 at 40 °C in MeOH for 1 h, prior to the
addition of the chiral alcohol (98% ee) and conc HCl (1.1
equiv) (Scheme 3). The mixture was subsequently stirred
under H2 (2 bar) at rt for 24 h to give full conversion to the
desired mefloquine HCl in a 85:15 erythro/threo ratio.
Purification of the crude residue by selective crystallization
was carried out by literature procedures to give highly pure
(+)-erythro mefloquine HCl (>98% ee) in 58% isolated yield.12
An isolated yield of 58% was slightly lower than had been
hoped, although this is 70% of the theoretical yield of the 85:15
mixture obtained from the hydrogenation. Later development
of a simplified purification of the racemic salt gave an 80%
overall yield, demonstrating the potential for improvement, had
the project continued.
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dx.doi.org/10.1021/op200354f | Org. Process Res. Dev. 2012, 16, 461−463

Organic Process Research & Development
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Table 1. Effect of the Ratio of Formic Acid to Triethylamine on the Catalytic Asymmetric Transfer Hydrogenation of Pyridyl
Ketone KI
a
b
c
entry
HCOOH/NEt3 ratio
s/c
conv 2 h
%ee 2 h
conv 20 h
%ee 20 h
1
2
3
4
5
10:1
5:2
500
500
5
56
98
57
29
8
>98
>99
99
96
96
97
92
96
96
96
92
1:1
500
d
1:1
1000
1000
0.75:1
99
a
Reaction conditions carried out in a 100 mL 3-N flask with a N2 bubbler. HCOOH is added dropwise to NEt3 in DMF prior to addition of
b
c
d
substrate and catalyst. Substrate to catalyst ratio. % conversion and ee measured by HPLC analysis. 5 equiv of HCOOH/NEt3 was used in this
reaction.
Scheme 3. Diastereoselective 5% Pt/C Reduction of Chiral Alcohol
approximately half by rotary evaporation. Water (300 mL) was
added to the MeOH solution, resulting in precipitation of a fine
white solid. The mixture was heated to 80 °C slowly and kept at
that temperature for 30 min. The mixture was cooled to 5 °C
and kept at that temp for 2 h. The resulting mixture was then
filtered and the white solid dried in a vacuum oven. The dried
solid was recrystallised again from MeOH/water12 to give pure
(+)-mefloquine HCl (14.4 g, 58% yield, >99% ee). HPLC
analysis of free base using a Chiralpak AD column (hexane/
EtOH: 0.025% Et2NH, 98:2). mp 170−171 °C (lit.5 170.5−
171.0).
REFERENCES
■
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(9) TsDACH: N-(p-toluenesulfonyl)-1,2-diaminocyclohexane.
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(S,S)TsDPEN 1 g £136.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rob@developmentchemicals.co.uk.
(11) s/c, substrate to catalyst molar ratio; TOF, catalyst turnover
frequency.
(12) Bomches, H.; Hardegger, B. (Hoffmann-La Roche). Purification
of Mefloquine Hydrochloride, US Patent 4,507,482, 1985.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Robert Tansley of Treague Ltd for awarding the
contract to Development Chemicals Ltd and Dr. Timothy
Wells of MMV for funding the project.
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dx.doi.org/10.1021/op200354f | Org. Process Res. Dev. 2012, 16, 461−463