First practical synthesis of enantiomerically pure (R)- and (S)-desmethylsibutramine (DMS) and unambiguous determination of their absolute configuration by single-crystal X-ray analysis

Article abstract of DOI:10.1016/S0957-4166(02)00086-1

A practical synthesis of enantiomerically pure (R)-desmethylsibutramine [(R)-DMS] and (S)-desmethylsibutramine [(S)-DMS] is outlined along with an improved synthesis of racemic desmethylsibutramine. This route was used for kilo-scale production of enantio

Full text of DOI:10.1016/S0957-4166(02)00086-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 107–109
First practical synthesis of enantiomerically pure (R)- and
(S)-desmethylsibutramine (DMS) and unambiguous determination
of their absolute configuration by single-crystal X-ray analysis
Zhengxu Han,a Dhileepkumar Krishnamurthy,a,* Derek Pflum,a Qun K. Fang,a Hal Butler,a
T. Stanley Cameron,b Stephen A. Walda and Chris H. Senanayakea,*
aChemical Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, MA 01752, USA
bDepartment of Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4J3
Received 13 September 2001; accepted 14 February 2002
Abstract—A practical synthesis of enantiomerically pure (R)-desmethylsibutramine [(R)-DMS] and (S)-desmethylsibutramine
[(S)-DMS] is outlined along with an improved synthesis of racemic desmethylsibutramine. This route was used for kilo-scale
production of enantiomerically pure (R)- and (S)-DMS. Racemic desmethylsibutramine was resolved with either (R)- or
(S)-mandelic acid, and the absolute stereochemistry of DMS was determined by single X-ray crystallography of its mandelate salt.
© 2002 Elsevier Science Ltd. All rights reserved.
Desmethylsibutramine (DMS) 1 is a pharmacologically
active metabolite of sibutramine 2, a new class of
compounds for the treatment of obesity.1 It has been
well documented that metabolites and/or enantiomers
often exhibit different biological activities and pharma-
cokinetics. In order to evaluate the effectiveness of
DMS towards attention deficit hyperactivity disorder
(ADHD) and depression, kilo quantities of both (R)-
and (S)-DMS in an enantiomerically pure form are
required.2 Recently, we reported the preparation of
enantiomerically pure (R)-DMS by demethylation of
corresponding (R)-sibutramine, which in turn was
obtained by resolution of ( )-sibutramine.3 Although
this method was useful in the preparation of multi-
gram quantities of enantiomerically pure sibutramine,
due to the use of potentially explosive diethyl azodicar-
boxylate (DEAD), application of this method to the
multi-kilo production of DMS was not desirable.
Herein, we report a short and efficient synthesis of both
enantiomers of DMS in enantiomerically pure form
using a direct resolution of ( )-1 with (R)- or (S)-man-
delic acid (Fig. 1).
scaleable process for the synthesis of ( )-1 and identifi-
cation of an inexpensive enantiomerically pure acid for
resolution of the racemic mixture.
Previously reported procedures for the synthesis of
( )-1 involve unoptimized and undesirable experimental
conditions with long reaction times.3–7 Therefore, this
second-generation synthesis begins with the identifica-
tion of a highly reproducible8 and scaleable synthesis
for ( )-DMS from the commercially available 1-(4-
chlorophenyl)-1-cyclobutylcarbonitrile
(CCBC)
3
(Scheme 1). The optimized procedure used the addition
of iso-BuMgCl to 3 at >105°C for 2 h, followed by
quenching with methanol. The intermediate imine 4 was
reduced using 1 equiv. of sodium borohydride at 0–
25°C for 1 h. Methylation of didesmethylsibutramine
(DDMS) 5 was carried out using a two-step protocol
NR1R2
To develop a practical route for the synthesis of enan-
tiomerically pure desmethylsibutramine, our synthetic
efforts focused on the development of a high yielding
Cl
1 R1=H, R2=CH3
2 R1=R2=CH3
* Corresponding authors.
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00086-1

108
Z. Han et al. / Tetrahedron: Asymmetry 13 (2002) 107–109
Scheme 1.
with the formation of formamide 6, followed by reduc-
tion with borane to afford ( )-1. This four-step, stream-
lined process provided an overall yield of 72% of
( )-1·HCl from 3 at multi kilo scale. The key features in
the synthesis follow. In the Grignard addition step, by
increasing the temperature of the reaction from 92 to
>105°C, the reaction time was reduced from 16 to 2 h.
In the reduction step, the amount of sodium borohy-
dride was reduced to 1 equiv. from 3 equiv., and the
temperature of the reaction was reduced to 0–25°C
from 90°C by replacing IPA with methanol.9
lected and washed with EtOAc/heptane to give a white
solid with 90–97% e.e. The salt was recrystallized from
EtOAc/heptane (1:1, v/v) in 90% yield and >99% e.e.
(R)-DMS·HCl salt ([h]D=+5, c 0.5, H2O) was prepared
from the diastereomerically pure mandelate salt ([h]D=
+5.3, c 5.8, CH3OH) by treatment with sodium hydrox-
ide followed by the addition of HCl/MTBE.10 The
enantiomeric excess (e.e.)11 of the (R)-desmethylsi-
butramine·(R)-mandelic acid salt was >99.7% with a
chemical purity of 99.8%. The overall yield for the
resolution process was 37–40%. The (S)-DMS was iso-
lated from the enriched mother liquor and was further
enriched with (S)-mandelic acid to give (S)-desmethyl-
sibutramine·(S)-mandalate (Scheme 2).12 The overall
yield for (R)-DMS from CCBC in this second-genera-
tion process was increased to 27 from 15%, with a
reduced number of isolations and reduced cycle time.
Once a scaleable method for the preparation of ( )-1
was developed, screening of resolving agents for the
resolution of ( )-DMS (e.g. tartaric acid, ditolyl tartaric
acid, dibenzoyl tartaric acid, and mandelic acid) in
various solvent systems (methanol, ethanol, ethyl ace-
tate, acetonitrile, isopropyl alcohol, water, hexane, hep-
tane and their combinations) was conducted. Mandelic
acid in ethyl acetate and heptane (1/0.4, v/v) was found
to be an excellent choice to resolve racemic desmethylsi-
butramine, as outlined in Scheme 2.
By slow crystallization of the (R)-desmethylsi-
butramine·(R)-mandelate salt (e.e. >99.5%) from
EtOAc/heptane, crystals suitable for X-ray structural
analysis were obtained. The structure of the (+)-
desmethylsibutramine·(R)-mandelate salt was found to
have (R)-configuration as determined from the X-ray
crystal structure (Fig. 2).
( )-DMS was treated with 1 equiv. of (R)-mandelic
acid in ethyl acetate and heptane at reflux for 1 h, then
cooled to approximately 60°C, seeded and further
cooled to 22°C. The resulting crystalline salt was col-
1.Cryst. w/EtOAc/heptane
1. NaOH/EtOAc
2. (R)-mandelic acid
2. NaOH
(R)-DMS.
(R)-MA
NHMe
NHMe
•HCl
3. HCl
•HCl
Cl
EtOAc/heptane
90-97% ee
Cl
(R)-DMS•HCl
(RS)-DMS•HCl
1. NaOH/EtOAc
2. (S)-mandelic acid
1. NaOH
2. HCl
(S)-DMS.
(S)-MA
(S)-DMS.
(R)-MA
NHMe
•HCl
3. Cryst. w/EtOAc/heptane
>99.9% ee
Cl
60% ee
(S)-DMS•HCl
Scheme 2.

Z. Han et al. / Tetrahedron: Asymmetry 13 (2002) 107–109
109
Figure 2. X-Ray structure of the (R)-DMS·(R)-mandelate salt ((R)-mandelic acid is omitted in the figure).
In summary, a practical resolution process for the
preparation of both enantiomers of enantiomerically
pure desmethylsibutramine was developed. This process
was used to prepare multi kilo quantities of enan-
tiomerically pure (R)-DMS and (S)-DMS. Based on
single-crystal X-ray structural analysis, the (+)-isomer
of the DMS·HCl salt has (R)-configuration. Current
efforts focus on the asymmetric synthesis of desmethyl-
sibutramine and its derivatives and the results will be
reported in due course.
3. Fang, Q. K.; Senanayake, C. H.; Han, Z.; Morency, C.;
Grover, P.; Malone, R. E.; Butler, H.; Wald, S. A.;
Cameron, T. S. Tetrahedron: Asymmetry 1999, 10, 4477.
4. Jeffery, J. E.; Kerrigan, F.; Miller, T. K.; Smith, G. J.;
Tometzki, G. B. J. Chem. Soc., Perkin Trans. 1 1996,
2583.
5. Butler, D. E.; Pollate, J. J. Org. Chem. 1971, 36, 1308.
6. Barkers J.; Michell C. S. WO 9,720,810, 1997.
7. Case, F. H. J. Am. Chem. Soc. 1934, 56, 715.
8. Recently, an article related to difficulties encountered
during the reproduction of the original work4 has
appeared: Reddy, G. O.; Sarma, M. R.; Chandrasekhar,
B.; Babu, J. M.; Prasad, A. S. R.; Haricharan Raju, C.
M. Org. Process. Res. Devel. 1999, 3, 488.
Acknowledgements
9. Use of IPA instead of methanol in the imine reduction
reaction requires vigorous reaction conditions with longer
reaction time.
We are grateful to Dr. Alex Jurgens and Dr. Jim
Hilborn from Sepracor Canada Limited for their con-
tribution to this work.
10. Gave satisfactory mp and [h]D values as reported in a
previous synthesis.3
11. Chirobiotic V column, 10 cm, 4.6 mm×25 cm. Mobil
phase: 20 mM ammonium acetate/IPA, (65:35). Reten-
tion time: R isomer 13.2 min, S isomer 14.8 min.
12. (S)-DMS·HCl gave satisfactory elemental analysis. Anal.
calcd for C16H25Cl2N: C, 63.57; H, 8.34; N, 4.63. Found:
C, 63.66; H, 8.39; N, 4.66%.
References
1. Buckett, W. R.; Thomas, P. C.; Luscomb, G. P. Prog.
Neuropsychopharmacol. Biol. Psychiatry 1988, 12, 575.
2. Young, J. W. PCT WO940047 and WO9400114.