New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS)

Article abstract of DOI:10.1016/j.tetasy.2003.08.042

An improved synthesis and efficient resolution method to prepare both enantiopures of DDMS using crystallization of enantiomerically pure tartaric acid salts of racemic DDMS are disclosed.

Full text of DOI:10.1016/j.tetasy.2003.08.042

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3553–3556
New resolution approach for large-scale preparation of
enantiopure didesmethylsibutramine (DDMS)
Zhengxu Han,* Dhileepkumar Krishnamurthy,† Q. Kevin Fang, Stephen A. Wald and Chris
H. Senanayake*,†
Chemical Research and Development, Sepracor Inc., 84 Waterford Drive, Marlborough, MA 0175, USA
Received 15 July 2003; accepted 28 August 2003
Abstract—An improved synthesis and efficient resolution method to prepare both enantiopures of DDMS using crystallization of
enantiomerically pure tartaric acid salts of racemic DDMS are disclosed.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
diastereomeric salts that were formed by treatment of
racemic amine with a homochiral acid in a solvent
system.6 Due to the fact that resolutions normally are
highly sensitive to both solvent systems and impurities,1
amines should be purified before use either by distilla-
tion, precipitation, or crystallization. Furthermore, this
method is not desirable because additional steps have
to be conducted, and it is limited if the purification of
amine by distillation or precipitation is not successful,
as in the case for DDMS free-base.
Didesmethylsibutramine (DDMS) 1b represents one of
the sibutramine 1a metabolites (Fig. 1)1–3 that was
reported to be a more potent noradrenaline and sero-
tonin reuptake inhibitor than the parent sibutramine
itself.4 Preliminary studies showed that the two enan-
tiomers of DDMS exhibit different biological activi-
ties.5 In order to support the preclinical studies, larger
quantities of both enantiomers of DDMS were
required. To meet this requirement, an efficient and
scalable process leading to the production of multi-kilo-
grams of enantiomeric pure (R)- and (S)-DDMS was
needed.
Herein, we disclose a new strategy for efficient produc-
tion of both enantiomers of DDMS by combining
isolation, purification, and salt formation resolution in
one-step, in which chemically pure racemic DDMS is
isolated from the reaction mixture as a salt of enan-
tiomerically pure tartaric acid to perform simple crys-
tallizations, to provide both enantiopure (R)- and
(S)-DDMS.
2. Results and discussion
Figure 1.
Initial efforts were focused on the development of
a
feasible method for the large-scale production
Traditionally, in the preparation of enantiopure chiral
amines using resolution methods, fractional crystalliza-
tion was commonly used to separate the two
of racemic DDMS. Previously reported procedures for
the synthesis of DDMS involved unoptimized and
undesirable experimental conditions.1,7 The reaction
was performed by Grignard addition to 1-(4-
chlorophenyl)-1-cyclobutylcarbonitrile (CCBC) 2 in tol-
uene at 90–95°C for 18 h, followed by reduction using
3 equiv. of NaBH4 in iso-propanol under reflux-
* Corresponding authors. Tel.: 508-357-7420; fax: 508-357-7808;
e-mail: steve.han@sepracor.com
† Present address: Bohringer-Ingelheim Pharmaceutical Inc., 900
Ridgebury Rd., Ridgefield, CT 06877, USA.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.042

3554
Z. Han et al. / Tetrahedron: Asymmetry 14 (2003) 3553–3556
ing for >20 h, and the reaction was quenched with
water to furnish the product. This protocol proved
unsatisfactory for large-scale production with the fol-
lowing associated problems: (1) long reaction time; (2)
moderate yield (<80%); and (3) inefficient reaction
quenching after reduction process, in which conglomer-
ation occurred in the reaction mixture making the
agitation difficult, and the hydrogen evolution uncon-
trollable. Therefore, a practical and reliable process was
desired for large-scale production of racemic DDMS.
The acid used should also meet the requirement of a
typical resolving reagent. Isolation of the salt in a
racemic form is important for producing both enan-
tiomers in a high chemical purity and yield.
After screening a number of enantiomerically pure
acids (e.g. tartaric acid, mandelic acid, ditolyl tartaric
acid), tartaric acid was found to be an excellent choice
for the isolation of DDMS from the reaction mixture.
Racemic DDMS in toluene was treated with
D-tartaric
acid (D-TA) in a water/acetone (2:1, v/v) mixture by
slow addition at 60–70°C, and the mixture was then
distilled under azeotropic condition to remove the
water, which included the salt formation with 0% de.8
The key features for this process follow. The addition
of acetone with water and controlling the addition
temperature allows the generation of a homogeneous
reaction mixture, and facilitates the salt formation.
Removal of water from the reaction mixture gradually
also benefits the salt formation and the yield. This
three-step streamline process (Scheme 1) provides an
overall yield of 95% of DDMS·D-TA 4 with 98%
chemical purity in a multi-kilogram scale.8,9
After a series of experiments an optimum procedure
was established, which uses the addition of iBuMgCl to
2 at >105°C for 2 h, followed by quenching with
methanol. The imine intermediate 3 was reduced using
one equivalent of NaBH4 at 0–25°C for 1 h. An
efficient quenching process was identified by adding the
reaction mixture to a 2 M HCl aqueous solution at 0°C,
which generated a homogeneous reaction mixture that
can be easily stirred. After work-up, this optimized
process afforded a crude racemic DDMS 1b in toluene
with excellent yield (>95%), The optimized experimen-
tal conditions proved highly desirable for large-scale
production (Scheme 1).
With 4 in hand, we focused on developing a solvent
system to separate the two diastereomers for (R)-
DDMS·D-TA 6a and (S)-DDMS·L-TA 6b by crystal-
lization (Scheme 2). Screening of different solvents and
solvent mixtures led to the discovery that the ACN/
H2O/MeOH combination was an excellent choice for
the resolution, which afforded 6a in optically enriched
form 5.8 Detailed studies show that the ratio of sol-
vents, the amount of water used, and the isolation
temperature have an impact on the diastereopurity and
Once a scalable method for the preparation of racemic
DDMS was developed, our efforts were directed
toward the isolation of DDMS free-base from the
reaction mixture. Isolation of DDMS by salt formation
with inorganic acids proved unsatisfactory. The salts
were either soluble in toluene, or precipitates were not
formed. With this problem, we sought a different strat-
egy for the isolation by using enantiomerically pure
acid.
Scheme 1.
Scheme 2.

Z. Han et al. / Tetrahedron: Asymmetry 14 (2003) 3553–3556
3555
yield of the product (see below). An optimized system
gave crude product 5 in 90% ee and 35% yield on a
multi-kilogram scale, in which ACN/H2O/MeOH was
used in a ratio of 8:1.3:0.5 (v/v/v)/ g salt, and the
isolation temperature was 20–25°C. Diastereomerically
pure (R)-DDMS·D-TA (>99.5% ee, [h]2D0=+58.7, c 1.0,
DMF) 6a10 was obtained by one additional crystalliza-
tion of 5 from the optimized solvent system of ACN/
H2O/EtOH (16:2:1, v/v/v) in 85% yield. The addition of
ethanol to the system was found to be crucial for
obtaining diastereopure product with single minimum
crystallization.
salt. This process was used to prepare multi-kilogram
quantities of (R)-DDMS and (S)-DDMS in an enan-
tiomerically pure form. Current efforts are focused on
the asymmetric synthesis of DDMS and the results will
be reported in due course.
3. Experimental
3.1. Preparation of (RS)-DDMS·D-TA
A 1 L three-necked round-bottomed flask was charged
with
1-(4-chlorophenyl)-1-cyclobutylcarbonitrile
As mentioned above, while the solvent ratio and
amount of solvents used are crucial for high yield and
high de of the final product in the crystallization pro-
cess, water content also has a high impact. To investi-
gate this effect, we undertook a systematic study, and
the result is shown in Figure 2. In this study, 80% ee of
(R)-DDMS·D-TA was used as the starting material,
and the solvent ratio of ACN/EtOH of 16:1 (v/v) and
the total amount of solvent (19 mL/g salt) were kept
constant. The result shows that ee increases with the
increase % of water, peaks at approx. 10.5% of water,
and then decreases slightly. The yield, on the other
hand is very sensitive to water, and decreases dramati-
cally as the % of water is increased. With only one
recrystallization, this procedure affords the final
product with excellent ee and yield.
(CCBC, 50.0 g, 261 mmol) and toluene (150 mL),
followed by iso-butyl magnesium chloride (395 mL, 1.0
M in MTBE), and the resulting mixture was distilled
until the internal temperature reached ]105°C. After
stirring at that temperature for 2 h, the mixture was
cooled to 0°C and methanol was added slowly (295
mL), followed by sodium borohydride (10.4 g, 1.06
equiv.) portion-wise. The resulting mixture was stirred
at rt for 15 min and was added to a 2N HCl solution
(330 mL) slowly, stirred for 15 min and the phases were
separated. The aqueous phase was extracted with tolu-
ene (300 mL), the combined organic phases were dis-
tilled to remove methanol, and then washed with
aqueous NaOH solution (1.5 M, 100 mL) and water
(100 mL) twice. The resulting organic phase was heated
to 50–60°C, followed by an addition of
D-tartaric acid
(40.0 g) in water (80 mL) and acetone (40 mL) slowly.
The reaction mixture was azeotrope distilled until the
internal temperature reached ]92°C and then cooled
to ambient temperature in 1–2 h. The slurry was
filtered, and the wet cake was washed with MTBE (100
mL) and dried at 40–45°C under reduced pressure to
afford (RS)-DDMS·D-TA (100.5 g) in 95.8% yield.
3.2. Preparation of (R)-DDMS·D-TA
A mixture of (RS)-DDMS·D-TA (50 g), acetonitrile
(400 mL), water (70 mL) and methanol (33 mL) was
heated to reflux for 30 min and then cooled to 64–66°C.
The reaction mixture was seeded with (R)-DDMS·D-
TA (0.5 g, >99% ee) and stirred for 15 min. After being
cooled to 25°C in about 60 min, the slurry was filtered
and the wet cake washed with the solvent mixture (30
mL), acetonitrile (50 mL×2), and then dried to afford
crude (R)-DDMS·D-TA (17.5 g) in 90% ee. After one
recrystallization of the above product from acetonitrile/
water/ethanol (280 mL/43.7 mL/18 mL) provided
diastereomerically pure (R)-DDMS·D-TA (14.8 g) in
99% ee10 and 30% overall yield. [h]2D0=+58.7, (c 1.0,
Figure 2.
The (S)-DDMS was isolated from the mother liquor
containing enriched (S)-DDMS·D-TA, which was
treated with base and then switched to the L-TA salt to
afford crude (S)-DDMS·L-TA 8 in 50% ee and 40%
yield. After two crystallizations, using the same solvent
system as described above gave the final product (S)-
DDMS·L-TA 6b, [h]2D0=−53.4, (c 1.0, DMF) in >99.5%
de and 85% yield.
1
DMF). H NMR (DMSO-d6): l 0.7–0.9 (m, 6H), 0.9–
1.05 (t, 1H), 1.1–1.24 (b, 1H), 1.5–1.8 (b, 2H), 1.8–2.02
(b, 1H), 2.1–2.4 (3, 3H), 2.4–2.6 (b, 1H), 3.5 (m, 1H),
4.0 (s, 2H), 7.1–7.6 (m, 4H, with 6H from NH2, OH
and COOH). 13C NMR l: 15.4, 21.5, 22.0, 22.2, 32.0,
32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0,
175.5. Anal. calcd for C19H28ClNO6, C, 56.78; H, 7.02;
Cl, 8.82; N, 3.49. Found: C, 56.08, H, 6.98, N, 3.61, Cl,
8.86.
In summary, a new and efficient resolution method for
the preparation of both enantiomers of enantiomeri-
cally pure didesmethylsibutramine (DDMS) was devel-
oped by simple crystallization of racemic DDMS·TA

3556
Z. Han et al. / Tetrahedron: Asymmetry 14 (2003) 3553–3556
3.3. Preparation of (S)-DDMS·L-TA
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 (23),
4477–4480.
The mother liquor from the preparation of (R)-DDMS
was treated with NaOH and after work-up, the free-
base was treated with L-tartaric acid to afford L-tartrate
4. Stock, M. J. Int. J. Obesity 1997, 21(Supp. 1), S25–S29.
5. Senanayake, C. H. and Fang, Q. K. US patent WO
00/10555, 2 March, 2000.
6. Kozma, D. Optical Resolutions via Diastereomeric Salt
Formation; CRC Press, 2002.
7. Jeffrey, J. E.; Kerrigan, F.; Miller, T. K.; Smith, G. J.;
Tometzki, G. B. J. Chem. Soc., Perkin Trans. 1 1996,
2583–2589.
8. Enantiopurity of DDMS was based on chiral HPLC
analysis with Chiralpak AD-RH column, 5 mm, 4.6 mm×
15 cm; mobile phase, 20 mM sodium borate (pH 9)/ACN
(25:75); 1.0 mL/min; 222 nm; (R)-DDMS, rt=9.46 min;
(S)-DDMS, rt=7.53 min.
salt with 50% ee and in 40% yield, using the same
method described above. After one crystallization of
the salt from acetonitrile/water/ethanol (16:2:1), the
solvent mixture afforded (S)-DDMS·L-TA in 99% ee
and 34% overall yield. [h]2D0=−53.4, (c 1.0, DMF).
1
NMR (DMSO-d6): H NMR l 0.7–0.9 (m, 6H), 0.9–
1.05 (m, 1H), 1.1–1.3 (b, 1H), 1.52–1.8 (b, 2H), 1.84–
2.05 (b, 1H), 2.15–2.4 (b, 3H), 2.4–2.6 (b, 1H),
3.65–3.58 (m, 1H), 4.0 (s, 2H), 6.7–7.3 (b, 6H from
NH2, OH and COOH) 7.1–7.6 (m, 4H). 13C NMR l:
15.4, 21.5, 22.0, 22.2, 32.0, 32.2, 38.4, 49.0, 54.0, 72.8,
128.8, 130.0, 132.0, 143.0, 175.5. Anal. calcd for
C19H28ClNO6, C, 56.78; H, 7.02; Cl, 8.82; N, 3.49.
Found: C, 56.12; H, 7.00; N, 3.57; Cl, 8.77.
9. Chemical purity analysis for DDMS was performed on
achiral HPLC with agilent SB-CN column, 5 mm, 4.6×150
mm; mobile phase, 0.05 M NaH2PO4–0.01 M sodium
octyl sulfate buffer, pH 3/THF, 60:40; 1.0 mL/min; 222
nm.
References
10. Determination of the absolute configuration of (R)-
DDMS or (S)-DDMS was achieved by converting
DDMS to desmethylsibutramine (DMS) by methylation,
followed by chiral HPLC analysis with known compound
as reported.2
1. Han, Z.; Krishnamurthy, D.; Pflum, D.; Fang, Q. K.;
Butler, H.; Cameron, T. S.; Wald, S. A.; Senanayake, C.
H. Tetrahedron: Asymmetry 2002, 13, 107–109.
2. Krishnamurthy, D.; Han, Z.; Wald, S. A.; Senanayake,
C. H. Tetrahedron Lett. 2002, 43, 2331–2333.