A method for the racemization of 2-methylpyrrolidine: A histamine H 3 receptor pharmacophore

Article abstract of DOI:10.1021/op500051x

This paper describes a method for the racemization of unwanted (S)-1 isomer arising from the resolution of (±)-1. The process of racemization involves thiyl radical-mediated reversible hydrogen abstraction at the chiral center, in the presence of AIBN in water. The racemized isomer was subsequently resolved by l-(+)-tartaric acid to get (R)-1, a histamine H₃ receptor pharmacophore. We foresee that such an approach of racemization will be industrially useful for recycling waste (S)-1 enantiomer.

Full text of DOI:10.1021/op500051x

Communication
pubs.acs.org/OPRD
A Method for the Racemization of 2‑Methylpyrrolidine: A Histamine
H3 Receptor Pharmacophore
Swapnil G. Yerande,* Ragini S. Yerande, Prashant P. Thakare, Deepak M. Shendage, Sharad Galave,
and Ashok Kumar Gangopadhyay
Acoris Research (A Division of Hikal Ltd.), 3A, International Biotech Park, Hinjewadi, Pune 411 057, Maharashtra, India
report an approach which leads to successful racemization and
recycling of the unwanted (S)-1 isomer.
ABSTRACT: This paper describes a method for the
racemization of unwanted (S)-1 isomer arising from the
resolution of ( )-1. The process of racemization involves
thiyl radical-mediated reversible hydrogen abstraction at
the chiral center, in the presence of AIBN in water. The
racemized isomer was subsequently resolved by L-
(+)-tartaric acid to get (R)-1, a histamine H3 receptor
pharmacophore. We foresee that such an approach of
racemization will be industrially useful for recycling waste
(S)-1 enantiomer.
RESULTS AND DISCUSSION
■
In order to improve the overall throughput of the resolution
process we devoted our efforts toward racemization and
recycling of the unwanted (S)-1 isomer. We were faced with
a challenge of racemizing the antipodal (S)-1 isomer which is
not equipped with functionality that is susceptible for
racemization. A literature search revealed that there are reports
on the racemization of inactivated amines, such as thiyl radical-
mediated racemization of nonactivated amines.11 We hypothe-
sized that our substrate, unwanted (S)-1 isomer, will racemize
under thiyl radical-mediated racemization in a similar manner.
To test this approach we required a reliable analytical
method for the determination of the chiral purity of 2-
methylpyrrolidine. Although reversed-phase HPLC for the
determination of diastereomer formed between 2-methylpyrro-
lidine and Cbz-valine anhydride is reported in the literature,12
we, however, adopted a GC method for the determination of
the chiral purity of 2-methylpyrrolidine directly to avoid the
additional step of derivatization. With a GC method in hand we
focused our attention towards the racemization and recycling of
unwanted (S)-1.
INTRODUCTION
■
Discovered by Pasteur in 1853, the separation of enantiomers
from a racemic mixture with the help of chiral resolving agents
is called the “classical method of resolution”.1 In the context of
large-scale enantiomer separations, crystallization techniques
are often straightforward and more economical than any other
method. Hence, classical resolution is still an essential tool in
the preparation of a majority of substances required in
enantiopure form in the synthesis of pharmaceuticals and
agrochemicals. To cite but a few examples, (S)-pregabalin,2 (S)-
naproxen,3 D-phenylglycine, and D-4-hydroxyphenylglycine are
produced by separation of diastereoisomeric salts.4
In our laboratory, resolution of ( )-1 to (R)-1 with L-
(+)-tartaric acid was achieved after five crystallizations in 28%
yield with >98% ee.13 Solvents from the mother liquor obtained
after the resolution step were distilled to obtain the tartaric acid
salt of 1 enriched with (S)-isomer. This salt was treated with
aqueous NaOH to liberate free amine, and analysis showed
typically around 70−75% of the unwanted (S)-1 enantiomer
along with 30−25% of the (R)-1 enantiomer. In order to make
this process economically viable, the racemization of 1 enriched
with (S)-1 recovered from the mother liquor was a necessity.
Table 1 summarizes our efforts for the racemization of this
amine. Initially we screened different solvents, keeping the
quantity of octanethiol (1.2 equiv) constant; smooth
racemization was observed in all the conditions tested (entries
1−3). With toluene being a preferred commercial solvent,
further reduction of the octanethiol quantity was tried
successfully, and 10 mol % of octanethiol was found to be
adequate (entry 4).
Histamine, a biogenic amine, acts as neurotransmitter and
exerts its biological action by combining with four distinct
cellular histamine G-protein-coupled receptors (H1−H4).5
These presynaptic histamine H3 receptor antagonists have
found application as treatment in a variety of CNS disorders,
such as cognitive disorders,6 and attention-deficit hyperactivity
disorder (ADHD).7 The imidazole-based histamine H3
receptor antagonist was discovered to have low clinical
acceptability due to the potential to give rise to drug−drug
interactions by inhibiting hepatic CYP (cytochrome P450)
enzymes and poor CNS permeability. For these reasons the
researchers are now emphasizing the development of non-
imidazole-based histamine H3 receptor antagonists. Figure 1
summarizes these H3 receptor antagonists which have (R)-1 as
a common pharmacophore.8
Even though various multistep asymmetric routes for the
preparation of (R)-1 are reported,9 classical resolution of the
inexpensive racemic ( )-1 with L-(+)-tartaric acid remains the
route of choice for making (R)-1 due to its commercial
scalability (Scheme 1).10 This route is also safe and does not
require isolation of multiple intermediates. The disadvantage of
this route is that the unwanted (S)-1 isomer is lost in the
mother liquor during the resolution step, hampering overall
yield of the process. Thus, to increase the overall yield we
Typically, it was found that the isolated, enriched (S)-1
obtained from distillation of the neutralized mother liquor of
the resolution step was contaminated with ∼10% water. We
Received: February 12, 2014
Published: April 7, 2014
© 2014 American Chemical Society
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Figure 1. (R)-2-Methylpyrrolidine: a histamine H3 receptor pharmacophore.
our approach for the resolution, racemization, and recovery of
(R)-1 (Figure 2)
Scheme 1. Chiral separation of ( )-1 into (R)-1 using
diasteromeric salt formation between (R)-1 and L-
(+)-tartaric acid
The ( )-1 was resolved by forming a diastereomeric salt with
L-(+)-tartaric acid. Solvents were distilled off from the mother
liquor, and residual salt was basified by addition of aqueous
NaOH. The enriched (S)-1 was distilled and racemized using
optimized conditions. The ( )-1 obtained in this way was
subjected to the next cycle of the resolution to realize 28% yield
of (R)-1 having >98% ee. The process executed in this fashion
shows increased overall yield of the resolution step up to
43.3%.14
Table 1. Racemization of 2-methylpyrrolidine
c
chiral purity by GC
a
b
CONCLUSION
entry
octanethiol (equiv)
solvent
S
R
■
We have described a process for the recycling of the unwanted
isomer from the mother liquor of the preparation of (R)-1 by
using thiyl radical-mediated racemization. Most significantly the
racemization could be achieved in water, a green solvent. The
racemized compound was subsequently resolved by L-
(+)-tartaric acid to get (R)-1 with the same efficiency as that
of the original resolution. Recycling of the unwanted isomer not
only helps to minimize the waste generated during the classical
resolution process but also decreases the production cost and
increases the overall throughput of the product.
1
2
3
4
5
6
7
1.2
dichloromethane
chloroform
toluene
49.68
49.88
49.92
50.10
50.05
50.10
59.19
50.32
50.12
50.08
49.90
49.95
49.90
40.81
1.2
1.2
0.1
toluene
0.1
water
0.05
0.025
water
water
a
All the reactions were done on 5 g scale using 2.0 volumes of solvent;
2 mol % AIBN was added in one lot. All the reactions were
maintained at reflux for 1 h. Racemized product was not isolated.
b
c
EXPERIMENTAL SECTION
■
experimentally found out that removal of the remaining water
from enriched (S)-1 was not a trivial job, and loss (4−6%) of
enriched (S)-1 was observed during the drying and distillation
steps. Therefore, it was decided to check the feasibility of the
racemization reaction in water so that the additional drying step
can be avoided. To our delight complete racemization of
enriched (S)-1 was observed in water with 10 mol % of
octanethiol (entry 5). The possibility of further reduction of
octanethiol was attempted, and it was observed that even 5 mol
% of octanethiol was adequate to racemize enriched (S)-1 in 1
h (entry 6); however, using 2.5 mol % of octanethiol was not
efficient (entry 7).
General. Reagents and materials were obtained from
commercial suppliers and used without additional purification.
All reactions were performed under nitrogen atmosphere.
Chiral GC analysis was done on Agilent 7890A GC system with
FID detector. Diluents: trifluoroacetic anhydride + MDC
Column: Chiraldex-G-TA (30 mm × 0.25 mm × 0.12 μ),
Conditions: 150 °C (110 °C/12) 250 °C. Flow rate 1.1 mL/
min (helium), injection volume 1.0 μL split 1:250. Rt = 9.93
min (S) isomer, Rt = 9.29 min (R) isomer. Chemical purity was
determined by GC analysis on Agilent 7890A GC system with
FID detector. Diluents: acetonitrile, Column: HP-5 (30 mm ×
0.32 mmID × 0.25 μ), Conditions 230 °C (50 °C/10 °C/min/
250 °C/0) 280 °C. Flow rate 1.0 mL/min (N2), Injection
volume 1.0 μL split 1:20.
With an optimized condition in hand, we decided to run this
process on preparative scale. The block-flow diagram explains
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Figure 2. Resolutions and racemization of ( )-1.
(R)-2-Methylpyrrolidine L-Tartrate. Absolute ethanol
(7.15 L, 5.64 kg), methanol (2.04 L, 1.65 kg), and L-tartaric
acid (0.85 kg, 5.63 mol) were charged to a 30-L all glass reactor.
Racemic 2-methylpyrrolidine 1 (0.48 kg, 5.63 mol) was charged
to the above reaction mixture. The mixture was heated to 72 °C
to ensure a homogeneous solution and was maintained for 30
min. The solution was then cooled to 25 °C at approximately
10 °C/h. The solution was stirred at 25 °C for 8 h. The slurry
was cooled to −5 °C, held for 1.0 h, filtered, and dried at 60 °C
under vacuum with a nitrogen bleed overnight to yield 1.02 kg
(ee >20%, Yield 77%) of the partially resolved tartrate. The
enantiomeric purity of the tartrate could be improved to >99%
by repeated recrystallizations from ethanol/methanol (78:22)
(16.24 L/kg of solid) as described above. After five
recrystallizations, 0.37 kg (ee 99.0%, Yield 28%) of the desired
product was isolated.
Racemization of 2-Methylpyrrolidine. To a 10-L four
neck RB flask equipped with overhead stirrer, condenser,
addition funnel and thermometer pocket was charged mother
liquor obtained from all the five crystallizations, and the
reaction mass was heated to distill ethanol and methanol. The
oily residue of 2-methypyrrolidine tartrate salt (0.95 kg, 4.04
mol) obtained was cooled to 10 °C. Sodium hydroxide solution
(3.20 kg, 40.04 mol) was added to the reaction mass,
maintaining the reaction temperature below 10 °C. The
reaction mass was stirred for 30 min at 30 °C. The temperature
was slowly raised to 100 °C for distilling 2-methypyrrolidine.
(Oil bath temperature is 100 °C, solution temperature is 95 °C
and vapor temperature is 68−80 °C.) 2-Methypyrrolidine
which weighs 0.36 kg (contains 12% moisture) was obtained.
Recovered (S)-enriched 1; 0.34 kg (purity based 0.30 kg) was
dissolved in 0.56 L of water. To this clear solution was charged
25.25 g (0.05 equiv) of octanethiol and 11.58 g of AIBN (0.02
equiv). The reaction mass was heated to reflux and maintained
at reflux for 1 h. The reaction mass was submitted for chiral GC
analysis (compound was found to be fully racemized). Reaction
mass was cooled to 25 °C, 0.36 kg of NaOH was charged to the
reaction, and then the product was recovered by distillation to
get ( ) 1 which was contaminated with 15% water. This
product was dried over KOH pellets to get 0.26 kg of ( ) 1;
yield 87%.
1H NMR [CDCl3]: 1.21 (d, J = 8.0 Hz, 3H), 1.74 (m, 2H),
1.84 (m, 2H), 2.81 (m, 1H), 3.07 (m, 2H).
13C NMR [CDCl3]: 21.0, 25.5, 33.5, 46.5, 54.4.
GC Purity: 97.55%, Chiral Purity (GC): 0.2% ee.
(R)-2-Methylpyrrolidine L-Tartrate. Absolute ethanol
(3.89 L, 3.06 kg) and methanol (1.11 L, 0.87 kg) were charged
to a 10-L glass reactor. To this were charged racemic 2-
methylpyrrolidine 1 (0.26 kg, 3.06 mol), and L-tartaric acid
(0.46 kg, 3.06 mol), and following the above resolution
method, after five recrystallizations, 0.20 kg (ee > 98.0%, 15.3%
based on initial 0.48 kg of ( )-1) of the desired product was
isolated.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +91 (20) 2727 2014. Email: swapnil_yerande@hikal.
com.
Notes
The authors declare no competing financial interest.
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cycle of racemization and diastereomeric crystallization, taking the
overall yield to 43.3%.
ACKNOWLEDGMENTS
■
The authors thank Acoris Research (Hikal Ltd.) management
for providing necessary facilities. R.S.Y. would like to thank
Acoris Research (a division of Hikal Ltd.) management for
awarding a research internship for carrying out Master in
Pharmaceutical chemistry research work. Special thanks are
extended to the Analytical Department of Acoris Research for
giving analytical support.
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(12) (a) For determination of chiral purity of (R)-1 and (S)-1 by
chiral HPLC derivitization with Cbz-valine, see ref 9c.
(13) L-(+)-Tartaric acid diasteromeric salt of (R)-1 was used as such
without converting it into free amine (R)-1; please see reference 10c.
(14) Resolution of ( )-1 with L-(+)-tartaric acid, after five
crystallisations gave 28% yield of L-(+)-tartaric acid diastereomeric
salt of (R)-1, while an additional 15.3% was obtained after the first
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