Industrially viable preparation of (R)-3-Quinuclidinol, a key building block of muscarine M1, M3 agonists and M3 antagonists

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Organic Preparations and Procedures
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Industrially Viable Preparation of (R)-3-
Quinuclidinol, a Key Building Block
of Muscarine M1, M3 Agonists and M3
Antagonists
Ramadas Chavakula a , Narayana Rao Mutyala a & Srinivasa Rao
Chennupati a
a Tyche Industries Limited , H. No. C-21/A, Road No. 9, Film Nagar,
Jubilee Hills, Hyderabad , 500 093 , India
Published online: 24 Oct 2013.
To cite this article: Ramadas Chavakula , Narayana Rao Mutyala & Srinivasa Rao Chennupati (2013)
Industrially Viable Preparation of (R)-3-Quinuclidinol, a Key Building Block of Muscarine M1, M3
Agonists and M3 Antagonists, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 45:6, 507-509, DOI: 10.1080/00304948.2013.835221
To link to this article: http://dx.doi.org/10.1080/00304948.2013.835221
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Organic Preparations and Procedures International, 45:507–509, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.835221
OPPI BRIEF
Industrially Viable Preparation
of (R)-3-Quinuclidinol, a Key Building
Block of Muscarine M1, M3 Agonists
and M3 Antagonists
Ramadas Chavakula, Narayana Rao Mutyala,
and Srinivasa Rao Chennupati
Tyche Industries Limited, H. No. C-21/A, Road No. 9, Film Nagar, Jubilee Hills,
Hyderabad-500 093, India
(R)-3-Quinuclidinol (R-1-azabicyclo[2,2,2]octan-3-ol, 2a) is used as a building block in
the synthesis of muscarine M1 and M3 agonists as well as for muscarine M3 antagonists.1
Talsaclidine fumarate (WAL 2014 FU),2 cevimeline HCl,3,4 and YM 9055 are all examples
of compounds where (R)-3-quinuclidinol (2a) constitutes an integral part of the molecular
entity. These products have shown potential in the treatment of Alzheimer’s disease, Sjogren
syndrome and urinary incontinence respectively making (R)-3-quinuclidinol (2a) is a highly
valuable building block for the synthesis of several important pharmaceutical chemicals.
(R)-3-Quinuclidinol (2a) can be obtained by kinetic resolution of racemic mixtures (1) of
R- and S-3- quinuclidinols.
Submitted by April 4, 2013.
Address correspondence to Ramadas Chavakula, Tyche Industries Limited, H. No. C-21/A, Road
No. 9, Film Nagar, Jubilee Hills, Hyderabad-500 093, India. E-mail: das.krishnac@gmail.com
507

508
Chavakula et al.
There are three known approaches to the synthesis of 2a. The first utilizes resolution
of 1 via diastereomeric salt formation with (1S)-(+)- camphorsulfonic acid.6 In second
method, racemic 3-quinuclidinol (1) was acetylated with acetic anhydride at 160◦C for
3 h to give the acetate, which was then treated with L-(+)-tartaric acid to form the tar-
taric acid salt. After four recrystallizations from 80% ethanol, the salt was neutralized
with 2 N sodium hydroxide at 75◦C for 2 h, and then the solution was saturated with
anhydrous K2CO3 and extracted with benzene at 75◦C give (R)-3-quinuclidinol.7 In a
third route, racemic 1 benzoate was treated with L-(+)-tartaric acid to form the tartaric
acid salt, purified by recrystallization from 80% ethanol. The salt was then neutralized
with 15% aqueous sodium hydroxide at 50◦C for 10 h to release (R)-3-quinuclidinol.8
However, all these methods require expensive reagents, high temperatures and tedious
recrystallization procedures. These factors led us to explore a more economical and ef-
ficient method for the preparation of bulk quantities of 2a and we now report the oper-
ationally simple, highly selective and efficient resolution of 2a from R,S-quinuclidinol
(1) and dibenzoyl-D(+)-tartaric acid monohydrate. Similarly, (S)-3-quinuclidinol (2b)
could be obtained from 1 with dibenzoyl-L(-)-tartaric acid monohydrate as the resolving
agent.
Experimental Section
Solvents were dried over sodium sulfate and freshly distilled prior to use. All chemicals
1
were reagent grade and available commercially. H NMR spectra were recorded on a
Brucker ADVANCE 400 MHz spectrometer, using CDCl3 as solvent and TMS as internal
standard. Infrared spectra were obtained on a Perkin-Elmer Spectrum 100 FT-IR spec-
trophotometer. Electrospray ionization mass spectroscopy was performed using an ion trap
mass spectrometer (Model 6310 Agilent). Gas chromatographic analysis was carried out
using a Shimadzu GC-2010 Plus equipped with an Alltech poly (dimethoxysiloxane) 30
meter capillary DB-1 column. HPLC analysis was performed using Shimadzu LC-2010
CHT, UV-vis detector and a Chiralcel OD-H (250 × 4.6 mm) column at 40◦C with flow
rate of 1.0 ml/min and run time of 30.0 min. Solvents: 97.1% n-Hexane + 2.7% IPA
+ 0.2% Diethylamine. HPLC sample was prepared as 1 mg of benzoate derivative in
1 ml of n-hexane. Optical rotations were recorded on a Perkin-Elmer 241 polarimeter at
25–26◦C.

Preparation of (R)-3-Quinuclidinol
Preparation of (R)-3-Quinuclidinol (2a)
509
A mixture of dibenzoyl-D(+)-tartaric acid monohydrate (150.0 g, 0.4 mol), methanol
(300 ml) and 3-quinuclidinol (100.0 g, 0.79 mol) was stirred for 30 min and then heated
to 60–65◦C and maintained at reflux for 3 h. The suspension containing the precipitated
solid was cooled to 0–5◦C and stirred for 1 h. The (R)-3-quinuclidinol dibenzoyl-D(+)-
tartrate salt was collected and washed with 100 ml of chilled methanol to yield 130.0 g
of a white crystalline solid. It was dissolved in methanol (600 ml) at 55–60◦C and stirred
for 30 min. The clear solution was cooled to 0–5◦C and stirred for 1 h. The resulting
solid was collected, washed with chilled methanol (100 ml), dried under vacuum to afford
pure (R)-3-quinuclidinol dibenzoyl-D(+)-tartrate salt (100.0 g, 83%) as a white solid, mp.
174–178◦C, [α]D = +550 (c = 2, MeOH).
25
The salt was dissolved in water (100 ml) and ethyl acetate was then added (250 ml),
and the mixture was stirred for 10 min. It was then treated with conc. HCl (42 ml) to adjust
the pH to 1–2 and stirred for 1 h at 25–30◦C. The aqueous and organic layers were separated
and then the organic layer was saved to recover dibenzoyl-D(+)-tartaric acid. The aqueous
layer was treated with aqueous NaOH (23.0 g in 50 ml of water) to adjust the pH 12–13
and extracted with chloroform (4 × 200 ml). The combined chloroform extracts were dried
over sodium sulfate and the solvent was evaporated completely under vacuum below 50◦C
to give a white solid (40.0 g). It was treated with mixture of methanol (10 ml) and acetone
(90 ml) and stirred at 55–60◦C for 30 min. The suspension containing the solid was cooled
to 0–5◦C and stirred for 1 h. The product was collected, washed with chilled acetone (30 ml)
to yield 38.0 g (91%) of a white crystalline solid, mp. 221–224◦C., lit.9 220–222◦C. [α]D
25
= −43.6◦ (c = 3, 1N HCl)., lit.9 [α]D = −43.8◦ (c = 3, 1N HCl). 99.9% chiral purity by
25
HPLC. IR (cm−1): 3400, 3095, 2940, 1445, 1340; 1H NMR: δ 1.25–2.0 (5H, m), 2.50–2.90
(5H, m), 3.05 (1H, m), 3.75 (1H, m, CH-OH); MS (ESI): m/z 128 (M +H).
Acknowledgement
The authors are thankful to Tyche Industries Ltd for financial support.
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