Organic Chemistry: An Indian Journal
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slide 1: Organic Chemistry: An Indian Journal
Research | Vol 14 Iss 3
Citation: Ramadas Chavakula Chakradhar Saladi JS Shankar NGB et al. A Large Scale Synthesis of Racemic 3-Quinuclidinol Under
Solvent Free Conditions. Org Chem Ind J. 2018143:127
© 2018 Trade Science Inc. 1
A Large Scale Synthesis of Racemic 3-Quinuclidinol under Solvent Free
Conditions
Chavakula R
1
Chakradhar Saladi JS
1
Shankar NGB
1
Subba Reddy D
1
and Raghu Babu K
2
1
Research and Development Aurobindo Pharma Limited Survey No: 71 and 72 Indrakaran Village Sangareddy Mandal
Medak Dist-502329 Telangna State India
2
Department of Engineering Chemistry Andhra University Visakhapatnam India
Corresponding author: Chavakula R Research and Development Aurobindo Pharma Limited Survey No: 71 and 72
Indrakaran Village Sangareddy Mandal Medak Dist-502329 Telangna State India Tel: +91 40 6672 5000 E-Mail:
ramadas.chavakulagmail.com
Received: August 20 2018 Accepted: August 22 2018 Published: September 06 2018
Introduction
The quinuclidine ring is used in synthesis of various therapeutically important molecules and also important intermediate and
synthesis of some drugs like azasetron benzoclidine palonosetron solifenacin cevimeline quinupramine etc. 1 and also
found in a number of natural products 2. The quinuclidinone derivatives have been reported to show various biological
activities 3-6. Quinuclidinone derivatives are reported to show anti-cancer 78 anti-inflammatory 9 central nervous
system stimulating activity 10 and antihistaminic activity 11 FIG. 1.
Abstract
An industrially viable synthesis of racemic 3-quinuclidinol under solvent free conditions a key intermediate of 3-R-Quinuclidinol
R-1-azabicyclo222octan-3-ol is used as a building block in the synthesis of muscarine M1 and M3 agonists as well as for
muscarine M3 antagonists has been described.
Keywords: M1 and M3 agonists 3-R-Quinuclidinol PTBO NaBH4 Alkylation Reduction
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FIG. 1. Quinuclidinone derivatives.
3-R quinuclidinol 1 can be obtained by kinetic resolution of racemic mixtures of R- and S-3-quinuclidinol 3 FIG. 2. 3-
R-QuinuclidinolR-1-azabicyclo222octan-3-ol 1 is used as a building block in the synthesis of muscarine M1 and M3
agonists as well as for muscarine M3 antagonists. See for example the recent review by Broadley and Kelly 12 concerning
muscarinic receptor agonist and antagonist. Talsaclidine fumarate WAL 2014 FU 13 cevimeline HCl 14 and YM 905
15 are all examples of products where 3-R quinuclidinol 1 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. 3-R quinuclidinol 1 consitutes therefore a highly valuable building block for the synthetic production of
several important pharmaceutical chemicals FIG. 2..
FIG.2. Synthesis of 3-R quinuclidinol
The reported synthesis 16-18 of racemic quinuclidinol FIG. 3 involved the use of large amount of solvents such as
toluene benzene isopropyl alcohol ethanol acetone methanol and con HCl. Both the reagents and solvents have to be
handled in large volumes because the product has to be produced commercially. This process was difficult to implement at
the production scale because they require costly solvents and tedious isolation procedures.
FIG. 3. Synthesis of Racemicquinuclidinol.
Keeping these points in mind we designed three-stage green process of racemic quinuclidinol. Two of them were completely
under solvent free conditions. Minimum amount of solvents were used and recovered in third one. Our synthesis is depicted
in FIG. 4. As a result of these changes the solvent usage was decreased resulting in a significant reduction in the cost of
racemic quinuclidinol production.
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Experimental
General
Solvents were dried over sodium sulfate and freshly distilled prior to use.
1
H NMR spectra were recorded on a Brucker
ADVANCE-400 MHz using CDCl
3
as Solvent and TMS as internal standard. Infrared spectra were obtained on a Perkin
Elmer spectrum 100 FT-IR spectrophotometer. Electrospray ionization mass spectroscopy was performed using an ion trap
mass spectrometer Model 6310 agilent. Gas chromatographic analysis was performed using a Shimadzu GC-2010 Plus
equipped with an Alltech poly dimethoxysiloxane 30 meter capillary DB-1 column.
Preparation of 1-Carbethoxymethyl-4-Carbethoxypiperidine 5: Method-1
To a solution of Ethyl isonipecotate 4 10.0 g 0.063 mol and Na
2
CO
3
10.1 g 0.095 mol in water 30 ml at 30ºC to
35ºC ethyl chloroacetate 9.2 g 0.075 mol was added in dropwise over 10 min. The reaction mixture was stirred for 4 hr at
80ºC to 84ºC. Completion of reaction was monitored by gas chromatography GC. The reaction mixture was diluted with
water 60 ml at 35ºC to 40ºC and stirred for 1 hr at 40ºC. The aqueous and organic layers were separated and the organic
layer was washed with water 60 ml. The traces of ethyl chloroacetate were removed under reduced pressure to give the pure
product 14.4 gr 93.0 as yellowish oil.
Preparation of 1-Carbethoxymethyl-4-Carbethoxypiperidine 5: Method-2
To a solution of Ethyl isonipecotate 4 10.0 g 0.063 mol and triethylamine 9.6 g 0.095 mol at 30ºC to 35ºC ethyl
chloroacetate 9.2 g 0.075 mol was added in drop wise over 10 min. The reaction mixture was stirred for 4 hr at 60ºC to
70ºC. Completion of reaction was monitored by gas chromatography GC. The reaction mixture was diluted with water 60
ml at 35ºC to 40ºC and stirred for 1 hr at 40ºC. The aqueous and organic layers were separated and the organic layer was
washed with water 60 ml. The traces of ethyl chloroacetate were removed under reduced pressure to give the pure product
14.7 gr 95.0 as yellowish oil.
Preparation of 3-Quinuclidinone 6
A solution of 1-carbethoxymethyl-4-carbethoxypiperidine 5 20.0 g 0.082 mol in tolune 10 ml was added dropwise to a
Potassium tertiary butoxide 14.0 g 0.125 mol in toluene 50 ml and THF 5 ml at reflux over 3 hr and the mixture was
stirred at reflux for 3 hr. Dilute sulfuric acid13 ml in 40 ml water added drop wise to a reaction mass at 500C and stir for 1
hr. Collected aqueous layer and heat to reflux and maintain for 6 hr. Then the PH of the mixture was adjusted with 50
sodium hydroxide solution to 10.5 at room temperature and stirred for 1 hr. Extracted the reaction mass with chloroform 3 X
500 L organic layer was dried over sodium sulphate and distill off solvent under reduced pressure to give crude 3-
quinuclidinone base. This product was purified by hexane to yield 7.0 g 69.0 of a white crystalline solid MP. 136-140
o
C
lit.16 140
o
C. 1H NMR: δ 1.6-2.0 4H m 2.3 1H m 2.6-3.0 4H m 3.2 2H s MS ESI: m/z 126 M
+
H.
Preparation of RS-3-Quinuclidinol 3
To a solution of Quinuclidinone 6 10.0 g 0.08 mol in water 30 ml at 30ºC to 35ºC sodium borohydride 1.5 g 0.04
mol was added in lot-wise over 1 hr. The reaction mixture was stirred for 4 hr at 30ºC to 35ºC. Completion of reaction was
monitored by gas chromatography GC. Extracted the reaction mass with chloroform 3X50 ml organic layer was dried
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4
over sodium sulphate and distill off solvent under reduced pressure to give RS-3-quinuclidinol crude. This product was
purified by acetone to yield 9.0 g 89.0 of a white crystalline solid MP. 221-224
o
C. lit16 220-222
◦
C.
1
H 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.
Results and Discussion
1-Carbethoxymethyl-4-Carbethoxypiperidine 5 is manufactured in a two-type of reaction process as shown in scheme 3.
Ethyl isonipecotate 4 was alkylated with ethyl chloroacetate in the presence of base potassium carbonate or triethylamine in
water or without solvent to give the 1-Carbethoxymethyl-4-Carbethoxypiperidine 5 in 97 yield. This 1-
Carbethoxymethyl-4-Carbethoxypiperidine 5 was cyclized to keto-ester in presence of potassium-tert-butoxide and
minimum usage of solvents. The keto-ester was saponified and decarboxylated on heating with aqueous sulphuric and 3-
quinuclidone 6 was isolated and further reduction with sodium borohydride in water to give of racemic quinuclidinol 3.
FIG. 4. Synthesis of 3-RS-Quinuclidinol.
Acknowledgement
The authors are thankful to Auroido Pharma Limited for financial assistance.
REFERENCES
1. Mazurov A Klucik J Miao L et al. 2-Arylmethyl-3-substituted quinuclidines as selective α7 nicotinic receptor ligands.
Bioorg Med Chem Lett. 200515:2073-7.
2. Kaufman TS Rúveda EA. The quest for quinine: those who won the battles and those who won the war. Angew Chem Int
Ed Engl. 200544:854-85.
slide 5: www.tsijournals.com | June-2018
5
3. Yang D Soulier JL Sicsic S et al. New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and
antagonists for 5-HT4 receptors. J Med Chem. 199740:608-21.
4. Bös M Canesso R. EPC‐Synthesis of S‐3‐Hydroxy‐3‐mercaptomethylquinuclidine a Chiral Building Block for the
Synthesis of the Muscarinic Agonist AF 102B. ChemInform. 199425.
5. Trost BM. On inventing reactions for atom economy. Acc. Chem. Res. 200235:695-705.
6. Frackenpohl J Hoffmann HM. Synthesis of Enantiopure 3-Quinuclidinone Analogues with Three Stereogenic Centers:1S
2R 4S-and 1S 2S 4S-2-Hydroxymethyl-1-azabicyclo 2.2.2 octan-5-one and Stereocontrol of Nucleophilic Addition to
the Carbonyl Group. J. Org. Chem. 200065:3982-96.
7. Bykov VJ Issaeva N Selivanova G et al. Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known
anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis.
200223:2011-8.
8. Bykov VJ Issaeva N Shilov A et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-
weight compound. Nat Med. 20028:282.
9. Warawa EJ Mueller NJ Jules R. Quinuclidine chemistry. 2. Synthesis and antiinflammatory properties of 2-substituted
benzhydryl-3-quinuclidinols. J Med Chem. 197417:497-501.
10. Warawa EJ Mueller NJ Gylys JA. Quinuclidine chemistry. 3 beta.-cis-2-4-Chlorobenzhydryl-3-quinuclidinol a new
central nervous system stimulant. Importance of the benzhydryl configuration. J Med Chem. 197518:71-4.
11. Gonnot V Nicolas M Mioskowski C et al. Expedient synthesis of mequitazine an antihistaminic drug by palladium
catalyzed allylic alkylation of sodium phenothiazinate. Chem Pharm Bull. 200957:1300-2.
12. Broadley KJ Kelly DR. Muscarinic receptor agonists and antagonists. Molecules. 20016:142-93.
13. Broadley KJ Kelly DR. Muscarinic receptor agonists and antagonists. Molecules. 20016:142-93.
14. Roman G. Perspectives in the treatment of vascular dementia. Drugs Today. 200036:641.
15. Messer CJ Eisch AJ Carlezon Jr WA et al. Role for GDNF in biochemical and behavioural adaptations to drugs of
abuse. Neuron. 200026:247-57.
16. Sternbach LH Kaiser S. Antispasmodics. I. Bicyclic basic alcohols. J Am Chem Soc. 195274:2215-8.
17. Langlois M Meyer C Soulier JL. Synthesis of R and S-3-Aminoquinuclidine from 3-Quinuclidinone and S and R-
1-Phenethylamine. Synth Commun. 199222:1895-911.
18. Y Soni J Premasagar V Thakore S. An improved and simple route for the synthesis of 3-quinuclidinone hydrochloride.
Lett Org Chem. 201512:277-9.
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