Industrially viable preparation of N-benzyl-4-formylpiperidine, a key intermediate of donepezil

Full text of DOI:10.1080/00304948.2013.765298

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Organic Preparations and Procedures
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Industrially Viable Preparation of N-
Benzyl-4-formylpiperidine, a Key
Intermediate of Donepezil
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 Hils, Hyderabad, 500 093, India
Version of record first published: 20 Mar 2013.
To cite this article: Ramadas Chavakula , Narayana Rao Mutyala & Srinivasa Rao Chennupati (2013):
Industrially Viable Preparation of N-Benzyl-4-formylpiperidine, a Key Intermediate of Donepezil,
Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 45:2,
168-170
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Organic Preparations and Procedures International, 45:168–170, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.765298
OPPI BRIEF
Industrially Viable Preparation
of N-Benzyl-4-formylpiperidine,
a Key Intermediate of Donepezil
Ramadas Chavakula, Narayana Rao Mutyala, and Srinivasa Rao
Chennupati
Tyche Industries Limited, H. No. C-21/A, Road No. 9, Film Nagar, Jubilee Hils,
Hyderabad-500 093, India
ꢀR
Donepezil hydrochloride (3) (Aricept ), a selective inhibitor of acetyl cholinesterase
(AChE) and the most promising agent for the treatment of mild to moderate demen-
tia (Alzheimer)1 has been synthesized2 by the aldol condensation of 5,6-dimethoxy-1-
indanone (1) with N-benzyl-4-formylpiperidine (2), followed by reduction of the double
bond (Scheme 1).
CHO
O
O
MeO
MeO
i
ii
CH2
NCH2Ph
+
MeO
MeO
N
Ph
3
1
2
ii). 10% Pd/C, ethanol, conc HCl
i). NaOMe, THF
Scheme 1
There are several known approaches to the synthesis of 2. Four of these processes
start from N-benzyl-4-piperidone.The first utilizes the Wittig reaction of (methoxymethyl)
triphenylphosphonium chloride with N-benzyl-4-piperidone followed by hydrolysis of the
resulting enol ether.3 In another method, trimethylsilyldiazomethane is condensed with
N-benzyl-4-piperidone followed by hydrolysis to give the final product.4 In a third
route, N-benzyl-4-piperidone is treated with trimethyloxosulfonium iodide to give the
Submitted by 22 June 2012.
Address correspondence to Ramadas Chavakula, Tyche Industries Limited, H. No. C-21/A, Road
No. 9, Film Nagar, Jubilee Hils, Hyderabad-500 093, India. E-mail: das.krishnac@gmail.com
168

Preparation of N-Benzyl-4-formylpiperidine
169
corresponding epoxide, which is then rearranged in the presence of magnesium bromide
etherate to lead to 2 in high yields.5 In 2007, a patent described the Darzens condensa-
tion of N-benzyl-4-piperidone with ethyl chloroacetate followed by decarboxylation.2 A
fifth preparation, involves the partial reduction of N-benzyl-4-ethoxycarbonylpiperidine
with sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) in the presence of N-
methylpiperazine6 or pyrrolidine7 to afford compound 2. Finally, a recent procedure utilizes
the Swern oxidation of 4 to furnish 2 in 73% yield after distillation.8 However, since all
these methods require expensive reagents, low temperature and tedious procedures and
thus we set out to find a more economical and efficient method for the preparation of
bulk quantities of 2 and now report the operationally simple, highly selective and efficient
oxidation of 2 from N-benzyl-4-hydroxymethylpiperidine by the Corey-Kim method.9,10
CH2OH
CHO
Me2S , Et3N
-100C
NCS ,
N
N
Ph
Ph
2
4
Experimental Section
Solvents were dried over sodium sulfate and freshly distilled prior to use. N-Benzyl-4-
hydroxymethylpiperidine was prepared from less expensive and commercially available
ethyl isonipecotate and other chemicals were reagent grade and available commercially. 1H
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 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 N-Benzyl-4-formylpiperidine (2)
To a solution of N-benzyl-4-hydroxymethylpiperidine (20.5 g, 0.10 mol) in toluene (400 ml)
at −10◦C to −15◦C, dimethyl sulfide (6.2 g, 0.10 mol) and triethylamine (12.4 g, 0.12 mol)
were added in a single lot under argon and stirred for 15–30 min. Then N-chlorosuccinimide
(36 g, 0.27 mol) was added portionwise over 1 hr while the internal temperature was
maintained at −10◦C to −15◦C. The reaction mixture was stirred for 3 hr at −10◦C to
−15◦C, completion of reaction was monitored by gas chromatography (GC). The reaction
mixture was treated cautiously with aqueous sodium hydroxide (8 g in 240 ml of water)
at −5◦C to −10◦C and then the mixture was allowed to warm to 20◦C and stirred for 1 hr
at 20◦C. The aqueous and organic layers were separated and then the aqueous layer was

170
Chavakula et al.
discarded. The organic layer was extracted with aqueous sodium bisulfite (28 g in 220 ml
of water) to form the bisulfite adduct of 2 (the toluene layer may be saved and recycled);
the aqueous layer was washed with dichloromethane (40 ml) to remove impurities (the
dichloromethane layer may be saved and recycled). The aqueous layer was then treated
with aqueous sodium carbonate (25%) to adjust the pH to 9.5–9.8 and extracted with
dichloromethane (120 ml) .The dichloromethane extract was evaporated in vacuo to give
the product. Distillation in vacuo gave 2 (17.0 g, 87.0%) as a colorless oil, bp. 115–120◦C
/ 0.1 mmHg., lit.7 130–134◦C /1 mmHg. IR : (KBr.cm−1): 3027, 2922, 2804, 2760, 1723;
1H NMR: δ 1.71 (2H, m, C-CH2), 1.90 (2H, m, C-CH2), 2.12 (2H, m, N-CH2), 2.28 (1H,
m, CH), 2.83–2.87 (2H, m, N-CH2), 3.54 (2H, s, N-CH2-Ph), 7.28 (5H, m, Ar), 9.68 (1H,
d, J = 1.2Hz, H-C = O); MS (ESI): m/z 204 (M +H).
This procedure has been scaled up using 100 g of compound 4.
Acknowledgement
The authors are thankful to Tyche Industries Ltd for financial support.
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