Received: April 21, 2019 | Accepted: June 6, 2019 | Web Released: August 3, 2019
CL-190288
Group-assisted Purification (GAP) Chemistry/Technology in Synthesizing the
Chiral Intermediate of Rivastigmine and Its ¡-Alkyl Benzylamine Analogues
Bing Yang,*1,3,# Chun-Yan Zhang,2,# Jing Xu,3,# Da-Jun Zheng,3 Xiao-Ying Wang,3
Hong Dai,*1 Yu-Jun Shi,1 and Hai-Liang Zhu*3
1School of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, P. R. China
2Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, P. R. China
3Institute of Chemistry and Biomedical Science, State Key Laboratory of Pharmaceutical Biotechnology,
Nanjing University, Nanjing 210023, P. R. China
E-mail: yangbing111@ntu.edu.cn (B. Yang), zhuhl@nju.edu.cn (H.-L. Zhu), dh123@ntu.edu.cn (H. Dai)
Introduction of (S)-configuration is the key step in the
synthesis of the anti-dementia drug Rivastigmine. Twenty-one
alkylation products were obtained through simple washing with
hexane/ethyl acetate (v/v: 10/1) in good yields (>85%) and
high diastereoselectivity (up to >99:1 dr). Moreover, the chiral
auxiliary could be easily dissociated and readily regenerated.
That is, the synthesis was proved to follow group-assisted
purification (GAP) chemistry/technology. In addition, the chiral
amine produced by this asymmetric alkylation reaction was
effectively used in the synthesis of Rivastigmine.
continuing study and the resulting atom economy would meet
the requirements of industrialized production.
A new approach called GAP (group-assisted purification)
was proposed by the Li group after they studied asymmetric
reactions of chiral N-phosphonyl16-20 and N-phosphinyl21
auxiliaries attached to imines. The GAP chemistry/technology
allows pure products with some special functional groups in
synthesis to be obtained by simply washing with common
solvents or component solvents instead of traditional methods
such as chromatography or recrystallization. For the past few
years, the Li group has investigated asymmetric additions of
various nucleophiles to N-protected imines with phosphorus-
containing auxiliaries for the synthesis of different chiral
amines.22 In the last 3 years, GAP chemistry/technology has
been efficiently applied in the synthesis of solution-phase-
peptides,23 amino acids,24 amino esters/amides,25,26 diamino
acid derivatives,27-29 and applied in many other reactions, such
as aza-MBH reaction,30,31 borylation reactions,32 and [3+2]
cycloaddition reactions.33 In these studies, final pure chiral
amines can be obtained by simply washing the solid crude
products with hexane or different ratios of hexane-EtOAc. Most
importantly, the chiral N-phosphonyl auxiliary can be easily
cleaved under acid-alcohol conditions, and can be quantitatively
recycled by extraction.20,34 Amongst the documentation on GAP
chemistry/technology, ¡-alkyl benzylamines such as homoal-
lylic amines,35 propargyl amines,36 and ¡-amino-1,3-dithianes37
were synthesized by the reaction of N-phosphonyl imines and
metal anion reagents (Scheme 1). However, there was no study
of ¡-alkyl benzylamines with m-position of the aromatic ring
substituted by alkyl or alkoxy. Meanwhile, only o-, p-substituted
homoallylic benzylamines and propargyl benzylamines were
reported, and only m-, p-substituted ¡-amino-1,3-dithianes were
synthesized. For N-phosphonyl imines produced from aliphatic
aldehydes (Scheme 1),38 eleven alkylated homoallylic amides
were prepared with good yields and high diastereoselectivity,
but the enantioenriched alkylated methyl amide cannot be
obtained by GAP procedure. The substrate scope was relatively
limited in above research. Besides, sterically hindered metal
anion reagents including allyl Grignard reagent, alkynyllithium
reagents, and lithiated 1,3-dithianes were involved in the GAP
synthesis at ¹78 °C. Methyl Grignard reagent has not been
successfully used in similar alkylation reactions, and these GAP
alkylations were not used for the synthesis of chiral drug
intermediates.
Keywords: Rivastigmine
| Chiral auxiliary |
GAP chemistry/technology
Chiral amine building blocks exist in 40% of new chemical
entities in drugs currently,1,2 and such a growing demand has
been driving the development of new and efficient methods for
synthesis of enantiomerically pure amines. In chiral amines,
enantioenriched ¡-alkyl benzylamines are widely used as chiral
materials in chemical synthesis and as chiral intermediates in
drug preparation. In recent studies, a range of enantioenriched
tertiary benzylamines react with various nucleophiles to form
chiral C-Cl,3 C-S, C-Se, C-C, and C-N bonds,4 delivering
benzylic compounds with inversion of configuration. For
relevant representative drugs, Rivastigmine {(S)-3-[1-(dimethyl-
amino)-ethyl]phenyl ethyl(methyl)carbamate}, a cholinesterase
inhibitor, is used to treat mild and moderate dementia patients
with Alzheimer’s disease or Parkinson’s disease. Rivastigmine
is the first FDA approved drug for the treatment of dementia,
introduced in 2006. Rivastigmine can inhibit both acetylcholin-
esterase (AChE) and butyrylcholinesterase (BuChE), and its
metabolism does not rely on the cytochrome P450 enzyme
system in the liver.5 From a structural point of view, the
introduction of (S)-configuration is obviously the key step in the
Rivastigmine synthesis. In methods of obtaining single config-
uration, chemical resolution wastes half of the racemate, and
natural chiral materials are sufficiently rare that their use
availability is very limited. Instead, more efficient methods are
the use of chiral auxiliaries and enantioselective catalysis.
However, asymmetric synthesis usually needs stoichiometric
chiral auxiliary and sulfimide auxiliaries cannot be recycled
in procedures related to Rivastigmine.6,7 Moreover, although
asymmetric catalysis in the synthesis of Rivastigmine such as
metal catalysis,8,9 enzyme catalysis,9-14 and organocatalysis15
have been widely studied, there is still a long way to go before
enantioselective catalysis is employed in mass production.
Hence, developing new recyclable auxiliaries should be worth
In view of recyclable chiral N-phosphonyl auxiliaries in
GAP chemistry/technology, we used chiral N-phosphonyl
imines to generate new chiral centers and products would be
© 2019 The Chemical Society of Japan | 1065
Yang, Bing
