Available online www.jocpr.com
Journal of Chemical and Pharmaceutical Research, 2012, 4(6):3171-3183
Research Article
ISSN : 0975-7384
CODEN(USA) : JCPRC5
Synthesis Design of ‘Rivastigmine’-A Potent Therapeutic Agent for
Alzheimer’s disease using Retrosynthetic Analysis
Chittaranjan Bhanja* and Satyaban Jena
Department of Chemistry, Utkal University, Bhubaneswar-751004, Odisha, India
_____________________________________________________________________________________________
ABSTRACT
Synthesis is an indispensable component in the multidisciplinary development process of small molecule
pharmaceuticals. Designing synthetic routes to the pharmaceuticals by retrosynthetic analysis /synthon
disconnection approach, developed by Prof.E.J.Corey of Harvard University has emerged as powerful means in
synthetic organic/medicinal chemistry. Keeping a bird’s eye view on the works published in journals and patent
literatures, some synthesis schemes have been proposed for a potent Alzheimer’s disease drug ‘Rivastigmine’ in a
novel way basing on the retrosynthetic analysis. The proposed synthesis planning being a theoretical exploration,
the actual laboratory execution requires the cross examination of a considerable number of factors such as
reactions, reagents and order of events. In actual practice, generally that route is most feasible which satisfies the
specific criterion for an ideal synthesis.
Key words: Acetyl cholinesterase inhibitor, Alzheimer’s disease, Retrosynthetic analysis, Rivastigmine, Synthesis,
Synthon disconnection approach
_____________________________________________________________________________________________
INTRODUCTION
Organic synthesis is not only the fundamental tool to find essential drug candidate molecules but also in charge of
the subsequent creation, exploration and evaluation of short, efficient, safe and economically viable synthetic routes
for the selected clinical candidates. The heart of any synthesis is the planning of synthetic routes to a molecule of
any interest. If there is any key to success in planning a synthesis, it is to work the problem in the backward/ reverse
direction of synthesis, called retrosynthetic analysis/synthon disconnection approach[1,2], a strategy developed
systematically by Noble Laureate Prof. E.J.Corey of Harvard University. By working backwards the aim of the
retrosynthetic analysis is to transform a synthesis target in to progressively simpler structures by making strategic
bond cleavages and functional group interconversions, following a pathway to commercially available starting
materials. Analysis of a target molecule in retrosynthetic direction usually results a large number of possible
synthetic routes. It is therefore necessary to critically assess each derived route in order to choose the single route
which meets the specific criterion for an ideal synthesis.
Alzheimer’s disease (AD) is an irreversible, complex, neurodegenerative disorder characterized by progressive
cognitive impairment, a variety of neuropsychiatric and behavioral disturbances and restrictions in activities of daily
life [3]. It is an age related disease and is the most common cause of dementia in old people, being diagnosed after
the age of 56, and affecting up to 10 % of the population over the age of 65. The disease affects 30% or more of the
population over the age of 80. In the developed world, AD is the fourth major cause of death after cardiovascular
disease, cancer, and cerebral accidents. With an increase in life expectancy due to medical advances in the treatment
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J. Chem. Pharm. Res., 2012, 4(6):3171-3183
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of the above diseases, the number of AD patients is anticipated to increase dramatically. Worldwide, there are
approximately 35 million people with AD, and that number is expected to grow to 107 million by 2050 [4]. The
etiology of AD is not known, however, the biochemical and pathophysiological findings on postmortem brain
examination of AD patients have shown that the loss of the basal forebrain cholinergic system is one of the most
significant aspects of neurodegeneration in the brains of AD patients, and it is thought to play a central role in
producing cognitive impairments [5–7]. One of the therapeutic strategies aimed at ameliorating the clinical
manifestations of Alzheimer’s disease is to enhance cholinergic neurotransmission in relevant parts of the brain by
the use of acetyl cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts.
Therefore, enhancement of cholinergic transmission has been regarded as one of the most promising methods for
treating AD patients. A number of drugs are presently in clinical trials for the treatment of AD and among the best
known of these are the acetyl cholinesterase inhibitors .Rivastigmine,(S)-3-[1-(dimethylamino) ethyl] phenyl ethyl
(methyl) carbamate I, with a phenylcarbamate structure, is the first U.S.FDA approved drug for the treatment of
mild to moderate dementia of the Alzheimer’s type[8-11]and for mild to moderate dementia related to Parkinson’s
disease[12].It works by blocking the acetylcholine esterase (AChE), the enzyme responsible for its degradation and
butyrylcholine esterase (BuChE), the enzyme responsible for hydrolysis of ACh, thereby increasing both the level
and duration of action of the neurotransmitter acetylcholine[13-14]. In particular, Rivastigmine appears to have
marked effects in patients showing a more aggressive course of disease, such as those with a younger age of onset or
a poor nutritional status, or those experiencing symptoms such as nausea and vomiting. The high potentiality of
Rivastigmine against Alzheimer’s disease deserves an appropriate position in the “Blockbuster Drug List”[15].
N
N
O
O
I: Rivastigmine
Few synthetic methodologies for Rivastigmine although well cited in the literature[16-34 ],some alternative
synthetic routs and improvement in its existing processes for manufacture are constantly required in pharmaceutical
industries for market development. Keeping a bird’s eye view on the published works both in journals and patent
literatures, we have focused our research attention to propose a good number of synthesis schemes for
‘Revastigmine’ based on retrosynthetic analysis / synthon disconnection approach . It is an innovative work that has
not been reported elsewhere. The choice of this molecule for synthesis planning is obvious as Alzheimer’s disease is
worlds’ 4th most prevalent, debilitating and progressive disease that covers more than 35 millions people world wide
and Rivastigmine is one of the potent acetyl cholinesterase inhibitor widely used for the treatment of mild to
moderate dementia of the Alzheimer’s type as well as Parkinson’s disease.
EXPERIMENTAL SECTION
The structure and information regarding Rivastigmine as drug candid has been collected from different books.[1-4 ].
The proposed synthesis planning are then exploited in a novel way from the result of retrosynthetic analysis of dug
structure using the basic principle outlined in the pioneering works of Prof. E.J. Corey. The terms, abbreviations and
symbols used during synthesis planning are synonymous to that represented in book. [5].The analysis–synthesis
schemes being theoretical propositions, obviously the synthesis have not been executed in the laboratory. Most of
the retrosynthesis schemes have been derived taking in to account the synthesis earlier done for its preparation as
found from different literatures. The actual laboratory execution requires the cross examination of a considerable
number of factors such as reagents, reactions, order of events, economical viability, environmental benign,
saftyness, short time and scalable synthesis.
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RESULTS AND DISCUSSION
Retrosynthetic Analysis-1
N
N
O
N
C-O
O
TM
N
N
Cl
HO
O
1
O-carbamoylation
MeO
FGI
+
de-methylation
2
5
C-N
C-N
NH +
Cl3O
3
O
OH
O
FGI MeO
MeO
NH
OCl3
4
+
6
H
8
7
Synthesis-1
O
MeO
NH,benzene MeO
6
00C, r.t.
8
4
OCl3
N
HO
NH
3
NaHCO3
CH2Cl2, r.t.
N
1 O
NaH
2
N
N
HBr
HO
reflux
5
7
O
Cl3O
N
OH
i.MeMgI,Et2O
MeO
reflux
H
ii.HBr,benzene
2
Cl
O
1
N
Cl
N
O
N
DTTA
resolve
O
N
O
O
(TM)
recemic product
Scheme: 1
Reaction of 3-Methoxy benzaldehyde 8 with MeMgI in ether and subsequent acidification forms 1-(3methoxyphenyl) ethanol 7.Condensation of this alcohol with dimethyl amine 6 produces 1-(3-methoxyphenyl)-N, Ndimethyl ethanamine 5. Demethylation of methoxy group of 5 by refluxing with HBr affords 3-(1(dimethylamino)ethyl)phenole 2(Stedman's procedure)[1].N-ethyl-N-methyl carbamoyl chloride 1, formed from
triphosgene 4 and N-ethyl-N-methyl amine 3 in presence of NaHCO3/CH2Cl2 condenses with aminophenol 2 to
produce the a racemic product, which on resolution using di-p-toluoyl-D-tartrate (DTTA) affords the required target
molecule (T M).
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Retrosynthetic Analysis-2
N
N
O
C-N
O
N
H
N
+
reductive amination
O
9
O
1
O
10
O
H2N
FGI
Cl + HO
N
O-carbamoylation
O
6
TM
O
C-O
O
O
O2N
FGI
FGA
reduction
diazotisation
nitration
12
11
13
Synthesis-2
O
O
O
O2N
Con.HNO3
Con.H2SO4
MeOH
Cl
1 O
K2CO3
acetone
O
N
O
O
i.NaNO2/HCl
00C
O
HO
ii.H+/H2O
11
12
13
N
H2N
H2,Pd/C
10
N
N
+
6 H ,cat.H
NaCNBH3
N
O
i.L-Tartatic acid
O
recemic product
9
N
ii.NaOH,H2O
N
O
(TM)
O
Scheme: 2
Nitration reaction of acetophenone 13 with Con.HNO3/H2SO4 forms 3-nitro acetophenone 12.It is then reduced,
diazotized and subsequent hydrolysis produces 3-hydroxy acetophenone 10.O-Carbamoylation of 10 with N-ethylN-methylcarbamoyl chloride 1 in presence of K2CO3 affords 9.Reductive amination of 9 with dimethyl amine 6
gives racemic mixture of the product which is then resolved with L(+)-tartaric acid to form the target molecule
(TM).
Retrosynthetic Analysis-3
N
N
O
N
C-O
O
N
O-carbamoylation
TM
Cl
HO
+
2
O
C-N
N
H
reductive amination
15
6
H2N
FGI
diazotisation
O
1
N
O2N
N
FGI
O2N
+
12
Synthesis-3
3174
reduction
14
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O
N
N ,MeOH O N
2
H6
Ti(OiPr)4 , r.t.
NaBH4
O2N
12
N
CH3OH,r.t.
15
14
N . CAS
N
HO
D-10-CSA
NaNO2/ H+
H2N
H2/Rany-Ni
HO
N
N
HO
Na2CO3
H2O-EtOAc
C2H5OAc/ C2H5OH
2
2
Cl
1 O
K2CO3
L-(+)-Tartaric acid
acetone, reflux
2
N
N
O
(TM)
O
Scheme: 3
The reductive amination of 3-nitroacetophenone 12 with dimethylamine 6 in presence of Ti (OiPr) 4 and NaBH4 in
methanol affords 3-(1-(dimethylamino) ethyl) nitrobenzene 15. Hydrogenation of 15 using Raney-Ni produces 3-(1(dimethylamino) ethyl) amino benzene 14.Diazotization of 14 with NaNO2/ H2SO4 gives the racemic 3-(1(dimethylamino) ethyl) phenole 2. The compound 2 is then converted to its CSA salt using D-10-camphorsulfonic
acid which produces the same free chiral aminophenol 2 on treatment with Na2CO3. Condensation of 2 with Nethyl-N-methyl carbamoyl chloride (EMCC) 1 affords the target molecule (TM) in the forms of its tartarate salt on
subsequent treatment with L+ tartaric acid.
Retrosynthetic Analysis:-4
N
N
N
O
N
C-O
O
TM
O-carbamoylation
HO
Cl
O
1
N
FGI
2
H
H
16
MeO
+
17
2 X C-N
+
de-methylation
5
2
reductive amination
O
P Ph
N
Ph
NH2
O
MeO
Me
MeO
FGI
Zn
+
Me
enantioselective
18
Nu-addition
Synthesis:-4
3175
H
19
O
MeO
H
8
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O
MeO
MeO
[Ph2P(O)NSO]
H
Kresze rectn.
19
8
O
NH2 .HCl
17
O
P Ph
HN
Ph
N
N
2
MeO
H 16 H
i.Cat. H+
ii.NaCNBH3
reductive amination
MeO
HCl/H2O
Me
Me
O
P Ph
P P
N
Ph
O
(BozPHOS) MeO
H
Me Me
i.Me2Zn
18
ii.Cu(OTf)2, toluene,r.t.
BBr3
de-methylation
HO
2
5
N
N
Cl
N
O
1 O
O
K2CO3
acetone
O-carbamoylation
(TM)
Scheme: 4
Reaction of 3-Methoxy benzaldehyde 8 with p, p-diphenyl N-sulfinylphosphoramidate [Ph2P(O)NOS] forms Ndiphenylphosphinoylimine 19.Copper catalyzed reaction of dimethyl zinc 18 with 19 in presence of bis (phosphine)
monoxide chiral ligand affords N-phosphinoylimine as an intermediate. Acid hydrolysis of the intermediate forms
amine 17 which on subsequent reductive amination forms 3-methoxy (1-methyl, N, N,-dimethyl) benzyl amine
5.De-methylation of 5 and subsequent reaction with ethylmethylcarbamoyl chloride 1 in presence of a base forms
the target molecule (TM).
Retrosynthetic Analysis:-5
N
N
N
NH2
C-N HO
O
O
TM
OH
oximination
reduction
methylation
O
FGI HO
FGI HO
FGI HO
C-O
de-amination
2
&
de-carbonylation
N
21
20
10
Synthesis-5
O
HO
N
NH2OH
HO
OH
NH2
LiAlH4 HO
H 16 H
HCO2H
HCl
10
21
20
3176
O
N
HO
2
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N
i. CDI
ii. 3
N
O
O
NH
O
N
N
O
(TM)
O
resolve
N
CDI :
N
N
N
recemic product
Scheme: 5
3-Hydroxy acetophenone 10 is converted to corresponding oxime 21.The oxime is then reduced with LiAlH4 to form
3-(1-aminoethyl) phenol 20.Methylation of the amino group of 20 by reaction with formaldehyde 16 in the presence
of formic acid affords 3-(1-(dimethylamino)ethyl)phenole 2.Reaction of 2 with N-methyl ethylamine 3 in presence
of carbonyl diimidazole (CDI) inserts a carbonyl group between phenolic oxygen and the N-atom of ethyl methyl
amine to form recemic product which on resolution affords the target molecule (TM).
Retrosynthetic Analysis:-6
N
N
N
O
N
C-O
N
HO
Cl
FGI
MeO
FGI
+
O
O
1
O-carbamoylation
TM
FGI
OAc
FGI
MeO
MeO
OH
MeO
FGI
enantioselective
O-acylation
22
7
17
reductive amination
5
OH
NH2
MeO
de-methylation
2
7
O
MeO
FGI
reduction
23
Synthesis:-6
OH
O
NaBH4
MeOH
MeO
MeO
OAc
vinyl acetate
MeO
CAL-B
0
TBME,30 C
K2CO3
MeOH-H2O, r.t.
(R)
7
23
OH
MeO
(R)
7
22
i.Phthalimide, PPh3 MeO
DEAD, THF, r.t.
ii.N2H4
(S)
H2O,THF-EtOH,600C
17
3177
N
NH2
HCHO, NaBH(OAc)3
Na2SO4,r.t.
MeO
(S)
5
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N
HBr,1000C
N
HO
(S)
Cl
N
N
1 O
NaH
CH2Cl2,r.t.
2
O
(TM)
O
Scheme: 6
3-Methoxy acetophenone 23 is reduced to 1-(3-methoxyphenyl) ethanol 7 using NaBH4.Enantiomeric esterification
of 7 with vinyl acetate forms 22 via Enzymatic Kinetic Resolution using CAL-B(Candida Antarctica Lipase-B) in
tetra butyl methyl ether (TBME) solvent. Alkali hydrolysis of 22 produces the corresponding (S) alcohol 7 without
the loss of optical purity. Under Mitsunobu reaction condition the alcohol 7 forms 1-(3-methoxyphenyl) ethanamine
17.Dimethylation of the amino group with aq.HCHO 16 followed by addition of Na2SO4 and
sod.triacetoxyborohydride (NaBH (OAc) 3) affords 5. Demethylation of 5 with aq.HBr provides 3-(1(dimethylamino) ethyl) phenol 2 .Reaction of phenol 2 with N-ethyl-N-methyl carbamoyl chloride 1 in presence of
NaH affords the target molecule (TM).
Retrosynthetic Analysis:-7
N
N
NH
O
O
C-N
H
O
H +
N
N
O
hydrogenolysis
24
N
Ph
O
O-carbamoylation
25
Ph
O
+
H
O
1
HN
Ph
N
Ph
MeO
H
+
16
27
26
Ph
O
MeO
HO
Cl
N
O
16
TM
N
N
28
O
diastereoselective
reductive amination
Ph
29
MeO
+
NH2
23
Synthesis:-7
O
HN
Ph
MeO
23
NH2
MeO
29
i.Ti(OiPr)4,EtOAc
ii.H2,Raney-Ni
HCl, r.t.
Ph O
H 16 H
N
MeO
Ph
HBr
HO
HCO2H
28
27
3178
26
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N
Cl
N
N
O
1 O
i.NaH,THF,r.t.
O
O
NH
Ph
Pd/C,H2
N
r.t.
O
N
N
H 16 H,HCO2H
L-tartaric acid
O
O
(TM)
O
24
25
Scheme: 7
Diastereoselective reductive amination of 3-methoxyacetophenone 23 with (S)-1-phenylethylamine 29 in presence
of titanium (IV) isopropoxide and Raney-Ni produces diastereomerically pure amine 28. Methylation of this amine
with formaldehyde and formic acid forms 27. Demethylation of ether group of 27 with aq.HBr provides phenol
26.O-Carbamoylation of phenol 26 with carbamoyl chloride 1 affords carbamate 25 and the α-methyl benzyl group
from the carbamate is removed by hydrogenolysis to form 24.Second methylation of 24 following the above
procedure affords the target molecule (TM) in the form of tartarate salt when treated with L (+)-tartaric acid.
Retrosynthetic Analysis:-8
N
N
O
N
O
amination
N
FGI
O
(R)
TM
O
O
30
OH
N
OAc
OH
FGI
O
FGI
(R)
enantioselective
O-acylation
31
O
O
N
FGI
O
C-O
O
reduction
O
O
Cl
+
O
1
O-carbamoylation
9
32
N
HO
10
Synthesis:-8
O
N
HO
10
Polymer-supported
Ru-catalyst (I)
Novozyme-435
isopropenyl acetate
K2CO3
tolune
N
N
O
O
OH
O
Cl
N
1 O
NaH
CH2Cl2
O
N
NaBH4,MeOH
O
O
O
00C
9
32
OH
OAc
N
O
O
K2CO3
MeOH/H2O
(R)
31
N
O
O
(R)
ii.Me2NH/THF
30
O
I:
(TM)
polystyrene
Scheme: 8
3179
i.MeSO2Cl,Et3N
CH2Cl2
Ph
Ph
O
Ph
Ru Cl
O Ph
OC CO
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O-Carbamoylation of 3-hydroxyacetophenone 10 with N-ethyl-N-methyl carbamoyl chloride 1 in presence of NaH
affords 9, which on reduction with NaBH4 gives 32. Enantiomeric esterification of 32 with isopropenyl acetate
forms 31 via Enzymatic Kinetic Resolution using Novozyme-435 and Ru-catalyst (I) in toluene solvent. Alkali
hydrolysis of 31 forms the alcohol 30 without the loss of optical purity. Transformation of 30 via a mesylated
intermediate affords the target molecule (TM).
Retrosynthetic Analysis:-9
N
N
OAc
O
N
FGI
O
enantioselective
O-acylation
TM
O
O
OH
FGI
31
32
O
O
N
C-O
O
O
O
(R)
O
N
N
FGI
O-carbomoylation
9
HO
Cl
+
O
10
1
Synthesis:-9
O
N
HO
1 O
K2CO3 ,acetone
reflux
10
N
N
(x)
COCl2
N
N
O
N
H
N
N
O
N
O
O
O
32
9
N
Me2NH
O
OH
NaBH4,MeOH
00C
OAc
vinyl acetate
CAL-B
N
H
O
Cl
0
10-20 C
N
O
O
(TM)
(R)
31
Scheme: 9
The reaction of 3-hydroxyacetophenone 10 with N-ethyl-N-methylcarbamoyl chloride 1 in presence of K2CO3
produces 9. Reduction of 9 with NaBH4 affords the recemic alcohol 32. Enantiomeric esterification of 32 with vinyl
acetate forms 31 via Enzymatic Kinetic Resolution using CAL-B and bis (heteroarylmethylene) ethane-1, 2diamines (x) in phosgene. The enantiopure acetate (R)-31 on treatment with excess of dimethylamine in toluene
affords the desired target molecule (TM).
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Retrosynthetic Analysis-10
N
N
N
O
O
N
reductive amination O
desulfinylation
TM
O
O-carbamoylation
34
O
S
N
FGI
HO
Cl
C-O
O
33
HN
N
HN
NH2
O
O
S
HO
O
S
FGI
+
O
1
O
S
35
O
HO
NH2
+
10
37
36
Synthesis-10
O
S
O
HO
NH2
37
N
O
S
HN
HO
NaBH4
O
S
N
HO
1 O
K2CO3
(S)-isomer
10
36
HN
N
O
alkali
O
35
O
S
dry HCl/MeOH
Cl
NH2
N
H 16 H
Cat H+
O
O
34
O
N
N
O
O
33
Scheme: 10
Reaction of 3-hydroxy acetophenone 10 with (S) t-butyl sulphinamide 37 first forms N-sulfinylimine 36, which on
reduction with NaBH4 forms its corresponding N-sulfinylamine 35. The amine forms its amido-ester 34 with Nethyl-N- methyl carbamoyl chloride 1. Hydrolysis of sulfinyl group of 34 with dry methanolic hydrogen chloride
subsequent alkali treatment gives 33.Finally N, N-dimethylation of amine 33 with formic acid and formaldehyde
solution furnishes the target molecule (TM).
CONCLUSION
The synthesis of a particular compound from commercially available starting materials is fundamental to nearly all
aspects of organic chemistry.Retrosynthetic analysis/synthon approach is expected to provide new and innovative
synthetic strategies in a logical manner for design, execution and development of new synthesis or effect
improvements in existing processes. It is a paper exercise; a full analysis of this type will provide many routes for
synthesising the target molecule. Exploiting this approach, we have outlined some theoretical propositions in the
planning of synthesis of a potent Alzheimer’s disease drug ‘Rivastigmine’.Scalable synthetic routes for newly
discovered drug molecules/drug intermediate, useful compounds not available in adequate quantities from natural
resources and even the target molecules that have never been synthesized earlier can be best provide by this
approach. With the manifestation of new reagents, enantiopure intermediates, chemical reactions and sophisticated
3181
(TM)
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______________________________________________________________________________
new methods of laboratory implementation, it is now time to rethink the synthesis of best selling drugs for market
development through this approach.
Acknowledgements:
The author CB thanks UGC, New Delhi, India for financial support as Teacher Fellow grants. The author also
thanks the authorities of IIT Bhubaneswar, IMMT Bhubaneswar and NISER, Bhubaneswar for permission to collect
information from books and journals from their library.
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