General strategy for large-scale synthesis of (+)-rivastigmine and (+)-NPS R-568

Article abstract of DOI:10.1080/00397911.2010.527425

An economically viable strategy for the total synthesis of (+)-rivastigmine and (+)-NPS R-568 has been reported. The strategy involves regioselective hydrogenation of diastereomerically pure bis amine to realize the desired a-methyl chiral substituted benzyl amine. The route is economical, scalable, and versatile enough to be adapted to similar classes of compounds. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.527425

This article was downloaded by: [University of Chicago Library]
On: 20 July 2013, At: 12:49
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
General Strategy for Large-Scale
Synthesis of (+)-Rivastigmine and (+)-NPS
R-568
Ramakrishna Rao a , Mukesh Padmakar Shewalkar a , Ramadevi
Nandipati a , Jhillu Singh Yadav b , Mukkanti Khagga c & Devanand
Baburao Shinde d
a Avra Laboratories Pvt. Ltd., Hyderabad, India
b Organic Chemistry Division-I, Indian Institute of Chemical
Technology, Hyderabad, India
c Jawaharlal Nehru Technological University, Hyderabad, India
d Department of Chemical Technology, Dr. Baba Saheb Ambedkar
Marathwada University, Aurangabad, India
Accepted author version posted online: 10 Aug 2011.Published
online: 17 Oct 2011.
To cite this article: Ramakrishna Rao , Mukesh Padmakar Shewalkar , Ramadevi Nandipati ,
Jhillu Singh Yadav , Mukkanti Khagga & Devanand Baburao Shinde (2012) General Strategy for
Large-Scale Synthesis of (+)-Rivastigmine and (+)-NPS R-568, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:4, 589-598, DOI:
10.1080/00397911.2010.527425
To link to this article: http://dx.doi.org/10.1080/00397911.2010.527425
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,

proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 42: 589–598, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.527425
GENERAL STRATEGY FOR LARGE-SCALE SYNTHESIS
OF (þ)-RIVASTIGMINE AND (þ)-NPS R-568
Ramakrishna Rao,1 Mukesh Padmakar Shewalkar,1
Ramadevi Nandipati,1 Jhillu Singh Yadav,2
Mukkanti Khagga,3 and Devanand Baburao Shinde4
1Avra Laboratories Pvt. Ltd., Hyderabad, India
2Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad, India
3Jawaharlal Nehru Technological University, Hyderabad, India
4Department of Chemical Technology, Dr. Baba Saheb Ambedkar
Marathwada University, Aurangabad, India
GRAPHICAL ABSTRACT
Abstract An economically viable strategy for the total synthesis of (þ)-rivastigmine and
(þ)-NPS R-568 has been reported. The strategy involves regioselective hydrogenation of
diastereomerically pure bis amine to realize the desired a-methyl chiral substituted benzyl
amine. The route is economical, scalable, and versatile enough to be adapted to similar
classes of compounds.
Keywords (R)-(þ)-1-Phenylethylamine; (S)-(ꢀ)-1-phenylethylamine; titanium tetra
isopropoxide
INTRODUCTION
A specific stereoisomer of a pharmaceutical drug having one or more stereo-
genic center tends to be responsible for the biological activity. In some cases, the
other isomer could cause damaging side effects.[1] The therapeutic inactive isomer
is regarded as an impurity that possesses different or undesirable pharmacological
Received August 19, 2010.
Address correspondence to Ramakrishna Rao, Avra Laboratories Pvt. Ltd., 54 Sai Enclave,
Habshiguda, Hyderabad 500007, India. E-mail: avralab@yahoo.com
589

590
R. RAO ET AL.
Figure 1. Rivastigmine tartarate and NPS R-568.
activity. This situation may become even more acute if the active enantiomer exhibits
a low therapeutic value or there is clinically significant toxicity. A well-known
example of a therapeutic specific pair is R and S enantiomers of thalidomide,
wherein the R enantiomer is an effective sedative and the S enantiomer is terato-
genic. Such biological responses and the need to reduce chemical and metabolic
waste necessitates better and more efficient synthesis of the single required drug iso-
mers. The drug rivastigmine, which is currently being used for the treatment of
dementia, was found to display a 10-fold greater affinity for brain monomeric G pro-
tein over the peripheral form of the enzyme.[2] It also shows dual inhibitory action on
both AchE and BchE and was found to demonstrate broad benefits across the sever-
ity of Alzheimer’s disease. We optimized the synthesis of rivastigmine, using an
asymmetric induction method, and patented this in 2005.[3] Our continued interest
in this chiral induction methodology led us to synthesize (þ)-NPS R-568. Calcimi-
metic (þ)-NPS R-568 has been found to activate the calcium-sensing receptors
and has a great potential as an innovative medical approach for the treatment of pri-
mary and secondary hyperparathyroidism.[4] Both of these molecules have one stereo
center having an a-methyl substituted chiral benzyl amine. Several research groups
have developed asymmetric syntheses and resolution strategies to prepare these
molecules.[5,6] Recently, Khair et al.[7] have shown the importance of N-isopropylsul-
finylimines as useful intermediates in the synthesis of chiral amines for the synthesis
of (þ)-NPS R-568. However, the majority of the synthetic routes involve resolution
and separation stages or multistep operations. We wanted to explore the scope and
plausibility to develop a commercially viable manufacturing process for making
these compounds enantiomerically pure while avoiding tedious resolution and
recycling of the wrong isomer.
We herein report the synthesis of substituted a-methyl chiral benzyl amine deri-
vatives and extension of this approach for the total synthesis of (þ)-rivastigmine and
(þ)-calcimimetic NPS R-568 (Fig. 1).
RESULTS AND DISCUSSION
Recently, Ishii et al.[8] have demonstrated the regioselective hydrogenolysis of
bis(a-methylbenzyl)amine derivatives and found that the regioselectivity arises
because of steric effects and is not governed by electronic effects. We envisaged that
a similar approach could be used efficiently to provide the desired a-methyl chiral
substituted benzyl amines with high enantioselectivity. Thus, the diastereomerically

SYNTHESIS OF (þ)-RIVASTIGMINE AND (þ)-NPS R-568
591
pure bis amine 5 obtained by reductive amination of 30-hydroxyacetophenone 3 and
commercially available (S)-(ꢀ)-1-phenylethylamine 4 can be regioselectively cleaved
to yield the required chiral substituted benzyl amine 6, which can be utilized as a key
intermediate for the synthesis of rivastigmine.
To complete the synthesis of rivastigmine using this strategy, we began with the
reductive amination of 30-hydroxyacetophenone and (S)-(ꢀ)-1-phenylethylamine in
presence of titanium(IV)isopropoxide and NaBH4 to produce amine 5. The amine
5 was methylated using formaldehyde and formic acid to get the tertiary amine
6.[9] Regioselective hydrogenation with Pd=C in ethanol yielded the required chiral
amine 7 with excellent enantioselectivity (>99%). The secondary amine 7 was again
methylated following the earlier procedure to afford 8. The phenolic functionality
was treated with N-ethyl-N-methyl carbomoyl chloride to yield the carbamate 9,
which was subsequently converted to the required tartarate salt 1 using L(þ)-tartaric
acid (see Scheme 1).
Similarly, the bis amine 11 obtained by the reductive amination of
30-hydroxyacetophenone and (R)-(þ)-1-phenylethylamine was cleaved under hydro-
genation conditions to yield 12 exclusively with >99% enantioselectivity. Protection
of the compound 12 with di-tert-butyl dicarbonate gave carbamate 13 in 81% yield.
The phenolic hydroxyl group was converted to the corresponding methyl ether by
treatment with dimethyl sulfate and potassium carbonate in refluxing acetone to
afford 14 in 74% yield. The product 14 was treated with 10 N HCl to deprotect
the Boc group and yield the salt 15. The salt 15 was treated with 2-chlorocinnamoyl
chloride in the presence of dichloroethane to get the carbamate 16. Hydrogenation of
the a,b-unsaturated amide with Pd=C yielded the saturated amide 17, which on
further treatment with diisobutylaluminium hydride(DIBAL)-H) gave the required
Scheme 1. Synthesis of rivastigmine tartarate.

592
R. RAO ET AL.
Scheme 2. Synthesis of NPS R-568.
target (þ)-NPS R-568 2. The product was compared with the earlier reported
analytical data and was found to be identical (see Scheme 2).
CONCLUSION
In conclusion, a commercially viable route for the total synthesis of rivastig-
mine and (þ)-NPS R-568 has been developed utilizing a simple reductive amination
followed by regioselective hydrogenation of the bis amines. Further extension of this
strategy for the synthesis of other biologically active molecules is currently being
investigated.
EXPERIMENTAL
The reactions were carried out under an N2 atmosphere in anhydrous solvents
such as CH2Cl2, tetrahydrofuran (THF), and EtOAc. THF was freshly distilled over
benzophenone prior to use. All reactions were monitored by thin-layer chromato-
graphy (TLC; silica-coated plates and visualized under ultraviolet light). Yields refer
to isolated yields. Air-sensitive reagents were transferred by a syringe or a
1
double-ended needle. H and 13C NMR spectra were recorded in CDCl3 solution
on a Brucker Avance 300 spectrometer. Chemical shifts are reported relative to tetra-
methylsilane (TMS) as an internal standard. Column chromatography was per-
formed on silica gel (60–120 mesh) supplied by Acme Chemical Co., India. TLC

SYNTHESIS OF (þ)-RIVASTIGMINE AND (þ)-NPS R-568
593
was performed on Merck 60 F-254 silica-gel plates. Optical rotations were recorded
on a Jasco P-1020 wavelen(Mþ þ H). HRMS m=z calculated for gth 589 polarimeter.
3-((S)-1-((S)-1-Phenylethylamino)ethyl)phenol (5)
Titanium(IV) isopropoxide (31.20 g, 110.13 mmol, 1.5 equiv) was added to a
stirred solution of 30-hydroxyacetophenone (10 g, 73.44 mmol) and S-
(a)-methylbenzylamine (8.89 g, 73.44 mmol, 1 equiv) in EtOAc (40 mL), and the mix-
ture stirred for 3 h. It was cooled to 0 ꢁC, and ethanol (100 mL) and sodium borohy-
dride (2.77 g, 73.44 mmol, 1 equiv) were added and stirred for 3 h. The mixture was
quenched at 0 ꢁC with acetic acid (3 mL). Solvents were concentrated. Water
(100 mL) and saturated Na2CO3 (100 mL) were added. The obtained solid was fil-
tered and washed with water (50 mL). The solid was taken into EtOAc (50 mL),
refluxed, and filtered hot. The process was repeated twice. The combined organic
layers were dried over Na2SO4 and concentrated. The residue was taken into dichlor-
omethane (DCM; 50 mL), stirred for 1 h, and filtered to give 5 (12.4 g, 71%) as a
white solid. Mp 118.5–119 ꢁC. [a]D ¼ ꢀ158 (c 1, MeOH). 1H NMR (300 MHz,
DMSO): d 1.13–1.18 (m, 6H) 3.25 (q, J ¼ 6.5 Hz, 1H), 3.39 (q, J ¼ 6.4, 1H),
6.58–6.45 (m, 3H), 7.03–7.08 (m, 1H), 7.17–7.29 (m, 5H). 13C NMR (75 MHz,
DMSO): d 25.38, 25.47, 55.11, 113.68, 113.87, 117.55, 126.84, 126.91, 128.62,
129.52, 146.73, 148.28, 157.82. MS-ESI: m=z 242.05 (Mþ þ H). HRMS m=z calcu-
lated for C16H20NO 242.1539; found 242.1529. HPLC method: column: Diacel chir-
alcel OD-H 250 ꢂ 4.6 mm, 0.5 u, Mp: 95% n-hexane þ 5% IPA þ 0.1% TFA, flow
rate: 0.8 ml=min, UV detection at 215 nm, sample concentration 1 mg=3 ml diluent,
retention time 8.2 min.
(1S)-N-((S)-1-(3-Hydroxyphenyl)ethyl)-N-methyl-1-
phenylethanamine (6)[5a]
Formaldehyde (37% in water, 50 mL) was added drop wise to a stirred solution
of 3-((S)-1-((S)-1-phenylethylamino)ethyl)phenol 5 (50 g, 0.20 mol) and formic acid
(47.68 g). The mixture stirred for 10 h at 70 ꢁC and concentrated. Water (100 mL)
and hexane (100 mL) were added, and layers were separated. The aqueous layer
was basified with 40% NaOH solution until the pH was 7.5 and extracted with
EtOAc (3 ꢂ 100 mL). The combined organic layers were dried over Na2SO4 and con-
centrated to give 6 (50 g, 95%) as a white solid, mp 98.6–99.9 ꢁC. [a]D ¼ ꢀ51 (c 1,
1
CHCl3); H NMR (300 MHz, CDCl3): d 1.29–1.35 (dd, J ¼ 6.84 Hz, 6H), 2.02 (s,
3H), 3.42–3.50 (bs, 1H), 3.75 (q, J ¼ 6.7 Hz, 1H), 3.81–3.88 (q, J ¼ 6.8 Hz, 1H),
6.70–6.73 (m, 1H), 6.90–7.16 (m, 2H), 7.19–7.37 (m, 6H). 13C NMR (75 MHz,
CDCl3): d 18.70, 19.02, 33.25, 59.39, 59.71, 114.46, 115.22, 120.39, 126.89, 128.12,
128.21, 129.43, 143.45, 146.12, 155.94. MS-ESI: m=z 256.10 (Mþ þ H).
3-[(S)-1-(Methylamino)ethyl]phenol (7)[5g]
To the solution of 6 (20 g, 78.32 mmol) in EtOH (100 mL), 10% Pd=C (2 g) was
added, and the mixture was hydrogenated at 75 psi for 16 h. The catalyst was filtered,
and the filtrate was concentrated. Toluene (100 mL) was added to the residue, stirred

594
R. RAO ET AL.
for 30 min, and filtered to give 7 (9.3 g, 82%) as brown solid. Mp 171–173 ꢁC.
1
[a]D ¼ ꢀ67.85 (c 5, pyridine). H NMR (300 MHz, CDCl3): d 1.35 (d, J ¼ 6.6 Hz,
3H), 2.30–2.32 (s, 3H), 3.58–3.64 (q, J ¼ 6.4 Hz, 1H), 6.70–6.73 (m, 1H), 6.82–6.84
(m, 2H), 7.15–7.25(m, 1H). 13C NMR (75 MHz, CDCl3): d 22.67, 32.95, 58.46,
112.06, 112.29, 115.88, 127.62, 145.89, 156.07. MS-ESI: m=z 152, (Mþ þ H).
3-[(S)-(Dimethyl Amino)ethyl]phenol (8)[5c]
Formaldehyde (37% in water, 16.1 mL) was added dropwise to a stirred sol-
ution of 7 (10 g, 66 mmol) in formic acid (12.7 mL). The mixture was stirred for
3 h at 70 ꢁC and concentrated. Water (75 mL) and EtOAc (75 mL) were added,
and the layers were separated. The aqueous layer was basified with 40% NaOH sol-
ution until the pH was 8 and extracted with EtOAc (3 ꢂ 50 ml). The combined
organic layers were dried over Na2SO4 and concentrated to give 8 (9.7 g, 90%) as
a white solid. Mp 102–112 ꢁC. [a]D ¼ ꢀ49 (c 5, EtOH). 1H NMR (300 MHz, CDCl3):
d 1.37–1.39 (d, J ¼ 6.7 Hz, 3H), 2.23 (s, 6H), 3.26–3.32 (q, J ¼ 6.7 Hz, 1H), 6.69–6.79
(m, 3H), 7.11–7.16 (m, 1H), 7.2–7.4 (bs, 1H). 13C NMR (75 MHz, CDCl3): d 19.08,
42.49, 65.61, 115.23, 115.82, 119.38, 129.36, 142.93, 157.23. MS-ESI: m=z 166.85
(Mþ þ H).
3-[(S)-(Dimethyl Amino)ethyl]phenyl N-Ethyl-N-methyl
Carbamate (9)[5a]
Pyridine (6.36 g, 80.52 mmol) and N-ethylmethyl amine (4.76 g, 80.52 mmol)
were added dropwise to a stirred solution of triphosgene (8.98 g, 30.26 mmol) in
CHCl3 (50 mL) at 0 ꢁC for 30 min and stirred for 1 h. The reaction mixture was con-
centrated, and the residue was taken into hexane (50 mL). The salts were filtered off,
and the filtrate was added to another reaction mixture containing 8 (5 g, 30.30 mmol)
and 60% NaH (0.78 g, 30.31 mmol) in THF (90 mL) at 0 ꢁC for 30 min and stirred for
14 h. The mixture was quenched at 0 ꢁC with ice-cold water (20 mL) and extracted
with EtOAc (3 ꢂ 25 mL). The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated. The oily residue was passed through short pad of
silica gel, and the pure product was isolated by eluting hexane=EtOAc (3:7) to give
9 (6.6 g, 86%) as colorless oil. [a]D ¼ ꢀ28.1 (c 5, EtOH). 1H NMR (300 MHz,
CDCl3): d 1.16–1.28 (m, 3H), 1.36 (d, J ¼ 6.7 Hz, 3H), 2.19–2.23 (s, 6H), 2.98–3.06
(m, 3H), 3.22–3.29 (q, J ¼ 6.6 Hz, 1H), 3.39–3.48 (q, J ¼ 8.3 Hz, 2H), 6.99–7.12 (m,
3H), 7.26–7.31 (m, 1H). 13C NMR (75 MHz, CDCl3): d 12.93, 13.62, 20.34, 34.25,
34.61, 43.41, 44.43, 66.05, 120.87, 121.23, 124.74, 129.32, 145.41, 151.92, 155.01.
MS-ESI: m=z 251.73 (Mþ þ H).
Tartaric Acid Salt of 3-[(S)-(Dimethyl Amino)ethyl]phenyl N-Ethyl-N-
methyl Carbamate (1)[5f]
EtOAc (70 mL) was added dropwise to a stirred solution of 9 (5 g, 20 mmol)
and L (þ) tartaric acid (2.9 g, 19.32 mmol) in EtOH (15 mL) at 60 ꢁC, and the mix-
ture was stirred at 25 ꢁC for 12 h. The solid was filtered to give 1 (5.1 g, 63%) as white
1
crystalline solid. Mp 120–122.8 ꢁC. [a]D ¼ þ 6 (c 5, EtOH). H NMR (300 MHz,

SYNTHESIS OF (þ)-RIVASTIGMINE AND (þ)-NPS R-568
595
CDCl3): d 1.13–1.24 (m, 3H), 1.67 (d, J ¼ 6.0 Hz, 3H), 2.65 (s, 6H), 3.96–3.06 (2S,
3H), 3.35–3.46 (m, 2H), 4.34–4.46 (m, 1H), 4.47 (S, 2H), 7.14–7.41 (m, 4H), 8.45
(s, 2H).13C NMR (75 MHz, CDCl3): d 12.45, 13.25, 16.42, 33.79, 34.20, 40.28,
44.08, 65.07, 72.62, 122.62, 123.06, 126.07, 130.81, 135.16, 151.68. 154.05, 154.20,
176.32. MS-ESI: m=z 251.05 (Mþ þ H ). Anal. calculated for C18H28N2O8:
C,53.99; H, 7.05; N, 7.0. Found: C, 53.92; H, 7.04; N, 6.95.
3-((R)-1-((R)-1-Phenylethylamino)ethyl)phenol (11)
Titanium(IV) isopropoxide (62.4 g, 220.26 mmol, 1.5 equiv) was added To a
stirred solution of 3-hydroxy acetophonone (20 g, 154.8 mmol) and R-
(a)-methylbenzylamine (18.7 g, 157.8 mmol, 1 equiv) in EtOAc (80 mL), and the mix-
ture was stirred for 3 h. It was cooled to 0 ꢁC, and ethanol (200 mL) and sodium bor-
ohydride (5.54 g, 146.88 mmol, 1 equiv) were added and stirred for 3 h. The mixture
was quenched at 0 ꢁC with acetic acid (6 mL). Solvents were concentrated. Water
(200 mL) and saturated Na2CO3 (200 mL) were added. The obtained solid was fil-
tered and washed with water (100 mL). The solid was taken into EtOAc (100 mL),
refluxed, and filtered hot. The process was repeated twice. Combined organic layers
were dried over Na2SO4 and concentrated. The residue was taken into DCM
(100 mL), stirred for 1 h, and filtered to give 11 (25 g, 70.5%) as a white solid. Mp
118.5–119 ꢁC. [a]D ¼ þ 158 (c 1, MeOH). 1H NMR (300 MHz, DMSO-d6): d
1.13–1.18 (m, 6H), 3.21–3.28 (q, J ¼ 6.5 Hz, 1H), 3.39 (q, J ¼ 6.4 Hz, 1H),
6.58–6.45 (m, 3H), 7.03–7.08 (m, 1H), 7.17–7.29 (m, 5H). 13C NMR (75 MHz,
DMSO-d6): d 25.38, 25.47, 55.11, 113.68, 113.87, 117.55, 126.84, 126.91, 128.62,
129.52, 146.8.28, 157.82. MS-ESI: m=z 242.05 (Mþ þ H). HRMS m=z calculated
for C16H20NO 242.1537: found 242.1531. HPLC method column: Diacel chiralcel
OD-H 250 ꢂ 4.6 mm, 0.5m, mp: 95% n-hexane þ 5% IPA þ 0.1% TFA, flow rate :
0.8 ml=min, UV detection at 215 nm, sample concentration 1 mg=3 ml diluent,
retention time 9.3 min.
3-((R)-1-Aminoethyl)phenol (12)[6g]
To a solution of 11 (14 g, 65.31 mmol) in AcOH (140 mL), 10% Pd=C (2 g) was
added, and the mixture was hydrogenated at 60 psi for 48 h. The catalyst was filtered
off, and filtrate was concentrated to give 12 (7 g, 89.7%). The crude product was
taken as such for the next reaction. An analytically pure sample was obtained by stir-
ring the crude with IPA and collected by filtration. Mp 155.1–158.6 ꢁC [a]D ¼ þ20.8
1
(c 1, MeOH). H NMR (300 MHz, DMSO-d6): d 1.36 (d, J ¼ 6.6 Hz, 3H), 4.03 (q,
J ¼ 6.4 Hz, 1H), 6.64–6.67 (m, 1H), 6.77–6.82 (m, 2H), 7.06–7.12(m, 1H) 13C
NMR (75 MHz, DMSO-d6): d 23.30, 50.08, 113.21, 114.41, 116.42, 129.20, 145.42,
157.68. MS-ESI: m=z 138.10 (Mþ þ H).
tert-Butyl (R)-1-(3-Hydroxyphenyl)ethylcarbamate (13)
Boc anhydride (12.4 g, 56.8 mmol, 1.14 equiv) was added to a stirred solution
of 12 (6.8 g, 49.56 mmol) and TEA (7.1 g, 70.29 mmol, 1.4 equiv) in MeOH (68 mL),
and the mixture was stirred for 6 h. It was then concentrated and diluted with DCM

596
R. RAO ET AL.
(75 mL). The organic layer was washed with water (2 ꢂ 30 mL) and brine (30 mL)
dried over Na2SO4, and concentrated to give 13 (9.4 g, 81.7%) as a thick liquid.
[a]D ¼ þ 57.65 (c 0.5, MeOH). 1H NMR (300 MHz, CDCl3): d 1.42 (s, 12H),
4.60–4.89 (bs, 2H), 6.70–6.84 (m, 3H), 7.14–7.19 (t, 1H). 13C NMR (75 MHz,
CDCl3): d 22.61, 28.40, 20.21, 79.87, 112.77, 114.42, 117.45, 129.65, 145.45,
155.58, 156.67. MS-ESI: m=z 236 (Mþ þ H).
tert-Butyl-(R)-1-(3-methoxyphenyl)ethylcarbamate (14)
Dimethylsulfate (4.9 g, 38.84 mmol, 1.01 equiv) was added dropwise to a stirred
solution of 13 (9.2 g, 38.77 mmol) and K2CO3 (8 g, 57.88 mmol, 1.5 equiv) in acetone
(92 mL) at 0 ꢁC and then refluxed for 12 h. The mixture was filtered through celite,
and the filtrate was concentrated. The residue was diluted with DCM (100 mL)
and washed with water (3 ꢂ 50 mL). The organic layer was dried and concentrated
1
to give 14 (7.2 g, 73.9%) as a thick clear liquid. [a]D ¼ þ62.56 (c 0.5, MeOH). H
NMR (300 MHz, CDCl3): d 1.42 (s, 9H), 3.80 (s, 3H), 4.60–4.89 (bs, 2H),
6.76–6.89 (m, 3H), 7.24–7.27 (m, 1H). 13C NMR (75 MHz, CDCl3): d 22.69,
28.39, 50.15, 55.17, 79.36, 111.75, 112.32, 118.14, 129.58, 145.83, 155.11, 159.76.
MS-ESI: m=z 252.43 (Mþ þ H).
(R)-1-(3-Methoxyphenyl)ethanamine Hydrochloride (15)[6b]
To a solution of 14 (7 g, 27.85 mmol) in MeOH (70 mL), 10 N HCl (7 mL) was
added and stirred overnight. The mixture was concentrated and codistilled using
toluene to give 15 (4.5 g, 86%) as HCl salt, which was taken as such for the next reac-
tion. The analytical sample was prepared by taking the salt in 10% NaOH solution
and extracted with DCM. Concentration of the solvent offered a thick liquid [a]
1
¼ þ21.2 (c 0.3, MeOH). H NMR (300 MHz, CDCl3): d 1.39–1.42 (d, J ¼ 6.6 Hz,
D
3H), 1.58–1.69 (bs, 2H), 3.82 (s, 3H), 3.90–4.25 (q, J ¼ 6.7 Hz, 1H), 6.72–6.80 (m,
1H), 6.94–6.90 (m, 2H), 7.24–7.29 (m, 1H). 13C NMR (75 MHz, CDCl3): d 25.57,
51.35, 55.25, 111.43, 112.16, 118.17, 129.52, 149.53, 159.82. MS-ESI: m=z 152
(Mþ þ H).
(E)-3-(2-Chlorophenyl)-N-((R)-1-(3-hydroxyphenyl)ethyl)acrylamide
(16)[6b]
(E)-3-(2-Chlorophenyl)acryloyl chloride (2.67 g, 13.32 mmol, 1 equiv) in DCM
(5 mL) was added dropwise to a stirred solution of 15 (2.5 g, 13.32 mmol), EDC
(25 mL), and TEA (3.1 g, 30.6 mmol, 2.6 equiv) and stirred at room temperature
for 2 h. The mixture was washed with water (2 ꢂ 10 mL), dried over Na2SO4, and
concentrated. It was purified by filter column using silica gel and 50% EtOAc in hex-
ane as eluent to give 16 (3.2 g, 81%) as a white solid. Mp 141–145 ꢁC. [a]D ¼ þ31.5 (c
1
0.5, CHCl3). H NMR (300 MHz, CDCl3): d 1.54–1.57 (d, J ¼ 6.9 Hz, 3H), 3.81 (s,
3H), 5.22–5.26 (q, J ¼ 7.2 Hz, 1H), 5.89 (d, J ¼ 6.84 Hz, 1H), 6.36–6.41 (d,
J ¼ 15.6 Hz, 1H), 6.80–6.83 (m, 1H), 6.90 (s, 1H), 6.96 (d, J ¼ 7.7 Hz, 1H),
7.29–7.30 (m, 3H), 7.39–7.41 (m, 1H), 7.52–7.55 (m, 1H), 7.96–8.02 (d, J ¼ 15.6 Hz,
1H). 13C NMR (75 MHz, CDCl3): d 21.62, 49.15, 55.37, 112.44, 112.71, 118.53,

SYNTHESIS OF (þ)-RIVASTIGMINE AND (þ)-NPS R-568
597
123.65, 126.96, 127.68, 129.82, 130.21, 130.40, 133.21, 134.82, 137.22, 144.76, 159.91,
164.42. MS-ESI: m=z 316.05 (Mþ þ H).
3-(2-Chlorophenyl)-N-((R)-1-(3-methoxyphenyl)ethyl)propanamide
(17)[6b]
The solution of 16 (1.5 g, 4.74 mmol) in MeOH (15 mL) was kept for hydrogen-
ation at 50 psi using 10% Pd=C (200 mg) for 3 h. The catalyst was filtered, and the
filtrate was concentrated. The product was purified by column chromatography
using silica gel and EtOAc–hexane (1:1) as an eluent to give 17 (1 g, 73.31%). Mp
1
88–92 ꢁC [a]D ¼ þ46.2 (c 1, CHCl3) H NMR (300 MHz, CDCl3): d 1.37–1.40 (d,
J ¼ 6.87 Hz, 3H), 2.44–2.49 (t, J ¼ 7.6 Hz, 2H), 2.93–2.98 (t, J ¼ 7.6 Hz, 3H), 3.78
(s, 3H), 5.01–5.11 (m, J ¼ 7.10 Hz, 1H), 5.50–5.53 (bs, 1H), 6.77–6.79 (m, 3H),
7.19–7.28 (m, 5H). 13C NMR (75 MHz, CDCl3): d 21.65, 31.77, 38.65, 48.71,
55.25, 112.35, 112.57, 118.42, 126.28, 128.43, 128.55, 129.70, 134.50, 136.11,
140.82, 144.75, 159.85, 171.10. MS-ESI: m=z 318.2 (Mþ þ H).
3-(2-Chlorophenyl)-N-((R)-1-(3-methoxyphenyl)ethyl)propan-
1-amine (2)[6b]
DIBAL-H (6 mL, 1 M in hexane, 6 mmol, 3.8 equiv) was added to a stirred
solution of 17 (0.5 g, 1.57 mmol) in DCM (2.5 mL) at 0 ꢁC and stirred at room tem-
perature for 16 h. It was quenched with MeOH (2 mL) at 0 ꢁC followed by 10%
NH4Cl (2.5 mL). The reaction mixture was passed through celite, and layers were
separated. The organic layer was dried over Na2SO4 and concentrated. It was pur-
ified by column chromatography using silica gel and EtOAC-hexane (1:1) as an elu-
1
ent to give 2 (0.32 g, 60%) as oil. [a]D ¼ þ40.3 (c 1, CHCl3). H NMR (300 MHz,
CDCl3): d 1.32–1.34 (d, J ¼ 6.6 Hz, 3H), 1.75–1.80 (m, 2H), 2.50–2.62 (m, 4H),
3.68–3.75 (q, J ¼ 6.7 Hz, 1H), 3.80 (s, 3H), 6.76–6.79 (m, 1H), 6.86–6.89 (m, 2H),
7.13–7.29 (m, 5H). 13C NMR (300 MHz, CDCl3): d 24.15, 31.78, 33.62, 47.35,
55.21, 58.48, 112.11, 112.35, 119.10, 125.72, 128.25, 128.36, 129.42, 142.13, 147.0,
159.85. MS-ESI: m=z 304 (Mþ þ H). HRMS m=z calculated for C18H29ClNO
303.8325; found 303.8318.
ACKNOWLEDGMENT
Mukesh Padmakar Shewalkar is thankful to A. V. Rama Rao for his valuable
guidance.
REFERENCES
1. Rouhi, A. M. Chiral business. Chem. Eng. News 2003, 81(18), 45–55.
2. Polinsky, R. Clinical pharmacology of rivastigmine: A new-generation acetylcholinesterase
inhibitor for the treatment of Alzheimer’s disease. Clin. Ther. 1998, 20, 634–647.
3. Ramakrishna, R.; Mukesh, P. S.; Chandrashekar, R.; Rao Rama, A. V. A process and
intermediate product for the production of rivastigmine. 747=MUM=2005 A, 2005.

598
R. RAO ET AL.
4. (a) Steffey, M. E.; Fox, J.; VanWagenen, B. C.; Delmar, E. G.; Balandrin, M. F.; Nemeth,
E. F. Calcimimetics: Structurally and mechanically novel compounds that inhibit hormonr
secretion from parathyroid cells. J. Bone Miner. Res. 1993, 8, S175; (b) Nemeth, E. F.;
Steffey, M. E.; Hammerland, L. G.; Hung, B. C. P.; VanWagenen, B. C.; DelMar,
E. G.; Balandrin, M. F. Calcimimetics with potent and selective activity on the parathyroid
calcium receptor. Proc. Natl. Acad. Sci. USA 1998, 95(7), 4040–4045; (c) Wada, M.;
Ishii, H.; Furuya, Y.; Fox, J.; Nemeth, E. F.; Nagano, N. NPS R-568 halts or reverses
osteitis fibrosa in uremic rats. Kidney Int. 1998, 53, 448.
5. For the synthesis of rivastigmine, see: (a) Hu, M.; Zhang, F.-L.; Xie, M.-H. Novel con-
venient synthesis of rivastigmine. Synth. Commun. 2009, 39, 1527–1533; (b) Abhay, G.;
Mangesh, M.; Sanjay, P. R. Novel process for the preparation of aminoalkyl phenyl carba-
mates. WO2005061446, 2005; (c) Boeaio, A. A.; Pytkowicz, J.; Cote, A.; Charette, A. B.
Asymmetric, catalytic synthesis of a-chiral amines using a novel bis(phosphine) monoxide
chiral ligand. J. Am. Chem. Soc. 2003, 125, 14260–14261; (d) Hana, S.; Josef, H.; Stanislav,
S. A method of production of (-)-(S)-3-[1-(dimethylamino)ethyl]phenyl-N-methyl-carba-
mate. WO2004037771, 2004; (e) Ma, D. W.; Pan, Q. B.; Pan, S. Process for preparation
of rivastigmine and tartrate. WO2007025481, 2007; (f) Weinstock Rosin, M.; Tashma, Z.
Phenyl carbamates. EP193926A2, 1986; (g) Enz, A. Phenylcarbamates. GB2203040,
1988; (h) Method of obtaining phenylcarbamates. EP1939172, 2008; (i) Juan, M.-S.; Marja,
R.-M.; Eduardo, B.; Vicente, G.-F.; Vicente, G. Chemoenzymatyic synthesis of rivastig-
mine based on lipase-catalyzed process. J. Org. Chem. 2009, 74, 5304–5310; (j) Han, K.;
Kim, C.; Park, J. Kim, M.-J. Chemoenzymatyic synthesis of rivastigmine via dynamic res-
olution as a key step. J. Org. Chem. 2010, 75, 3105–3108.
6. For synthesis of NPS R-568, see (a) Han, K.; Kim, Y.; Park, J.; Kim, M.-J. Chemoenzy-
matyic synthesis of calcimimetic (þ)-NPS R-568 via asymmetric reductive acylation of
ketoxime intermediate. Tetrahedron Lett. 2010, 51, 3536–3537; (b) Fernandez, I.; Valdivia,
´
V.; Khiar, N. N-Isopropylsulfinylimines as useful intermediates in the synthesis of chiral
amines expeditive asymmetric synthesis of calcimimetic (þ)-NPS R-568. J. Org. Chem.
2008, 73, 745–748; (c) Atobe, M.; Yamazaki, N.; Kibayashi, C. Enantioselective synthesis
of primary 1-(aryl)alkyl amines by nucleophilic 1,2 addition of organolithium reagents to
hydroxyoxime ethers and application to asymmetric synthesis of G-protein coupled recep-
tor ligands. J. Org. Chem. 2004, 69, 5595–5607; (d) Yamazaki, N.; Atobe, M.; Kibayashi,
C. Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation
of 1-(aryl)alkylamines and application to a synthesis of calcimimetic(þ)-NPS R-568 and its
thio analogue. Tetrahedron Lett. 2001, 42, 5029–5032; (e) Hansen, M. C.; Buchwald, S. L.
Synthesis of NPS R-568 utilizing titanium-catalyzed asymmetric hydrosilylation. Tetra-
hedron Lett. 1999, 40, 2033–2034; (f) Barmore, R. M.; Logan, S. R.; VanWagenen, B. C.
The addition of amines to diisobutylaluminum-imine complexes: Preparation of NPS R-
568 hydrochloride. Tetrahedron Lett. 1998, 39, 3451–3454; (g) Klaus, D. Method for pro-
ducing optically active aminoalkyl phenols. WO2006136538, 2006.
7. Fernandez, I.; Valdivia, V.; Khiar, N. N-Isopropylsulfinylimines as useful intermediates in
the synthesis of chiral amines: Expeditive asymmetric synthesis of calcimimetic (þ)-NPS R-
568. J. Org. Chem. 2008, 73, 745–748.
8. Kanai, M.; Yasumoto, M.; Kuriyama, Y.; Inomiya, K.; Katsuhara, Y.; Higashiyama, K.;
Ishii, A. Highly regioselective hydrogenolysis of bis(a -methylbenzyl)amine derivatives
affected by the trifluoromethyl substituent on the aromatic ring. Org. Lett. 2003, 5,
1007–1010.
9. Tsuge, H.; Okano, T.; Eguchi, S.; Kimoto, H. Asymmetric 1,3-dipolar cycloaddition of
optically active trifluoromethylated a,b-unsaturated aryl sulfones with nitrones: The use
of o-dialkylaminoethyl chiralauxiliaries. J. Chem. Soc., Perkin Trans. 1 1997, 10, 1581–
1586.