An improved process for the production of rivastigmine tartrate, a cholinesterase inhibitor

Article abstract of DOI:10.2174/157017810790796246

An improved and scalable process for the production of rivastigmine tartrate is reported. The improved process provides rivastigmine tartrate at considerably lower cost and allows the omission of hazardous chemicals. The overall yield is increased from 4.66% (reported process) to 17% with the improved process.

Full text of DOI:10.2174/157017810790796246

Letters in Organic Chemistry, 2010, 7, 149-154
149
An Improved Process for the Production of Rivastigmine Tartrate, a
Cholinesterase Inhibitor
Vajrala Venkata Reddya,b, Mandava Venkata Naga Brahmeswara Raoa, Varanasi Ganesha,
Adla Vijaya Kumara, Cherukupally Praveena, Khagga Mukkantib, Ganta Mahesh Reddya and
Ganta Madhusudhan Reddy*,a
aResearch and Development, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Survey
Nos 42, 45, 46 and 54, Bachupally, Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh, India; bCenter for
Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, Andhra
Pradesh, India
Received August 29, 2009: Revised December 25, 2009: Accepted January 05, 2010
Abstract: An improved and scalable process for the production of rivastigmine tartrate is reported. The improved process
provides rivastigmine tartrate at considerably lower cost and allows the omission of hazardous chemicals. The overall
yield is increased from 4.66% (reported process) to 17% with the improved process.
Keywords: Rivastigmine tartrate, a cholinesterase inhibitor, alzheimer’s disease, improved process, impurities.
INTRODUCTION
rivastigmine (7). Finally compound 7 on treatment with L-
(+)-tartaric acid in the mixture of ethanol and ethyl acetate
yielded rivastigmine tartrate (1) with an overall yield of
4.66%.
Rivastigmine hydrogen tartrate, (S)-N-ethyl-3-[(1-
dimethylamino)ethyl]-N-methylphenyl carbamate hydrogen
tartrate (1) is an acetylcholinesterase inhibitor of the
carbamate type and approved for the treatment of
Alzheimer’s disease [1, 2]. Alzheimer’s disease is a progre-
ssive neuro degenerative disorder characterized by loss of
short-term memory and immediate recall and decline in other
cognitive functions such as attention [3, 4]. Rivastigmine has
received approval for use in 60 countries including all the
members of the European Union where it was introduced in
1998 and the US where it was introduced in 2000. The
methods aiming at determining this relatively new parasym-
pathomimetic agent are of clinical and pharmacokinetic
importance.
In short, this process was encumbered by several
disadvantages such as (a) low overall yield (4.66%) (b)
formation of more number of impurities during the reaction
(c) difficulty in controlling the impurities in active
pharmaceutical ingredient (API), (d) handling of chemicals
like NaH, expensive raw materials like S-(+)-camphor-10-
sulfonic acid is difficult. These factors made the process less
viable for commercial production. Several other procedures
for syntheses of rivastigmine have been reported [6-12],
which are either too long or contain unacceptable operations,
and thus those are not suitable for plant-scale operations.
Most important of all, none of the procedures gave high
enantiomeric excess of rivastigmine.
The reported synthetic method [5] for this molecule
involves six steps (Scheme 1). 3-Methoxy acetophenone (2)
on reaction with dimethylamine in the presence of titanium
isopropoxide followed by reduction with NaBH4 at 10 °C in
ethanol yielded, [1-(3-methoxyphenyl)ethyl]dimethylamine
(3). Reaction of compound 3 with hydrobromic acid at reflux
temperature yielded, 3-(1-dimethylaminoethyl)phenol (4),
which was subjected to resolution using S-(+)-camphor-10-
sulfonic acid in a mixture of ethyl acetate and ethanol,
furnished the S-(-)-(3-(1-dimethylaminoethyl)phenol cam-
phor sulfonate salt (5). Desaltification of diastereomeric salt
We describe an improved, scalable and economic process
in this report [13], which is designed to overcome drawbacks
inherent with these reported methods. This improved process
provides, substantially impurities free synthesis of
1
(Scheme 2) and that meets regulatory quality requirements
with an overall yield of around 17%. Our process involved
seven steps, starting from 3-hydroxy acetophenone (8).
RESULTS AND DISCUSSION
5
with Na2CO3 in water provided the S-(-)-(3-(1-
dimethylamino ethyl)phenol (6). Condensation of compound
6 with N-ethyl-N-methyl carbamoyl chloride in the presence
of a strong base, NaH in tetrahydrofuran at 25-30 °C gave
In our efforts to develop a robust and scalable process for
rivastigmine tartrate 1, we started with a commercially
available, inexpensive key starting material, 3-hydroxy-
acetophenone (8), and methylation of compound 8 with
various methylating agents such as dimethylcarbonate,
methyl iodide using different organic bases such as
potassium carbonate, sodium carbonate, sodium hydroxide
and potassium hydroxide in solvents like acetone,
acetonitrile, toluene, methyl isobutyl ketone as solvent
*Address correspondence to this author at the Research and Development,
Integrated Product Development, Innovation Plaza, Dr. Reddy’s
Laboratories Ltd., Survey Nos 42, 45, 46 and 54, Bachupally, Qutubullapur,
R. R. Dist. 500 072, Andhra Pradesh, India; Tel: +91 9959098098; E-mail:
madhusudanrg@drreddys.com
DRL Communication number: IPDO-IPM-00123.
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

150 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Reddy et al.
NMe2
CH3
NMe2
CH3
O
MeO
HO
MeO
a
b
c
CH3
2
(+)-4
(+)-3
.S-(+)-Camphor-10-
sulfonic acid
NMe2
NMe2
CH3
CH3
N
NMe2
CH3
HO
HO
H3C
O
CH3
d
e
O
(S)-7
(S)-6
NMe2
CH3
(S)-5
CH3
OH
H3C
N
O
COOH
f
.
HOOC
O
OH
(S)-1
Scheme 1. Reported synthesis of rivastigmine tartratea.
aReagents and conditions: (a) dimethylamine, titanium isopropoxide, EtOH, 10 °C, 10 h, NaBH4, 24 h; (b) HBr, 75-80 °C, 12 h; (c) S-(+)-
camphor-10-sulfonic acid, EtOAc, EtOH (4:1), 70 °C, 30 min; (d) Na2CO3, water, DCM, 25-30 °C; (e) NaH, THF, ethylmethylcarbamoyl
chloride, 25-30 °C; (f) L-(+)-tartaric acid, EtOH /EtOAc (1:4), 75-80 °C, 30 min.
NH2
CH3
O
O
MeO
HO
MeO
c
a
b
CH3
CH3
(+)-9
8
2
NH2
CH3
NMe2
NMe2
CH3
.L-(+)-Mandelic acid
MeO
MeO
HO
f
d
e
CH3
(S)-6
(S)-11
(S)-10
CH3
N
NMe2
CH3
CH3
NMe2
CH3
OH
H3C
O
H3C
N
O
COOH
g
.
HOOC
O
O
OH
(S)-7
(S)-1
Scheme 2. Modified synthesis of rivastigmine tartratea.
aReagents and conditions: (a) dimethyl sulphate, K2CO3, acetone, 50-55 °C, 60 min, 95%; (b) ammonium formate, 180-185 °C, 2 h, i-
PrOH.HCl (18%), EtOAc, 75-80 °C, 3 h, 75%; (c) L-(+)-mandelic acid, i-PrOH, 75-80 °C, 45 min, 40%; (d) formaldehyde (40%), formic
acid (98%), 95-100 °C, 5 h 92%; (e) aqueous HBr, 100-110 °C, 6 h, 85%; (f) ethylmethyl carbamoyl chloride, pyridine, tetrabutyl ammonium
bromide, 25-30 °C, 15 h, 85%; (g) L-(+)-tartaric acid, acetone, 55-60 °C, 30 min, 90%.
medium were unsuccessful even at high temperatures (Table
1). When the reaction was conducted using dimethylsulphate
and potassium carbonate in acetone, 95% crude yield of
compound 2 was obtained (Scheme 2).
aminating agents like 10% methanolic ammonia,
hydroxylamine hydrochloride and reducing catalysts, 5%
palladium on carbon, Raney Nickel under hydrogen gas
pressure for longer hours did not proceed to completion and
yield was 45% only. When the reaction was conducted [14]
using ammonium formate without using any solvent at 180
Our next endeavor was to design a robust process for a
new intermediate 9. Reductive amination of 2 using different

An Improved Process for the Production of Rivastigmine Tartrate
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
151
Table 1. Selection of O-Methylating Agent
Entry
Reagent
Yield (%)
Purity (%)
Remarks
01
02
03
DMCa
DMSb
-
96
-
-
99.8
-
reaction not completed
-
c
MeI/K2CO3
reaction not completed
aDimethyl carbonate, bDimethyl sulphate, cMethyl iodide and potassium carbonate.
°C and followed by the addition of isopropyl alcohol.HCl in
ethyl acetate yielded primary amine derivative 9 with 75%
yield [15].
dimethyl sulfoxide proceeded with formation of impurities
were very high. However, when the reaction was conducted
using pyridine as a base and tetra-n-butylammonium
bromide as a catalyst in methyl isobutyl ketone at 25-30 °C,
the desired product 7 was obtained in 85% yield with > 99%
purity. To our delight, tartaric acid salt formation of 7 with
L-(+)-tartaric acid in acetone at reflux temperature furnished
1 having more than 99.7% purity and 90% yield.
As the resolution with S-(+)-camphor-10-sulfonic acid
gave poor yield and high R-isomer of 9, we developed a new
resolution method using chiral acid, L-(+)-mandelic acid.
Resolution [8] of 9 using L-(+)-mandelic acid in isopropyl
alcohol and recrystallisation from isopropyl alcohol resulted
compound 10 as mandelate salt with 99.9% purity (vide
HPLC) with 40% yield and having >99% desired isomer (S-
isomer). Process was also developed to racemise the
unwanted isomer into racemic mixture by heating with
NaOH in dimethylformamide.
Related substances (impurities) 13, 14 and 16 were
observed in this process. These related substances were
characterized as N,N-dimethyl-3-[1-(dimethylamino)ethyl-
phenyl carbamate (Dimethyl rivastigmine, 13) and N,N-
diethyl-3-[1-(dimethylamino)ethylphenyl carbamate (Diethyl
rivastigmine, 14) and these impurities were formed due to
contamination of trace level of dimethyl carbamoyl chloride,
diethyl carbamoyl chloride in N-ethyl-N-methyl carbamoyl
chloride, respectively. Traces of compound 12 in compound
11 leads to the formation of desmethyl rivastigmine 16
(Scheme 3). After knowing the structures of all these
impurities, process was optimized to control these impurities
at less than 0.10% in order to fulfill regulatory requirements.
The overall yield and purity of 1 obtained from this process
were summarized in Table 2.
N,N-Dimethylation [16] of compound 10 with excess
formic acid and formaldehyde in water at 100 °C yielded,
dimethylated product 11 with 92% and having 99% purity by
HPLC. The cleavage of the O-methyl bond of 11 using
aqueous hydrobromic acid without using any solvent at 110
°C yielded de-methylated derivative 6 with 85% yield [17].
Condensation of compound
6 with N-ethyl-N-methyl-
carbamoyl chloride in the presence of potassium carbonate,
sodium carbonate, sodium methoxide, sodium hydroxide and
potassium hydroxide as a base in various solvents such as
dimethyl formamide, toluene, dimethyl acetamide, and
NMe2
CH3
NHMe
CH3
NH2
.L-(+)-Mandelic acid
Formaldehyde
Formic acid
MeO
MeO
MeO
CH3
+
12
11
10
Aq. HBr
Aq. HBr
NMe2
CH3
Dimethyl
carbamoyl
chloride
NHMe
CH3
CH3
N
NMe2
CH3
HO
O
HO
H3C
O
15
6
13
Ethylmethyl
carbamoyl chloride
Diethylcarbamoyl
chloride
H3C
H3C
CH3
NHMe
CH3
NMe2
CH3
H3C
N
O
N
O
O
O
14
16
Scheme 3. Pathway for the formation of related substances of rivastigmine.

152 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Reddy et al.
Table 2. The Trend of Impurities in Rivastigmine Tartrate (1)
Entry
Puritya (%)
Imp (13)b (%)
Imp (14)c (%)
Imp (16)d (%)
Yield (%)
Assay (%)
01
02
03
99.91
99.90
99.89
0.006
0.004
ND
NDe
ND
ND
ND
ND
ND
17.2
17.0
17.3
99.8
99.0
100.2
aRivastigmine tartrate, bDimethyl rivastigmine, cDiethyl rivastigmine, dDesmethyl rivastigmine, eNot detected.
CONCLUSION
Preparation of 1-(3-methoxyphenyl)ethylamine (+)-9
We have a developed large-scale preparation route of
rivastigmine tartrate (1) by improving the original route
A mixture of 3-methoxy acetophenone (2) (500 g, 3.33
mol) and ammonium formate (925 g, 14.7 mol) was heated
to 180 °C and stirred for 2 h by removing water
azeotropically. The reaction mass was cooled to 25-30 °C
and quenched with water (1.5 L). The reaction mass
extracted with ethyl acetate (3 x 500 mL) and to the
combined organic layer hydrochloric acid in isopropyl
alcohol (1.5 L, assay: 18%) was added. The resulting
reaction mass was heated to 75-80 °C for 3 h and the solvent
was distilled off under reduced pressure. Ethyl acetate (1.5
L) was added to the cooled reaction mass at 25-30 °C and
maintained for 30 min. The obtained solid was filtered and
washed with ethyl acetate (500 mL). The wet solid was taken
in to water (1.5 L), stirred for 10 min. The pH of solution
was adjusted to 11 with caustic lye, stirred for 10 min and
extracted with ethyl acetate (2 x 1 L). Organic layers were
combined and the solvent was distilled off under reduced
pressure to give title compound. Yield 380 g (75%); HPLC
purity 99 %; MS: m/z (EI):152.1 (M+ + H), 174 (M+ + Na);
1H NMR (DMSO-d6, 400 MHZ): ꢀ 1.50 (d, J = 6.8 Hz, 3H),
3.77 (s, 3H), 4.34 (q, J = 6.8 Hz, 1H), 6.92 (dd, J1 = 2.4 Hz,
J2 = 8.4 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 7.17 (s, 1H), 7.32 (t,
J = 7.6 Hz, 1H), 8.58 (br s, 2H).
starting
from
inexpensive
readily
available
3-
hydroxyacetophenone (8) and which is substantially free
from impurities and meets all the regulatory requirements.
The process utilizes a Leuckart [14] reaction to provide a
novel solid intermediate 1-(3-methoxyphenyl)ethylamine (9)
and new resolution process was developed with L-(+)-
mandelic acid for this intermediate to provide intermediate
10. We have also examined various possibilities to reduce
the identified/unidentified impurities and optimized several
parameters such as temperature, amount of dimethylating
reagent and resoluting agent etc. The new process was scaled
up on multikilo scale to afford desired product 1 in high
yield and good quality.
EXPERIMENTAL SECTION
1
The H NMR spectra were recorded on Varian Mercury
plus and Gemini-2000 at 400 MHz. The infrared spectra
were recorded in the solid sate as KBr dispersion medium
using Perkin Elmer, Spectrumone FT IR spectrophotometer.
The mass analysis was performed on AB-4000 Q-trap LC-
MS/MS mass spectrometer. Melting points were determined
on a Polmon digital capillary melting-point apparatus, MP96
and are uncorrected. The solvents and reagents were used
without further purification.
Preparation of S-(-)-1-(3-methoxyphenyl)ethylamine
mandalate (10)
To a solution of 1-(3-methoxyphenyl)ethyl amine (9)
(200 g, 1.32 mol) in isopropyl alcohol (7 L) was added L-
(+)-mandelic acid (206 g, 1.35 mol) at 25-30 °C. The
reaction mass was heated to 75 °C and stirred for 45 min.
The reaction mass was cooled to 37 °C and stirred for about
10 min. The precipitated solid was filtered and washed with
isopropyl alcohol (400 mL). The wet solid was added to
isopropyl alcohol (2.4 L) then heated under reflux for 45
min. The resulting solution was cooled to 37 °C and stirred
for 10 min. The solid was filtered, washed with isopropyl
alcohol (100 mL) and dried at about 55 °C under reduced
pressure to give the title compound. Yield 160 g (40%);
HPLC purity 99.9%; MS: m/z (EI):152.1 (M+ + H), 174 (M+
An in-house LC method was developed for the analysis
of rivastigmine, where a column (Intersil ODS-3V, 250 x 4.6
mm, 5.0 ꢀm) with a mobile phase consisting of A: buffer
(1.6 g of KH2PO4 and 2.16 g of 1-Octane sulfonic acid
sodium salt in 1000 ml of Milli-Q water), adjusted the pH to
3 with 10% v/v phosphoric acid and acetonitrile in the ratio
of 80:20 (v/v), and mobile phase B consisting of buffer and
acetonitrile in the ration of 20:80 (v/v), with a timed gradient
program of T/%B: 00/10, 10/10, 20/20, 30/30, 40/40, 50/50,
55/50, 55.1/10, 65/10 with a flow rate of 1.0 mL/min, UV
detection at 217 nm was used.
1
+ Na); SOR: -20.84 ° (c 5 in ethanol); H NMR (DMSO-d6,
400 MHZ): ꢀ 1.41 (d, J = 6.8 Hz, 3H), 3.74 (s, 3H), 4.26 (q, J
Preparation of 3-methoxyacetophenone (2)
To a heterogeneous solution of 3-hydroxyacetophenone
(8) (2 kg, 14.7 mol) and K2CO3 (2.43 kg, 17.58 mol) in
acetone (4 L) was added dimethyl sulfate (2.036 kg, 16.14
mol) over a period of 1 h at 45 °C. The reaction mass was
stirred for 1 h at 45 °C and after completion of reaction (vide
TLC), reaction mass was cooled to 25 °C and quenched with
water (1.4 L). Organic layer was separated and distilled off
under reduced pressure to yield 2.09 kg (95%); HPLC purity
98.5%; MS: m/z 151 (M + + H).
= 6.4 Hz, 1H), 4.53 (s, 1H), 6.87-7.37 (m, 9H).
Preparation of S-(-)-[1-(3-methoxyphenyl)ethyl]-N,N-
dimethylamine (11)
To a solution of S-(-)-1-(3-methoxyphenyl)ethylamine
mandalate (diasteromeric salt, 10) (200 g, 0.66 mol) in water
(800 mL) was added 40% formaldehyde (148.5 g, 1.98 mol)
and 98% formic acid (182 g, 3.88 mol). The reaction mass

An Improved Process for the Production of Rivastigmine Tartrate
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
153
was heated to 100 °C and stirred for 5 h. After completion of
the reaction, reaction mass was cooled to 25-30 °C and
washed with toluene (3 X 100 mL). pH of the aqueous
solution was adjusted to11.0 using 40% caustic lye (160 mL)
and aqueous solution was extracted with ethyl acetate (2 X
500 mL). Combined organic layer was washed with water (2
X 400 mL) and distilled off under reduced pressure to yield
the title compound. Yield 109 g (92%); HPLC purity
sodium hydroxide solution (750 mL). Extracted with MIBK
(2 X 2 L) and the combined organic layer was washed with
water (2 X 2 L). The organic layer was distilled off under
reduced pressure at 60 °C. Yield: 1.286 kg, (85%): Purity by
HPLC 99.33%; MS: m/z (EI): 251 (M+ + H); 1H NMR
(CDCl3, 400 MHZ): ꢀ 1.20-1.35 (m, 3H), 1.37 (t, 3H), 2.21
(s, 6H), 2.90-3.10 (m, 3H), 3.25 (q, 1H), 3.36-3.50 (m, 2H),
6.90-7.21 (m, 3H), 7.25-7.30 (m, 1H); SOR: -32 ° (c 5 in
ethanol) {lit. [18] [ꢀ] 20D = -32.1 (c 5 in ethanol)}.
1
99.15%; MS: m/z (EI):180 (M+ + H); H NMR (CDCl3, 400
MHZ): ꢀ 1.35 (d, J = 6.4 Hz, 3H), 2.20 (s, 6H), 3.20 (q, J =
6.8 Hz, 1H), 3.8 (s, 3H), 6.76-6.79 (m, 1H), 6.87 (t, J = 6.8
Hz, 2H), 7.19-7.26 (m, 1H).
Preparation of rivastigmine tartrate (1)
To a mixture of rivastigmine (7) (3 kg, 11.98 mol,) in
acetone (105 L) was added L-(+)-tartaric acid (1.8 kg, 11.99
mol) at 25-30 °C and stirred for 10 min. The reaction mass
was heated to 60 °C and maintained for 30 min for complete
dissolution. The resulting solution was passed through celite
and celite bed was washed with acetone (13.5 L). The
obtained clear solution was distilled off up to 50% of the
total volume under reduced pressure. Leftover solution was
cooled to 30 °C and stirred for about 60 min for solid
separation. The separated solid was filtered and washed with
acetone (3 L). Solid was dried at 60 °C for 9 h under reduced
pressure to afford title compound. Yield 4.32 kg (90%);
Purity by HPLC 99.9%; mp:125-127 °C {lit. [18] mp:123-
Preparation of (S)-(-)-[3-(1-dimethylamino)ethyl]phenol
(6)
A solution of S-(-)-[1-(3-methoxyphenyl)ethyl]dimethyl-
amine (11) (1 kg, 5.58 mol) in hydrobromic acid (5.65 kg,
33.51 mol, 48%) was heated to 110 °C and maintained for 6
h. The resulting reaction mass was cooled to 25-30 °C and
pH was adjusted to 10 using 20% sodium hydroxide solution
(6.5 L). Extracted with ethyl acetate (3 X 1.5 L) and the
combined organic layer was washed with water (2 X 3 L)
and treated with charcoal. The organic layer was filtered
through celite and washed with ethyl acetate (2 L). The
filtrate was distilled off under reduced pressure at below 55
°C. The residue was isolated from ethyl acetate (2 L) at 5 °C.
The obtained solid was dried at about 55 °C for 2 h to give
the title compound. Yield 790 g (85%); HPLC purity
20
125 °C};MS: m/z (EI): 251 (M+ + H); SOR: [ꢀ] D = +5.1 (c
20
1
5 in ethanol) {lit. [18] [ꢀ]
= +4.70 (c 5 in ethanol)}; H
D
NMR (CDCl3, 400 MHZ): ꢀ 1.10 (t, 3H), 1.46 (d, 3H), 2.40
(s, 6H), 2.9 (s, 3H), 3.31 (q, 2H), 3.95 (q, 1H), 4.15 (s, 2H),
1
13
99.88%; MS: m/z (EI):166 (M+ + H); H NMR (CDCl3, 400
7.11 (d, 1H), 7.2 (s, 1H), 7.28 (d, 1H), 7.40 (t, 1H);
C
MHZ): ꢀ 1.36 (d, J = 6.4 Hz, 3H), 2.22 (s, 6H), 3.30 (q, J =
6.8 Hz, 1H), 6.70-6.78 (m, 3H), 7.13 (t, J = 7.6 1H), 7.26 (br
s, 1H); 13C NMR: (CD3OD, 100 MHZ): ꢀ 158.5, 145.4,
130.5, 120.8, 115.7, 115.9, 67.8, 20.4; SOR: -53.5 ° (c 1.55
in methanol).
NMR: (CD3OD, 100 MHZ): ꢀ 12.3, 17.6, 33.6, 41.1, 41.1,
43.6, 64.2, 72.08, 72.08, 121.7, 121.8, 125, 140.4, 151, 154,
174.1, 174.1.
ACKNOWLEDGEMENTS
We thank the colleagues of Research and Development
and the colleagues of Analytical Research and Development,
Integrated Product Development, Dr. Reddy’s Laboratories
Limited.
Preparation of (S)-N-ethyl-N-methyl-3-[1-dimethyl-
amino)ethyl]phenyl carbamate (Rivastigmine, 7)
To a mixture of S-(-)-(3-(1-dimethylaminoethyl)phenol
(12) (1 kg, 6.05 mol), pyridine (574 g, 7.25 mol) and
tetrabutyl ammonium bromide (196 g, 0.60 mol) in methyl
isobutyl ketone (MIBK) (2.0 L) was added N-ethyl-N-
methylcarbamoyl chloride (662 g, 5.45 mol) slowly for about
30 min at 25-30 °C under nitrogen atmosphere. Reaction
mass was stirred for 15 h at 25-30 °C. After completion of
reaction, water (8 L) was added and pH of the solution was
adjusted to about 1.5 using aqueous hydrochloric acid (620
mL) and stirred for 30 min. Aqueous layer was separated and
washed with MIBK (2 X 2 L). Aqueous layer was separated
from organic layer and the pH adjusted to 12.5 using 40%
aqueous sodium hydroxide (1 L). The aqueous layer was
then extracted with MIBK (2 X 2.5 L) and organic layer was
washed with water (2 X 2 L). Separated organic layer was
distilled off under reduced pressure at about 60 °C to afford
residue. EtOAc (8 L) was added to the residue and pH of the
solution was adjusted to 2 using 18% hydrochloric acid in
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isopropyl alcohol (1 L) at 5 C and stirred for about 90 min
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154 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
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