Efficient approach to pure entacapone and related compounds

Article abstract of DOI:10.1080/00397911.2010.539894

A new and efficient process through a new intermediate, (2E)-2-cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15, has been described for preparing substantially pure entacapone 1. This new intermediate 15 was prepared by Knoevenagel condensation of 3,4-dihydroxy-5-nitrobenzaldehyde 2 with 2-cyanoacetic acid 14 and was further condensed with diethylamine to get pure entacapone 1. Some of the important process-related impurities of entacapone (17, 18, 19, and 20) were also prepared easily from this intermediate 15. Copyright Taylor & Francis Group, LLC.

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Efficient Approach to Pure Entacapone
and Related Compounds
G. Srikanth a b , Uttam Kumar Ray a , D. V. N. Srinivas Rao a , P.
Badarinadh Gupta a , P. Lavanya a & Aminul Islam a
a Chemical Research and Development, Aurobindo Pharma Limited,
Hyderabad, India
b Jawaharlal Nehru Technological University, Hyderabad, India
Accepted author version posted online: 21 Oct 2011. Version of
record first published: 11 Jan 2012
To cite this article: G. Srikanth, Uttam Kumar Ray, D. V. N. Srinivas Rao, P. Badarinadh Gupta, P.
Lavanya & Aminul Islam (2012): Efficient Approach to Pure Entacapone and Related Compounds,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:9, 1359-1366
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Synthetic Communications1, 42: 1359–1366, 2012
Copyright # Aurobindo Pharma Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.539894
EFFICIENT APPROACH TO PURE ENTACAPONE AND
RELATED COMPOUNDS
G. Srikanth,1,2 Uttam Kumar Ray,1 D. V. N. Srinivas Rao,1
P. Badarinadh Gupta,1 P. Lavanya,1 and Aminul Islam1
1Chemical Research and Development, Aurobindo Pharma Limited,
Hyderabad, India
2Jawaharlal Nehru Technological University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A new and efficient process through a new intermediate, (2E)-2-cyano-3-
(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15, has been described for preparing
substantially pure entacapone 1. This new intermediate 15 was prepared by Knoevenagel
condensation of 3,4-dihydroxy-5-nitrobenzaldehyde 2 with 2-cyanoacetic acid 14 and was
further condensed with diethylamine to get pure entacapone 1. Some of the important
process-related impurities of entacapone (17, 18, 19, and 20) were also prepared easily
from this intermediate 15.
Keywords Aluminum chloride; cyanoacetic acid; impurities; Knoevenagel condensation;
Parkinson’s disease; piperidine
INTRODUCTION
Entacapone 1, chemically known as (2E)-2-cyano-3-(3,4-dihydroxy-5-nitro-
phenyl)-N,N-diethylprop-2-enamide, is a catechol-O-methyl transferase (COMT)
inhibitor.[1,2] Entacapone 1 is approved under the trademark Comtan by the U.S.
Food and Drug Administration for the treatment of Parkinson’s disease.[3,4] Many
synthetic approaches have been reported for the synthesis of entacapone 1.[5–10] The
Received September 10, 2010.
Address correspondence to Uttam Kumar Ray, Chemical Research and Development, Aurobindo
Pharma Limited, Hyderabad 500 072, Andhra Pradesh, India. E-mail: ukray@aurobindo.com
1359

1360
G. SRIKANTH ET AL.
Scheme 1. (i) Piperidineacetate, ethanol, reflux.
first process for the synthesis of entacapone 1 was disclosed by Backstrom et al.[5,6]
They prepared entacapone 1 along with a mixture of two geometric isomers 4,
wherein the ratio of E=Z isomers is approximately 70:30 through the condensation
reaction between 3,4-dihydroxy-5-nitrobenzaldehyde
2
and N,N-diethyl-2-
cyanoacetamide 3 (Scheme 1). However, they have not reported any crystallization
methods to remove the unwanted Z-isomer from the mixture.
Further, Pippuri et al.[7] also prepared entacapone 1 by following this method,
they but crystallized the mixture of isomers 4 from lower aliphatic carboxylic acid,
such as a HCOOH and CH3COOH in the presence of catalytic amounts of HCl
or HBr to obtain pure entacapone 1 (Scheme 2).
Venkateshwarulu et al.,[8] disclosed the preparation of 1 from 3-O-alkylated
entacapone 6, which in turn is prepared by condensing 3-alkoxy-4-hydroxy-5-nitro-
benzaldehyde 5 with N,N-diethyl-2-cyanoacetamide 3. 3-O-Alkylated entacapone 6
on treatment with AlCl3 results in the mixture of 4, which is purified by crystalliza-
tion using a mixture of methanol and toluene to get pure entacapone 1 (Scheme 3).
All these processes have some drawbacks such as longer reaction time, use of
hazardous and corrosive reagents, and need for crystallization by purification to
remove unwanted isomer to get the pure entacapone 1. In another report by
Cziaky et al.,[9] vanillin 7 is reacted with N,N-diethyl-2-cyanoacetamide 3. The
Scheme 2. (i) CH3COOH, HBr, 90 ꢀC.
Scheme 3. (i) Piperidine, CH3COOH, toluene, 110 ꢀC; (ii) AlCl3, 5 ꢀC; and (iii) methanol and toluene.

EFFICIENT APPROACH TO ENTACAPONE
1361
Scheme 4. (i) Diethyl amine, CH3COOH, toluene, reflux; (ii) HNO3; and (iii) AlCl3, DMF, 100 ꢀC.
resulting (2E)-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)-N,N-diethylprop-2-enamide
8 is nitrated to get (2E)-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-N,N-
diethylprop-2-enamide 9, which is demethylated to give crude entacapone
(Scheme 4). This crude product is purified from isopropyl alcohol and then from a
mixture of acetone and acetic acid to give entacapone 1. The main drawbacks of
the method are longer reaction time, use of hazardous and corrosive reagents, and
requirement for recrystallization to obtain pure entacapone 1.
Sanmarti et al.,[10] reported another method for synthesis of entacapone 1,
which is depicted as shown (Scheme 5). In this route, 3,4-dimethoxy-5-nitrobenzoic
acid 10 was treated with SOCl2 to get 3,4-dimethoxy-5-nitrobenzoylchloride 11,
which is then reacted with N,N-diethyl-2-cyanoacetamide 3 to get 2-cyano-3-
(3,4-dimethoxy-5-nitrophenyl)-3-hydroxy-N,N-diethyl-prop-2-enamide 12. Reaction
of 12 with NaHB(OAc)3 results in 3,4-dimethoxy entacapone 13, which is then
demethylated to give entacapone 1 (Scheme 5).
In this process also, hazardous chemicals such as AlCl3 and NaH have been
used. It is obvious that there is a need to have a better process for the preparation
of entacapone 1. We report here an efficient synthesis of entacapone 1.
Scheme 5. (i) SOCl2, toluene, 60 ꢀC; (ii) NaH, N,N-diethyl-2-cyanoacetamide, THF, ꢁ5 ꢀC;
(iii) NaHB(OAc)3, 45 ꢀC; and (iv) AlCl3, pyridine, 80 ꢀC.

1362
G. SRIKANTH ET AL.
RESULTS AND DISCUSSION
The condensation reaction of the 3,4-dihydroxy-5-nitrobenzaldehyde 2 with
N,N-diethyl-2-cyanoacetamide 3 proceeds as per the Knoevenagel condensation.
This Knoevenagel condensation reaction is very useful and widely used in synthetic
organic chemistry.[11–16] However, it is also reported in many cases that condensation
will not produce always the pure cis (Z) or trans (E) isomeric compounds.[11–16] The
selectively formation of the isomers depend on the condition of reaction and the nat-
ure of the substitutent in the active methylene compounds.[13,15] Inokuchi et al.[13]
have worked on the Knoevenagel condensation on different aromatic aldehyde
and active methylene compounds and reported the formation of mixture of E
and Z isomers. Similarly, as described in the first process of Backstrom et al.,[5,6]
condensation between 3,4-dihyrroxy-5-nitrobenzaldehyde 2 and N,N-diethyl-2-
cyanoacetamide 3 results in the mixture of E and Z isomers of entacapone 4 in
the ratio of 70:30. This is the major drawback of this process, and further crystalliza-
tion is required to remove the undesired Z-isomer, thereby resulting in poor yield.
To circumvent these difficulties, we have devised an efficient process for the
preparation of substantially pure entacapone 1 through a new intermediate (2E)-2-
cyano-3-(3,4-dihydroxy-5-nirtrophenyl) prop-2-enoic acid 15, which is prepared by
Knoevenagel condensation between the 3,4-dihydroxy-5-nitrobenzaldehyde 2 and
2-cyanoaceticacid 14. Compound 15 is obtained with good yield and purity. The
major advantages of this new intermediate preparation are shorter reaction time
and no need for further purification to get pure E-isomer of compound 15.
Compound 15 was converted into its corresponding chloride 16 using thionyl
chloride. This chloride 16 was condensed with diethyl amine to yield entacapone 1
(Scheme 6), which is highly pure. The formation of intermediate 15 is stereoselective
and yields mostly pure (E)-isomer. With this quantity of intermediate 15, we are able
to prepare pure Entacapone 1 having <0.1% undesired Z-isomer. The content of E
and Z isomers in entacapone is determined through high-pressure liquid chromato-
graphy (HPLC).[17]
Using this efficient method for the preparation of entacapone 1, we have suc-
cessfully prepared some of the related compounds of entacapone 1, which may be
present as impurities in entacapone. The related compounds 17, 18, 19, and 20 have
been reported[17] as impurities in entacapone. These impurities are prepared as per
Scheme 6. (i) Piperidine, CH3COOH, ethanol, 80 ꢀC; (ii) SOCl2, 80 ꢀC; and (iii) diethyl amine, 0 ꢀC.

EFFICIENT APPROACH TO ENTACAPONE
1363
Scheme 7. (i) SOCl2, 80 ꢀC; and (ii) R-H, 0 ꢀC. (Figure is provided in color online.)
the process depicted in Scheme 7 with good yield and purity. All these compounds
1
(17, 18, 19, and 20) are well characterized by H NMR, 13C NMR, Mass, and
infrared (IR) analysis.
CONCLUSION
In conclusion, we have developed an efficient synthetic route for entacapone
and some of its process-related impurities. Entacapone with substantiate purity will
be prepared by this process without doing any extensive purification.
EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used with-
out purification. Melting points were determined on a Polmon-melting point appar-
atus. All melting points were uncorrected. The 1H NMR and 13C NMR spectra were
recorded on a Bruker 300-MHz spectrometer. The chemical shifts are reported in
parts per million (d ppm) relative to tetramethylsilane (TMS). The IR spectra
were recorded in solid state as KBr dispersion using a Perkin-Elmer Fourier trans-
form (FT)-IR spectrometer. The mass spectra were recorded on an API 2000
Perkin-Elmer PE-SCIEX mass spectrometer.
(2E)-2-Cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic Acid (15)
A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde 2 (100 g, 547 mmol), 2-cya-
noacetic acid 14 (69.67 g, 820 mmol), piperidine (86.1 g, 101 mmol), acetic acid
(42 g, 700 mmol), and ethanol (900 ml) were heated to reflux for 4 h. The reaction
mixture was concentrated under reduced pressure and then diluted with ethyl acetate
(100 ml) and water (100 ml). The resulting solution was basified with 10% w=v aque-
ous sodium hydroxide solution (ꢂ200 ml). The aqueous layer was separated
and acidified with concentrated HCl (ꢂ50 ml). The precipitate obtained was stirred
for 1 h at 5 ꢀC, filtered, and dried to get (2E)-2-cyano-3-(3,4-dihydroxy-5-
nirtrophenyl)prop-2-enoic acid 15 (80 g, 58.6%). Mp 124–126 ꢀC; IR (KBr, cmꢁ1):
1
3255 (OH), 1684 (CO), 1364 (NO2); H NMR (DMSO-d6, d ppm): 7.87 (s, 1H,
H-Ar), 8.O8 (s, 1H, H-Ar), 8.23 (s, 1H, H-C C); 13C-NMR (75 MHz, DMSO-d6)
=

1364
G. SRIKANTH ET AL.
d: 93.18, 109.3, 113.3, 118.1, 127.3, 135.1, 151.8, 153.7, 160.8, and 165.2; MS (ESI)
m=z: 249 (M-H). Anal. calcd. for C10H6N2O6: C, 48.04; H, 2.42; N, 15.97. Found:
C, 48.2; H, 2.45; N, 11.30.
(2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-
diethylprop-2-enamide (Entacapone 1)
(2E)-2-cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15 (5 g,
20 mmol) was added to SOCl2 (25 ml) at 25–30 ꢀC and heated for 4 h at 75 to
80 ꢀC. The reaction mass was concentrated under reduced pressure to get residue
(2E)-2-cyano-3-(3,4-dihydroxy-5-nirtrophenyl)-2-propenoyl chloride 16. The crude
16 in dichloromethane (50 ml) was added to a solution of diethyl amine (2.92 g,
40 mmol) in dichloromethane (50 ml) at ꢁ5 to 0 ꢀC in 20 min and stirred for 2 h at
ꢁ5 to 0 ꢀC. Thereafter, the reaction mass was concentrated and diluted with ethyl
acetate (50 ml) and water (50 ml). The solution was stirred for 30 min at 5 to 10ꢀC.
The organic layer was separated and concentrated under reduced pressure. Ethyl
acetate (15 ml) was added to the residue. The slurry was stirred for 1 h at 5 to
10ꢀC. The product was filtered and dried to get (2E)-2-cyano-3-(3,4-dihydroxy-5-
nitrophenyl)-N,N-diethylprop-2-enamide 1 (4 g, 65.5%). MP: 162–163ꢀC; IR (KBr,
1
cmꢁ1): 3339 (OH), 1628 (CO), 1372 (NO2); H NMR (DMSO-d6, d ppm): 1.15,
(m, 6H, diethyl amine CH3), 3.42 (m, 4H, diethyl amine CH2), 7.64 (s, 1H, H-Ar),
7.76 (s, 1H, H-Ar), 7.93 (s, 1H, H-C C), 10.95 (brs, 2H, OH); 13CNMR (75 MHz,
=
DMSO-d6) d: 12.8, 13.3, 40.3, 43.0, 104.8, 116.2, 117.8, 118.5, 122.8, 137.2, 144.9,
147.2, 148.0, and 162.7; MS (ESI) m=z: 304 (M-H). Anal. calcd. for C14H15N3O5:
C, 55.13; H, 4.95; N, 13.77. Found: C, 55.2; H, 4.98; N, 13.9.
General Procedure for the Preparation of Impurities 17, 18,
19, and 20
(2E)-2-Cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15 (20 mmol)
was added to SOCl2 (25 ml) at 25–30 ꢀC and heated for 4 h at 75 to 80 ꢀC.
Thionylchloride was removed under reduced pressure to get chloride 16. This
chloride 16 was reacted with monomethylamine (40 mmol) to precipitate compound
17 in dichloromethane (50 ml), reacted with piperidine (40 mmol) to precipitate com-
pound 18 in dichloromethane (50 ml), reacted with ethanol (50 ml) to precipitate
compound 19, and reacted with n-propanol (50 ml) to precipitate compound 20.
Later on, precipitated compounds (17, 18, 19, and 20) we isolated through filtration
and further dried to obtain compounds 17, 18, 19, and 20. The spectral data for these
compounds are presented.
(2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-methyl
prop-2-enamide (17)
Mp: 246–250 ꢀC. IR (KBr, cmꢁ1) 3429 (OH), 1623 (CO), 1352 (NO2). 1H NMR
(DMSO-d6, d ppm) 2.73–2.74 (d, 3H, J ¼ 1.67, methylamine CH3), 7.79 (s, 1H,
H-Ar), 7.96 (s, 1H, H-Ar), 8.05 (s, 1H, H-C C), 8.33 (m, 1H, H-N-CH3); 13C
=
NMR (75 MHz, DMSO-d6) d: 26.8, 104.3, 116.3, 118.2, 119.2, 122.2, 137.3, 145.4,

EFFICIENT APPROACH TO ENTACAPONE
1365
148.1, 148.7, 161.4; MS (ESI) m=z: 261.8 (M-H). Anal. calcd. for C11H9N3O5: C,
50.23; H, 3.44; N, 15.97. Found: C, 50.3; H, 3.50; N, 16.00.
(2E)-3-(3,4-Dihydroxy-5-nitrophenyl)-2-(piperidin-yl-1-carbonyl)
prop-2-ennitrile (18)
Mp: 206–208 ꢀC. IR (KBr, cmꢁ1) 3436 (OH), 1621 (CO), 1352 (NO2). 1H NMR
(DMSO-d6, d ppm) 1.55–1.62 (m, 6H, piperidine CH2), 3.52 (m, 4H, piperidine
CH2), 7.63 (s, 1H, H-Ar), 7.76 (s, 1H, H-Ar), 7.93 (m, 1H, H-C C); 13C NMR
=
(75 MHz, DMSO-d6) d: 21.6, 22.2, 23.8, 25.4, 43.8, 103.6, 116.4, 116.8, 119.1,
121.8, 136.9, 146.3, 147.8, 148.3, and 162.1; MS (ESI) m=z: 316 (M-H). Anal. calcd.
for C15H15N3O5: C, 56.83; H, 4.76; N, 13.25. Found: C, 56.9; H, 4.78; N, 13.28.
Ethyl (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)prop-2-enoate
(19)
Mp: 205–207 ꢀC (lit.[5]). IR (KBr, cmꢁ1) 3230 (OH), 1620 (CO), 1356 (NO2). 1H
NMR (DMSO-d6, d ppm) 1.28–1.33 (t, 3H, CH3), 4.27–4.34 (q, 2H, OCH2), 7.90 (s,
1H, H-Ar), 8.11 (s, 1H, H-Ar), 8.29 (s, 1H, H-C C); 13CNMR (75 MHz, DMSO-d6)
=
d: 14.01, 62.23, 100.20, 115.69, 117.95, 121.12, 121.49, 137.34, 146.65, 148.20, 153.28,
and 162.03; MS (ESI) m=z 277 (M-H). Anal. calcd. for C12H10N2O6: C, 51.84; H,
3.62; N, 10.07. Found: C, 51.86; H, 3.65; N, 10.10.
Propyl (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)prop-2-enoate
(20)
Mp: 190–192 ꢀC. IR (KBr, cmꢁ1) 3221 (OH), 1626 (CO), 1358 (NO2). 1H NMR
(DMSO-d6, d ppm) 0.93–0.95 (t, 3H, CH3), 1.64-1.68 (m, 2H, CH2), 4.18–4.24 (t, 2H,
OCH2), 7.90 (s, 1H, H-Ar), 8.11 (s, 1H, H-Ar), 8.29 (s, 1H, H-C C); 13C NMR
=
(75 MHz, DMSO-d6) d: 10.18, 21.43, 67.55, 100.15, 115.61, 117.94, 121.2, 121.5,
137.26, 146.7, 148.24, 153.28, and 162.11; MS (ESI) m=z: 291 (M-H). Anal. calcd.
for C13H12N2O6: C, 53.47; H, 4.14; N, 9.59. Found: C, 53.5; H, 4.20; N, 9.60.
ACKNOWLEDGMENTS
The authors thank the management of Aurobindo Pharma Ltd., Research and
Development Centre, for supporting this work. The authors also thank the Analyti-
cal Research Department for their valuable contribution.
REFERENCES
1. Axelrod, J.; Tomchich, R. Enzymatic o-methylation of epinephrine and others catechols.
J. Biol. Chem. 1958, 233, 702–705.
2. Cedarbaum, J. M. Clinical pharmacokinetics of anti-Parkinsonian drugs. Clin. Pharmaco-
kinetics 1987, 13, 141–178.
3. Mannisto, P. T.; Kaakkolo, S. New selective COMT inhibitors: Useful adjuncts for
Parkinson’s disease? Trends Pharamacol. Sci. 1989, 10, 54–56.

1366
G. SRIKANTH ET AL.
4. Mannisto, P. T.; Kaakkolo, S. Rationale for selective COMT inhibitors as adjuncts in the
drug treatment of Parkinson’s disease. Pharmacol. Toxicol. 1990, 66, 317–323.
5. Backstrom, R.; Honkanen, E.; Pippuri, A.; Mannisto, P. T.; Kaakkola, S.; Pohto, P.
Synthesis of some novel potent and selective catechol O-methyl transferase inhibitors.
J. Med. Chem. 1989, 32, 841–846.
6. Backstom, R. J.; Heinola, K. E.; Honkanen, K. J.; Kaakkola, S. K.; Kairisalo, P. J.;
Linden, Y.; Mannisto, P. I.; Nissinen, E. A. O.; Photo, P. Preparation of pyrocatechol
derivatives for treating Parkinson’s disease. Ger. Offen. DE Patent 3, 740,383, 1988;
Chem. Abstr. 1988, 109, 128570x.
7. Pippuri, A.; Honkanen, E.; Haarala, T. Stable polymorphic form of E-N,N-diethyl-2-
cyano-3-(3,4-dihydroxy-5-nitrophenyl) acryl amide and the process for its preparation.
EP Patent 426468 1992; Chem. Abstr. 1991, 115, 214830n.
8. Venkateswarlu, J.; Veera Reddy, A.; Rajendiran, C.; Samjuddin, M. Methods for the
preparation of entacapone. WO Patent 63,693, 2005; Chem. Abstr. 2005, 143, 115355 h.
9. Cziaky, Z. Process for the preparation of (E)-N,N-diethyl-2-cyano-3(3,4-dihydroxy-5-
nitro-phenyl)-acryl amide in stable polymorphic form and intermediates of the process.
WO Patent 2006064296, 2006; Chem. Abstr. 2006, 145, 83129k.
10. Sanmarti, B.; Rocabert, S.; Nicolau, P.; Ponce, M. Process for the preparation of entaca-
pone and intermediates thereof. WO Patent 2008119793, 2008; Chem. Abstr. 2008, 149,
425635 t.
11. Balalaie, S.; Barajanian, M. Efficient and green procedure for the Knoevenagel conden-
sation catalyzed by diammonium hydrogen phosphate in water. Synth. commun. 2006,
36, 2549–2557.
12. Kim, S. Y.; Kwon, P. S.; Kwon, T. N. Microwave-enhanced knoevenagel condensation of
ethyl cyano acetate with aldehyde. Synth. commun. 1997, 27(4), 533–541.
13. Inokuchi, T.; Kawafuchi, H. E- or Z-selective Knoevengel condensation of acetoacetic
derivatives: Effect of acylated substituent, that is, TEMPO and amines, as an auxiliary
and new accesses to trisubstituted E- and Z-2-alkenals and furans. J. Org. Chem. 2006,
71, 947–953.
14. Augustine, J. K.; Naik, Y. K.; Mandal, A. B.; Chodappa, N.; Praveen, V. B.
gem-Dibromomethylarens: A convenient substitute for noncommercial aldehyde in the
Knoevenagel–Doebner reaction for the synthesis of the a,b-unsaturated carboxylic acids.
J. Org. Chem. 2007, 72, 9854–9856.
15. Courtheyn, D.; Verhe, R.; Kimpe, M. P.; Buyck, L. D.; Schamp, N. Synthesis of electro-
philic allyl dichlorides. J. Org. Chem. 1981, 46, 3226–3229.
16. Mukhopadhyay, C.; Datta, A. A simple, efficient, and green procedure for the knoevena-
gel condensation of aldehydes with N-methyl piperazine at room temperature under sol-
vent condition. Synth. Commun. 2008, 38, 2103–2112.
17. European Pharmacopoeia, 7th ed.; European Directorate for the Quality of Medicines
(EDQM): Strasbourg, France, 2010; pp. 1924–1925.