Facile New Alternative Method for the Synthesis of 1-(3-Methyl-1-phenyl-1H-pyrazole-5-yl)piperazine from 1-Methylpiperazine and 1-Benzylpiperazine

Full text of DOI:10.1080/00304948.2020.1858688

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Facile New Alternative Method for the Synthesis of
1-(3-Methyl-1-phenyl-1H-pyrazole-5-yl)piperazine
from 1-Methylpiperazine and 1-Benzylpiperazine
Dnyanadeo J. Kesarkar, Bharat B. Kashid & Sunil S. Sukthankar
To cite this article: Dnyanadeo J. Kesarkar, Bharat B. Kashid & Sunil S. Sukthankar (2021) Facile
New Alternative Method for the Synthesis of 1-(3-Methyl-1-phenyl-1H-pyrazole-5-yl)piperazine from
1-Methylpiperazine and 1-Benzylpiperazine, Organic Preparations and Procedures International,
53:2, 105-111, DOI: 10.1080/00304948.2020.1858688
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 2, 105–111
https://doi.org/10.1080/00304948.2020.1858688
EXPERIMENTAL PAPER
Facile New Alternative Method for the Synthesis of
1-(3-Methyl-1-phenyl-1H-pyrazole-5-yl)piperazine from
1-Methylpiperazine and 1-Benzylpiperazine
Dnyanadeo J. Kesarkara, Bharat B. Kashidb, and Sunil S. Sukthankara
aPrecise Chemipharma Pvt. Ltd., C-384, T.T.C, Indira Nagar, MIDC Industrial Area, Turbhe, Navi Mumbai,
b
Maharashtra, India; Chemistry Research Laboratory, School of Chemical Sciences, Solapur University,
Solapur, India
ARTICLE HISTORY Received 18 March 2020; Accepted 2 August 2020
Pyrazole and its derivatives continue to be subjects of considerable importance due to
their wide spectrum of biological applications.1–7 For example, the Type 2 Diabetes
(T2D) drug Teneligliptin hydrobromide incorporates a 1,3,5-substituted pyrazole moi-
ety. Teneligliptin (I, Figure 1) was marketed under the trade name of Tenelia and
approved in Japan in 2012 for treatment of T2D.8–11 Teneligliptin has been well-
received in the market, so synthetic chemists have focused considerable attention on the
designing of new economical routes to produce this drug at scale while still meeting
stringent quality requirements. The original synthetic route is certainly suitable for the
production of gram quantities of the desired drug with the required quality; however,
the need for timely and economical manufacture of this active pharmaceutical ingredi-
ent on multi-kilogram scale in the appropriate purity12–15 motivated us towards the
development of a new route. Crucial to this is the preparation of 5-piperazine pyrazole
derivative (6, Scheme 1), an improved method for which is the subject of this report.
An examination of the available literature shows that prior preparations of 6 have had
such drawbacks as the instability of starting materials,16 use of expensive catalysts,17 or
the commercial unavailability of reactants.18,19 In particular, the use of alkoxycarbonyl
protecting groups leads to formation of impurities and decreased yield. In the same vein,
there are also serious safety considerations, particularly with scale-up in mind.20–23
In our view, an important consideration for the preparation of 6 is the protection of
the piperazine moiety with a methyl or benzyl group (Scheme 1). Our synthesis of 6
begins with commercially available 1-methyl- or 1-benzylpiperazine, 1 or 1’, respect-
ively. In the first stage, a solution of t-butyl acetoacetate in refluxing toluene is pre-
pared. Using a Dean-Stark apparatus for the removal of generated t-butanol, slow
addition of N-methylpiperazine produces ketoamide 2 (95%) (or 2’ for the benzylic
case). The ketoamide is then treated with phenylhydrazine hydrochloride to obtain com-
pound 3 (or 3’) as its hydrochloride salt. Compound 3 is then cyclized with POCl3 to
obtain the protected pyrazole 4 (or 4’). The protected pyrazole is treated with ethyl
CONTACT Dnyanadeo J. Kesarkar
dnyaneshwar_kesarkar@rediffmail.com
Precise Chemipharma Pvt. Ltd., C-384,
T.T.C, Indira Nagar, MIDC Industrial Area, Turbhe, Navi Mumbai, Maharashtra 400703, India
Supplemental data for this article can be accessed here.
ß 2021 Taylor & Francis Group, LLC

106
D. J. KESARKAR ET AL.
Figure 1. The T2D drug Teneligliptin.
Scheme 1. Synthesis of key intermediate 6.
chloroformate in the presence of triethylamine to obtain carbamate 5. Compound 5 is
subsequently hydrolyzed in ethanolic KOH to produce the crucial intermediate 6.
Alternatively, if R is a benzyl group, compound 6 is obtained by debenzylation of the
related benzylic congener 4’ in the presence of H2/Pd-C, and the hydrogenation catalyst

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
107
Table 1. Screening of reagents for the conversion of 3 into 4.
Entry
1.
Reagents
Reaction in hours
8
Safety, workup, and remarks
% yields
40
Lawesson’s
Reagent
Toxic, degradation of product during
reaction, tedious workup, expensive
reagent and THF solvent for reaction.
Toxic, tedious workup, more time,
less conversion,
Toxic, less time, good conversion, expensive
reagent and THF as solvent.
Industrially feasible, less time, very good
conversion, affordable reagent,
recoverable and reusable toluene
as solvent.
2.
3.
4.
P4S2
10
5 hr
4
50
80
88
P2S5
POCl3
may be recovered and re-cycled. All of the novel compounds in this method were fully
characterized (see Experimental section).
As part of our work, we screened different cyclization reagents for the conversion of
3 into 4, and the results are reported in Table 1.
Our new preparation avoids the use of labile protecting groups and thus has the
potential to improve the impurity profile of the key intermediate 6. The method uses
commercially available reactants and does not require the use of highly unstable, expen-
sive or hazardous reagents. It is our hope that these preparative advances will facilitate
the upgraded production of the important active pharmaceutical ingredient,
Teneligliptin.
Experimental section
All of the raw materials used were procured from commercial manufacturing sources.
Reagent grade materials were purchased from Sigma Aldrich. Solvents were purchased
from Merck and SD Fine Chemicals. We used palladium on carbon (10%) from
Hindustan Platinum Pvt. Ltd. The FT-IR spectra were determined on a Perkin Elmer
Spectrum 100 instrument using the KBr pellet technique. 1H NMR spectra were
obtained at 500 MHz, on a Bruker Avance instrument. Chemical shifts (d) were deter-
mined using TMS as the internal standard. HPLC-Mass analyses were performed on a
Shimadzu 2020 apparatus. Thin-layer chromatography (TLC) was done with Merck
TLC Silica Gel 60 F254 (0.25 mm) plates visualized by UV light at 254 nm and iodine
vapor. Elemental analyses were obtained using a Perkin Elmer 2400 CHNS/O Series II
System (100V) elemental analyzer. Melting points were determined on a Mettler Toledo
apparatus and are uncorrected.
1-(4-Methylpiperazine-1-yl)butane-1,3-dione (2)
t-Butyl acetoacetate (20.00 kg, 126.43 mol) and toluene (92.0 L) were heated up to
110 ꢀC. We then added 1-methylpiperazine (1, 11.5 kg, 114.81 mol), and the reaction
mixture was stirred at the same temperature for 5.5 hours. Completion of reaction was
confirmed by TLC (CHCl3:CH3OH 90:10). The reaction mass was cooled to 60 ꢀC and
distilled under reduced pressure (700 mm Hg) at 60-65 ꢀC to obtain 2, 20.12 kg, 95%,

108
D. J. KESARKAR ET AL.
brown viscous oil, TLC Rf 0.50 (CHCl3:CH3OH 90:10). IR (cmꢁ1): 2940, 2799,
1722, 1635, 1448, 1295, 1143. 1H-NMR (DMSO-d6): d 2.17-2.14 (s, 3H, COCH3),
2.24-2.22 (s, 2H), 2.27-2.25 (t, 4H), 3.32-3.29 (t, 2H), 3.45-3.42 (s, 2H, CO-CH2-CO),
3.62 (s, 3H, N-CH3); (M þ H)þ: m/z ¼ 184.9.
Anal. Calcd for C9H16N2O2: C, 58.67; H, 8.75; N, 15.21. Found: C, 58.61; H, 8.72;
N, 15.26.
1-(4-Methylpiperazine-1-yl)-3-(2-phenylhydrazilidine)butane-2-one
hydrochloride (3)
1-(4-Methylpiperazine-1-yl)butane-1,3-dione (2, 20.00 kg, 108.55 mol) was dissolved in
200 L ethanol and the reaction mixture cooled at 20-25 ꢀC; phenylhydrazine hydrochlor-
ide (16.34 kg, 151.1 mol) was added slowly such that the temperature did not exceed
25 ꢀC. After the addition, the reaction mixture was kept at 25-30 ꢀC for 12 hours.
Completion of reaction was confirmed by TLC (CHCl3:CH3OH 90:10). The solid was
filtered off and washed with ethanol to obtain 3, as its hydrochloride salt, 29.15 kg, 86%,
cream colored solid, mp 159 ꢀC, TLC Rf 0.19 (CHCl3:CH3OH 90:10). IR (cmꢁ1): 3433,
1
2996, 2927, 2434, 1661, 1596, 1515, 1488, 1452, 974, 759. H-NMR (DMSO-d6): d 1.89
(s, 3H), 2.69 (s, 3H), 3.40-3.14 (t, 4H), 3.73-3.58 (t, 4H), 3.89 (s, 2H, -CO-CH2-C ¼ N);
7.17-6.67 (m, 5H), 8.86 (C ¼ N-NH-Ar), 11.33 (s, 1H, -N-NHꢂHCl); (M þ H)þ: m/z ¼ 274.9.
Anal. Calcd for C15H22N4O: C, 65.67; H, 8.08; N, 20.42. Found: C, 65.74; H, 8.06;
N, 20.39.
1-Methyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (4)
1-(4-Methylpiperazine-1-yl)-3-(2-phenylhydrazylidine)butane-2-one hydrochloride (3,
29.00 kg, 93.3 mol) was suspended in 58.0 L toluene. Then 29.0 L of pyridine was added.
The mixture was heated to 100 ꢀC, POCl3 (30.44 kg, 198.5 mol) was added and the reaction
mass heated for 4 hours at 100 ꢀC. Completion of reaction was confirmed by TLC
(CHCl3:CH3OH 90:10). The reaction mass was cooled to 30 ꢀC and 10% NaOH solution
was added to pH 12. The product was extracted into ethyl acetate and washed with brine.
Evaporation gave 4, 21.01 kg, 88%, off white solid, 89 ꢀC, TLC Rf 0.62 (CHCl3:CH3OH
1
90:10). IR (cmꢁ1): 3062, 2959, 2927, 1594, 1559, 1502, 1448, 905, 770. H-NMR (DMSO-
d6): d 2.14 (s, 3H), 2.17 (s, 3H), 2.75-2.35 (t, 4H), 2.78-2.77 (t, 4H), 5.78 (s, 1H), 7.74-7.24
(m, 5H); 13C NMR (DMSO-d6): d 152.10, 148.79, 140.21, 128.78, 126.11, 122.51, 94.00,
54.56, 50.86, 46.02, 14.05; (M þ H)þ: m/z ¼ 257.1.
Anal. Calcd for C15H20N4: C, 70.28; H, 7.86; N, 21.86. Found: C, 70.20; H, 7.90;
N, 21.90.
1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (6)
1-Methyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (4, 18.00 kg, 70.21 mol), trie-
thylamine (4.25 kg, 42.0 mol) and 72.0 L toluene was heated at 80 ꢀC. Then ethyl chlorofor-
mate (7.92 kg, 72.98 mol) was slowly added to the reaction mixture. The reaction mixture
was refluxed for 2 hours. Completion of reaction was confirmed by TLC. Then 180.00 L of

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
109
water was added slowly at 30-35 ꢀC. The organic layer was separated and the aqueous layer
was washed with 90.00 L of toluene. The combined organic layers were washed with
90.00 L water. The organic layer was dried over anhydrous sodium sulfate. After filtration,
the solvent was distilled out under reduced pressure (700 mm Hg) to obtain ethyl 4-(3-
methyl-1-phenyl-1H-pyrazol-5-yl)piperazine-1-carboxylate 5, 21.0 kg, 95%, TLC Rf 0.66
(CHCl3:CH3OH 95:5). The mass was dissolved in 90.00 L isopropyl alcohol. To this was
added potassium hydroxide (29.81 kg, 53.23 mol). The reaction mixture was refluxed for
4 hours. The solvent was distilled out under reduced pressure (700 mm Hg). To the mass
thus obtained was added 180.00 L of water at 30-35 ꢀC. The reaction mixture was stirred
for 2.5 hours at 15-20 ꢀC. The crystallized product was filtered off and washed with 36.00 L
water. The wet solid was dried under vacuum at 50-55 ꢀC for 5.5 hours to obtain 6,
14.97 kg, 88%, off-white solid, mp 107 ꢀC, TLC Rf 0.20 (CHCl3:CH3OH 90:10), HPLC pur-
1
ity 99.5%. IR (cmꢁ1): 3398, 2834, 2822, 1596, 1559, 1503, 1457, 915, 774.3. H-NMR
(DMSO-d6): d 2.14 (s, 3H), 2.69 (t, 4H), 2.70 (t, 4H), 3.40 (s, 1H), 5.76 (s, 1H); 7.76-7.24
(m, 5H). (M þ H)þ: m/z ¼ 242.9.
Anal. Calcd for C14H18N4: C, 69.39; H, 7.49; N, 23.12. Found: C, 69.46; H, 7.45;
N, 23.09.
1-(4-Benzylpiperazin-1-yl)butane-1,3-dione (2’)
Using N-benzylpiperazine (1.744 kg, 4.5 mol) and t-butylacetoaceate (1.721 kg,
10.88 mol) in the same manner as described above for 2, we obtained 2’, 2.45 kg, 95%,
1
brown viscous oil, TLC Rf 0.52 (CHCl3:CH3OH 90:10). H-NMR (DMSO-d6): d 1.69 (s,
2H), 2.14 (s, 3H), 2.74-2.69 (t, 8H), 4.55 (s, 2H, N-CH2-Ar), 7.28-7.24 (t, 1H), 7.46-7.42
(m, 2H), 7.76-7.74 (m, 2H).
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C, 69.27; H, 7.70;
N, 10.80.
3-(2-Phenylhydrazono)-1-(4-benzylpiperazin-1-yl)butan-1-one hydrochloride (3’)
Using compound 2’ (2.45 kg, 9.41 mol) and phenylhydrazine hydrochloride (1.90 kg,
13.1 mole) in the same manner as described for 3 above, we obtained 3’, as its hydro-
chloride salt, 3.24 kg, 89%, as a pale yellow solid, mp 210 ꢀC, TLC Rf 0.22
(CHCl3:CH3OH 90:10).
Anal. Calcd for C21H26N4O: C, 71.97; H, 7.48; N, 15.99. Found: C, 71.93; H, 7.55;
N, 16.02.
1-Benzyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (4’)
Using compound 3’ (2.0 kg, 5.17 mol) and POCl3 (2.65 kg, 17.28 mol) we prepared 1-
benzyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine 4’, 1.45 kg, 84%, brown viscous
1
oil, TLC Rf 0.58 (CHCl3:CH3OH 90:10). H-NMR(DMSO-d6): d 1.86 (s, 3H), 2.35-2.30
(s, 4H), 3.30 (s, 2H, N-CH2-Ar), 3.45 (t, 4H), 6.68-6.66 (s, 1H), 7.04-7.02 (m, 2H), 7.16-
7.12 (t, 2H), 7.26-7.22 (m, 2H), 7.33-7.28 (m, 4H).

110
D. J. KESARKAR ET AL.
Anal. Calcd for C21H24N4: C, 75.87; H, 7.28; N, 16.85. Found: C, 75.80; H, 7.30;
N, 16.90.
1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (6) from Compound 4’ via
Hydrogenolysis
1-Benzyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (4’, 1.0 kg, 3.0 mol) was dis-
solved in 10.0 L methanol at 30 ꢀC in an autoclave. The apparatus was flooded with
nitrogen and 100 g of Pd-C was added to the reaction mixture. A pressure of hydrogen
(4 kg/cm2) was applied at 45-50 ꢀC for 8 hours. Completion of reaction was confirmed
by TLC, and the reaction mass was cooled to 30 ꢀC. The autoclave was flooded with
nitrogen and the catalyst was filtered off. The filtrate was concentrated under vacuum
(700 mm Hg) to obtain1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine 6, 0.67 kg, 92%,
as an off white solid, mp 107 ꢀC, TLC Rf 0.20 (CHCl3:CH3OH 90:10), HPLC purity
1
99.2%. H-NMR (DMSO-d6): d2.14 (s, 3H), 2.74-2.69 (t, 8H), 4.55 (s, 1H), 5.77 (s, 1H),
þ
7.28-7.24 (t, 1H), 7.46-7.42 (t, 2H), 7.76-7.74 (d, 2H). (M þ H) : m/z ¼ 242.9.
Anal. Calcd for C14H18N4: C, 69.39; H, 7.49; N, 23.12. Found: C, 69.35; H, 7.55;
N, 23.10.
Acknowledgments
The authors are thankful to the management of Precise Chemipharma Pvt. Ltd., for providing
the opportunity to explore this research work and the Analytical Development Laboratory for
continuous analysis support.
References
1. S. P. Singh, Om Prakash and R. K. Vaid, Indian J. Chem., 23B, 191 (1998).
2. V. K. Ahluwalia, V. K. Garag and A. Gupta, Indian J. Chem., 33B, 761 (1964).
3. K. A. Rao, J. N. Gadreand and S. Pednekar, Indian J. Chem., 36B, 410 (1997).
4. D. Bhaskar Reddy, N. Subbha Reddy and T. Balaji, Indian J. Chem., 23B, 983 (1984).
5. V. J. Ram and M. Nath, Indian J. Chem., 33, 1048 (1994).
6. H. M. Virupakshaiah, M. B. Talawar, U. V. Laddi, Y. S. Somannavar, V. V. Badiger and S. C.
Bennur, Ind. J. Het. Chem., 6, 63 (1996).
7. X. Zhang, J. Kang, P. Niu, J. Wu, W. Yu and J. Chang, J. Org. Chem., 79, 10170 (1997). doi:
10.1021/jo501844x
8. N. Kumar, S. R. Devineni, K. Aggile, P. R. Gajjala, P. Kumar and S. K. Dubey, Res. Chem.,
44, 567 (2018). doi:10.1007/s11164-017-3120-3
9. J. Bronson, A. Black, T. G. Murali Dhar, B. A. Ellsworth and J. A. Merritt, Ann. Rep. Med.
Chem., 48, 471 (2013).
10. M. Goda and T. Kadowaki, Drugs Today (Barc), 49, 615 (2013). doi:10.1358/dot.2013.49.10.
2035882
11. T. Yoshida, F. Akahoshi, H. Sakashita, M. Nakamura, S. Sonda, M. Takeuchi, Y. Tanaka, S.
Sekiguchi, T. Ishige, K. Shima, M. Nabeno, Y. Abe, J. Anabuki, A. Soejima, Y. Takashina and
Y. Hayashi, Bioorg. Med. Chem., 20, 5705 (2012). doi:10.1016/j.bmc.2012.08.012
12. T. Yoshida, H. Sakashita, N. Ueda, S. Kirihara, S. Uemori, R. Tsutsumiuchi and F. Akahoshi,
US2011/0282058 A1 (2011).
13. F. Akahoshi and K. Shinji, WO2012/165547 A1 (2012).

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
111
14. M. K. Suresh, P. K. Bipin, V. K. Ramachandran, P. P. Jayant, Y. Venkataramana Reddy,
N. B. Shailendra, P. C. Uddhav, D. P. Ulhas and B. B. Shekhar, WO2014/041560 A2 (2014)
15. T. Wang, J. F. Kadow, Z. Zhang, Z. Yin, N. A. Meanwell, A. Regueiro-Ren, J. Swidorski, Y.
Han, D. J. Carini and L. G. Hamann, US2008/0139572 A1 (2008).
16. H. Kitajima, H. Sakashita, F. Akahoshi and Y. Hayashi, US Patent 7, 074, 794, (2006).
17. Z. Hongwen and Z. Qiang, WO2012/099915 (2012).
18. A. K. Kapoor, D. C. Barman, A. Nath and Mohan Prasad, WO/2015/063709A1 (2015).
19. S. Zhichun, H. Dandan, J. Yuwei and Z. Xiaoqing, CN104177295A (2014).
20. P. Giri, A. Tendolkar, A. K. Kapoor, D. C. Barman, A. Nath and M. Prasad, WO/2015/
019239 (2015).
21. K. Hiroshi, S. Hiroshi, A. Fumihiko and H. Yoshiharu, WO/2002/014271 (2002).
22. Z. Baofu, X. Jijun, G. Qiang, Z. Xianshu, L. Shufang and L. Haiwang, CN102675321A (2012).
23. S. S. Sukthankar and D. J. Kesarkar, Indian Patent 2016/21027674 A (2016).