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Research Article

Synthesis of Novel Mannich Bases of Pioglitazone

Ramit Kapoor, Rashmi Arora, Ravinesh Mishra, Manu Arora and Pooja Mittal
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Thiazolidinediones (TZDs) acts by stimulating PPAR that improves glycaemic control by decreasing insulin resistance. Although the use of Thiazolidinediones had long been associated with cardiovascular risk factors but it is commonly used as a potent anti-diabetic. The use of Thiazolidinediones (TZDs) in the management of type 2 diabetes mellitus (T2DM) had been associated with an increased risk of peripheral oedema. Mainly class include Ciglitazone, Rosiglitazone, Troglitazone and Pioglitazone. Mannich reaction have proved to be more effective and leads to generation of new compounds which are less toxic but pharmacologically more active than their parent drugs. Mannich Bases of Pioglitazone were synthesized by making use of the abstractable hydrogen in the Pioglitazone and it was aminomethylated using DMF as solvent. The subjected mixture was stirred with continuous addition of formaldehyde and was refluxed to yield various potent biological mannich bases of Pioglitazone. These considerations have provoked Mannich bases of secondary amine by Mannich reaction.

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Ramit Kapoor, Rashmi Arora, Ravinesh Mishra, Manu Arora and Pooja Mittal, 2014. Synthesis of Novel Mannich Bases of Pioglitazone. Current Research in Chemistry, 6: 10-15.

DOI: 10.3923/crc.2014.10.15

Received: November 21, 2013; Accepted: January 22, 2014; Published: April 16, 2014


Thiazolidinediones (TZDs) have been the subject of extensive researches because of their deep involvement in the regulation of different physiological processes. Thiazolidinediones derivatives have shown to possess many pharmacological activities like oncostatic, anti-diabetic, anti-inflammatory activities (Gustafson et al., 2003). TZDs such as troglitazone, pioglitazone and rosiglitazone are potent reducer of plasma glucose level in vivo. Besides their anti-diabetic potency, these TZDs have been shown to exert anti-inflammatory effects on vascular cells (Kurebayashi et al., 2005). TZDs were also found to inhibit the production of inflammatory cytokines and the expression of inducible nitric oxide syntheses in monocytes macrophages (Jeong et al., 2004; Ricote et al., 1998) (Fig. 1).

Considering the broad spectrum of activities of Thiazolidinediones like anti-inflammatory, analgesic, anti-diabetic, antimicrobial and anticancer activities (Panigrahy et al., 2002; Elstner et al., 1998), it was decided to synthesize various derivatives of Thiazolidinedione category drug Pioglitazone (Fig. 2).


Chemicals: Carrageenan was obatined from HiMedia Labs, Mumbai. All other chemical reagents were used of analytical grade, which were procured from different companies (Loba Chem, Merck Limited and S D Fine).

Image for - Synthesis of Novel Mannich Bases of Pioglitazone
Fig. 1: Basic structure of thiazolidiene

Image for - Synthesis of Novel Mannich Bases of Pioglitazone
Fig. 2: Structure of pioglitazone

The progress of the reaction was monitored on readymade silica gel plates (Merck) using chloroform-methanol (5:5) as a solvent system. Iodine was used as a developing agent. Melting points were determined with a Buchi 530 melting point apparatus in open capillaries. IR spectra were recorded on KBr discs, using a Perkin-Elmer Model 1600 FT-IR spectrometer. The proton magnetic resonance spectra (1H-NMR) were recorded on Perkin Elmer Spectrophotometer-300 MHz in DMSO-d6 using TMS as an internal standard. Elemental analysis was performed by CHNS (O) Analyzer (Arora et al., 2012).

Animals: The wistar albino rats (150-200 g) of either sex were obtained from Zoin Co. Biologicals, near science market, Ambala. They were kept at standard laboratory diet, environmental temperature and humidity. A 12 h light and dark cycle was maintained throughout the experimental protocol.

General synthesis of mannich bases of pioglitazone (5a-5e): Pioglitazone (1) (2.5 g, 0.006 mol) was added in Dimethyl formamide (2) (10 mL, 0.131 mol). Formaldehyde (2) (10 mL, 0.131 mol) was added drop wise. The mixture was subjected to stirring for 30 min to yield a methyl derivative. To the another beaker various secondary amines (5a-5e) (Table 1) (3) (2.5 g, 021 mol) was added in Dimethyl formamide (2) (10 mL, 0.131 mol). The methyl derivative was transferred to secondary amines and was stirred for few minutes. The contents of the beaker were refluxed for 4 h, the reaction procedure was monitored over TLC. The precipitate was filtered, dried and recrystallized using (methanol: chloroform) (Fig. 3) (Table 2).

Image for - Synthesis of Novel Mannich Bases of Pioglitazone
Fig. 3: Synthesis of novel pioglitazone mannich bases 5(a-e)

Table 1: Structures of secondary amines
Image for - Synthesis of Novel Mannich Bases of Pioglitazone


3-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-5-(4-(2-(6-ethylpyridin-2-ylamino) ethoxy)benzyl)thiazolidine-2,4-dione. (5a)
Elemental analysis: C26H26N6O3S.

Calculated: C, 62.13%; H, 5.21%; N, 16.72%, O, 9.55%.

Observed: C, 62.01%; H, 5.09%; N, 16.51%, O, 9.77%.

Table 2: Physiochemical parameters of some novel 2, 4, 5 triphenyl imidazole mannich bases
Image for - Synthesis of Novel Mannich Bases of Pioglitazone

FTIR (cm-1): 3271 (N-H, str), 2984 (C-H, str, alk), 1650 and 1453 (C = C, Ar), 1069 (C-N), 865 (opp. C-H, bend), 1453 (N-H, bend), 1067 (C-O), 1236 (N = N), 1756 (C = O), 903 (C = S).

1HNMR (DMSO-d6) (δ ppm): 8.29 (1H,s, H1), 7.99 (1H, d, H2), 7.68 (1H, s, H3), 7.20-7.23 (1H, d, H4), 7.19-7.18 (2H, d, H13,H10), 4,76 (2H, s, H5, H6), 4.21 (1H, t, H7), 6.72 (2H, d, H12, H11), 3.30 (2H, t, H16, H17), 7.20 (1H, d, H18), 7.64 (1H, d, H19), 3.42 (2H, d, H8,H9), 4.50 (2H, t, H14, H15), 2.94-2.92 (2H, q, H21,H20), 2.21 (3H, t, H22, H23, H24), 8.19 (1H, s, H25).

3-((1H-benzo[d]imidazol-4-yl)methyl)-5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl) thiazolidine-2,4-dione (5b)
Elemental analysis: C27H26N4O3S.

Calculated: C, 66.65%; H, 5.39%; N, 11.51%, O, 9.86%.

Observed: C, 66.01%; H, 5.69%; N, 16.55%, O, 9.95%.

FTIR (cm-1): 3223 (N-H, str), 2979 (C-H, str.), 1513 and 1454 (C = C, Ar), 1308 (C-N), 1693 (C = C, str), 1386 (C-H, bend), 1451 (N-H, bend), 1072 (C-O),, 841 (opp. C-H, bend), 1238 (N = N), 1746 (C = O), 903 (C = S).

1HNMR (DMSO-d6) (δ ppm): 7.92 (1H, d, Ha), 8.02 (1H,d, H1), 7.90 (1H, d, H2), 7.67 (1H, d, H3), 7.25-7.24 (1H, d, H4), 4.13 (IH, t, H7), 7.38-7.40 (2H, d, H13,H10), 6.62 (2H, d, H12, H11), 3.78-3.76 (2H, t, H8, H9), 3.30 (2H, t, H16, H17), 7.21-7.86 (1H, d, H18, H19), 4.74 (2H, s, H5, H6), 4.40-4.25 (2H, t, H14, H15), 2.50-2.33 (2H, q, H21, H20), 1.05-1.00 (3H, t, H22, H23, H24).

5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)3((dimethylamino)methyl) thiazolidine-2,4-dione (5c)
Elemental analysis: C22H27N3O3S.

Calculated: C, 63.90%; H, 6.58%; N, 10.16%, O, 11.61%.

Observed: C, 63.01%; H, 5.87%; N, 16.87%, O, 9.99%.

FTIR (cm-1): 3438 (N-H, str), 2858 (C-H, str), 1511 and 1454 (C = C, Ar), 1308 (C-N), 1656 (C = C, str), 1386 (C-H, bend), 1451 (N-H, bend), 1078 (C-O), 1679 (C = O), 829 (opp. C-H, bend), 1270 (N = N), 916 (C = S).

1HNMR (DMSO-d6) (δ ppm): 7.41-7.43 (2H, d, H13, H10), 6.91 (2H, d, H12, H11), 3.51-3.47 (2H, t, H8, H9), 5.42 (2H, s, H5, H6), 3.55 (1H, t, H7), 4.31-4.25 (2H, t, H14, H15), 3.27 (2H, t, H16, H17), 7.48-7.45 (1H, d, H18, H19), 2.50-2.49 (2H, q, H21, H20), 2.51 (6H, s, H1, H2, H3, H4, H26, H25), 1.19-1.15 (3H, t, H22, H23, H24).

5-(4-(2-(5-ethylpyridin-2-yl) ethoxy) benzyl)-3-((morpholin-3-yl) methyl) thiazolidine -2,4-dione (5d)
Elemental analysis: C24H29N3O4S.

Calculated: C, 63.27%; H, 6.42%; N, 9.22%, O, 14.05%.

Observed: 63.20%; H, 6.18%; N, 9.13%, O, 14.45%.

FTIR (cm-1): 2852 (C-H, str), 1487 and 1455 (C = C, Ar), 1323 (C-N), 1600 (C = C, str), 1394 (C-H, bend), 1437 (N-H, bend), 1072 (C-O), 1810 (C = O), 840 (opp. C-H, bend), 1254 (N = N), 987 (C = S).

1HNMR (DMSO-d6) (δ ppm): 7.37-7.31 (2H, d, H13, H10), 6.95 (2H, d, H12, H11), 3.55-3.53 (2H, t, H8, H9), 4.17 (1H, t, H7), 3.27 (2H, t, H16, H17), 7.34-7.55 (1H, d, H18, H19), 4.17-4.05 (2H, t, H14, H15), 2.50-2.49 (2H, q, H21,H20), 1.17-1.10 (3H, t, H22, H23, H24), 3.93-3.90 (1H, t, H3), 3.76-3.67 (4H, d, H2, H2, H5, H6), 3.54 (1H, m, H1).

3-((diethylamino)methyl)-5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl) thiazolidine-2,4-dione (5e)
Elemental analysis: C24H31N3O3S.

Calculated: C, 65.28%; H, 7.08%; N, 9.52%, O, 10.87%.

Observed: C, 65.15%; H, 6.31%; N, 9.17%, O, 14.42%.

FTIR (cm-1): 2978 (C-H, str), 1487 and 1455 (C = C, Ar), 1323 (C-N), 1600 (C = C, str), 1367 (C-H, bend), 1437 (N-H, bend), 1013 (C-O), 1679 (C = O), 862 (opp. C-H, bend), 1265 (N = N), 931 (C = S).

1HNMR (DMSO-d6) (δ ppm): 7.36-7.34 (2H, d, H13, H10), 6.98-6.95 (2H, d, H12, H11), 3.83-3.81 (2H, t, H8, H9), 4.30 (2H, s, H5, H6), 4.17 (1H, t, H7), 3.27 (2H, t, H16, H17), 7.34-7.55 (1H, d, H18, H19), 4.14-4.11 (2H, t, H14, H15), 2.86-2.80 (2H, q, H21, H20), 2.68-2.60 (4H, q, H1, H2, H3, H4,), 1.22-1.20 (3H, t, H22, H23, H24), 1.19-1.15 (6H, t, H25, H30, H26, H27, H28, H29).


The Synthesis of Mannich Bases of Pioglitazone was carried out and benzotriazoles, morpholine or phthalimide can be successfully used as amine components in direct aminomethylation reactions (Sahoo et al., 2006). Until the mid-seventies, arylamines were only sporadically presented to react with substrates containing an active hydrogen atom, such as heterocyclic compounds or phenols. Lately, Chinese researchers have intensively studied arylaminomethylation of acetophenones through their addition to a Schiff base formed in situ and produced a large number of arylamine Mannich bases. The amine exchange reaction between an alkylamine Mannich base and arylamines also offers easy access to arylamine Mannich bases in high yield under mild reaction conditions. There is versatile utility of the Mannich bases in polymers, dispersants in lubricating oil and pharmaceutical chemistry too. These considerations have provoked Mannich bases of secondary amine by Mannich reaction. This reaction offers a convenient method for introduction of the basic aminoalkyl chain, which alters the biological profile and physiochemical characteristics (Manikpuri et al., 2010). Various drugs obtained from Mannich reaction have proved more effective and less toxic than their parent drugs.


The various Mannich bases of Pioglitazone have been synthesized and were characterized by HNMR, FTIR and TLC. The Mannich bases synthesized were obtained in good yields. The Diethl amine derivative (5e) was obtained in high yield as compared to other derivatives and rf values of all the derivatives lie in between 0.50-0.70 region. The melting point of morpholine derivative (5d) was highest that is 78.6°C.


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