Synthesis of Novel Mannich Bases of Pioglitazone

MATERIALS AND METHODS

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).

Fig. 1:	Basic structure of thiazolidiene

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).

Fig. 3:	Synthesis of novel pioglitazone mannich bases 5(a-e)

Table 1:	Structures of secondary amines

RESULTS

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

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, H_21,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, H_a), 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, H_21,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).

DISCUSSION

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.

CONCLUSION

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.