*3.1.1.2.1.1 Pazopanib One drug different Synthetic Routes*

In the procedure reported by Qi et al. the methylation of 3-methyl-6-nitroindazole (36) was carried in the presence of dimethyl carbonate (DMC) and 1,4-diazabicyclo [2.2.2] octane (DABCO) ending in the N2,3-dimethyl-6-nitroindazole (36) in high yield. In another report the methylation of 3-methyl-6-nitroindazole (36) was performed using trimethyl orthoformate in the presence of BF3OEt to give rise to the N2,3-dimethyl-6-nitroindazole (37) in 65% yield.

**Figure 2.** *Types of 2,4-disubstitited pyrimidines (X = O, S, C, NH; Y = X = O, S, C, NH).*

#### *Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

The reduction step was carried out under hydrogenation of (36) in the presence of Pd/C and H2 to afford the aminoindazole derivative (37) in 97% yield [60]. The subsequent condensation of aminoindazole derivative (37) with 2,4-dichloropyrimidine (38) to yield the pyrimidinylaminoindazole (39) and (40). A second methylation at the secondary aniline nitrogen of (40) with CH3I and Cs2CO3 resulted gave (41) in 83% yield, which was afterwards condensed with aniline derivative 5-amino-2-methylbenzenesulfonamide (42) in acidic alcohol solution (HCl/ isopropanol) to furnish the target compound (21) as hydrochloride salt in 81% yield.

Allowing 6-amino-2,3-dimethyl-2H-indazole (37) to react with 2,4-dichloropyrimidine (38) gave rise exclusively to the C4-aminated product (40) indicating regioselectivity of the reaction with 2,4-dichloropyrimidine (38). The intermediate (40) was transformed into (41) following the reaction with the sulfonamide aniline derivative i.e. 5-amino-2-methylbenzenesulfonamide (42).

The coupling of the aniline derivative like 5-amino-2-methylbenzenesulfonamide (42) to (41) was accomplished in good to high yields in refluxing ethanol.

To overcome the reduced regioselectivity in the methylation reaction of N-H indazoles, usually yielded a mixture of N-alkyl 1*H*-indazoles and N-alkyl 2*H*-indazoles regioisomers (**Figures 3** and **4**).

YiCheng Mei *et al* reported a synthetic process where the 2,3-dimethyl-6-nitro-2*H*indazol (36) was prepared in a regioselective manner (**Figure 5**) [61].

3-Methyl-6-nitro-1*H*-indazole (35) was prepared 93.9% yield by allowing 2-ethyl-5 nitroaniline (45) to react with sodium nitrite in glacial acetic acid. The regioselective conversion of 3-methyl-6-nitro-1*H*-indazole (35) to prepare N2,3-dimethyl-6-nitro-2Hindazole (37) was accomplished using trimethyl orthoformate in toluene and DMF (10, 1 mL) at room temperature (should be kept below 35°C). These conditions

#### **Figure 3.**

*Synthesis of Pazopanib (21). Reagents and conditions: a) DMC, DABCO, DMB; b) Pd/C, H2, EtOH; c) NaHCO3, EtOH; d) CH3I, Cs2CO3, DMF; e) EtOH [60].*

**Figure 4.** *Regioselective methylation of 1H-indazoles.*

**Figure 5.**

*Synthesis of Pazopanib (21) following YiCheng Mei* et al *report. Reagents and conditions: a)* t*-BuONO, acetic acid; b) trimethyl oxonium tetraflouroborate; c) tin(II) chloride; d) 2,4-dichloropyrimidine (38); e) MeI, rt.; f) sodium nitrite, acetic acid; g) trimethyl orthoformate, DMF, sulfuric acid, toluene, reflux; h) MeOH, Pd/C, H2, paraformaldehyde, NaH, NaBH4; i) 2,4-dichloropyrimidine (38); j) 5-amino-2-methylbenzenesulfonamide, reflux.*

produce the N2-methylated isomer. The nitro-derivative was subjected to hydrogenation (Pd/C catalyst) of (36) followed by methylation using Eschweiler-Clarke methylation reaction [62], providing N-2,3-dimethyl-6-nitro-2H-indazole intermediate (37) in 63.0% yield after recrystallization from the ethanol. Worth noting that in the patent disclosed Kumar and colleagues the reduction of the N2,3-dimethyl-6 nitro-2H-indazole (36) was converted to the amino-derivative using Raney nickel in 95% yield [63].

The secondary amine in N2,3-trimethyl-2H-indazol-6-amine (37a) was reacted with 2,4-dichloropyrimidine (38) in DMF under basic conditions and elevated temperature (100°C, 3 hr) afforded N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine (41) in 88.4% yield. The final product as hydrochloric salt was prepared as a result of reacting N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2*H*indazol-6-amine (41) with 5-amino-2-methylbenzenesulfonamide (42) in isopropanol under acidic conditions in 76.0% yield. N-(2-chloropyrimidin-4-yl)-N,2,3-dimethyl-2*H*-indazol-6-amine (40) was prepared by allowing N2,3-trimethyl-2H-indazol-6 amine (37a) to react with 2,4-dichloropyrimidine (38) in a mixture of H2O/MeOH for 24 hr. at temperature ranges between 25 and 30°C in 86.7% yield.

The N-methylation was performed using methyl iodide in DMF under basic conditions (Cesium carbonate) with N-(2-chloropyrimidin-4-yl)-N,2,3-dimethyl-2*H*indazol-6-amine (40) to afford N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine (41) in 90% yield.

Pazopanib hydrochloride salt was prepared by allowing N-(2-chloropyrimidin-4 yl)-N,2,3-trimethyl-2H-indazol-6-amine (41) to react with 5-amino-2*Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

methylbenzenesulfonamide (42) in refluxing acidified (4 M HCl) isopropanol for 10– 12 hr. in 97% yield. In cases the last step was performed under acidic conditions (HCl in isopropanol) then Pazopanib hydrochloride salt (21) was collected.
