Mirabegron Intermediate 1

To a stirred solution of R-Mandelic acid (97.61 g) in acetonitrile (1000 mL), trimethylborate (66.66 g) was added at 28°C (±2). After addition of trimethylborate, reaction temperature was raised to 58°C (±2) and maintained for 90 minutes. To this solution, 2-(4-Nitro-phenyl)- ethylamine hydrochloride (NPA HCI) (100.0 g) was added at same temperature. To this solution, N, N-Diisopropylethyl amine (82.92 g) was added slowly and then reaction temperature was set to reflux for 12 hrs. The reaction temperature was lowered to 30°C (±2) and then diluted with ethyl acetate (1100 mL) and aqueous HCI (1M) solution (1400 mL). The separated organic layerwas washed successively with 1M hydrochloric acid aqueous solution. The organic layer was washed with 5percent sodium hydroxide aqueous solution and brine. The organic layer was concentrated in vacuo; the residue was recrystallized from toluene (500 mL). The solid was filtered, washed with toluene and dried under vacuo at 48°C (±2) to obtain pale yellow crystals of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl] -2-phenylacetamide. VYield: 125 g (84.3percent); Purity by HPLC: 98.65percent.(R) - mandelic acid (15.0g, 0.0986mol) and nitrobenzene hydrochloride (20.0g, 0.0986mol) in 75mlN, N- dimethyl formamide, stirring triethylamine, last added HOBT and EDC, 30 reaction 6h.TLC monitoring (GFExample-1: Preparation of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (or) (Formula-4) (R)-2-hydroxy-2-phenylacetic acid compound of formula-2 (75 gms), triethylamine (49.8 gms), hydroxybenztriazole (HOBt) (66.6 gms) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (94.5 gms) were added to a mixture of 2-(4-nitrophenyl)ethylamine hydrochloride compound of formula-3a (100 gms) in N, N-dimethylformamide (370 ml) at 25-30°C and stirred for 15 hrs at the same temperature. Water (1860 ml) was added to the reaction mixture at 25-30°C and stirred for 30 mins at the same temperature. Ethyl acetate (1500 ml) was added to the reaction mixture at 25-30°C and stirred for 30 mins. Separated the both aqueous and organic layers and the organic layer was washed with 1M HCl solution, followed by 20percent (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide aqueous potassium carbonate solution and finally with water. Distill off the solvent completely from the organic layer under reduced pressure. Toluene (600 ml) was added to the obtained compound, heated the reaction mixture to 80-85°C and stirred for 15 mins at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 12 hrs at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound. Yield: 129.8 gms.2-(4-nitrophenyl)ethylamine hydrochloride (6g) was added to dichloromethane (50ml) and stirred for 30 minutes at 25-30°C. The mixture was then cooled to 0-5 °C and triethylamine (13ml) was added. To say cooled mixture was then slowly added a mixture of (R)-2-hydroxy -2-phenyl acetic tosyl ester (lOg) and dichloromethane (50ml). The temperature of reaction mixture was then raised to reflux temperature and maintained for 5 hours. After completion of reaction, water (50ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. The organic phase was separated and distill out completely under reduced pressure to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide Yield-70percent, Purity-96percent18 g of the intermediate I was dissolved in 150 mL of THF, 18.2 g of 4-nitrophenethylamine was added, and the reaction was carried out at 40°C for 3 hours, and the TLC controlled reaction was completed, and the mixture was allowed to reach room temperature. The solvent was concentrated in vacuo, dissolved in 60 mL of methanol at 50°C, naturally decanted and crystallized for 12 hours, filtered, washed with 30 mL of methanol, dried to give a white solid 13.7 g, ie, mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenylethyl)-2-phenylacetamide, yield 92percent, purity 99.78percent.Acetonitrile (2.0 L), (R)-mandelic acid (3, 225.3 g, 1.48 mol) and trimethyl borate (153.8 g, 1.48 mol) was addedinto a RBF at 25–30 °C and stirred to obtain clear solution.The obtained clear solution was heated to 60 °C for 90min. Amine (2, 200 g, 0.987 mol) and DIPEA (191 g, 1.48mol) was added to the obtained solution at 60 °C and thereaction mixture was heated to reflux and stirred for 11 h.Completion of the reaction was monitored by HPLC. Acetonitrile(1.2 L) was distilled at atmospheric pressure. Theconcentrated reaction mixture was cooled to 25–30 °C andwas diluted with ethyl acetate (1.4 L). Reaction mixture wasthen twice washed with 1N HCl (1.2 L and 0.8 L) followedby washing with 5percent sodium hydroxide solution (1.2 L and0.8 L). Organic layer was further washed with 10percent brinesolution (1.2 L) and then concentrated under vacuum below65 °C to obtain residue. To the obtained residue toluene(1.2 L) was added, heated to 95 °C for 30 min, cooled to20 °C and stirred for 1–2 h. Precipitated solid was filtered, washed with toluene (100 mL) and dried in a vacuum ovenat 50±5 °C for 2–3 h. The dry weight of the amide 4 was 256g (86.4percent yield). Purity by HPLC: 98.9percent; m/z [M + H]+ calcd.for C16H16N2O4: 300.30; found: 301. 1H NMR (300 MHz, DMSO-d6): δ 2.85–2.88 (t, 2H), 3.29–3.43 (m, 2H), 4.83–4.84 (d, 1H), 6.12–6.13 (d, 1H), 7.23–7.31 (m, 5H), 7.38–7.40 (d, 2H), 8.05–8.10 (m, 3H). 13C NMR (75.5 MHz, DMSO-d6): δ 172.20, 147.89, 145.97, 141.33, 130.04, 127.86, 127.34, 126.59, 123.24, 73.56, 39.00, 34.77.

Molecular Weight:300.31
XLogP3:2.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:300.11100700
Monoisotopic Mass:300.11100700
Topological Polar Surface Area:95.2
Heavy Atom Count:22
Complexity:369
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes