BENZOIC ACID, 2-[[(2'-CYANO[1,1'-BIPHENYL]-4-YL)METHYL]AMINO]-3-NITRO-METHYL ESTER Chemical Properties

Melting point:

133-135°C

Boiling point:

595.5±50.0 °C(Predicted)

Density 

1.33±0.1 g/cm3 (20 ºC 760 Torr)

storage temp. 

under inert gas (nitrogen or Argon) at 2–8 °C

solubility 

Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly)

form 

Solid

pka

-2.55±0.10(Predicted)

color 

Off-White to Light Yellow

BENZOIC ACID, 2-[[(2'-CYANO[1,1'-BIPHENYL]-4-YL)METHYL]AMINO]-3-NITRO-METHYL ESTER Usage And Synthesis

Chemical Properties

Yellow Solid

Uses

Intermediate in the synthesis of nonpeptide angiotensin II receptor antagonists. Candesartan (C175575) impurity. Candesartan Cilexetil (C175580) impurity.

Synthesis

30.1 g of methyl 2-((tert-butoxycarbonyl)((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-nitrobenzoate [BAN], 40.8 g of potassium carbonate, and 160 ml of acetonitrile were mixed, and the reaction system may have contained unreacted 2-(4-methylphenyl)benzylcarbonitrile [MPB] and, as a by-product, 2-(4,4-dibromomethylphenyl) benzyl cyanide. The reaction was stirred at 82°C for 5 hours. After completion of the reaction, it was cooled to room temperature, the precipitated crystals were collected by filtration and the filtrate was concentrated to give methyl 2-[N-tert-butoxycarbonyl-N-[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate [BBN]. The concentrate was dissolved in 190 g of methanol and 106 g of concentrated hydrochloric acid was added slowly and dropwise. The reaction solution was heated to reflux temperature and kept at reflux stirring for 2 hours. After cooling, the precipitated crystals were collected by filtration and dropwise addition to give 35.1 g of methyl 2-[N-(2'-cyanobiphenyl-4-yl)methylamino]-3-nitrobenzoate [MBN] in 76.1% yield (based on 2-(4-methylphenyl)benzonitrile [MPB]). In Reference Example 4 (2), the resulting concentrate (BBN) was mixed with 3200 L of methanol at 30°C or lower and 1050 L of 35% concentrated hydrochloric acid was added over about 4 hours. The mixture was heated to reflux temperature (67-69°C) at a rate not exceeding 10°C/hour and stirred at reflux for about 1.5 hours. The reaction solution was cooled, 800 L of methanol was added and stirred at 3 to 10 °C for about 1 hour. The precipitated crystals were separated, washed with methanol and dried to give 407 kg of methyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate [MBN] in 75% yield (based on MPB). Melting point: 140 to 141 °C. 1H-NMR (200 MHz, DMSO-d6) δ: 3.84 (3H, s), 4.26 (2H, m), 6.86 (1H, t), 7.46 (2H, d), 7.54-7.65 (4H, m), 7.79 (1H, d), 7.95 (1H, dd), 8.05-8.11 ( 2H, m), 8.67 (1H, t).

References

[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 15, p. 2182 - 2195
[2] Patent: EP1420016, 2004, A1. Location in patent: Page 16-17; 18

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