由腈混合物脒

s added 75 gm ammonium carbonate and reaction mixture was warmed to 28-32°C and stirred for 10-12 hr. completion of reaction was monitored by HPLC. Reaction mixture was filtered and the residue was washed with ethanol 500 ml. combined filtrate was concentrated under vacuum to obtain residue. To the obtained residue was added 500 ml ethanol and 1000 ml ethyl acetate. Mixture was refluxed for 30 mm. and then cooled to 25-30°C. precipitated product was stirred for 60 mm. at 25-30°C and then filtered and dried at 40-45°C to obtain crude Ethyl3-{[(2-{[(4- {carbamimidoyl } phenyl)amino]methyl} -1-methyl-i H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino } propanoate.Yield: l00g (96.61percent); Purity by HPLC: 95.3 percent.

【 Synthesis 2003, 1603–1609】

【 Tetrahedron 2008, 64, 11594–11602】

4、N-乙酰基半胱硫酸酸先决条件

In four flask equipped with a mechanical stirrer, thermometer, reflux condenser. take For bromoxynil 36.4g (0.2mol) was poured into a beaker, add 100ml of absolute ethanol, stirring to dissolve completely; then weighed 32.4g N- acetylcysteine (0.2mol), into another beaker was then added 150ml of absolute ethanol, stirring the mixture to complete dissolution, then a solution of ethanol will bromoxynil and N- acetylcysteine ethanol solution was poured into four flask, stirred and heated to 45 The reaction 20h . Weigh 8.6g ammonium carbamate (0.11 mol), was slowly added portionwise to a 4-neck flask, 20h, after complete dissolution the reaction, the reactionAfter completion of standing 48h, suction filtered, the filter cake was washed with ethanol, and drying, a white solid product was obtained 38g of bromobenzene formamidine (Compound ), yield 95.4percent, HPLC purity was 99.6percent.

Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[ d]imidazole-5-carboxamido) propanoate of Formula (ll)using N-acetyl cysteine 10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was dissolved in 600 ml EtOH.NH3 (15-18percentw/w) and stirred at 25°C. Added 3.38 g (0.020 mol) of N-acetyl

cysteine to the reaction mass and stirred for 24 hours at 70-75°C under 2.0-2.3 kg of pressure. The ethanol was distilled under vacuum and residue was purified by column. Yield: 5.5 g Efficiency: 53percent

【 Patent; CIPLA LIMITED; KING, Lawrence; RAO, Dharmaraj Ramachandra; MALHOTRA, Geena; PULLELA, Venkata Srinivas; ACHARYA, Vinod Parameshwaran; SINARE, Sudam Nanabhau; (43 pag.); WO2016/27077；(2016); (A1) English】

A solution of Boc-Aze-NH-CH2-((5-cyano)-2-pyrimidinyl) (0.83 g, 2.6 mmol; see step (iv) above), N-acetylcysteine (0.43 g, 2.6 mmol) and ammonium acetate (0.60 g, 7.8 mmol) in 10 mL of methanol was heated at 60° C. under nitrogen for 2 days. The solvent was evaporated and the crude material was purified by preparative RPLC using a gradient of CH3CN: 0.1M NH4OAc (5:95 to 100:0).

The fractions of interest were freeze dried to give 1.0 g (93percent) of the desired material. 1H NMR (300 MHz, D2O, signals obscured by the HDO signal) δ9. 17 (s, 2H), 4.1-3.9 (m, 2H), 2.60 (m, 1H), 2.29 (m, 1H), 1.93 (s, 3H), 1.44 (s, 9H)

【Patent; Inghardt, Tord; Johansson, Anders; Svensson, Arne; US2004/19033; (2004); (A1) English】

5、三羟基硅先决条件下重排

14.5 mL (29 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 20 mL of toluene containing 1.55 g (28.9 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 2 g (28.9mmol) of isobutironitrile was added thereto and the resulting mixture was heated to 85°C for 9 hours. After completion of a reaction, the reaction solution was poured into 200 mL of chloroform containing 500 g of silicagel and filtered. The residue was washed with 200 mL of methanol and distillation was conducted to give 2.3 g (26.7 mmol) of the title compound in a yield of 92percent. Mass(EI) 87(M++.)

Adamantane amidine hydrochloride (5). Cold Me3Al 1 (25 mL, 50 mmol) in PhMe was added gradually with stirring to a suspension of NH4Cl 2 (2.9 g, 54 mmol) in dry PhMe (20 mL) at 5 C under N2. The mixture was warmed to r.t. and stirred for 2 h until CH4 evolution stopped, the cyano adamantane 4 (4.83 g, 30 mmol) was added in 10 mL PhMe and the mixture was heated to 80 C under Ar for 18 h (TLC). The mixture was poured into a slurry of SiO2 (15 g) and CHCl3 (50 mL) and after 5 min silica was filtered and washed with MeOH and the combined solvents were concentrated to 15 mL. NH4Cl was filtered off and MeOH/HCl (10 mL, conc 2 g, 54 mmol) followed by Et2O (400 mL)

was added. After 10 h of stirring, filtration provided 5.8 g of crude 5. Recrystallization (4:1 iPrOH: Me2CO) afforded 4.1 g of 5 (64%), mp 257–259 C.

【Moss RA, Tet Lett ., 1995, 36, 8761】

14.5 mL (29 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 20 mL of toluene containing 1.55 g (28.9 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 2 g (28.9mmol) of isobutironitrile was added thereto and the resulting mixture was heated to 85°C for 9 hours. After completion of a reaction, the reaction solution was poured into 200 mL of chloroform containing 500 g of silicagel and filtered. The residue was washed with 200 mL of methanol and distillation was conducted to give 2.3 g (26.7 mmol) of the title compound in a yield of 92percent. Mass(EI) 87(M++.)

6、乙醚先决条件

To a solution of 3-(3-bromo-4-fluorophenyl)propanenitrile (5.0 g, 21.05 mmol) in toluene (20 mL) and methanol (6.32 mL, 156 mmol) at 0°C was added acetyl chloride (7.51 mL, 105 mmol) dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was cooled to 0°C by an ice bath, to which ammonia (30.1 mL, 210 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to give a crude product. Recrystallization from toluene/methanol (1: 1) then afforded the title compound as a white solid (5.2 g, 93 percent yield). [M+H+] =245

【 Patent; GLAXO GROUP LIMITED; JIN, Yun; WAN, Zehong; ZHANG, Qing; WO2012/76435; (2012); (A1) English】

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