2-Hydroxy-4-(phenylmethoxy)benzaldehyde

2, 4-Dihydroxybenzaldehyde (3.0g, 1.0equiv) was dissolved in acetonitrile (220ml) and treated with NaHCOAnhydrous NaHCOAnhydrous sodium bicarbonate (0.1 g, 1.2 mmol) was added to a solution of 2, 4-dihydroxy-benzaldehyde (0.138 g, 1 mmol) in 10 mL of acetonitrile and the mixture was stirred for 1 hour at RT. Benzylbromide (0.13 mL, 1.1 mmol) was added and the mixture was refluxed for 6 hours.Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2, 4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 h. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 percent yield as a white solid. Mp.Anhydrous sodium bicarbonate (1.2 mmol) was added to a solution of 2, 4-dihydroxy-benzaldehyde (1 mmol) in acetonitrile and the mixture was stirred for 1 hour at room temperature. Benzylbromide (1.1 mmol) was added and the mixture was refluxed for 24 hours. After disappearance of the reactant (TLC), the reaction was poured into ice water with vigorous stirring. A white solid precipitated was filter and purified by column chromatography (using ethyl acetate/n-hexane (1:9) as the eluent) to obtain 80 percent yield as a white solid. Mp.2, 4-dihydroxybenzaldehyde (10 g, 0.072 mol) was dissolved in acetonitrile (83 mL). To this solution was added NaHCOA mixture of sodium bicarbonate (1.216 g, 14.48 mmol), benzyl bromide (2.477 g, 14.48 mmol) and 2, 4-dihydroxybenzaldehyde (2 g, 14.48 mmol)) in acetonitrile (50 mL) was stirred at 85 °C for 20 hours. The solvent was removed to give a brown oil The residue was diluted with 80 mL of water, extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over Na2S04, filtered through glass funnel and concentrated to give an orange oil. The crude material was purified by silica gel column chromatography and eluted with 5percent ethyl acetate/heptane. The following fractions were collected and concentrated to give the title compound 4- (benzyloxy)-2-hydroxybenzaldehyde (2.2 g, 8.67 mmol, 59.9 percent yield) as a white solid.LCMS(ESI-MS): m/z: 312.1 [M + H]To 2, 4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g, 7.2 mmoi), and NaHC0To 2, 4-dihydroxybenzaldehyde (2.0 g, 14 mmol), Nal (1.0 g, 7.2 mmol), and NaHCO3 (1.5 g, 17 mmol) in acetonitrile (30mE, 0.50 M)was added benzyl bromide (1.7 mE, 14 mmol).The reaction mixture was stirred at 80° C. for 18 h under argon, cooled to RT, diluted with EtOAc (100 mE), washed with H20 and brine, and dried over MgSO4, and filtered. The filterate was concentrated and purified by flash chromatography (silica, EtOAc:hexanes=1 :8) to provided compound 3 aswhite solid (49percent). ‘H NMR (CDC13, 300 MHz): ö 11.48 (1H, s), 9.72 (1H, s), 7.51-7.32 (6H, m), 6.62 (1H, dd, J=8.7, 2.3 Hz), 6.54 (1H, d, J=2.3 Hz), 5.11 (2H, s). ‘3C NMR (CDC13, 100 MHz): ö 194.5, 166.0, 164.6, 135.8, 135.4, 128.9, 128.5, 127.6, 115.5, 109.0, 101.8, 70.5. ERMS (APCI+): Calc’d for C, 4H, 203 228.1 mlz, measured 229.2 (MH+).Intermediate 98: 4-(Benzyloxy)-2-hydroxybenzaldehydeTo a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added 2, 4-dihydroxybenzaldehyde (8.0 g, 57.0 mmol), potassium carbonate (15.77 g, 114.0 mmol). The reaction mixture was brought to 0 °C, was added benzyl bromide (9.905 g, 57.0 mmol) in acetonitrile (100 mL) drop wise and stirred at room temperature for 3 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous NaEXAMPLE I General procedure: A mixture of 2, 4-dihydroxybenzaldehyde (1.38 g, 0.01 mol), substituted benzyl chloride (0.011 mol), NaHCO2, 4-dihydroxybenzaldehyde (100 mg, 0.72 mmol), potassium iodide (179.3 mg, 1.08 mmol) and sodium bicarbonate (90.7 mg, 1.08 mmol) were dissolved in acetonitrile (15 mL), then benzyl chloride (100 uL, 0.87 mmol) were added slowly to the resulted solution. The mixture was stirred at refluxing overnight, and then the reaction was quenched with water and extracted with ethyl acetate (20 mL .x. 3). The combined organic layer was washed with brine (15 mL .x. 3), dried with sodium sulphate anhydrous, concentrated under vacuum, and purified by flash chromatography with eluent (petroleum ether: ethyl acetate = 10:1), to get a colorless solid. Yield 67percent; m.p. 70-72 °C; The reaction of 2, 4-dihydroxybenzaldehyde with benzyl chloride, To give 2-hydroxy-4-benzyloxybenzaldehyde, As shown in Scheme 5, The specific preparation method is as follows: To a solution of2, 4-dihydroxybenzaldehyde (5.00 g, 36 mmol) and benzylchloride (5.50 g, 43.5 mmol) in CH3CN (50 mL), KI (5.50g, 54 mmol) and NaHCO3 (4.50 g, 54 mmol) were added.The mixture was refluxed overnight and cooled to roomtemperature. The reaction was quenched with water andextracted by ethyl acetate. The combined organic extractswere washed with brine, dried over anhydrous Na2SO4, concentrated and purified over silica gel column (elution:10/1 petroleum ether/ethyl acetate) to give compound 1(5.25 g, 64 percent) as white solid. 1H NMR (CDCl3, 300 MHz):δ = 5.11 (s, 2H, OCH2Ph), 6.51–6.52 (d, 1H, J = 3.0 Hz, ArH), 6.60–6.63 (dd, 1H, J = 1.5 Hz, 7.5 Hz ArH), 7.36–7.46 (m, 6H, ArH), 9.72 (s, 1H, OH), 11.48 (s, 1H, OH).2, 4-dihydroxybenzaldehyde (5.00 g, 36 mmol) was dissolved in acetonitrile (500 mL)Then potassium iodide (9.00 g, 54 mmol) and sodium bicarbonate (4.50 g, 54 mmol) were added, Benzyl chloride (5.50 g, 43.5 mmol) was slowly added dropwise and refluxed for 12 h.After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: : 1)4- (benzyloxy) -2-hydroxybenzaldehyde5.25 g (white solid, yield 64percent).(Example 197)2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl] -2, 3 -dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride (Exemplification compound number 4-136)(a) 4-Benzyloxy-2-hydoxy-benzaldehydeTo a solution of 2, 4-dihydroxybenzaldehyde (50.0 g, 362 mmol) in acetonitrile (350 ml) were added sodium hydrogen carbonate (34.6 g, 412 mmol), potassium iodide (6.0 g, 36 mmol), and benzyl chloride (54.0 ml, 470 mmol), and the resulting mixture was refluxed for 24 hours under a nitrogen atmosphere. At the end of the reaction, 1N hydrochloric acid (400 ml) was added, and the resulting mixture was extracted with ethyl acetate (400 ml ' 2). The organic layer was washed successively with 3percent aqueous potassium carbonate solution (300 ml ' 2), water (300 ml ' 1), 1N hydrochloric acid (300 ml ' 1) and saturated aqueous sodium chloride solution (300 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was recrystallized from a mixture of t-butyl methyl ether and hexane to afford the title compound (45.9 g, yield: 56percent) as pale orange crystals. Mp 71-72C.1H NMR (CDCl3, 500MHz) ' ppm : 5.11 (2H, s), 6.51 (1H, d, J=2.0Hz), 6.62 (1H, dd, J=2.0, 8.5Hz), 7.35-7.45 (6H, m), 9.72 (1H, s), 11.46 (1H, s).(b) 4-Benzyloxy-2-methoxymethoxy-benzaldehyde o a solution of -benzyloxy-2-hydoxy-benzaldehyd (44.9 g, 197 mmol) synthesized in step (a) of Example 197 in dichloromethane (200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethyl chloride (20.5 ml, 270 mmol) at 0C with stirring, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with dichloromethane (200 ml ' 2). The organic layer was washed successively with water (300 ml ' 1) and saturated aqueous sodium chloride solution (300 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (42.2 g, yield: 79percent) as a colorless oil.1H NMR (CDCl3, 500MHz) ' ppm : 3.51 (3H, s), 5.11(2H, s), 5.26 (2H, s), 6.68 (1H, dd, J=2.0, 9.0 Hz), 6.80 (1H, d, J=9.0Hz), 7.34-7.43 (5H, m), 7.81 (1H, d, J=9.0Hz), 9.72 (1H, s), 11.46 (1H, s).(c) Ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate To a suspension of 55percent sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0C with stirring, and the resulting mixture was stirred for 2 hours at 0C under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml ' 2). The organic layer was washed successively with water (100 ml ' 1) and saturated aqueous sodium chloride solution (100 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (9.32 g, yield: 99percent) as a colorless oil.1H NMR (CDCl3, 400MHz) ' ppm : 1.32 (3H, t, J=7.2 Hz), 3.47 (3H, s), 4.24 (2H, q, J=7.2Hz), 5.05 (2H, s), 5.21 (2H, s), 6.39 (1H, d, J=16.0Hz), 6.62 (1H, dd, J=2.0, 8.8Hz), 6.81 (1H, d, J=2.0Hz), 7.30-7.43 (5H, m), 7.45 (1H, d, J=8.8Hz), 7.95 (1H, d, J=16.0Hz). (d) Ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate To a solution of (S)-N-benzyl-1-phenylethylamine (4.24 g, 20.1 mmol) in tetrahydrofuran (40 ml) was added 1.6 M solution of n-butyllithium in hexane (12.4 ml, 18.9 mmol) at -78C with stirring, and the resulting mixture was stirred for 20 minutes at -78C under a nitrogen atmosphere. Subsequently, a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate (4.32 g, 12.6 mmol) synthesized in Example 3 in tetrahydrofuran was added dropwise at -78C with stirring, and the resulting mixture was stirred for 30 minutes at -78C under a nitrogen atmosphere. After stirring, a saturated aqueous ammonium chloride solution (40 ml) was added at -78C with stirring, and the resulting mixture was extracted with ethyl acetate (50 ml ' 2). The organic layer was washed with saturated aqueous sodium chloride solution (50 ml ' 1), dried over anhydrous e product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (3.48 g, yield: 82percent) as a colorless oil. [?]D23 +48.0 (c 1.09, CHCl3) .1H NMR (CDCl3, 400MHz) ' ppm : 1.43 (9H, s), 1.94 (2H, dt, J=4.8, 6.0Hz), 3.00 (3H, s), 3.08 (3H, s), 3.30 (1H, br s), 3.49 (3H, s), 3.61-3.74 (2H, m), 5.06 (1H, q, J=5.6Hz), 5.23 (2H, dd, J=6.4, 10.8Hz), 5.47 (1H, d, J=9.6Hz), 6.74 (1H, dd, J=2.4, 8.8Hz), 6.90 (1H, d, J=2.4Hz), 7.19 (1H, d, J=8.8Hz). (h) -[(1R)-Amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxyphenyl dimethylcarbamate To a solution of t-butyl (1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-carbamate (1.63 g, 4.08 mmol) synthesized in step (g) of Example 197, 4-methylthiophenol (660 mg, 4.50 mmol) and triphenylphosphine (1.60 g, 6.12 mmol) in tetrahydrofuran (15 ml), was added dropwise 40 wt percent solution of diethyl azodicarboxylate in toluene (2.66 g, 6.12 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the crude product (2.74 g) containing hydrazine dicarboxylate. Subsequently, to a solution of the crude product (2.74 g) in methanol (18 ml) was added concentrated hydrochloric acid (6 ml), and the resulting mixture was stirred overnight at room temperature. After stirring, the reaction mixture was neutralized with 15percent aqueous sodium hydroxide solution and adjusted to pH 10 with saturated aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate (50 ml ' 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1:0-5:1) as the eluent to afford the title compound (1.05 g, yield: 69percent) as a colorless oil. [?]D23 -66.5 (c 0.77, CHCl3).1H NMR (CDCl3, 500MHz) ' ppm : 2.12-2.18 (1H, m), 2.21-2.28 (1H, m), 2.44 (3H, s), 2.99 (3H, s), 3.07 (3H, s), 3.89 (1H, dt, J=4.0, 10.0Hz), 4.00 (1H, dt, =5.0, 10.0Hz), 4.43 (1H, t, J=7.5Hz), 6.51 (1H, dd, J=2.5, 8.0Hz), 6.60 (1H, d, J=2.5Hz), 6.82 (2H, d, J=8.5 Hz), 6.86 (1H, d, J=8.0Hz), 7.25 (2H, d, J=8.5Hz). (i) t-Butyl [(1R) - 4-dimethylcarbamoyloxy-2-hydroxy-phenyl) -3-(4-methylthiophenoxy)-propyl]-carbamate To a solution of -[(1R)-amino-3-(4-methylthiophenoxy)-propyl] -3-hydroxy-phenyl dimethylcarbamate (1.05 g, 2.80 mmol) synthesized in step (h) of Example 197 in methanol (10 ml) were added triethylamine (0.83 ml, 6.0 mmol) and di-t-butyl dicarbonate (650 mg, 3.00 mmol), and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 0:1) as the eluent to afford the title compound (1.34 g, yield: 100percent) as a colorless solid. [?]D23 +14.3 (c 0.52, CHCl3).1H NMR (CDCl3, 400MHz) ' ppm : 1.40 (9H, s), 2.26-2.37 (2H, m), 2.44 (3H, s), 3.00 (3H, s), 3.07 (3H, s), 3.89-3.95 (1H, m), 3.98-4.03 (1H, m), 5.00 (1H, dd, J=8.0, 15.2Hz), 5.25 (1H, br s), 6.63 (1H, dd, J=3.2, 8.0Hz), 6.66 (1H, d, J=3.2Hz), 6.81 (2H, d, J=8.8Hz), 7.10 (1H, d, J=8.0Hz), 7.24 (2H, d, J=8.8Hz).(j) t-Butyl [(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl] -carbamate To a solution of t-butyl [(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-propyl] -carbamate (1.34 g, 2.80 mmol) synthesized in step (i) of Example 197 in dichloromethane (10 ml) were added pyridine (0.48 ml, 6.0 mmol) and trifluoromethanesulfonic anhydride (0.50 ml, 3.0 mmol) at 0C with stirring, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, water (20 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (20 ml ' 2). The organic layer was washed successively with 0.5N hydrochloric acid (20 ml ' 1) and saturated aqueous sodium chloride solution (20 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude triflate derivative (1.48 g).1H NMR (CDCl3, 500MHz) ' ppm : 1.38 (9H, br s), 2.17-2.34 (2H, m), 2.44 (3H, s), 3.01 (3H, s), 3.09 (3H, s), 3.97 (2H, t, J=6.0Hz), 5.13 (1H, dd, J=8.0, 12.5Hz, 5.44 (1H, br s), 6.82 (2H, d, J=8.5Hz), 7.14 (1H, d, J=8.5Hz), 7.15 (1H, s), 7.25 (2H, d, J=8.5Hz), 7.43 (1H d, J=8.5Hz). Subsequently, to a solution of the crude triflate derivative (1.48 g) obtained above in 1, 4-dioxane (20 ml) were added tetrakis(triphenylphosphine)palladium (647 mg, 0.560 mmol), 2, 6-di-t-butylphenol (5 mg), lithium chloride (356 mg, 8.40 mmol) and tributyl(vinyl)tin (0.88 ml, 3.0 mmol), and the resulting mixture was stirred for 3 hours at 100C under a nitrogen atmosphere. Subsequently, saturated aqueous potassium fluoride solution (10 ml) was added, and the resulting mixture was stirred for 2 hours at room temperature and then filtered and evaporated in vacuo. To the residue obtained was added water (40 ml), and the resulting mixture was extracted with ethyl acetate (50 ml ' 2). The organic layer was washed successively with 1N hydrochloric acid (40 ml ' 1) and saturated aqueous sodium chloride solution (40 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1 - 1:1) as the eluent to afford the title compound (1.08 g, yield: 79percent) as a colorless oil. [?]D23 -7.7 (c 0.58, CHCl3).1H NMR (CDCl3, 400MHz) ' ppm : 1.40 (9H, s), 2.18 (2H, br m), 2.44 (3H, s), 3.01 (3H, s), 3.09 (3H, s), 3.84-3.96 (2H, m), 5.23 (1H, br s), 5.31 (1H, d, J=10.8Hz), 5.58 (1H, dd, J=1.2, 16.8Hz), 6.80 (2H, d, J=8.0Hz), 7.00-7.16 (1H, br m), 7.02 (1H, dd, J=2.8, 8.8Hz), 7.19-7.28 (4H, m).(k) t-Butylallyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinylphenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate To a solution of t-butyl [(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl) -3-(4-methylthiophenoxy)-propyl) -carbamate (1.08 g, 2.22 mmol) synthesized in step (j) of Example 197 in dimethylformamide (10 ml) was added sodium hydride (160 mg, 6.66 mmol), being prepared free from mineral oil by washing with hexane, at 0C, and the resulting mixture was stirred for 30 minutes at 0C under a nitrogen atmosphere. Subsequently, allyl bromide (0.57 ml, 6.7 mmol) was added at 0C, and the resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added, and the resulting mixture was extracted with ethyl acetate (30 ml ' 2). The organic layer was washed successively with water (30 ml ' 1) and saturated aqueous sodium chloride solution (30 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:1) as the eluent to afford the title compound (932 mg, yield: 80percent) as a colorless oil. [?]D23 +76.1 (c 0.63, CHCl3).1H NMR (CDCl3, 500MHz) ' ppm : 1.43 (9H, s), 2.29-2.42 (1H, br m), 2.40-2.52 (1H, br m), 2.43 (3H, s), 3.02 (3H, s), 3.11 (3H, s), 3.47 (2H, brs), 3.97 (1H, dt, J=6.0, 8.0Hz), 4.06 (1H, br q, J=8.0Hz), 4.82 (1H, d, J=17.0Hz), 4.84 (1H, d, J=9.5Hz), 5.28 (1H, d, J=10.5Hz), 5.48 (1H, br s), 5.58 (1H, d, J=16.5Hz), 5.67 (1H, br s), 6.82 (2H, d, J=8.5Hz), 7.02 (1H, dd, J=10.5, 16.5Hz), 7.04-7.06 (1H, m), 7.24-7.26 (3H, m), 7.34 (1H, d, J=7.5Hz).(1) t-Butyl 7-dimethylcarbamoyloxy-(1R)-[2(4-methylthiophenoxy)-ethyl] -1, 3-dihydro-benzo[c]azepine-2-carboxylate To a solution of t-butyl allyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate (907 mg, 1.72 mmol) synthesized in step (k) of Example 197 in dichlorometane (100 ml) was added tricyclohexylphosphine [1, 3-bis(2, 4, 6-trimethylphenyl)-4, 5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium(IV) dichloride (146 mg, 0.172 mmol), and the resulting mixture was stirred for 3 hours at 45C under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:1) as the eluent to afford the title compound (796 mg, yield: 93percent) as a colorless oil. [?]D23 -43.8 (c 0.71, CHCl3).1H NMR (CDCl3, 500MHz) ' ppm : 1.29 (6H, s), 1.38 (3H, s), 2.27 (1H, br s), 2.36 (1H, br s), 2.44 (3H, s), 3.00 (3H, s), 3.09 (3H, s), 3.77-4.18 (3H, br m), 4.74 (0.34H, d, J=16.0Hz), 4.99 (0.66H, br s), 5.23 (0.66H, br s), 5.35 (0.34H, br s), 5.78 (0.34H, d, J=11.5 Hz), 5.84 (0.66H, d, J=11.5Hz), 6.35 (1H, d, J=11.5Hz), 6.80 (0.68H, d, J=7.5Hz), 6.82 (1.32H, d, J=7.5 Hz), 6.88 (1H, br s), 6.96 (1H, s), 7.08 (1H, br s), 7.20-7.26 (2H, m). (m) -Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2, 3-dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride The title compound was obtained as an amorphous solid using t-butyl 7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1, 3-dihydro-benzo [c] azepine-2-carboxylate obtained in step (1) of Example 197 by conducting successively reactions similar to those mentioned in step (d) of Example 6 and Example 3. [?]D23 -24.2 (c 0.73, CHCl3).1H NMR (CDCl3, 400MHz) ' ppm : 2.03-2.15 (1H, m), 2.43 (3H, s), 2.53 (3H, s), 2.64-2.76 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.76-3.79 (2H, m), 3.92 (1H, quintet, J=5.2Hz), 4.19 (1H, br s), 4.63 (1H, d, J=7.6Hz), 5.84 (1H, d, J=12.4Hz), 6.60 (1H, d, J=12.4Hz), 6.76 (2H, d, J=8.8Hz), 7.00 (1H, dd, J=2.0, 8.0Hz), 7.14 (1H, d, J=2.0Hz), 7.15 (1H, d, J=8.0Hz), 7.21 (2H, d, J=8.8Hz).sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (10:1 - 5:1) as the eluent to afford ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) containing a small amount of (S)-N-benzyl-1-phenylethylamine.1H NMR (CDCl3, 500MHz) ' ppm : 0.98 (3H, t, J=7.0Hz), 1.23 (3H, d, J=7.0Hz), 2.60 (1H, dd, J=9.0, 13.5Hz), 2.73 (1H, dd, J=7.0, 15.0Hz), 3.47 (3H, s), 3.73 (2H, dd, J=14.5, 22.5Hz), 3.79-3.92 (2H, m), 4.08 (1H, q, J=7.0Hz), 4.80 (1H, dd, J=6.0, 8.0 Hz), 5.03 (2H, s), 5.15 (2H, dd, J=7.0, 17.0Hz), 6.61 (1H, dd, J=2.5, 8.5 Hz), 6.83 (1H, d, J=2.5Hz), 7.13-7.44 (16H, m).Subsequently, to a solution of ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-(benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) obtained above as a yellow oil in a mixture of methanol/water/acetic acid (80 ml/8 ml/4 ml) was added 20percent palladium hydroxide (1.8 g), and the resulting mixture was stirred for 4 hours at room temperature. After stirring, the reaction mixture was filtered through celite and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1 : 0-3 : 1) as the eluent to afford the title compound (2.77 g, yield: 67percent) as an amorphous solid. [?]D23 -8.0 (c 0.82, MeOH) .1H NMR (CD3OD, 400MHz) ' ppm : 1.20 (3H, t, J=7.6Hz), 1.90 (3H, s), 2.93 (1H, dd, J=6.0, 16.4Hz), 2.98 (1H, dd, J=8.8, 16.4Hz), 3.49 (3H, s), 4.13 (2H, q, J=7.6Hz), 4.71 (1H, t, J=7.4Hz), 5.24 (2H, s), 6.45 (1H, dd, J=2.4, 8.8Hz), 6.69 (1H, d, J=2.8Hz), 7.12 (1H, d, J=8.8Hz). (e) Ethyl (3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate To a solution of ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate (4.26 g, 12.9 mmol) obtained in step (d) of Example 197 in methanol (20 ml) were added triethylamine (3.62 ml, 26.0 mmol) and di-t-butyl dicarbonate (3.27 g, 15.0 mmol) with stirring, and the resulting mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the title compound (4.64 g, yield: 97percent) as a colorless solid. The optical purity of the title compound obtained was determined to be 98.8percent ee by chiral liquid chromatography (Dicel Chiral cel OJ, hexane : isopropanol = 95:5, 1 ml/min, R-isomer: 20.48 min and S-isomer: 23.68 min). Mp 82-86C. [?]D23 +42.3 (c 0.86, CHCl3).1H NMR (CDCl3, 500MHz) ' ppm : 1.16 (3H, t, J=7.0Hz), 1.43 (9H, s), 2.79 (1H, dd, J=7.0, 14.5Hz), 2.86 (1H, dd, J=6.0, 14.5Hz), 3.45 (3H, s), 4.05 (2H, q, J=7. Hz), 4.85-5.20 (3H, m), 5.43 (0.2H, br s), 5.81 (0.8H, d, J=8.0Hz), 6.28 (1H, d, J=8.0Hz), 6.50 (1H, br s), 6.57 (1H, br s), 6.98 (1H, d, J=8.0Hz). (f) Ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcaramoyloxy-2-methoxymethoxy-phenyl)-propionate To a solution of ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate (2.35 g, 6.36 mmol) synthesized in step (e) of Example 197 in dimethylformamide (10 ml) were added potassium carbonate (1.80 g, 13.0 mmol) and N, N-dimethylcarbamoyl chloride (0.65 ml, 7.0 mmol) with stirring, and the resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 ml ' 2). The organic layer was washed with saturated aqueous sodium chloride solution (40 ml ' 1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1 - 1:2) as the eluent to afford the title compound (2.73 g, yield: 97percent) as a colorless oil. [?]D23 +25.3 (c 1.09, CHCl3) .1H NMR (CDCl3, 500MHz) ' ppm : 1.17 (3H, t, J=7.0Hz), 1.41 (9H, s), 2.77-2.89 (2H, m), 2.99 (3H, s), 3.07 (3H, s), 3.49 (3H, s), 4.01-4.10 (2H, m), 5.24 (2H, dd, J=7.0, 10.0Hz), 5.30 (1H, br s), 5.74 (1H, br d, J=9.0Hz), 6.73 (1H, dd, J=2.0, 9.0Hz), 6.89 (1H, d, J=2.0Hz), 7.23 (1H, d, J=9.0Hz).(g) t-Butyl [(1R) (4-dimethylcarbamoyloxy-2-methoxymethoxyphenyl)-3-hydroxypropyl]-carbamate To a solution of ethyl 3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-propionate (4.68 g, 10.6 mmol) synthesized in step (f) of Example 197 in tetrahydrofuran (30 ml) was added lithium aluminum hydride (524 mg, 13.8 mmol) at -50C with stirring, and the resulting mixture was stirred successively for 10 minutes at -50C and for 15 minutes at 0C under a nitrogen atmosphere. After stirring, to the reaction mixture were added water (0.5 ml), 15percent aqueous sodium hydroxide solution (0.5 ml) and water (1.5 ml) at 0C in this order, and the resulting mixture was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crudGeneral procedure: A clean, oven dried 2 dram screw cap vial was charged with ZnCl2 (1.05 equiv) and DCE (1 mL). A solution of ortho-protected phenol (0.15 mmol, 1 equiv) in DCE (0.5 mL) was added via syringe and the reaction stirred at the indicated temperature until starting material was consumed as determined by TLC analysis. The reaction was then diluted with saturated aqueous NH4Cl (20 mL), the layers were separated, and the aqueous phase extracted with CH2Cl2 (3 x 10 mL). The combined organic fractions were washed with saturated aqueous NaCl (20 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography eluting with hexanes/EtOAc to give the ortho-deprotected phenol 33 mg (72percent) as white solidStep 1 4-Ben7ry1oxy-2-hydτoxy-ben7:aldehvdeA solution of 2, 4-dihydroxy-benzaldehyde (101 g, 0.731 mol) in acetonitrile (700 mL) is treated with KI (12.1 g, 73.1 mmol) and NaHCO

Molecular Weight:228.24
XLogP3:3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:228.078644241
Monoisotopic Mass:228.078644241
Topological Polar Surface Area:46.5
Heavy Atom Count:17
Complexity:236
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes