methyl 2-dimethoxyphosphorylacetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2S)-2-[(tert-butoxy)carbonylamino]-N-methoxy-N-methylpropanamide (13.05 g, 56.18 mmol) in ethyl ether (560 mL) was chilled with an ice water bath and then 95% lithium aluminum hydride (2.80 g, 70.23 mmol) was added. The reaction was stirred at room temperature for 20 minutes and then a solution of aqueous potassium hydrogen sulfate (300 mL, 0.33M) was added. The resulting mixture was extracted three times with ethyl ether. The combined organic layers were washed three times with 1N hydrogen chloride, three times with saturated aqueous sodium hydrogen carbonate, and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting solid was dissolved in anhydrous tetrahydrofuran (430 mL) then added to a cold solution of trimethyl phosphonoacetate (27.3 mL, 168.5 mmol) and sodium hydride (112 mmol) in anhydrous tetrahydrofuran (130 mL) that had been previously stirred at room temperature for 30 minutes. The reaction was stirred for 5 minutes in a ice water bath, at room temperature for 20 minutes, and then water (500 mL) was added. The reaction mixture was diluted with brine and ethyl acetate, stirred, and the layers separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 0-30% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (8.85 g, 69%): ES-MS (m/z) 230.4 [M+1]+. The resulting mixture was extracted three times with ethyl ether The combined organic layers were washed three times with 1N hydrogen chloride, three times with saturated aqueous sodium hydrogen carbonate The solution was then dried over anhydrous sodium sulfate filtered the solvent evaporated The resulting solid was dissolved in anhydrous tetrahydrofuran (430 mL) had been previously stirred at room temperature for 30 minutes The reaction was stirred for 5 minutes in a ice water bath, at room temperature for 20 minutes stirred the layers separated The organic layer was dried over anhydrous sodium sulfate filtered the solvent evaporated The resulting residue was purified by chromatography on a normal phase silica gel column with 0-30% ethyl acetate in hexanes Fractions containing clean product the solvent evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid: To a cooled (0° C.) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to rt and stirred at rt for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off-white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from recrystallization, adding methanol, sonicating, and collecting the solid product by filtration. A total of 0.829 g (57%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR (CDCl3, 500 MHz) δ: 8.80 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.8, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.25 (d, J=16.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 3.78 (s, 3H). To a white suspension of this ester (0.140 g, 0.529 mmol) in MeOH (3.0 mL) was added 1.0 M sodium hydroxide (1.587 ml, 1.587 mmol). The resulting suspension was stirred vigorously at rt for 2.5 h. The yellow suspension was neutralized with 1.0 N HCl (1.60 mL), and concentrated to give a beige solid. The solid was partitioned between 1.0 N HCl and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (100%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid as a white solid. LCMS m/z 251.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ: 12.72 (s, 1H), 9.87 (s, 1H), 8.24 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8.8, 2.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 6.98 (d, J=16.0 Hz, 1H), 6.70 (d, J=16.0 Hz, 1H). to facilitate mixing was added The yellow/green suspension was stirred vigorously After 30 min extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated to give a green/blue solid filtered through a plug of silica gel eluting with EtOAc The green filtrate was concentrated to give a greenish solid Recrystallization from EtOAc gave an off-white solid Additional product was obtained by concentrating the filtrate from recrystallization adding methanol sonicating collecting the solid product by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 39 ml (262.4 mmol) of trimethyl phosphonoacetate in 450 ml of tetrahydrofuran was added dropwise at 0° to a suspension of 9.54 g (238.5 mmol) of sodium hydride (55% in mineral oil) in 450 ml of tetrahydrofuran and the mixture was stirred for 30 minutes. Subsequently, the white suspension was treated with a solution of 33.15 g (119.5 mmol) of 3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-one in 450 ml of tetrahydrofuran and the mixture was stirred at 50° for 2 hours. After cooling to room temperature the mixture was poured on to 500 ml of ice-water and extracted three times with 400 ml of diethyl ether. The organic phases were washed with 400 ml of water and 400 ml of saturated sodium chloride solution, dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 19:1) and recrystalization from hexane yielded 36.33 g (91%) of methyl (E)-[3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-ylidene]acetate as pale yellow crystals of m.p. 110-112°. the mixture was stirred at 50° for 2 hours extracted three times with 400 ml of diethyl ether The organic phases were washed with 400 ml of water and 400 ml of saturated sodium chloride solution dried (Na2SO4) filtered evaporated Chromatography (silica gel, methylene chloride/methanol 19:1) and recrystalization from hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In tetrahydrofuran (40 ml), methyl dimethylphosphonoacetate (1.8 ml) was dissolved. To the resulting solution, 60% oily sodium hydride (450 mg) was added under ice cooling, followed by stirring under the same condition. After the addition of a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (tetrahydrofuran: 10 ml) and stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate. To the diluted solution, 2N hydrochloric acid was added. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=6:1), whereby the title compound (2.35 g, 92%) was obtained. stirring at room temperature for 30 minutes The organic layer was separated washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution dried over anhydrous sodium sulfate The solvent was then distilled off under reduced pressure The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=6:1), whereby the title compound (2.35 g, 92%) was obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a THF (1 mL) solution of NaHMDS at 0° C. was added trimethyl phosphonoacetate (0.18 mL, 1.1 mmol), dropwise. After stirring for 1 hour, a THF (1 mL) solution of crude 3-benzyl-3-formyl-piperazine-1-carboxylic acid tert-butyl ester (0.34 mg, 0.92 mmol), prepared analogous to the compound of Example 198, Step A, was added and the reaction was allowed to warm to room temperature. After stirring for 16 hours, the product was isolated by extraction from water with EtOAc (2×) and methylene chloride (2×). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The product was then purified by silica gel chromatography using methylene chloride, then 5% MeOH in methylene chloride as eluents to afford a 7:3 E:Z mixture of olefins of the compound of Example 201, Step A (0.38 g, 81%), where the Z isomer had lactamized: +APcl MS (M+1, ester)+ 361, (M-tButyl+1, ester)+ 305, (M-tBu+1, lactam)+ 273, (M-BOC+1, ester)+ 261, (M-BOC+1, lactam)+ 229; 1H NMR (400 MHz, CDCl3) δ: 7.30-7.05 (arom, series of m, 5 H), 6.91 (lactam olefin, d, 0.3H), 6.75 (ester olefin, d, 0.7H), 6.09 (lactam olefin, d, 0.3H), 5.88 (ester olefin, d, 0.7H), 3.71 (ester Me, s 2.1H), 1.47 (BOC, s, 9H). was added After stirring for 16 hours The combined extracts were washed with brine dried (MgSO4) concentrated The product was then purified by silica gel chromatography 5% MeOH in methylene chloride as eluents to afford a 7:3 E

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of trimethyl phosphonoacetate (0.81 g, 4.5 mmol) in dry tetrahydrofuran (20 ml) under an argon atmosphere at 15–20° C. sodium hydride (0.12 g, 5.0 mmol) was added. The mixture was stirred at ambient temperature for 1 hour, and a solution of 3-(3-oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54a) (0.44 g, 1.5 mmol) in dry tetrahydrofuran (20 ml) was added dropwise at 15–20° C. The reaction mixture was stirred at ambient temperature for 1 hour and quenched by 3% HCl (20 ml). The product was extracted with ethyl acetate (50 ml), the extract was washed with 5% NaHCO3, water and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate-hexane (1:2, v/v) as eluent to give the title compound (0.39 g, 74%) as a white solid. M.p. 134–136° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.73 (3H, s, CH3); 6.49 (1H, d, J=15.5 Hz, CH); 7.03 (1H, d, J=15.5 Hz, CH); 7.01–7.38 (5H, m, C6H5); 7.41–7.89 (4H, m, C6H4); 10.34 (1H, s, NH). The reaction mixture was stirred at ambient temperature for 1 hour quenched by 3% HCl (20 ml) The product was extracted with ethyl acetate (50 ml) the extract was washed with 5% NaHCO3, water dried (Na2SO4) The solvents were removed under reduced pressure the residue was chromatographed on silica gel with ethyl acetate-hexane (1:2

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of sodium 2-formylbenzenesulfonate hydrate (31) (tech., purity 75%; 1.33 g, 4.79 mmol), potassium carbonate (1.32 g, 9.56 mmol), and trimethyl phosphonoacetate (1.05 g, 5.77 mmol) in water (2.5 ml) was vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered and carefully washed with methanol. The methanol extract was evaporated to give the title compound (0.66 g, 52%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 6.43 (1H, d, J=16.0 Hz); 7.18–7.96 (4H, m); 8.83 (1H, d, J=16.0 Hz). The precipitate was filtered carefully washed with methanol The methanol extract was evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By the procedure of Example 6, 26.43 g. (0.10 mol.) of (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman was reacted with trimethyl phosphonoacetate and then with 80 ml. of pyridine and 120 ml. of acetic anhydride by stirring under N 2 overnight. The solution was poured into ice-H 2 O and worked up and dried in the manner of Example 2. The crude product was filtered throgh 750 g. of 0.05-0.2 mm silica gel with 95:5 parts by volume benzene ether and then distilled to give (±)-methyl-(6-acetoxy-2, 5,7,8-tetramethylchroman-2-yl) acetate as a colorless resin: b.p. 147°-149°C./10 mmHg. dried in the manner of Example 2 The crude product was filtered throgh 750 g of 0.05-0.2 mm silica gel with 95:5 parts by volume benzene ether and then distilled