2-ethylpropanedioyl dichloride

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

Procedure: To a stirred solution of 3-trifluoromethylaniline (1.90 g, 11.8 mmol), triethylamine (1.43 g, 14.5 mmol) and 4-N,N-dimethylaminopyridine (1 mg) in dichloromethane (20 ml) is added at 0° C. ethyl malonyl chloride (1.78 g, 11.8 mmol). The reaction mixture is warmed to room temperature overnight, then allowed to stand for two days. Water (20 ml) is added and the product is extracted with dichloromethane (1 l). The organic phase is washed with saturated ammonium chloride solution (500 ml) and saturated sodium chloride solution (200 ml), dried over magnesium sulphate monohydrate, filtered and concentrated. The crude product is chromatographed over silica gel with cyclohexane/ethyl acetate mixtures as eluent. the product is extracted with dichloromethane (1 l) The organic phase is washed with saturated ammonium chloride solution (500 ml) and saturated sodium chloride solution (200 ml) dried over magnesium sulphate monohydrate filtered concentrated The crude product is chromatographed over silica gel with cyclohexane/ethyl acetate

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

Procedure: To a mixture of 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (230 g. 1.01 mol) prepared as described in Intermediate 12, in acetonitrile (1.5 L) and triethylamine (197 mL, 1.41 mol, 1.4 eq) is added ethyl malonyl chloride (180 mL, 1.41 mol, 1.4 eq) over 0.5 h while keeping the reaction temperature less than 30° C. with an ice bath. After the addition is complete the reaction is stirred 1.5 h at room temperature. A second charge of Triethylamine (140 mL, 1.01 mol, 1.0 eq) is added and the reaction is stirred for 4.5 hours. Water (2.1 L) is added slowly followed by conc. HCl (115 mL). The slurry is stirred overnight at rt, filtered, and the solid washed with water (460 mL). The solid is then dried under high vacuum (about 1 mm Hg) at 40° C. to give 270 g (83%) 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid ethyl ester as a yellow solid. HRMS (EI+): calc for C15H14NO5Cl: 323.0561, Found: 323.0556. prepared the reaction temperature less than 30° C. After the addition is added the reaction is stirred for 4.5 hours The slurry is stirred overnight at rt filtered the solid washed with water (460 mL) The solid is then dried under high vacuum (about 1 mm Hg) at 40° C.

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

Procedure: To a solution of 1-benzyl-4-[(3-fluorophenyl)amino]piperidine-4-carbonitrile (Intermediate 1A.1-1, 9.0 g, 29.1 mmol) in dichloromethane (150 ml) were added ethyl malonyl chloride (4.9 ml, 37.8 mmol) and 2,6-lutidine (5.1 ml, 43.6 mmol). The reaction was allowed to stir at rt for 2.5 h. Additional ethyl malonyl chloride (1.1 ml, 8.7 mmol) was added, and the reaction was allowed to stir for 30 min. The reaction was diluted with dichloromethane and washed with water and brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to yield a 1:1 mixture of desired ester ethyl 3-[(1-benzyl-4-cyanopiperidin-4-yl)(3-fluorophenyl)amino]-3-oxopropanoate and its acid 3-[(1-benzyl-4-cyanopiperidin-4-yl)(3-fluorophenyl)amino]-3-oxopropanoic acid (quant). to stir for 30 min washed with water and brine The organic portion was dried over sodium sulfate filtered concentrated in vacuo to yield

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To dissolve 3-Amino-4,4,4-trifluorocrotonic acid ethyl ester (100 g/546 mmol) in dichloromethane (600 mL) was added pyridine (53 mL/660 mmol). Placed under nitrogen and cooled to 5° C. by suspending in an ice-bath. Ethyl malonyl chloride was added dropwise over approx 1 hr such that temperature did not exceed 20° C. Resulting pale brown solution was stirred at 5° C. for 3 hrs then allowed to warm to room temperature overnight to give a dark green solution. Washed with 1M HCl(aq) (200 mL) then saturated NaHCO3(aq) (250 mL). Aqueous washings sequentially re-extracted with further dichloromethane (2×250 mL). Organics combined, dried over Na2SO4, filtered and concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g). A portion of the crude (120 g) was dissolved in ethanol (300 mL) and placed under nitrogen. Potassium tert-butoxide (54 g/480 mmol) was added in several portions such that temperature did not exceed 60° C. resulting in a purple solution. Heated at 70° C. for 3 hrs. Added ethanol (100 mL) to reduce viscosity and heated at 80° C. for a further hour. Allowed to cool and concentrated in vacuo to a red solid. Dissolved in water (500 mL) and added citric acid (180 g) causing precipitation. Added ethyl acetate (600 mL). Poured into separating funnel and ran off aqueous. The organic layer containing much undissolved solid was filtered to give the title compound (46.5 g) as a white solid. Concentration of the organic filtrate and trituration with methanol afforded 2,4-dihydroxy-6-trifluoromethyl-nicotinic acid ethyl ester (15.3 g) as a white solid. by suspending in an ice-bath did not exceed 20° C Resulting pale brown solution to warm to room temperature overnight to give a dark green solution Washed with 1M HCl(aq) (200 mL) Aqueous washings sequentially re-extracted with further dichloromethane (2×250 mL) dried over Na2SO4 filtered concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g) A portion of the crude (120 g) was dissolved in ethanol (300 mL) did not exceed 60° C. resulting in a purple solution Heated at 70° C. for 3 hrs heated at 80° C. for a further hour Allowed to cool concentrated in vacuo to a red solid Dissolved in water (500 mL) added citric acid (180 g) precipitation Poured into separating funnel The organic layer containing much undissolved solid was filtered

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

Procedure: To a mixture of 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (230 g. 1.01 mol) prepared as in example 15, in acetonitrile (1.5 L) and triethylamine (197 mL, 1.41 mol, 1.4 eq) is added ethyl malonyl chloride (180 mL, 1.41 mol, 1.4 eq) over 0.5 h while keeping the reaction temperature less than 30° C. with an ice bath. After the addition is complete the reaction is stirred 1.5 h at room temperature. A second charge of triethylamine (140 mL, 1.01 mol, 1.0 eq) is added and the reaction is stirred for 4.5 hours. Water (2.1 L) is added slowly followed by conc. HCl (115 mL). The slurry is stirred overnight at rt, filtered, and the solid washed with water (460 mL). The solid is then dried under high vacuum (about 1 mm Hg) at 40° C. to yield 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid ethyl ester as a yellow solid. HRMS (EI+): calc for C15H14NO5Cl: 323.0561, Found: 323.0556. the reaction temperature less than 30° C. After the addition is added the reaction is stirred for 4.5 hours The slurry is stirred overnight at rt filtered the solid washed with water (460 mL) The solid is then dried under high vacuum (about 1 mm Hg) at 40° C.

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

Procedure: A mixture of ethyl malonyl chloride (6.4 ml) in DCM (50 ml) was added dropwise at room temperature to a solution of intermediate (6-d) (15 g) and pyridine (10.7 ml) in DCM (150 ml). The mixture was stirred at room temperature overnight. Water was added and the mixture was decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (21 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/2-propanol/NH4OH 921810.4). The desired fractions were collected and the solvent was evaporated, yielding 10.9 g (60%) of (±)-ethyl 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylate (comp. 144). the mixture was decanted The organic layer was dried filtered the solvent was evaporated The residue (21 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/2-propanol/NH4OH 921810.4) The desired fractions were collected the solvent was evaporated

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

Procedure: 3-[7-(3-Fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-3-oxo-propionic acid ethyl ester: The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and ethyl malonic acid chloride with triethylamine as the base. Yield: 70% of theory as a colourless oil; MS: m/e=386 (M+H)+.

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

Procedure: A solution of 60 g (0.4 mol) of ethyl malonyl chloride in 150 ml of dichloromethane is added over 0.5 hours to a cold (10° C.) solution of 72.76 g (0.4 mol) of L-leucine methyl ester hydrochloride and 86.02 g (0.85 mol) of triethylamine in 1.5 L of dichloromethane with stirring and keeping the temperature at 10° C. during the addition. The solution is allowed to warm to room temperature, stirred another 0.5 hours and poured into 500 ml of water plus ice chips and 80 ml of 1N hydrochloric acid solution. The organic layer is separated and washed successively with 500 ml of cold water, 500 ml of a 2% aqueous solution of sodium bicarbonate and 500 ml of water. The organic layer is separated, dried over magnesium sulfate, charcoaled and filtered. The filtrate is concentrated to afford 101.8 g of (S)-2-[(3-ethoxy-1,3-dioxopropyl)amino]-4-methylpentanoic acid, methyl ester as a viscous oil. Thin layer chromatography (TLC) (ethyl acetate, silica gel, iodine) Rf =0.75. This material is used directly in the next ring closure step. at 10° C. during the addition stirred another 0.5 hours The organic layer is separated washed successively with 500 ml of cold water, 500 ml of a 2% aqueous solution of sodium bicarbonate and 500 ml of water The organic layer is separated dried over magnesium sulfate filtered The filtrate is concentrated

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

Procedure: Ethyl malonyl chloride (3.8 ml, 29.89 mmol) was added dropwise to a solution of 2-amino-4-phenyl-3-furonitrile (5 g, 27.17 mmol) and triethylamine (4.2 ml, 29.89 mmol) in THF (30 ml) maintaining temperature below 5° C. under nitrogen. This was allowed to warm up to room temperature and stirred for 2 hr. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined and washed with brine and dried over MgSO4. The solution was filtered and solvent removed under reduced pressure. The residue was purified by column chromatography using DCM isolating an orange oil (3.7 g, 46%). maintaining temperature below 5° C. under nitrogen extracted with DCM washed with brine dried over MgSO4 The solution was filtered solvent removed under reduced pressure The residue was purified by column chromatography

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

Procedure: Ethyl malonyl chloride (3.8 ml, 29.89 mmol) was added dropwise to a solution of 2-amino-4-phenyl-3-furonitrile (5 g, 27.17 mmol) and triethylamine (4.2 ml, 29.89 mmol) in THF (30 ml) maintaining temperature below 5° C. under nitrogen. This was allowed to warm up to room temperature and stirred for 2 hr. The reaction mixture was diluted with water and extracted with DCM. The organic layers were combined and washed with brine and dried over MgSO4. The solution was filtered and solvent removed under reduced pressure. The residue was purified by column chromatography using DCM isolating an orange oil (3.7 g, 46%). maintaining temperature below 5° C. under nitrogen extracted with DCM washed with brine dried over MgSO4 The solution was filtered solvent removed under reduced pressure The residue was purified by column chromatography

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

Procedure: A solution of 44.4 g (0.296 mol) of ethyl malonyl chloride in 80 ml of tetrahydrofuran and a solution of 29.6 g (0.296 mol) of potassium bicarbonate in 100 ml of water were added simultaneously over a 45 minute interval to a solution of 43.2 g (0.296 mol) of dithiocarbazic acid potassium salt in 200 ml of tetrahydrofuran and 200 ml of water at 5°. The reaction mixture was stirred at 5° for 1 hour then at ambient temperature for 12 hours. The solvents were evaporated and the residue was taken up into 350 ml of ethanol and refluxed on a steam bath for 1.5 hours. The mixture was evaporated to dryness, 300 ml of ethyl acetate and 175 ml of water were added to the residue and it was acidified to pH 2.3 by addition of 3N hydrochloric acid. The layers were separated and the aqueous phase was extracted twice more with 250 ml portions of ethyl acetate. The combined organic extracts were dried (MgSO4), then the solvent was evaporated to give a residue which was dissolved in methylene chloride. The methylene chloride solution was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel with 98:2:3 chloroform-ethanol-formic acid as eluant to give 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol as a viscous oil. at ambient temperature for 12 hours The solvents were evaporated refluxed on a steam bath for 1.5 hours The mixture was evaporated to dryness, 300 ml of ethyl acetate and 175 ml of water were added to the residue and it was acidified to pH 2.3 by addition of 3N hydrochloric acid The layers were separated the aqueous phase was extracted twice more with 250 ml portions of ethyl acetate The combined organic extracts were dried (MgSO4) the solvent was evaporated to give a residue which The methylene chloride solution was filtered the filtrate was evaporated to dryness The residue was chromatographed on silica gel with 98:2:3 chloroform-ethanol-formic acid as eluant

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

Procedure: A solution of 44.4 g (0.296 mol) of ethyl malonyl chloride in 80 ml of tetrahydrofuran and a solution of 29.6 g (0.296 mol) of potassium bicarbonate in 100 ml of water were added simultaneously over a 45 minute interval to a solution of 43.2 g (0.296 mol) of dithiocarbazic acid potassium salt in 200 ml of tetrahydrofuran and 200 ml of water at 5°. The reaction mixture was stirred at 5° for 1 hour then at ambient temperature for 12 hours. The solvents were evaporated and the residue was taken up into 350 ml of ethanol and refluxed on a steam bath for 1.5 hours. The mixture was evaporated to dryness, 300 ml of ethyl acetate and 175 ml of water were added to the residue and it was acidified to pH 2.3 by addition of 3N hydrochloric acid. The layers were separated and the aqueous phase was extracted twice more with 250 ml portions of ethyl acetate. The combined organic extracts were dried (MgSO4), then the solvent was evaporated to give a residue which was dissolved in methylene chloride. The methylene chloride solution was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel with 98:2:3 chloroform-ethanol-formic acid as eluant to give 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol as a viscous oil. at ambient temperature for 12 hours The solvents were evaporated refluxed on a steam bath for 1.5 hours The mixture was evaporated to dryness, 300 ml of ethyl acetate and 175 ml of water were added to the residue and it was acidified to pH 2.3 by addition of 3N hydrochloric acid The layers were separated the aqueous phase was extracted twice more with 250 ml portions of ethyl acetate The combined organic extracts were dried (MgSO4) the solvent was evaporated to give a residue which The methylene chloride solution was filtered the filtrate was evaporated to dryness The residue was chromatographed on silica gel with 98:2:3 chloroform-ethanol-formic acid as eluant