3-ethoxy-2,2-dimethyl-3-oxopropanoic acid

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

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

Procedure: To a solution of 3-ethoxy-2,2-dimethyl-3-oxopropionic acid (30.78 mmol) in anhydrous CH2Cl2 (20 mL) was added portionwise CDI (40.02 mmol). The reaction mixture was stirred at room temperature during 30 minutes. This solution was added dropwise at −40° C.<T<−30° C. to a solution of 2-mercaptoethanol (41.21 mmol) in anhydrous CH2Cl2 (60 mL). The mixture was stirred at −40° C.<T<−30° C. during 2 hours. The reaction mixture was washed with ice-cold water (×3), dried through a phase separator and evaporated in vacuo while keeping the crude mixture below 25° C. The crude was purified by chromatography on a silica gel column (eluent: petroleum ether/EtOAc 95/5 to 50/50) to give the expected compound as a colorless oil in 30% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.15 (t, J=7.05 Hz, 3H), 1.38 (s, 6H), 2.94 (t, J=6.59 Hz, 2H), 3.43-3.48 (m, 2H), 4.10 (q, J=7.04 Hz, 2H), 4.96 (t, J=5.44 Hz, 1H); MS (ESI) m/z=243 (MNa+). The mixture was stirred at −40° C.<T<−30° C. during 2 hours The reaction mixture was washed with ice-cold water (×3) dried through a phase separator evaporated in vacuo the crude mixture below 25° C The crude was purified by chromatography on a silica gel column (eluent: petroleum ether/EtOAc 95/5 to 50/50)

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

Procedure: 19 g 2,2-Dimethyl-malonic acid monoethyl ester were weighed into a round-bottomed flask and under N2 atmosphere and room temperature, 200 ml tetrahydrofurane, 15.6 ml 4-(2-Aminoethyl)-morpholine and 32.6 ml N-Methylmorpholine were added. The reaction was stirred and cooled down to 5° C. Then, 43.8 g TBTU were added and the mixture was allowed to stir for another 1.5 hours. Finally the solvent was removed and the residue dissolved in 400 ml dichloromethane. This organic phase was washed two times with 500 ml NaHCO3 solution. The dichloromethane phase was dried then the solvent was evaporated. Purity of the product was judged by gas chromatography. to stir for another 1.5 hours Finally the solvent was removed the residue dissolved in 400 ml dichloromethane This organic phase was washed two times with 500 ml NaHCO3 solution The dichloromethane phase was dried the solvent was evaporated

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

Procedure: 25 g 2,2-Dimethyl-malonic acid diethyl ester, 7.8 g potassium hydroxide and 500 ml ethanol were mixed in a round-bottomed flask and refluxed for 3 hours. Then again 2.2 g potassium hydroxide were added and the mixture was refluxed overnight. The solvent was removed on a rotovap, 250 ml H2O were added and the mixture was washed with ether. The aqueous phase was acidified with HCl to pH 3-4 followed by two extractions with dichloromethane. The organic solvent was dried and evaporated and the resulting product was characterized by 1H-NMR. refluxed for 3 hours the mixture was refluxed overnight The solvent was removed on a rotovap, 250 ml H2O were added the mixture was washed with ether followed by two extractions with dichloromethane The organic solvent was dried evaporated

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (543 mg, 3.39 mmol) in toluene (25 mL) at RT under nitrogen was added TEA (1.182 mL, 8.48 mmol), DPPA (0.731 mL, 3.39 mmol) and the reaction mixture was heated to 85° C. and stirred for 1 h. The reaction mass was cooled to RT and in to it was added a solution of Intermediate 185B (500 mg, 1.697 mmol) in THF (4 mL) and stirred at RT for 12 h. The reaction mass was concentrated and the residue was extracted with ethyl acetate (3×10 mL) The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was triturated with diethyl ether to afford Intermediate 213A as an off-white solid (550 mg, 70% yield). MS(ES): m/z=452 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.2, 2.3 Hz, 1H), 7.68 (s, 1H), 7.51-7.42 (m, 1H), 7.40-7.32 (m, 1H), 7.25-7.14 (m, 1H), 7.06 (s, 1H), 4.73 (s, 2H), 4.17-4.09 (m, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.89-3.79 (m, 2H), 1.37 (s, 6H), 1.09 (t, J=7.0 Hz, 3H). The reaction mass was cooled to RT and in to it stirred at RT for 12 h The reaction mass was concentrated the residue was extracted with ethyl acetate (3×10 mL) The combined organic layer was washed with water, brine dried over Na2SO4 filtered the filtrate concentrated The crude product was triturated with diethyl ether

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (543 mg, 3.39 mmol) in toluene (25 mL) at RT under nitrogen was added TEA (1.182 mL, 8.48 mmol), DPPA (0.731 mL, 3.39 mmol) and the reaction mixture was heated to 85° C. and stirred for 1 h. The reaction mass was cooled to RT and in to it was added a solution of Intermediate 185B (500 mg, 1.697 mmol) in THF (4 mL) and stirred at RT for 12 h. The reaction mass was concentrated and the residue was extracted with ethyl acetate (3×10 mL) The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was triturated with diethyl ether to afford Intermediate 213A as an off-white solid (550 mg, 70% yield). MS(ES): m/z=452 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.2, 2.3 Hz, 1H), 7.68 (s, 1H), 7.51-7.42 (m, 1H), 7.40-7.32 (m, 1H), 7.25-7.14 (m, 1H), 7.06 (s, 1H), 4.73 (s, 2H), 4.17-4.09 (m, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.89-3.79 (m, 2H), 1.37 (s, 6H), 1.09 (t, J=7.0 Hz, 3H). The reaction mass was cooled to RT and in to it stirred at RT for 12 h The reaction mass was concentrated the residue was extracted with ethyl acetate (3×10 mL) The combined organic layer was washed with water, brine dried over Na2SO4 filtered the filtrate concentrated The crude product was triturated with diethyl ether

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

Procedure: Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=501(M+H+).

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

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

Procedure: Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=501(M+H+).

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (Example 2b, 100 mg), potassium hydrogen carbonate (107 mg), and DMF (8 mL), sodium iodide (113 mg) and 2,2-dimethylmalonic acid monoethyl ester [CAS No. 5471-77-2] (121 mg) were added, and the resulting mixture was stirred at 45° C. overnight. The reaction mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a racemate of the captioned compound. 5471-77-2] (121 mg) were added The reaction mixture was filtered the filtrate obtained was concentrated under reduced pressure The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a racemate of the captioned compound

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

Procedure: Diethyl dimethylpropanedioate (10 g, 53 mmol) in 170 mL EtOH was treated with 3.00 g (53 mmol) KOH at ambient temperature for 4 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The aqueous phase was isolated, combined with fresh EtOAc and the pH adj to 2 with 6N HCl. The organic phase was isolated and the aqueous portion extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to give 6.56 g (41 mmol) 3-(ethyloxy)-2,2-dimethyl-3-oxopropanoic acid as a clear oil. 1H NMR (300 MHz, CDCl3) d 4.20 (q, J=7.1 Hz, 2H), 1.46 (s, 6H), 1.26 (t, J=7.1 Hz, 3H). The reaction mixture was concentrated to dryness partitioned between EtOAc and water The aqueous phase was isolated The organic phase was isolated the aqueous portion extracted twice with EtOAc dried over MgSO4 filtered concentrated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzenesulfonamide was made by adding benzenesulfonyl chloride to a solution of ammonia in tetrahydrofuran and evaporating to a solid. Benzenesulfonamide (87 mg, 0.50 mmole) was added to a shaken suspension of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (100 mg, 0.62 mmole) reactivated on PS-DCC resin (1.62 g, 1.25 mmole) and 1.50 mmole of N,N-dimethylpyridin-4-amine in DCE. When reaction is complete the resin is filtered off and the organic layer washed with 1N HCl dried and evaporated. The resulting residue was dissolved in 6 ml of ethanol and 6 ml of 1N LiOH was added and heated to 40° C. The reaction was neutralized with 1N HCl and evaporated to afford 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid as a crude product which was used with no further purification. evaporating to a solid When reaction is filtered off the organic layer washed with 1N HCl dried evaporated The resulting residue was dissolved in 6 ml of ethanol 6 ml of 1N LiOH was added evaporated