3,3-dimethyl-2-oxobutanoic acid

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

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

Procedure: Trimethylpyruvic acid of formula (VI) can be subjected to a condensation reaction with 1 to 1.5 moles of thiocarbohydrazide (NH2 --NH--CS--NH--NH2) in aqueous solution containing a hydrogen halide acid, at a temperature between 20° and 100° C., to give 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one of formula (VII).

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

Procedure: which is formed in step (1) and which was hitherto unknown, is reacted, in a second stage, either directly in the solution obtained or after intermediate isolation and if appropriate after prior saponification to give free trimethylpyruvic acid (VI), with thiocarbohydrazide (H2N--NH--CS--NH--NH2) in an aqueous solution containing a hydrogen halide acid, at a temperature from about 20° to 100° C. in a manner which is in itself known to give 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (VII), and this compound is alkylated in alkaline solution, in a third stage, by means of methyl iodide or methyl bromide or other alkylating agents (especially ethyl iodide or ethyl bromide) in a known manner. which is formed in step (1) and which is reacted, in a second stage directly in the solution obtained from about 20° to 100° C.

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

Procedure: A 83 ml portion of ethanol was added to a mixture of 4.14 g of trimethylpyruvic acid synthesized in accordance with the method of Jaeger et al. (J. Am. Chem. Soc., pp.717-732, 1979) and 3.02 g of o-phenylenediamine. The thus prepared mixture was refluxed for 3 hours in an atmosphere of nitrogen. By concentrating the resulting reaction solution, 3.15 g of 2-t-butyl-3, 4-dihydro-3-oxoquinoxaline was obtained. The thus prepared mixture was refluxed for 3 hours in an atmosphere of nitrogen By concentrating the resulting reaction solution

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8.9 g (47 mmol) of (S)-(2,2-dimethylpropylidene)-(1-phenylethyl)-amine (J. L. Fauchure, C. Petermann, Helv. Chim. Acta 1980, 63, 824) were dissolved in 10 ml of diethyl ether with the exclusion of moisture. 8.1 g (50 mmol) of trimethylpyruvic acid in 10 ml of diethyl ether were added dropwise to this solution while cooling with ice. Subsequently, the mixture was stirred at 0° C. for a further 2 hours and at room temperature for 6 hours. Colorless crystals form over 2 days and these were suspended in 50 ml of diethyl ether, filtered off and washed twice with 5 ml of diethyl ether each time. After drying in a vacuum there were obtained 8.9 g (81%) of (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyric acid (internal salt) of melting point 135°-136° C. [α]=-14.4 (c=0.16, CH2Cl2). while cooling with ice Colorless crystals form over 2 days filtered off washed twice with 5 ml of diethyl ether each time After drying in a vacuum there

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8.9 g (47 mmol) of (S)-(2,2-dimethylpropylidene)-(1-phenylethyl)-amine (J. L. Fauchure, C. Petermann, Helv. Chim. Acta 1980, 63, 824) were dissolved in 10 ml of diethyl ether with the exclusion of moisture. 8.1 g (50 mmol) of trimethylpyruvic acid in 10 ml of diethyl ether were added dropwise to this solution while cooling with ice. Subsequently, the mixture was stirred at 0° C. for a further 2 hours and at room temperature for 6 hours. Colorless crystals form over 2 days and these were suspended in 50 ml of diethyl ether, filtered off and washed twice with 5 ml of diethyl ether each time. After drying in a vacuum there were obtained 8.9 g (81%) of (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyric acid (internal salt) of melting point 135°-136° C. [α]=-14.4 (c=0.16, CH2Cl2). while cooling with ice Colorless crystals form over 2 days filtered off washed twice with 5 ml of diethyl ether each time After drying in a vacuum there

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl-2-(cyclohexylhydrazono)-3,3-dimethylbutanoate. To a solution of trimethylpyruvic acid (0.6 g, 2.77 mmol) in MTBE (4.0 ml) was added DBU (0.58 ml, 3.85 mmol) followed by bromoethane (0.5 ml, 6.70 mmol) at room temperature. The reaction was heated in the microwave at 120° C. for 20 minutes. The reaction was cooled and 10% NaHCO3 (aq) added. The layers were separated and the organic layer was washed again with 10% NaHCO3 (aq). The aqueous layer backextracted with Et2O several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The resulting oil was redissolved in Ethanol (5.0 mL) and cyclohexylhydrazine hydrochloride (0.500 g, 3.32 mmol) and DBU (0.500 ml, 3.32 mmol) were added. The reaction was heated in the microwave at 150° C. for 25 minutes. The reaction was cooled to room temperature and 1N HCl added. The solution was diluted with H2O and EtOAc and the layers separated. The aqueous layer was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 5-15% EtOAc/Hexanes) to give the title compound as a colorless oil (0.403 g, 57%). 1H NMR (400 MHz, DMSO-d6) d ppm 9.32 (d, J=4.80 Hz, 1H) 4.20 (q, J=7.07 Hz, 2H) 3.08-3.26 (m, 1H) 1.79-1.94 (m, 2H) 1.48-1.74 (m, 3H) 1.26 (t, J=7.07 Hz, 3H) 1.22-1.37 (m, 5H) 1.15 (s, 9H). The reaction was cooled The layers were separated the organic layer was washed again with 10% NaHCO3 (aq) The combined organic layers were washed with Brine dried (MgSO4) filtered concentrated The resulting oil was redissolved in Ethanol (5.0 mL) The reaction was heated in the microwave at 150° C. for 25 minutes The reaction was cooled to room temperature the layers separated The combined organic layers were washed with Brine dried (MgSO4) filtered concentrated The product was purified by column chromatography (SiO2, 5-15% EtOAc/Hexanes)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl-2-(cyclohexylhydrazono)-3,3-dimethylbutanoate. To a solution of trimethylpyruvic acid (0.6 g, 2.77 mmol) in MTBE (4.0 ml) was added DBU (0.58 ml, 3.85 mmol) followed by bromoethane (0.5 ml, 6.70 mmol) at room temperature. The reaction was heated in the microwave at 120° C. for 20 minutes. The reaction was cooled and 10% NaHCO3 (aq) added. The layers were separated and the organic layer was washed again with 10% NaHCO3 (aq). The aqueous layer backextracted with Et2O several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The resulting oil was redissolved in Ethanol (5.0 mL) and cyclohexylhydrazine hydrochloride (0.500 g, 3.32 mmol) and DBU (0.500 ml, 3.32 mmol) were added. The reaction was heated in the microwave at 150° C. for 25 minutes. The reaction was cooled to room temperature and 1N HCl added. The solution was diluted with H2O and EtOAc and the layers separated. The aqueous layer was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 5-15% EtOAc/Hexanes) to give the title compound as a colorless oil (0.403 g, 57%). 1H NMR (400 MHz, DMSO-d6) d ppm 9.32 (d, J=4.80 Hz, 1H) 4.20 (q, J=7.07 Hz, 2H) 3.08-3.26 (m, 1H) 1.79-1.94 (m, 2H) 1.48-1.74 (m, 3H) 1.26 (t, J=7.07 Hz, 3H) 1.22-1.37 (m, 5H) 1.15 (s, 9H). The reaction was cooled The layers were separated the organic layer was washed again with 10% NaHCO3 (aq) The combined organic layers were washed with Brine dried (MgSO4) filtered concentrated The resulting oil was redissolved in Ethanol (5.0 mL) The reaction was heated in the microwave at 150° C. for 25 minutes The reaction was cooled to room temperature the layers separated The combined organic layers were washed with Brine dried (MgSO4) filtered concentrated The product was purified by column chromatography (SiO2, 5-15% EtOAc/Hexanes)

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

Procedure: 4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 3,3-dimethyl-2-oxobutanoic acid [1.6 g (60%), 7.39 mmol], DIPEA (3 ml, 17.4 mmol), and HATU (1.5 g, 3.92 mmol) were mixed in DMF (50 ml). After the resulting reaction mixture was stirred at room temperature for 87 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by preparative TLC (EA:PE=1:1) to afford the desired product (30 mg, 9.1%) as an off white solid. After the resulting reaction mixture the reaction mixture was partition between DCM and water (100 ml each) The aqueous phase was extracted with DCM (100 ml) the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine dried over sodium sulphate filtered concentrated to yield the crude product Then the crude product was purified by preparative TLC (EA:PE=1:1)

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

Procedure: 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (310 mg, 0.65 mmol), 3,3-dimethyl-2-oxobutanoic acid [1.37 g (60%), 6.3 mmol], DIPEA (2 ml, 11.6 mmol), and HATU (1030 mg, 2.72 mmol) were mixed in DMF (50 ml), the resulting reaction mixture was stirred at room temperature for 44 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was firstly purified by column chromatography on silica gel (DCM:MeOH=100:1) and re-purified by preparative TLC (DCM:MeOH=40:1) to afford the desired product (150 mg, 46.9%) as a off white solid. the resulting reaction mixture The reaction mixture was then partitioned between DCM and water (100 ml each the water phase was extracted with DCM (100 ml) The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine dried over sodium sulphate filtered concentrated to yield the crude product Then the crude product was firstly purified by column chromatography on silica gel (DCM:MeOH=100:1) re-purified by preparative TLC (DCM:MeOH=40:1)

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

Procedure: Analogously to instructions given by A. Dornow and others (Chem. Berichte 97 (1964), page 2173-2178), 53 g (0.5 mole) of thiocarbohydrazide are dissolved in 500 ml of boiling water and 65 g (0.5 mole) of trimethylpyruvic acid are added slowly. A colorless precipitate is deposited, which is filtered off, washed with water and dried in vacuo at 50° C. 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5(4H)-one is obtained from this reaction in almost quantitative yield. which is filtered off washed with water dried in vacuo at 50° C