ethyl 2-cyano-3-methylbutanoate

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

Procedure: A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 20.72 g, 133.5 mmol), ethyl urea (3a, 12.35 g, 140.2 mmol) and MeOH (97.2 mL). To the slurry at room temperature was added sodium methoxide in methanol (25% w/w soln, 36.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4-12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×50 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10, white to off-with solids began forming and, as the pH was further reduced to 3 to 4, (by pH paper) white slurry resulted. This slurry was aged for 0.5 to 24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40 to 50° C. giving 18.63 g (60%) of 1-ethyl-5-isopropyl-6-amino uracil 2 (HCl salt). The heterogeneous reaction mixture was then heated to reflux The reaction was refluxed for 4-12 h Upon reaction completion the reaction mixture was concentrated leaving a basic 1-2 vol. solution in ACN white to off-with solids began forming and, as the pH resulted filtered The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE The white to off-white solids were then dried in a vacuum oven at 40 to 50° C.

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

Procedure: A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 10.0 g, 64.4 mmol), ethyl urea (3a, 5.96 g, 67.6 mmol) and EtOH (129 mL). To the slurry at room temperature was added sodium ethoxide in ethanol (21% w/w soln, 28.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4 to 12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×20 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10 white to off-with solids began forming and as the pH was further reduced to 9 (by pH paper) white slurry resulted. This slurry was aged for 0.5-24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40-50° C. giving 4.99 g (39%) of 1-ethyl-5-isopropyl-6-amino uracil 2: The heterogeneous reaction mixture was then heated to reflux The reaction was refluxed for 4 to 12 h Upon reaction completion the reaction mixture was concentrated leaving a basic 1-2 vol. solution in ACN began forming and as the pH resulted filtered The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE The white to off-white solids were then dried in a vacuum oven at 40-50° C.

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

Procedure: Under nitrogen atmosphere, 0.37 g of metallic potassium was added into 40 ml of absolute ethanol, to prepare potassium ethoxide. The prepared potassium ethoxide was added dropwise into a 100 ml flask containing 1.48 g of ethyl 3-methyl-2-cyanobutyrate. The reaction mixture was stirred at room temperature for 1 h, and then evaporated off the solvent to afford white solids. The white solids were dissolved in 25 ml of tetrahydrofuran, and then the resultant solution was slowly added dropwise into a solution of 2.2 g of ethyl 2-bromoisopentanoate in 30 ml of tetrahydrofuran, and the reaction mixture was heated to reflux for 9 h. Then the solvent was evaporated, to afford a mixture of yellow sticky liquid and pale yellow solids. To this mixture were added with 75 ml of diethyl ether and 20 ml of water, and an organic phase was separated. The organic phase was washed with 20 ml of 10% aqueous NaHCO3 solution twice, and then with water until the organic phase was neutral. The organic phase was dried over anhydrous magnesium sulfate over night, filtered, and evaporated off the solvent, to afford a yellow clear liquid. The yellow clear liquid was separated on a silica chromatographic column (eluent: petroleum ether and chloroform), to afford a pale yellow clear liquid. evaporated off the solvent to afford white solids the reaction mixture was heated to reflux for 9 h Then the solvent was evaporated to afford a mixture of yellow sticky liquid and pale yellow solids an organic phase was separated The organic phase was washed with 20 ml of 10% aqueous NaHCO3 solution twice The organic phase was dried over anhydrous magnesium sulfate over night filtered evaporated off the solvent to afford a yellow clear liquid The yellow clear liquid was separated on a silica chromatographic column (eluent: petroleum ether and chloroform) to afford a pale yellow clear liquid

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

Procedure: With reference to FIG. 3, a preferred embodiment of the invention will be described below, wherein diethyl 2,3-diisopropylsuccinate is obtained. Absolute ethanol and metallic potassium are charged into a reactor R101, or potassium ethoxide and absolute ethanol are charged into the reactor R101, to prepare a solution of potassium ethoxide; ethyl 3-methyl-2-cyanobutyrate is charged into a reactor R102, and then the prepared solution of potassium ethoxide is added thereto at a temperature ranging from −10° C. to 45° C.; upon the completion of the reaction, the reaction mixture is transferred to a reactor R103 and the solvent is removed, then tetrahydrofuran or acetonitirle is added thereto, followed by the addition of ethyl 2-bromoisopentanoate, and then the reaction mixture is heated to reflux; upon the completion of the reaction, the solvent is removed again, the resultant mixture is transferred to a separator R104, water is added thereto to dissolve solids, and the mixture is extracted with diethyl ether or methyl tert-butyl ether; the extract liquor is passed through a drying column T101 so as to be dried, and then is fed to a separating column T102, where diethyl 2,3-diisopropyl-2-cyanosuccinate is separated; the diethyl 2,3-diisopropyl-2-cyanosuccinate is added into a reactor R201, and a 60-90% aqueous solution of sulfuric acid is added dropwish thereto to conduct hydrolysis and decarboxylation reaction; upon the completion of the reaction, the reaction mixture is diluted with water and transferred to a separator R202 to be extracted with methyl tert-butyl ether; the obtained methyl tert-butyl ether extract liquor is charged into a reactor R203, and an aqueous solution of potassium hydroxide is added thereto; then the reaction mixture is transferred to a separator R204 to be separated; an aqueous layer separated is acidized with hydrochloric acid in a reactor R205 to obtain precipitates; the precipitates are centrifugally dried in a centrifuge C201, and then dried to afford 2,3-diisopropylsuccinic acid; the 2,3-diisopropylsuccinic acid and absolute ethanol are charged into a reactor R301, and a catalytic amount of sulfuric acid is added thereto, to conduct esterification reaction; upon the completion of the reaction, the ethanol is removed, and methyl tert-butyl ether is added into the reaction mixture; the resultant mixture is transferred to a separator R302 and wished with an aqueous solution of sodium bicarbonate; the organic layer is passed through a drying column T301 so as to be dried, and then is fed to a reactor R303, where the solvent is removed to obtain a crude product; the obtained crude product is fed to a separator R304, wished there with an aqueous solution of potassium hydroxide, and extracted with methyl tert-butyl ether; the extract liquor is dried in a drying column T302, and then fed to a reactor R305, where the solvent is removed to obtain diethyl 2,3-diisopropylsuccinate. is obtained are charged into the reactor R101 ranging from −10° C. to 45° C. upon the completion of the reaction the reaction mixture is transferred to a reactor R103 and the solvent is removed tetrahydrofuran or acetonitirle is added followed by the addition of ethyl 2-bromoisopentanoate the reaction mixture is heated to reflux upon the completion of the reaction the solvent is removed again is added to dissolve solids the mixture is extracted with diethyl ether or methyl tert-butyl ether so as to be dried is separated the diethyl 2,3-diisopropyl-2-cyanosuccinate is added into a reactor R201 a 60-90% aqueous solution of sulfuric acid is added dropwish hydrolysis and decarboxylation reaction upon the completion of the reaction to be extracted with methyl tert-butyl ether the obtained methyl tert-butyl ether extract liquor is charged into a reactor R203 an aqueous solution of potassium hydroxide is added to be separated an aqueous layer separated is acidized with hydrochloric acid in a reactor R205 to obtain precipitates the precipitates are centrifugally dried in a centrifuge C201 dried