2-(2-methylpropyl)propanedioic acid

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

Procedure: A solution of 860 ml (3.74 mole) of 25% of NaOCH3 in CH3OH and an equal volume of CH3OH is warmed to near reflux. Dimethyl malonate (425 ml, 3.74 mole) is added, followed by 410 ml (3.74 mole) of 1-bromo-2-methyl propane. Heating back to reflux gives a clear yellow solution. Refluxing under N2 for 18 hours gives a slurry. While at reflux a total of 425 ml of 50% NaOH is added plus enough water to dissolve the precipitated salts, for a total reaction volume of 5 liters. The basic (pH=14) mixture is refluxed until little cloudiness is observed on dilution of a sample with water. Distillation until T≅90°, cooling in ice, acidification with 25% H2SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying and evaporation, a slurry. Benzene is added and the slurry evaporated to a solid. Trituration with hexane, filtering and drying in air gives 402 g, m.p. 101°-105° (67%). An additional 25 g, m.p. 92°-101°, were obtained on further extraction with ethyl acetate and rework of the mother liquors, for a total of 427 g (71%). A 410 g (2.56 mole) sample of isobutyl malonic acid is dissolved in 3.5 liters of water. This yellow solution is cooled in ice and treated with 288 g (2.56 mole) of 40% aqueous dimethylamine. Stirring with cooling is continued, and when the internal temperature equals 10° C., 210 g (2.56 mole) of 37% formalin is added. The resulting clear yellow solution is stored at 5° C. for 21/2 days, whereupon it is a solid mass of white solid. This mixture is carefully brought to near reflux (foaming) with stirring, and held there until the solution is clear and CO2 is no longer evolved to a significant extent (heated 2 hours after complete solution). The mixture is cooled in ice and acidified strongly with 350 ml of 7.2 M H2SO4 (pH=1). Extraction with 2 liters of hexane and drying (Na2SO4) gives 206 g of isobutyl acrylic acid. Extraction with another 2 liters of hexane gives 6 g, for a total of 212 g (65%) of the unsaturated acid. to near reflux Heating back to reflux gives a clear yellow solution Refluxing under N2 for 18 hours gives a slurry to dissolve the precipitated salts Distillation until T≅90° cooling in ice acidification with 25% H2SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying evaporation Benzene is added the slurry evaporated to a solid Trituration with hexane, filtering drying in air gives 402 g, m.p. 101°-105° (67%) This yellow solution is cooled in ice with cooling is stored at 5° C. for 21 2 days to near reflux (foaming) with stirring The mixture is cooled in ice Extraction with 2 liters of hexane drying (Na2SO4)

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

Procedure: 2-Carboxy-4-methylpentanoic acid (67 g) is suspended in 400 ml of water and cooled to 5° C. Aqueous 40% dimethylamine (50 g) is added to the suspension followed by aqueous 37% formaldehyde (35.7 g). The resulting solution is stirred for about 16 hours and solid product is filtered and dried in vacuo to yield 57.3 g of the title compound, melting point 134°-137° C. with carbon dioxide and dimethylamine given off. solid product is filtered dried in vacuo

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

Procedure: A solution of 91.1 g of 2-(ethyloxycarbonyl)-4-methylpentanoic acid, ethyl ester in 300 ml of methanol is treated for 6 hours at 80° C. with 400 ml of 10% sodium hydroxide. The solution is concentrated in vacuo to 400 ml and acidified with 10% hydrochloric acid. The product is extracted with ethyl acetate to yield 67.6 g of the title compound, which crystallizes on standing. Recrystallization from ethyl acetate-hexane yields the title compound, melting point 102°-105° C. The solution is concentrated in vacuo to 400 ml The product is extracted with ethyl acetate

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

Procedure: A solution of 91.1 g of 2-(ethyloxycarbonyl)-4-methylpentanoic acid, ethyl ester in 300 ml of methanol is treated for 6 hours at 80° C. with 400 ml of 10% sodium hydroxide. The solution is concentrated in vacuo to 400 ml and acidified with 10% hydrochloric acid. The product is extracted with ethyl acetate to yield 67.6 g of the title compound, which crystallizes on standing. Recrystallization from ethyl acetate-hexane yields the title compound, melting point 102°-105° C. The solution is concentrated in vacuo to 400 ml The product is extracted with ethyl acetate

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

Procedure: To a stirred mixture of 14.0 g of isobutylmalonic acid and 37 mL of 37% formalin was added 9.05 mL of diethylamine at room temperature. The mixture was stirred at room temperature for 3 h and refluxed for an additional 2 h. The reaction mixture was cooled to room temperature and diluted with CHCl3, and extracted with saturated aqueous NaHCO3. The aqueous layer was acidified with 1M HCl and extracted with CHCl3. The organic extract was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 11.0 g at 98% yield of 4-methyl-2-methylenepentanoic acid as a clear liquid which was used without further purification. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ6.32 (d, J=2 Hz, 1H), 5.62 (d, J=2 Hz, 1H), 2.17 (dd, J=1, 7 Hz, 2H), 1.82 (m, 1H), 0.90 (d, J=7 Hz, 6H); 13C NMR (300 MHz) δ173.6, 139.4, 128.4, 40.7, 26.9, 22.0. refluxed for an additional 2 h The reaction mixture was cooled to room temperature extracted with saturated aqueous NaHCO3 extracted with CHCl3 The organic extract was dried over anhydrous Na2SO4 evaporated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8.34 g (38.6 mmol) of diethyl isobutylmalonate in 35 mL of 95% EtOH was added a solution of 9.0 g (161 mmol) of KOH in 110 mL of 95% EtOH. The mixture was stirred at 25° C. for 16 hours and then at reflux for 1 hour. The mixture was cooled, diluted with water and extracted with CH3Cl. The aqueous layer was cooled to 0° C. and acidified to pH<1 with 30 mL of concentrated HCl, then it was extracted with CHCl3. The aqueous layer was further continuously extracted with CHCl3 overnight. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to afford 5.44 g (33.9 mmol, 88%) of isobutylmalonic acid as a solid which was essentially pure according to 1H NMR and which was used without further purification. Characteristic analytical data are as follows: mp 108°-110° C.; 1H NMR (300 MHz, CDCl3) δ3.52 (t, J=8 Hz, 1H), 1.84 (t, J=8 Hz, 2H), 1.66 (m, 1H), 0.94 (d, J-7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ175.6 (C=O), 49.7 (CH), 37.1 (CH2), 25.7 (CH), 21.7 (CH3). at reflux for 1 hour The mixture was cooled extracted with CH3Cl The aqueous layer was cooled to 0° C. it was extracted with CHCl3 The aqueous layer was further continuously extracted with CHCl3 overnight The combined organic extracts were dried over anhydrous Na2SO4 evaporated

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

Procedure: To a stirred mixture of 14.0 g of isobutylmalonic acid and 37 mL of 37% formalin was added 9.05 mL of diethylamine at room temperature. The mixture was stirred at room temperature for 3 h and refluxed for an additional 2 h. The reaction mixture was cooled to room temperature and diluted with CHCl3, and extracted with saturated aqueous NaHCO3. The aqueous layer was acidified with 1M HCl and extracted with CHCl3. The organic extract was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 11.0 g at 98% yield of 4-methyl-2-methylenepentanoic acid as a clear liquid which was used without further purification. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ6.32 (d, J=2 Hz, 1H), 5.62 (d, J=2 Hz, 1H), 2.17 (dd, J=1, 7 Hz, 2H), 1.82 (m, 1H), 0.90 (d, J=7 Hz, 6H); 13C NMR (300 MHz) δ173.6, 139.4, 128.4, 40.7, 26.9, 22.0. refluxed for an additional 2 h The reaction mixture was cooled to room temperature extracted with saturated aqueous NaHCO3 extracted with CHCl3 The organic extract was dried over anhydrous Na2SO4 evaporated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8.34 g (38.6 mmol) of diethyl isobutylmalonate in 35 mL of 95% EtOH was added a solution of 9.0 g (161 mmol) of KOH in 110 mL of 95% EtOH. The mixture was stirred at 25° C. for 16 hours and then at reflux for 1 hour. The mixture was cooled, diluted with water and extracted with CH3Cl. The aqueous layer was cooled to 0° C. and acidified to pH<1 with 30 mL of concentrated HCl, then it was extracted with CHCl3. The aqueous layer was further continuously extracted with CHCl3 overnight. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to afford 5.44 g (33.9 mmol, 88%) of isobutylmalonic acid as a solid which was essentially pure according to 1H NMR and which was used without further purification. Characteristic analytical data are as follows: mp 108°-110° C.; 1H NMR (300 MHz, CDCl3) δ3.52 (t, J=8 Hz, 1H), 1.84 (t, J=8 Hz, 2H), 1.66 (m, 1H), 0.94 (d, J-7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ175.6 (C=O), 49.7 (CH), 37.1 (CH2), 25.7 (CH), 21.7 (CH3). at reflux for 1 hour The mixture was cooled extracted with CH3Cl The aqueous layer was cooled to 0° C. it was extracted with CHCl3 The aqueous layer was further continuously extracted with CHCl3 overnight The combined organic extracts were dried over anhydrous Na2SO4 evaporated

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

Procedure: A solution of 860 ml (3.74 mole) of 25% of NaOCH3 in CH3OH and an equal volume of CH3OH is warmed to near reflux. Dimethyl malonate (425 ml, 3.74 mole) is added, followed by 410 ml (3.74 mole) of 1-bromo-2-methyl propane. Heating back to reflux gives a clear yellow solution. Refluxing under N2 for 18 hours gives a slurry. While at reflux a total of 425 ml of 50% NaOH is added plus enough water to dissolve the precipitated salts, for a total reaction volume of 5 liters. The basic (pH=14) mixture is refluxed until little cloudiness is observed on dilution of a sample with water. Distillation until T≅90°, cooling in ice, acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying and evaporation, a slurry. Benzene is added and the slurry evaporated to a solid. Trituration with hexane, filtering and drying in air gives 402 g, m.p. 101°-105° (67%). An additional 25 g, m.p. 92°-101°, were obtained on further extraction with ethyl acetate and rework of the mother liquors, for a total of 427 g (71%). A 410 g (2.56 mole) sample of isobutyl malonic acid is dissolved in 3.5 liters of water. This yellow solution is cooled in ice and treated with 288 g (2.56 mole) of 40% aqueous dimethylamine. Stirring with cooling is continued, and when the internal temperature equals 10° C., 210 g (2.56 mole) of 37% formalin is added. The resulting clear yellow solution is stored at 5° C. for 21/2 days, whereupon it is a solid mass of white solid. This mixture is carefully brought to near reflux (foaming) with stirring, and held there until the solution is clear and CO2 is no longer evolved to a significant extent (heated 2 hours after complete solution). The mixture is cooled in ice and acidified strongly with 350 ml of 7.2 M H2SO4 (pH=1). Extraction with 2 liters of hexane and drying (Na2SO4) gives 206 g of isobutyl acrylic acid. Extraction with another 2 liters of hexane gives 6 g, for a total of 212 g (65%) of the unsaturated acid. to near reflux Heating back to reflux gives a clear yellow solution Refluxing under N2 for 18 hours gives a slurry to dissolve the precipitated salts Distillation until T≅90° cooling in ice acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying evaporation Benzene is added the slurry evaporated to a solid Trituration with hexane, filtering drying in air gives 402 g, m.p. 101°-105° (67%) This yellow solution is cooled in ice with cooling is stored at 5° C. for 21 2 days to near reflux (foaming) with stirring The mixture is cooled in ice Extraction with 2 liters of hexane drying (Na2SO4)

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

Procedure: A solution of 860 ml (3.74 mole) of 25% of NaOCH3 in CH3OH and an equal volume of CH3OH is warmed to near reflux. Dimethyl malonate (425 ml, 3.74 mole) is added, followed by 410 ml (3.74 mole) of 1-bromo-2-methyl propane. Heating back to reflux gives a clear yellow solution. Refluxing under N2 for 18 hours gives a slurry. While at reflux a total of 425 ml of 50% NaOH is added plus enough water to dissolve the precipitated salts, for a total reaction volume of 5 liters. The basic (pH=14) mixture is refluxed until little cloudiness is observed on dilution of a sample with water. Distillation until T≅90°, cooling in ice, acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying and evaporation, a slurry. Benzene is added and the slurry evaporated to a solid. Trituration with hexane, filtering and drying in air gives 402 g, m.p. 101°-105° (67%). An additional 25 g, m.p. 92°-101°, were obtained on further extraction with ethyl acetate and rework of the mother liquors, for a total of 427 g (71%). A 410 g (2.56 mole) sample of isobutyl malonic acid is dissolved in 3.5 liters of water. This yellow solution is cooled in ice and treated with 288 g (2.56 mole) of 40% aqueous dimethylamine. Stirring with cooling is continued, and when the internal temperature equals 10° C., 210 g (2.56 mole) of 37% formalin is added. The resulting clear yellow solution is stored at 5° C. for 21/2 days, whereupon it is a solid mass of white solid. This mixture is carefully brought to near reflux (foaming) with stirring, and held there until the solution is clear and CO2 is no longer evolved to a significant extent (heated 2 hours after complete solution). The mixture is cooled in ice and acidified strongly with 350 ml of 7.2 M H2SO4 (pH=1). Extraction with 2 liters of hexane and drying (Na2SO4) gives 206 g of isobutyl acrylic acid. Extraction with another 2 liters of hexane gives 6 g, for a total of 212 g (65%) of the unsaturated acid. to near reflux Heating back to reflux gives a clear yellow solution Refluxing under N2 for 18 hours gives a slurry to dissolve the precipitated salts Distillation until T≅90° cooling in ice acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying evaporation Benzene is added the slurry evaporated to a solid Trituration with hexane, filtering drying in air gives 402 g, m.p. 101°-105° (67%) This yellow solution is cooled in ice with cooling is stored at 5° C. for 21 2 days to near reflux (foaming) with stirring The mixture is cooled in ice Extraction with 2 liters of hexane drying (Na2SO4)

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

Procedure: A solution of 860 ml (3.74 mole) of 25% of NaOCH3 in CH3OH and an equal volume of CH3OH is warmed to near reflux. Dimethyl malonate (425 ml, 3.74 mole) is added, followed by 410 ml (3.74 mole) of 1-bromo-2-methyl propane. Heating back to reflux gives a clear yellow solution. Refluxing under N2 for 18 hours gives a slurry. While at reflux a total of 425 ml of 50% NaOH is added plus enough water to dissolve the precipitated salts, for a total reaction volume of 5 liters. The basic (pH=14) mixture is refluxed until little cloudiness is observed on dilution of a sample with water. Distillation until T≅90°, cooling in ice, acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying and evaporation, a slurry. Benzene is added and the slurry evaporated to a solid. Trituration with hexane, filtering and drying in air gives 402 g, m.p. 101°-105° (67%). An additional 25 g, m.p. 92°-101°, were obtained on further extraction with ethyl acetate and rework of the mother liquors, for a total of 427 g (71%). A 410 g (2.56 mole) sample of isobutyl malonic acid is dissolved in 3.5 liters of water. This yellow solution is cooled in ice and treated with 288 g (2.56 mole) of 40% aqueous dimethylamine. Stirring with cooling is continued, and when the internal temperature equals 10° C., 210 g (2.56 mole) of 37% formalin is added. The resulting clear yellow solution is stored at 5° C. for 21/2 days, whereupon it is a solid mass of white solid. This mixture is carefully brought to near reflux (foaming) with stirring, and held there until the solution is clear and CO2 is no longer evolved to a significant extent (heated 2 hours after complete solution). The mixture is cooled in ice and acidified strongly with 350 ml of 7.2 M H2SO4 (pH=1). Extraction with 2 liters of hexane and drying (Na2SO4) gives 206 g of isobutyl acrylic acid. Extraction with another 2 liters of hexane gives 6 g, for a total of 212 g (65%) of the unsaturated acid. to near reflux Heating back to reflux gives a clear yellow solution Refluxing under N2 for 18 hours gives a slurry to dissolve the precipitated salts Distillation until T≅90° cooling in ice acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying evaporation Benzene is added the slurry evaporated to a solid Trituration with hexane, filtering drying in air gives 402 g, m.p. 101°-105° (67%) This yellow solution is cooled in ice with cooling is stored at 5° C. for 21 2 days to near reflux (foaming) with stirring The mixture is cooled in ice Extraction with 2 liters of hexane drying (Na2SO4)

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

Procedure: To a solution of 72.9 g (0.455 mol) of isobutylmalonic acid in 650 ml of ethyl acetate 54.2 ml (38.3 g, 0.524 mol) of diethylamine was added dropwise at 5° C. To the obtained suspension 19.2 g (0.640 mol) of paraform was added. The resulting mixture was refluxed for 5 h, then cooled to 5° C., and 350 ml of ether and 1000 cm3 of 2M HCl were added. After mixing the organic layer was separated, the aqueous layer was additionally extracted with 2×500 ml of ether. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Rectification of the residue in vacuum gave the title product, bp 75-77° C./6 mm Hg. Yield 51.5 g (88%) of colorless liquid. The resulting mixture was refluxed for 5 h After mixing the organic layer was separated the aqueous layer was additionally extracted with 2×500 ml of ether The combined organic extract was dried over Na2SO4 evaporated to dryness