2-methylpropanoyl 2-methylpropanoate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 166 g of ethylvanillin are introduced into a 500 ml three-neck flask fitted with a 30 cm packed column and melted, and 189.6 g of isobutyric anhydride are added at a maximum temperature of 100° C. The reaction is only slightly exothermic. When addition is complete, the isobutyric acid can firstly be distilled off at a still temperature of 120° C. and 150 mbar, and iso-butyric acid and excess anhydride can finally be distilled at up to 130° C. and 20 mbar. The system is allowed to cool to 90° C., 500 ml of isopropanol are added and crystallization takes place upon further stirring and cooling to 7° C. The crystals are filtered off with suction, washed twice with 60 ml of cold isopropanol and dried, giving 182 g of ethylvanillin isobutyrate. Repeated crystallization from the mother liquor produces another 22.8 g of ethylvanillin isobutyrate. fitted with a 30 cm When addition the isobutyric acid can firstly be distilled off at a still temperature of 120° C. and 150 mbar, and iso-butyric acid and excess anhydride can finally be distilled at up to 130° C. 500 ml of isopropanol are added crystallization cooling to 7° C The crystals are filtered off with suction washed twice with 60 ml of cold isopropanol dried

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

Procedure: A 100 ml reaction vessel was charged with 4.18 g of dihydroxyacetone (monomer), 11.2 ml of pyridine and 10 mg of 4-dimethylaminopyridine and the mixture was stirred at room temperature. Thereto was added dropwise 16.7 ml of isobutyric anhydride over 30 minutes. After the dropping, the resulting liquid was further stirred for 1 hour and then 1 ml of methanol was added thereto and the resulting liquid was further stirred for 1 hour. To the reaction mixture was added ethyl acetate and the organic layer was separated. The organic layer was washed with water and further washed with saturated aqueous solution with sodium bicarbonate and 1N HCl. Then, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7.47 g of the desired compound. A 100 ml reaction vessel After the dropping, the resulting liquid was further stirred for 1 hour the resulting liquid was further stirred for 1 hour the organic layer was separated The organic layer was washed with water further washed with saturated aqueous solution with sodium bicarbonate and 1N HCl Then, the solvent was removed under reduced pressure The residue was distilled under reduced pressure

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

Procedure: A 100 ml reaction vessel was charged with 4.18 g of dihydroxyacetone (monomer), 11.2 ml of pyridine and 10 mg of 4-dimethylaminopyridine and the mixture was stirred at room temperature. Thereto was added dropwise 16.7 ml of isobutyric anhydride over 30 minutes. After the dropping, the resulting liquid was further stirred for 1 hour and then 1 ml of methanol was added thereto and the resulting liquid was further stirred for 1 hour. To the reaction mixture was added ethyl acetate and the organic layer was separated. The organic layer was washed with water and further washed with saturated aqueous solution with sodium bicarbonate and 1N HCl. Then, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7.47 g of the desired compound. A 100 ml reaction vessel After the dropping, the resulting liquid was further stirred for 1 hour the resulting liquid was further stirred for 1 hour the organic layer was separated The organic layer was washed with water further washed with saturated aqueous solution with sodium bicarbonate and 1N HCl Then, the solvent was removed under reduced pressure The residue was distilled under reduced pressure

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

Procedure: Isobutyric anhydride (0.5 mL) is added to a mixture of 131 (45 mg) in methylene chloride (10 mL). The mixture is stirred at room temperature for 1 hour. The solvent is removed to get residue, LC-MS (M+1) 398.17. The residue is dissolved in POCl3 (1 mL), and the mixture is heated at 85° C. for 1 hour. Excess POCl3 is removed. The residue is dissolved in methylene chloride, and washed with sat. NaHCO3, dried, and purified by TLC with 5% MeOH in methylene chloride to give the title product (156). 1H NMR δ (CDCl3) 1.02 (t, 3H, J=5.4 Hz), 1.43 (d, 6H, J=6.0 Hz), 1.71 (p, 2H, J=5.4 Hz), 2.93 (m, 2H), 3.29 (sep, 1H, J=6.0 Hz), 5.57 (s, 2H), 7.22–7.36 (m, 2H), 7.70–7.82 (m, 2H), 8.82 (d, 1H, J=3.3 Hz), 9.04 (s, 1H). LC-MS (M+1) 380.17. The solvent is removed to get residue, LC-MS (M+1) 398.17 the mixture is heated at 85° C. for 1 hour Excess POCl3 is removed The residue is dissolved in methylene chloride washed with sat. NaHCO3 dried purified by TLC with 5% MeOH in methylene chloride

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

Procedure: 2-Methylpyrazolo[1,5-a]pyridine was worked up according to the same process as shown in example 1, with an excess isobutyric anhydride in the presence of 2-3 drops of concentrated sulfuric acid to prepare 3-isobutyryl-2-methylpyrazolo[1,5-a]pyridine (139-140°/5 mmHg). Yield 40%.

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

Procedure: A solution of 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl]guanine (0.16 mmol), 4-dimethylaminopyridine (0.01 mmol), triethylamine (0.48 mmol) and isobutyric anhydride (0.48 mmol), in acetonitrile (1 ml) was stirred at room temperature for 6 hours. The reaction mixture was hydrolysed with a NaHCO3 saturated solution. Ethyl acetate was added. The organic phase was separated, washed with NaCl saturated solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM/EtOH) to yield the title compound White powder. Molecular Formula C20H24FN5O6 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.02-1.22 (m, 12H), 2.53-2.59 (m, 1H), 2.65-2.70 (m, 1H), 4.04 (d, J=4.77 Hz, 1H), 4.35-4.40 (m, 3H), 5.88-5.94 (dd, J=9.39 Hz and J=8.21 Hz, 1H), 6.21-6.25 (d, J=17.28 Hz, 1H), 6.58 (s, 2H), 7.09 (s, 1H), 10.82 (s, 1H). Scan ES+ 450.0 (M+H)+, UV λmax 251 nm The organic phase was separated washed with NaCl saturated solution dried over Na2SO4 filtered concentrated under reduced pressure The crude material was purified by flash column chromatography (DCM/EtOH)

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

Procedure: A solution of 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl]guanine (0.16 mmol), 4-dimethylaminopyridine (0.01 mmol), triethylamine (0.48 mmol) and isobutyric anhydride (0.48 mmol), in acetonitrile (1 ml) was stirred at room temperature for 6 hours. The reaction mixture was hydrolysed with a NaHCO3 saturated solution. Ethyl acetate was added. The organic phase was separated, washed with NaCl saturated solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM/EtOH) to yield the title compound White powder. Molecular Formula C20H24FN5O6 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.02-1.22 (m, 12H), 2.53-2.59 (m, 1H), 2.65-2.70 (m, 1H), 4.04 (d, J=4.77 Hz, 1H), 4.35-4.40 (m, 3H), 5.88-5.94 (dd, J=9.39 Hz and J=8.21 Hz, 1H), 6.21-6.25 (d, J=17.28 Hz, 1H), 6.58 (s, 2H), 7.09 (s, 1H), 10.82 (s, 1H). Scan ES+ 450.0 (M+H)+, UV λmax 251 nm The organic phase was separated washed with NaCl saturated solution dried over Na2SO4 filtered concentrated under reduced pressure The crude material was purified by flash column chromatography (DCM/EtOH)

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

Procedure: A 30-g (0.33 mol) sample of trioxane was added to a solution of 158 g (1 mol) isobutyric anhydride and 0.5 ml 70% perchloric acid over a 30-minute period at 65°-70° C. The reaction mixture was then stirred until the temperature decreased to 27° C. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ether. The ether extracts were dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was distilled on a 30-cm column to give 112 g of methylene bisisobutyrate, b.p. 43°-48° C. at 0.2-0.3 mm of Hg and 30 g of oxybis-methylene isobutyrate, b.p. 57°-63° C. at 0.2-0.3 mm of Hg. decreased to 27° C extracted with ether The ether extracts were dried over magnesium sulfate evaporated under reduced pressure The resulting residue was distilled on a 30-cm column

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

Procedure: A 30-g (0.33 mol) sample of trioxane was added to a solution of 158 g (1 mol) isobutyric anhydride and 0.5 ml 70% perchloric acid over a 30-minute period at 65°-70° C. The reaction mixture was then stirred until the temperature decreased to 27° C. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ether. The ether extracts were dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was distilled on a 30-cm column to give 112 g of methylene bisisobutyrate, b.p. 43°-48° C. at 0.2-0.3 mm of Hg and 30 g of oxybis-methylene isobutyrate, b.p. 57°-63° C. at 0.2-0.3 mm of Hg. decreased to 27° C extracted with ether The ether extracts were dried over magnesium sulfate evaporated under reduced pressure The resulting residue was distilled on a 30-cm column

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

Procedure: A solution of 9-[(2R)-2-Deoxy-2-C-ethynyl-2-fluoro-β-D-erythro-furanosyl]guanine (0.16 mmol), 4-dimethylaminopyridine (0.01 mmol), triethylamine (0.48 mmol) and isobutyric anhydride (0.48 mmol), in acetonitrile (1 ml) was stirred at room temperature for 6 hours. The reaction mixture was hydrolysed with a NaHCO3 saturated solution. Ethyl acetate was added. The organic phase was separated, washed with NaCl saturated solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCMlEtOH) to yield the title compound White powder. Molecular Formula C20H24FN5O6 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.02-1.22 (m, 12H), 2.53-2.59 (m, 1H), 2.65-2.70 (m, 1H), 4.04 (d, J=4.77 Hz, 1H), 4.35-4.40 (m, 3H), 5.88-5.94 (dd, J=9.39 Hz and J=8.21 Hz, 1H), 6.21-6.25 (d, J=17.28 Hz, 1H), 6.58 (s, 2H), 7.09 (s, 1H), 10.82 (s, 1H). Scan ES+ 450.0 (M+H)+, UV λmax 251 nm The organic phase was separated washed with NaCl saturated solution dried over Na2SO4 filtered concentrated under reduced pressure The crude material was purified by flash column chromatography (DCMlEtOH)

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

Procedure: To a solution of tert-butyl cis-4-aminocyclohexylcarbamate (500 mg, 2.333 mmol) in DCM (20 mL) was added isobutyric anhydride (0.407 mL, 2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirred at RT overnight. The resulting white precipitate was collected by vacuum filtration and dried in vacuo to generate N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride as an off-white powder (508 mg, 99% yield). After 16 hours the reaction was stirred at RT overnight The resulting white precipitate was collected by vacuum filtration dried in vacuo

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 166 g of ethylvanillin are introduced into a 500 ml three-neck flask fitted with a 30 cm packed column and melted, and 189.6 g of isobutyric anhydride are added at a maximum temperature of 100° C. The reaction is only slightly exothermic. When addition is complete, the isobutyric acid can firstly be distilled off at a still temperature of 120° C. and 150 mbar, and iso-butyric acid and excess anhydride can finally be distilled at up to 130° C. and 20 mbar. The system is allowed to cool to 90° C., 500 ml of isopropanol are added and crystallization takes place upon further stirring and cooling to 7° C. The crystals are filtered off with suction, washed twice with 60 ml of cold isopropanol and dried, giving 182 g of ethylvanillin isobutyrate. Repeated crystallization from the mother liquor produces another 22.8 g of ethylvanillin isobutyrate. fitted with a 30 cm When addition the isobutyric acid can firstly be distilled off at a still temperature of 120° C. and 150 mbar, and iso-butyric acid and excess anhydride can finally be distilled at up to 130° C. 500 ml of isopropanol are added crystallization cooling to 7° C The crystals are filtered off with suction washed twice with 60 ml of cold isopropanol dried