METHYL 4-PHENYLBUTYRATE

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

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

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 25.0 g of methyl 4-phenylbutyrate in 100 ml of carbon disulfide, 37.3 g of anhydrous aluminium chloride was added and then a solution of 43.3 g of phenylacetyl chloride in 25 ml of carbon disulfide was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed with aqueous potassium carbonate solution, dried, and then the solvent was removed. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1→methylene chloride) to afford 27.3 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 54°~54.5° C. extracted with methylene chloride The methylene chloride layer was washed with aqueous potassium carbonate solution dried the solvent was removed The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1→methylene chloride)

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

Procedure: 8 L of 3.0 M methylmagnesium chloride in ether was transferred to a 22 L 3-necked, round-bottomed flask using N2 pressure. This flask was equipped with argon flow inlet. The solution had been chilled to 0° in an ice-acetone bath and 1283 g (7.2 moles) quantity of methyl-4-phenylbutyrate was added under argon over 4 h maintaining the temperature between 0° C. and 11° C. The reaction mixture was stirred for 1H and an aliquot was withdrawn, quenched in water and extracted with ether. The ether extract was concentrated and the residual oil was assayed by NMR spectrum. This confirmed that no starting material remained. The reaction mixture was rechilled to 0° and 4 L of water was added over 3 to 4H. This caused vigorous gas evolution and slurrying during the initial stages of the addition and caused precipitation of a white solid. The reaction mixture was stirred for 1H following the water addition and the mixture was then filtered using Buchner funnel and the filtrate was separated. The aqueous phase was extracted with 2 L of ether-hexane mixture and the organic phases combined and concentrated to give 1200 g of yellow oil 94% yield. round-bottomed flask using This flask was equipped with argon flow inlet The solution had been chilled to 0° in an ice-acetone bath maintaining the temperature between 0° C. and 11° C an aliquot was withdrawn quenched in water extracted with ether The ether extract was concentrated was rechilled to 0° 4 L of water was added over 3 to 4H This caused vigorous gas evolution and slurrying during the initial stages of the addition precipitation of a white solid The reaction mixture was stirred for 1H the water addition the mixture was then filtered the filtrate was separated The aqueous phase was extracted with 2 L of ether-hexane mixture concentrated

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

Procedure: 8 L of 3.0 M methylmagnesium chloride in ether was transferred to a 22 L 3-necked, round-bottomed flask using N2 pressure. This flask was equipped with argon flow inlet. The solution had been chilled to 0° in an ice-acetone bath and 1283 g (7.2 moles) quantity of methyl-4-phenylbutyrate was added under argon over 4 h maintaining the temperature between 0° C. and 11° C. The reaction mixture was stirred for 1H and an aliquot was withdrawn, quenched in water and extracted with ether. The ether extract was concentrated and the residual oil was assayed by NMR spectrum. This confirmed that no starting material remained. The reaction mixture was rechilled to 0° and 4 L of water was added over 3 to 4H. This caused vigorous gas evolution and slurrying during the initial stages of the addition and caused precipitation of a white solid. The reaction mixture was stirred for 1H following the water addition and the mixture was then filtered using Buchner funnel and the filtrate was separated. The aqueous phase was extracted with 2 L of ether-hexane mixture and the organic phases combined and concentrated to give 1200 g of yellow oil 94% yield. round-bottomed flask using This flask was equipped with argon flow inlet The solution had been chilled to 0° in an ice-acetone bath maintaining the temperature between 0° C. and 11° C an aliquot was withdrawn quenched in water extracted with ether The ether extract was concentrated was rechilled to 0° 4 L of water was added over 3 to 4H This caused vigorous gas evolution and slurrying during the initial stages of the addition precipitation of a white solid The reaction mixture was stirred for 1H the water addition the mixture was then filtered the filtrate was separated The aqueous phase was extracted with 2 L of ether-hexane mixture concentrated

Conditions: temp:49.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1800 g (10.98 moles) of 4-phenylbutyric acid, crystalline in a glass bottle was heated with a heating blanket for 2 h to melt the acid. The liquid was poured in 8 L of methanol in a 22 L reaction flask (3-necked round-bottom flask fitted with stirrer and thermometer adapters). The solution was stirred under Argon, temperature 20° C.-33° C., and 400 mL concentrated sulfuric acid was added in 50 mL portions. The temperature increased to 49° C. The solution was stirred under argon over the week-end and allowed to cool to ambient temperature. The solution was transferred to a quench tank and diluted with 8 L of water. The oil formed was separated and the aqueous phase was extracted with 2×1 L of ethyl acetate. The extracts were combined with the oil and the solution concentrated to give 1753 g of clear oil in 90% yield. The solution was stirred under argon over the week-end to cool to ambient temperature The oil formed was separated the aqueous phase was extracted with 2×1 L of ethyl acetate the solution concentrated

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

Procedure: To a solution of 25.0 g of methyl 4-phenylbutyrate in 100 ml of carbon disulfide, 37.3 g of anhydrous aluminium chloride was added and then a solution of 43.3 g of phenylacetyl chloride in 25 ml of carbon disulfide was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed with aqueous potassium carbonate solution, dried, and then the solvent was removed. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1→methylene chloride) to afford 27.3 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 54°~54.5° C. extracted with methylene chloride The methylene chloride layer was washed with aqueous potassium carbonate solution dried the solvent was removed The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1→methylene chloride)

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

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

Procedure: Preparation D8, Step 1: 2-Amino-5-chlorobenzamide (Avocado) (0.50 g, 2.93 mmol, 1 eq.), methyl 4-phenylbutyrate (3.14 g, 17.6 mmol, 6 eq.), NaOEt in ethanol (3.09 M, 5.69 mL, 17.6 mmol, 6 eq.) and ethanol (20 mL) were refluxed overnight. Cooled to 25° C. Added 10 mL of 10% HOAc/H2O. Solids formed which were filtered, the solids rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc to give 6-chloro-2-(3-phenyl-propyl)-quinazolin-4-ol as a tan solid (200 mg). MS found: (M+H)+=299. Solids formed which were filtered the solids rinsed with 5 mL H2O dissolved in 20 mL of EtOAc/THF Dried followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc

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

Procedure: Preparation D8, Step 1: 2-Amino-5-chlorobenzamide (Avocado) (0.50 g, 2.93 mmol, 1 eq.), methyl 4-phenylbutyrate (3.14 g, 17.6 mmol, 6 eq.), NaOEt in ethanol (3.09 M, 5.69 mL, 17.6 mmol, 6 eq.) and ethanol (20 mL) were refluxed overnight. Cooled to 25° C. Added 10 mL of 10% HOAc/H2O. Solids formed which were filtered, the solids rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc to give 6-chloro-2-(3-phenyl-propyl)-quinazolin-4-ol as a tan solid (200 mg). MS found: (M+H)+=299. Solids formed which were filtered the solids rinsed with 5 mL H2O dissolved in 20 mL of EtOAc/THF Dried followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc

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

Procedure: Preparation D8, Step 1: 2-Amino-5-chlorobenzamide (Avocado) (0.50 g, 2.93 mmol, 1 eq.), methyl 4-phenylbutyrate (3.14 g, 17.6 mmol, 6 eq.), NaOEt in ethanol (3.09 M, 5.69 mL, 17.6 mmol, 6 eq.) and ethanol (20 mL) were refluxed overnight. Cooled to 25° C. Added 10 mL of 10% HOAc/H2O. Solids formed which were filtered, the solids rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc to give 6-chloro-2-(3-phenyl-propyl)-quinazolin-4-ol as a tan solid (200 mg). MS found: (M+H)+=299. Solids formed which were filtered the solids rinsed with 5 mL H2O dissolved in 20 mL of EtOAc/THF Dried followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc