alpha-氨基-gamma-丁内酯氢溴酸

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and α-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174-177° C. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification was by silica gel chromatography. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylic acid (AA01, 250 mg, 0.788 mmol) which had been obtained in Example 1 was made to be the acid chloride according to the conventional method, and the acid chloride was dissolved in THF. Then, the solution was dropped into the DMF (2 mL) mixed liquid of 3-amino-dihydro-furan-2-one hydrobromide (187 mg, 1.03 mmol) and triethylamine (0.38 mL, 2.36 mmol) while cooling with ice. After that, the mixture was stirred at the same temperature for 30 minutes, and further stirred continuously at room temperature for 3 hours. The mixture was subjected to the same after-treatment as described above, and then refined with silica gel column chromatography (hexane-ethyl acetate (40 to 60%)), and I-072 was obtained as a colorless solid (242 mg, 77%, mp: 136-140° C.). while cooling with ice further stirred continuously at room temperature for 3 hours

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 6-[1-(3-amino-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid (1 g) was added to a co-solvent of tetrahydrofuran (25 ml) and methylene chloride (15 ml) and with the successive addition of 1.3-dicyclohexylcarbodimide (1.3 g) and 1-hydroxybenzotriazole (0.46 g) at 15° C.˜20° C., the mixture was stirred for 2 hours. A mixture of α-amino-γ-butyrolactone hydrobromide (1.1 g) and triethylamine (0.9 ml) was added again to the mixture at 20° C. and stirred at 20° C.˜25° C. for 3 hours. With the addition of methylene chloride (50 ml), the mixture was washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization and recrystallized with chloroform and tetrahydrofuran to give a desired compound of 1.07 g (yield: 71%). was added again to the mixture at 20° C. stirred at 20° C.˜25° C. for 3 hours the mixture was washed with water 3 times dried over magnesium sulfate concentrated under reduced pressure The concentrated residue was treated with ether for crystallization recrystallized with chloroform and tetrahydrofuran

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring solution of 2,4-dichloroaniline (4.27 g, 26.37 mmol), in anhydrous methylene chloride (100 mL) under N2 at 0° C. (ice-water bath), was added dropwise, trimethylaluminum (39.56 mL of a 2M solution in hexane, 79.11 mmol). The resultant mixture was stirred under N2 at room temperature for 24 h. The mixture was cooled and (±)-α-amino-γ-butyrolactone hydrobromide (39.56 mL, 74.11 mmol, Aldrich Chemical Co., Milwaukee, Wis.) was then added portionwise and the reaction mixture then allowed to stir at room temperature for 48 h. The reaction mixture was cooled to 0° C., treated with 6N hydrochloric acid until the pH of the mixture was 2 to 3. The resultant solid was filtered and suspended in 100 mL of water. The suspension was made basic with 50% aqueous NaOH (pH=13) and 300 mL of methylene chloride was added. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 50% ethyl acetate in hexane. The desired fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (2.3 g, 36%), mp 89°-91° C. IR (Nujol, cm-1), C=O (1658), N--H (3323.9), OH (3265.9). 1H NMR (400 MHz, CDCl3) spectrum was consistent with the title product. Analysis calculated for C10H12Cl2N2O: C, 45.65; H, 4.60; N, 10.68; Cl, 26.90; Found: C, 45.69; H, 4.60; N, 10.53; Cl, 26.70. The mixture was cooled The reaction mixture was cooled to 0° C. The resultant solid was filtered was added The organic layer was separated dried over magnesium sulfate evaporated under reduced pressure The residue obtained was chromatographed on silica gel eluting with 50% ethyl acetate in hexane evaporated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring solution of 2,4-dichloroaniline (4.27 g, 26.37 mmol), in anhydrous methylene chloride (100 mL) under N2 at 0° C. (ice-water bath), was added dropwise, trimethylaluminum (39.56 mL of a 2M solution in hexane, 79.11 mmol). The resultant mixture was stirred under N2 at room temperature for 24 h. The mixture was cooled and (±)-α-amino-γ-butyrolactone hydrobromide (39.56 mL, 74.11 mmol, Aldrich Chemical Co., Milwaukee, Wis.) was then added portionwise and the reaction mixture then allowed to stir at room temperature for 48 h. The reaction mixture was cooled to 0° C., treated with 6N hydrochloric acid until the pH of the mixture was 2 to 3. The resultant solid was filtered and suspended in 100 mL of water. The suspension was made basic with 50% aqueous NaOH (pH=13) and 300 mL of methylene chloride was added. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 50% ethyl acetate in hexane. The desired fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (2.3 g, 36%), mp 89°-91° C. IR (Nujol, cm-1), C=O (1658), N--H (3323.9), OH (3265.9). 1H NMR (400 MHz, CDCl3) spectrum was consistent with the title product. Analysis calculated for C10H12Cl2N2O: C, 45.65; H, 4.60; N, 10.68; Cl, 26.90; Found: C, 45.69; H, 4.60; N, 10.53; Cl, 26.70. The mixture was cooled The reaction mixture was cooled to 0° C. The resultant solid was filtered was added The organic layer was separated dried over magnesium sulfate evaporated under reduced pressure The residue obtained was chromatographed on silica gel eluting with 50% ethyl acetate in hexane evaporated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 3.84 g of α-amino-γ-butyrolactone hydrogenbromide in 40 ml of dichloromethane is added 2.15 ml of benzaldehyde, followed by5.9 ml of triethylamine and excess magnesium sulfate. After stirring at room temperature for 20 hours, the mixture is filtered and the filtrate concentrated. A 200 ml portion of ether is added and the resulting suspension filtered. The filtrate is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 100 ml portions of ether. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.) to give 3.5 g of N-benzylidene-α-amino-γ-butyrolactone as an oil which solidifies on storage in a freezer: the mixture is filtered the filtrate concentrated A 200 ml portion of ether is added the resulting suspension filtered The filtrate is washed with 50 ml of saturated aqueous sodium chloride The aqueous phase is extracted with two 100 ml portions of ether The combined organic phase is dried (magnesium sulfate) filtered concentrated The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 3.84 g of α-amino-γ-butyrolactone hydrogenbromide in 40 ml of dichloromethane is added 2.15 ml of benzaldehyde, followed by5.9 ml of triethylamine and excess magnesium sulfate. After stirring at room temperature for 20 hours, the mixture is filtered and the filtrate concentrated. A 200 ml portion of ether is added and the resulting suspension filtered. The filtrate is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 100 ml portions of ether. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.) to give 3.5 g of N-benzylidene-α-amino-γ-butyrolactone as an oil which solidifies on storage in a freezer: the mixture is filtered the filtrate concentrated A 200 ml portion of ether is added the resulting suspension filtered The filtrate is washed with 50 ml of saturated aqueous sodium chloride The aqueous phase is extracted with two 100 ml portions of ether The combined organic phase is dried (magnesium sulfate) filtered concentrated The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of α-amino-γ-butyrolactone hydrobromide in 30% HBr in HOAc was heated at 100° C. in a sealed tube for 5 days. The mixture was concentrated to give a white solid that was washed with Et2O to provide 23.1 g (64%) of 2-amino-4-bromo-butyric acid hydrobromide. The mixture was concentrated to give a white solid that was washed with Et2O

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and α-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174-177° C. The reaction was monitored by tlc on silica gel (Rf=0.52: in 10% methanol/dichloromethane) and purification was by silica gel chromatography. The reaction was monitored by tlc on silica gel (Rf=0.52: in 10% methanol/dichloromethane) and purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and α-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174-177° C. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification was by silica gel chromatography. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound is prepared by a modification of the procedure used by Nollet, Huting and Pandit to prepare tertiary butyl 2-(N-carbobenzyloxy)amino-4-bromobutyrate. (Tetrahedron, 25, 5971 (1969) ##STR11## To 3.64 g (20.0 mmoles) of 2-aminobutyrolactone hydrobromide is added 182 ml of glacial acetic in a 500 ml three-necked flask equipped with a fritted glass gas bubbler, calcium chloride drying tube, and magnetic stirrer. Hydrogen bromide gas is then vigorously bubbled into the resultant suspension while stirring at ambient temperature. After three hours, all of the starting material has gone into solution and hydrogen bromide addition is discontinued. The reaction mixture is stirred at ambient temperature overnight and then is concentrated to dryness at reduced pressure yielding 5.2 g of crude 2-amino-4-bromobutyric acid hydrobromide as a white solid. This crude acid is dissolved in 25 mls absolute methanol after which hydrogen bromide gas is bubbled in for one minute. Monitoring reaction progress by NMR (BrCH2 --:CH3 --O-integration) indicates negligible reaction after stirring overnight at room temperature. After refluxing for 72 hours the reaction is judged to be complete. The reaction mixture is then concentrated to dryness at reduced pressure yielding crude methyl 2-amino-2-bromobutyrate hydrobromide as a colorless oil. To a solution of this crude ester in 25 ml water is added 3.70 g (44.0 mmoles) of sodium bicarbonate while stirring vigorously in an ice bath. Immediately, 3.8 mls (4.1 g; 24 mmoles) of benzylchloroformate is added dropwise over ca. two minutes. After ten minutes, the ice bath is removed, allowing the reaction mixture to warm to room temperature over 30 minutes. It is then poured into a separatory funnel and extracted with ether (3×25 ml), the combined portions of which are washed with saturated sodium bicarbonate (3×25 ml), dried over magnesium sulfate and concentrated, yielding 5.44 g of an oily white solid. Recrystallization from hexane-ether yields 1.96 of methyl-2-(N-carbobenzyloxy)-amino-4-bromo-butyrate (A) as white clusters having mp 87°-9°. This represents a 30% overall yield from 2-amino-butyrolactone hydrobromide. Tlc (Silica Gel F-254; CHCl3) shows one spot having Rf =0.15. This compound is prepared by a modification of the procedure Hydrogen bromide gas is then vigorously bubbled into the resultant suspension all of the starting material has gone into solution and hydrogen bromide addition The reaction mixture is stirred at ambient temperature overnight is concentrated to dryness at reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and α-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174–177° C. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification was by silica gel chromatography. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification