(7S)-7-氨基-5,7-二氢苯并[d][1]苯并氮杂-6-one

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

实验步骤: A solution of 350 mg (1.56 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 327 mg (1.72 mmol) (R/S)-2-hydroxy-2-isobutyl-malonic acid monomethyl ester in 30 ml tetrahydrofuran were cooled to 0° C. and 232 mg (1.72 mmol) 1-hydroxy-benzotriazole hydrate, 584 μl (3.43 mmol) diisopropylethylamine and 329 mg (192 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Extraction with water/ethylacetate and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50) yielded 470 mg (76%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid methyl ester as a colorless foam, MS (m/e): 397.3 (M+H)+. Extraction with water/ethylacetate and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50)

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

实验步骤: A solution of 135 mg (0.60 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one, and 154 mg (0.60 mmol) (S or R )-2-hydroxy-2-(3,3,3-trifluoro-propylcarbamoyl)-pentanoic acid, entity B, in 10 ml tetrahydrofuran were cooled to 0° C. and 93.8 mg (0.60 mmol) 1-hydroxy-benzotriazole hydrate, 210 μl (1.20 mmol) diisopropylethylamine and 117 mg (0.60 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 10:90 to 100:0) yielded 221 mg (80%) (S or R)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-N-(3,3,3-trifluoro-propyl)-malonamide, entity B: MS (m/e): 462.0 (M−H)−. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 10:90 to 100:0)

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

实验步骤: A solution of 135 mg (0.60 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one, and 154 mg (0.60 mmol) (R or S )-2-hydroxy-2-(3,3,3-trifluoro-propylcarbamoyl)-pentanoic acid, entity A, in 10 ml tetrahydrofuran were cooled to 0° C. and 93.8 mg (0.60 mmol) 1-hydroxy-benzotriazole hydrate, 210 μl (1.20 mmol) diisopropylethylamine and 117 mg (0.60 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 10:90 to 100:0) yielded 218 mg (78%) (R or S)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-N-(3,3,3-trifluoro-propyl)-malonamide, entity A: MS (m/e): 462.0 (M−H)−. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 10:90 to 100:0)

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

实验步骤: A solution of 500 mg (2 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 466 mg (2 mmol) (RS)-2-hydroxy-2-propyl-malonic acid monoethyl ester in 40 ml tetrahydrofuran were cooled to 0° C. and 331 mg (2 mmol) 1-hydroxy-benzotriazole hydrate, 830 μl (5 mmol) diisopropylethylamine and 470 mg (2 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50) yielded 630 mg (71%) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid ethyl ester as a colorless foam, MS (m/e): 397.3 (M+H)+. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50)

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

实验步骤: A solution of 250 mg (1.12 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 256 mg (1.12 mmol) (RS)-2-hydroxy-2-(2,2,2-trifluoro-ethylcarbamoyl)-butyric acid in 24 ml tetrahydrofuran were cooled to 0° C. and 174 mg (0.94 mmol) 1-hydroxy-benzotriazole hydrate, 390 μl (2.23 mmol) diisopropylethylamine and 218 mg (1.12 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane 2/8 yielded 330 mg (68%) (R/S)-2-ethyl-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide as a colorless oil, MS (m/e): 436.1 (M+H)+. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane 2/8

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

实验步骤: A solution of 70.0 mg (0.31 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 73.9 mg (0.34 mmol) (S)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid in 6 ml tetrahydrofuran were cooled to 0° C. and 46.4 mg (0.34 mmol) 1-hydroxy-benzotriazole hydrate, 117 μl (0.69 mmol) diisopropylethylamine and 65.8 mg (0.34 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued for 16 hours. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75) yielded 104 mg (79%) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide, MS (m/e): 422.0 (M+H)+. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75)

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

实验步骤: A solution of 70.0 mg (0.31 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 73.9 mg (0.34 mmol) (R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid in 6 ml tetrahydrofuran were cooled to 0° C. and 46.4 mg (0.34 mmol) 1-hydroxy-benzotriazole hydrate, 117 μl (0.69 mmol) diisopropylethylamine and 65.8 mg (0.34 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued for 16 hours. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75) yielded 101 mg (77%) (R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide, MS (m/e): 422.0 (M+H)+. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 100/0 to 25/75)

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

实验步骤: A solution of 210 mg (0.94 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 215 mg (0.94 mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid in 50 ml tetrahydrofuran were cooled to 0° C. and 129 mg (0.94 mmol) 1-hydroxy-benzotriazole hydrate, 327 μl (1.87 mmol) diisopropylethylamine and 183 mg (0.94 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. The mixture was poured on ice/water and 1 N aqueous hydrochloric acid was added until pH=1 was reached. Extraction with first diethylether and second with ethylacetate, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/heptane 2/1 yielded 150 mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,3-trifluoro-propyl)-malonamide as a white solid, MS (m/e): 436.1 (M+H)+. was added until pH=1 Extraction with first diethylether second with ethylacetate, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/heptane 2/1

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

实验步骤: A solution of 101 mg (0.45 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 119 mg (0.45 mmol) (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in 15 ml tetrahydrofuran were cooled to 0° C. and 61.8 mg (0.45 mmol) 1-hydroxy-benzotriazole hydrate, 157 μl (0.90 mmol) diisopropylethylamine and 87.6 mg (0.45 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. The mixture was poured on ice/water and 1 N aqueous hydrochloric acid was added until pH=1 was reached. Extraction with diethylether, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/cyclohexane 1/1 yielded 86.1 mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as a white solid, MS (m/e): 472.1 (M+H)+. was added until pH=1 Extraction with diethylether washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/cyclohexane 1/1

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

实验步骤: A solution of 0.20 g (0.9 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one in 8 ml tetrahydrofurane was treated at 0° C. with 0.09 g (0.99 mmol) L-lactic acid, 0.14 g (0.9 mmol) 1-hydroxybenzotriazole hydrate, 314 μl (1.8 mmol) N-ethyldiisopropylamine and 0.18 g (0.9 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) yielded 0.19 g (70%) (S)-2-hydroxy-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide as white solid; MS: m/e: 297.1 (M+H+). was extracted with 1N aqueous hydrochloric acid/ethylacetate Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0)

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

实验步骤: A solution of 0.55 g (1.6 mmol) (S)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one, 3.74 ml (50 mmol) trifluoroacetic acid and 1.4 ml (16 mmol) trifluormethane sulfonic acid in 38 ml dichloromethane was stirred at room temperature for 4 hours. The solvent was distilled off and extraction with aqueous sodium bicarbonate solution/ethyl acetate followed by chromatography on silicagel with ethylacetate/methanol (100-95/0-5) yielded 0.35 g (96%) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one as orange solid; MS: m/e: 225.4 (M+H+). The solvent was distilled off extraction with aqueous sodium bicarbonate solution/ethyl acetate

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

实验步骤: In an analogous manner to that described in Example 1 a), the condensation of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester (96.9% e.e.) yielded the title compound as a white solid; MS: m/e=371 (M+H)+. The (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester was obtained by stereoselective hydrolysis of the corresponding diester by Candida cylindracea hydrolase following the procedure described in J. Org. Chem. 1986, 51, 1003-6.