(1R)-1-phenylpropan-1-amine

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

Procedure: To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil. the crude solution was evaporated to dryness on a rotary evaporator triphosgene was added (11.67 g, 39.3 mmol) the resulting suspension was stirred The reaction mixture was concentrated An aliquot (170 mL) was concentrated to give a colorless oil

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

Procedure: The title compound was prepared by the same procedure for (6,4′-dimethoxybiphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from (R)-(+)-1-phenyl-propylamine (405 mg, 3.0 mmol, Lancaster Synthesis Ltd.), 6,4′-Dimethoxybiphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol)

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

Procedure: The title compound was prepared by the same procedure for (6,4′-dimethoxybiphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from (R)-(+)-1-phenyl-propylamine (405 mg, 3.0 mmol, Lancaster Synthesis Ltd.), 6,4′-Dimethoxybiphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (100 mg, 0.256 mmol) in MeCN (2 ml) and EtOH (1 ml) under N2 at RT was added (R)-(+)-alpha-ethylbenzylamine (58.8 mg, 0.435 mmol) and triethylamine (0.142 ml, 1.02 mmol) and the reaction mixture was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo to give a yellow solid which was loaded onto a 1 g pre-packed silica column, dissolving in the minimal amount of 5% MeOH in DCM. Purification was carried out eluting with 10-40% EtOAc in iso-hexane and the appropriate fractions were concentrated under vacuum to give a yellow glassy solid. The solid was dissolved in EtOAc and washed four times with 1M HCl (aq). The organic portion was dried (sodium sulfate) and concentrated in vacuo to yield a brown gummy solid. Trituration with iso-hexane afford the title compound as a solid brown solid; [M+H]+ 180. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.9 (2H, m, CH2), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 5.1 (1H, m, CH), 7.2-7.5 (6H, m, Ar—H), 8.0 (1H, d, Ar—H). The reaction mixture was concentrated in vacuo to give a yellow solid which Purification was carried out eluting with 10-40% EtOAc in iso-hexane the appropriate fractions were concentrated under vacuum to give a yellow glassy solid washed four times with 1M HCl (aq) The organic portion was dried (sodium sulfate) concentrated in vacuo to yield a brown gummy solid

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

Procedure: A solution of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 12a) (200 mg, 0.551 mmol), molybdenum(0) hexacarbonyl (44 mg, 0.165 mmol), trans-di-(μ-acetato)bis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) (52 mg, 0.055 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 3.31 mmol) and (R)-1-phenyl-propylamine (745 mg, 5.51 mmol) in dry tetrahydrofuran (5 ml) was heated for 30 min at 130° C. in a microwave reactor, then aqueous sodium hydrogencarbonate was added and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, evaporated to dryness and the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 86 mg (35%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide] as white solid. LC/MS (method 4): Rt=1.28 min; m/z=446.38 (M+H+). 1H-NMR: δ (ppm)=8.44 (1H, d), 8.15 (1H, d), 7.25-7.40 (9H, m), 7.22 (2H, q), 4.80-5.00 (4H, m), 4.15 (2H, m), 3.87 (2H, m), 1.73-1.80 (4H, m), 0.85-0.90 (6H, m). the mixture was extracted 3 times with dichloromethane The combined organic layers were dried over sodium sulfate evaporated to dryness the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

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

Procedure: A solution of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 12a) (200 mg, 0.551 mmol), molybdenum(0) hexacarbonyl (44 mg, 0.165 mmol), trans-di-(μ-acetato)bis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) (52 mg, 0.055 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 3.31 mmol) and (R)-1-phenyl-propylamine (745 mg, 5.51 mmol) in dry tetrahydrofuran (5 ml) was heated for 30 min at 130° C. in a microwave reactor, then aqueous sodium hydrogencarbonate was added and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, evaporated to dryness and the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 86 mg (35%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide] as white solid. LC/MS (method 4): Rt=1.28 min; m/z=446.38 (M+H+). 1H-NMR: δ (ppm)=8.44 (1H, d), 8.15 (1H, d), 7.25-7.40 (9H, m), 7.22 (2H, q), 4.80-5.00 (4H, m), 4.15 (2H, m), 3.87 (2H, m), 1.73-1.80 (4H, m), 0.85-0.90 (6H, m). the mixture was extracted 3 times with dichloromethane The combined organic layers were dried over sodium sulfate evaporated to dryness the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (300 mg, 0.914 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (136 mg, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-phenyl-propylamine (85 mg, 1 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 243 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16a; compounds with a compound number starting with “16” are compounds of the formula I) as white solid. LC/MS (method 4): Rt=1.12 min; m/z=396.22 (M+H+). 1H-NMR: δ (ppm)=8.07 (1H, d), 7.26-7.35 (5H, m), 7.19-7.22 (1H, m), 4.98 (1H, d), 4.81-4.89 (2H, m), 4.17-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.68 (2H, bs), 2.03-2.09 (1H, m), 1.92-1.99 (1H, m), 1.74-1.84 (3H, m), 1.53-1.59 (1H, m), 1.18 (3H, d), 0.88 (3H, t). the mixture was stirred at 25° C. overnight the solid which precipitated was filtered off washed with a small amount of water purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (300 mg, 0.914 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (136 mg, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-phenyl-propylamine (85 mg, 1 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 243 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16a; compounds with a compound number starting with “16” are compounds of the formula I) as white solid. LC/MS (method 4): Rt=1.12 min; m/z=396.22 (M+H+). 1H-NMR: δ (ppm)=8.07 (1H, d), 7.26-7.35 (5H, m), 7.19-7.22 (1H, m), 4.98 (1H, d), 4.81-4.89 (2H, m), 4.17-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.68 (2H, bs), 2.03-2.09 (1H, m), 1.92-1.99 (1H, m), 1.74-1.84 (3H, m), 1.53-1.59 (1H, m), 1.18 (3H, d), 0.88 (3H, t). the mixture was stirred at 25° C. overnight the solid which precipitated was filtered off washed with a small amount of water purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

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

Procedure: To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid (Comp. No. 8b) (6.22 g, 37.7 mmol) in dimethylformamide (125 ml) was added 1-hydroxybenzotriazole (5.60 g, 41.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.94 g, 41.4 mmol). The mixture was stirred for 30 min at 25° C., then (R)-1-phenyl-propylamine (6.11 g, 45.2 mmol) was added and the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h. The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added and the mixture was extracted 3 times with ethyl acetate, the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid, then 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness. The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 9.33 g (88%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 5): Rt=3.15 min; m/z=283.15 (M+H+). the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added the mixture was extracted 3 times with ethyl acetate the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

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

Procedure: To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid (Comp. No. 8b) (6.22 g, 37.7 mmol) in dimethylformamide (125 ml) was added 1-hydroxybenzotriazole (5.60 g, 41.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.94 g, 41.4 mmol). The mixture was stirred for 30 min at 25° C., then (R)-1-phenyl-propylamine (6.11 g, 45.2 mmol) was added and the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h. The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added and the mixture was extracted 3 times with ethyl acetate, the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid, then 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness. The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 9.33 g (88%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 5): Rt=3.15 min; m/z=283.15 (M+H+). the mixture was stirred at 25° C. overnight and at 45° C. for additional 24 h The mixture was concentrated in vacuo to 20% of its volume, 70 ml water and 30 ml ethyl acetate were added the mixture was extracted 3 times with ethyl acetate the combined organic layers were washed with 50 ml 1 N aqueous hydrochloric acid 50 ml aqueous sodium hydrogencarbonate, and evaporated to dryness The crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (comp. no. 8a) (5 g, 29.9 mmol) in dimethylformamide (50 ml) was added 1-hydroxybenzotriazole (4.45 g, 32.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.31 g, 32.9 mmol). The mixture was stirred for 1 h at 50° C., then (R)-1-phenyl-propylamine (4.45 g, 32.9 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the precipitate was filtered off, washed with a small amount of water and dried in vacuo to give 5.05 g (59%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 2): Rt=1.05 min; m/z=285.23 (M+H+). the mixture was stirred at 25° C. overnight the precipitate was filtered off washed with a small amount of water dried in vacuo

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

Procedure: A stirred solution of the product from Step 4 (2.00 g, 0.00711 mol), (R)-(+)-1-phenylpropylamine (1.06 g, 0.00784 mol), N-methylmorpholine (1.69 ml, 0.0154 mol) and isopropanol (13.3 ml) was refluxed, under nitrogen, until the reaction was shown to be complete by TLC (28 hours). It was then concentrated and the residue chromatographed on silica gel with 1 to 4% MeOH-CHCl3. A solution of the product thus obtained in MeOH-EtOAc was decolorized with Darco (activated charcoal) and crystallized from EtOAc-hexane to give 1.02 g, m.p. 109°-111° C. and 0.120 g, m.p. 107°-113° C. of the titled product. to be complete by TLC (28 hours) It was then concentrated the residue chromatographed on silica gel with 1 to 4% MeOH-CHCl3 A solution of the product thus obtained in MeOH-EtOAc crystallized from EtOAc-hexane