(2S)-2-methyloxirane

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

Procedure: The manner in which optically active forms of arylmethoxy aliphatic amines, such as (2S)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine type compounds, are provided can vary. In one approach, a 3-aminobenzyl alcohol type compound (N-protected as the phthalimide) can be alkylated with a chiral 1-bromo-2-propanol type compound containing an O-protecting group, such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran using a base such as sodium hydride and a solvent such as N,N-dimethylformamide or tetrahydrofuran. The tetrahydropyranyl protecting group of the resulting chiral arylmethyl ether type compound can be removed with aqueous sulfuric acid in methanol, affording (2S)-1-[(3-aminophenyl)methoxy]-propan-2-ol. The resulting chiral alcohol intermediate can be converted to its corresponding tosylate, followed by tosylate displacement with methylamine with inversion of configuration, and finally removal of the N-phthaloyl group to give the chiral amine (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine. Chiral side chain compounds such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran can be prepared from (2S)-1-bromo-2-propanol by treatment with 3,4-dihydro-2H-pyran in dichloromethane with p-toluenesulfonic acid as a catalyst according to the method of S. A. M. Nieuwenhuis et al., Tetrahedron 50: 13207-13230 (1994). The required (2S)-1-bromo-2-propanol can be obtained from (S)-propylene oxide (commercially available from Fluka) by treatment with hydrogen bromide in acetic acid at 0° C. The corresponding optical antipode, (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine can be prepared in an analogous manner from (R)-propylene oxide (commercially available from Fluka) by using the synthetic procedure of S. A. M. Nieuwenhuis et al. to prepare the tetrahydropyranyl ether of (2R)-1-bromo-2-propanol and by using the synthetic sequence described above.

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

Procedure: A solution of 4-phenoxyphenol (2.14 g, 11.5 mmol) in toluene (7 ml) was poured into an aqueous solution (3 ml) of sodium hydroxide (0.92 g, 23.0 mmol), and (S)-(-)propylene oxide (1.0 g, 17.24 mmol; a reagent manufactured by Aldrich; [α]D20 =-7.2° (CHCl3, c=1)) was added thereto while stirring. To the resultant mixture, tetra-n-butyl-ammonium bromide (185 mg) was added, and the mixture was stirred at room temperature for 12 hours, followed by addition of (S)-(-)-propylene oxide (1 g). After stirring at room temperature for 6 hours, the reaction mixture was vigorously stirred with addition of water (20 ml) and toluene (20 ml). The toluene layer was separated and washed with a 20 % aqueous sodium hydroxide solution and an aqueous sodium chloride solution in order and dried over magnesium sulfate. Removal of the solvent gave crude (S)-(+)-1-methyl-2-(4-phenoxyphenoxy)ethanol (2.35 g), which was further purified by silica gel column chromatography to give (S)-(+)-1-methyl-2-(4-phenoxyphenoxy)ethanol (1.97 g). [α]D23 =+14.0° (CHCl3, c=1). ee.: 72.9%. the mixture was stirred at room temperature for 12 hours After stirring at room temperature for 6 hours The toluene layer was separated washed with a 20 % aqueous sodium hydroxide solution an aqueous sodium chloride solution in order and dried over magnesium sulfate Removal of the solvent gave crude (S)-(+)-1-methyl-2-(4-phenoxyphenoxy)ethanol (2.35 g), which was further purified by silica gel column chromatography

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

Procedure: A mixture of 2,3-dihydro-1H-indole (5.74 g, 48.2 mmol), and (S)-propylene oxide (2.8 g, 48.2 mmol) in ethanol (200 mL) is heated at reflux for 18 hours. The resulting mixture is cooled to room temperature, and evaporated to give a crude oil. The material is purified by flash chromatography (25% ethyl acetate/hexanes) to give 5.37 g (63%) of 2,3-dihydro-1-(2-hydroxypropyl)indole. is heated at reflux for 18 hours evaporated to give a crude oil The material is purified by flash chromatography (25% ethyl acetate/hexanes)

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

Procedure: A 150 mL tube was charged with 5-methyl-4-phenoxy-pyrrolo[2,1-f][1,2,4]triazin-6-ol (5.93 g, 24.6 mmol), THF (2 mL) and sodium methanethiol (5.17 mg, 73.7 mmol). The tube was sealed and the mixture was heated at 80° C. for 4 h. The mixture was cooled to RT, water was added (100 mL) and the solution was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with water (200 mL), 1N aqueous solution of sodium hydroxide (2×200 mL), brine (200 mL), dried and concentrated in vacuo to afford (3.2 g, 67%) of 5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-ol as an beige solid. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (1H, s), 8.11 (1H, s), 7.39 (1H, s), 2.58 (3H, s), 2.34 (1H, s). m/z 196 (M+H+). B. A 10 mL tube was charged with 5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-ol (75 mg, 0.38 mmol), tert-butylalcohol (2 mL), (S)-propylene oxide (0.134 mL, 1.92 mmol) and triethylamine (5 μL, 0.04 mmol). The tube was sealed and the mixture was heated at 80° C. for 17 h. The mixture was cooled to RT and concentrated in vacuo. The crude material was purified by flash chromatography eluting a mixture of 50% ethyl acetate in hexane to give (56 mg, 58%) of (S)-1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol as an white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (1H, s), 7.78 (1H, s), 4.88 (1H, m), 3.95 (m, 1H), 3.82 (2H, m), 2.59 (3H, s), 2.36 (3H, s), 1.13 (3H, d, J=6.3 Hz). m/z 254 (M+H+). C. To a solution of (S)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-6-ol (20 mg, 0.08 mmol) in chloroform (1.0 mL) at 0° C., was added a solution of peracetic acid in acetic acid (51 μL, 0.24 mmol, 32% wt solution). The mixture was allowed to reach RT and stirred for an additional 2.0 h. A saturated solution of ammonium chloride was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL), the organic layers were combined, washed with water (100 mL), brine (100 mL), dried and concentrated in vacuo. The resulting sulfone was used without any purification. D. At −78° C., sodium hydride (60% in oil, 3.1 mg, 0.08 mmol) was added to a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol (13 mg, 0.09 mmol, see Example 4) in dimethyl formamide (1 mL). The mixture was stirred at 0° C. for 30 min. and cooled back down to −78° C. (S)-1-(4-methanesulfonyl-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (22 mg, 0.08 mmol) was then added and the mixture was stirred at RT for 2 h, quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was purified by preparative HPLC to yield (10 mg, 36%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J=9.3 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.61 (1H, t, J=3.1 Hz), 6.59 (1H, dd, J=1.98, 3.3 Hz), 4.01-3.97 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J=6.3 Hz). m/z 358 (M+H+). The tube was sealed The mixture was cooled to RT concentrated in vacuo The crude material was purified by flash chromatography eluting a mixture of 50% ethyl acetate in hexane

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

Procedure: A 150 mL tube was charged with 5-methyl-4-phenoxy-pyrrolo[2,1-f][1,2,4]triazin-6-ol (5.93 g, 24.6 mmol), THF (2 mL) and sodium methanethiol (5.17 mg, 73.7 mmol). The tube was sealed and the mixture was heated at 80° C. for 4 h. The mixture was cooled to RT, water was added (100 mL) and the solution was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with water (200 mL), 1N aqueous solution of sodium hydroxide (2×200 mL), brine (200 mL), dried and concentrated in vacuo to afford (3.2 g, 67%) of 5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-ol as an beige solid. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (1H, s), 8.11 (1H, s), 7.39 (1H, s), 2.58 (3H, s), 2.34 (1H, s). m/z 196 (M+H+). B. A 10 mL tube was charged with 5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-ol (75 mg, 0.38 mmol), tert-butylalcohol (2 mL), (S)-propylene oxide (0.134 mL, 1.92 mmol) and triethylamine (5 μL, 0.04 mmol). The tube was sealed and the mixture was heated at 80° C. for 17 h. The mixture was cooled to RT and concentrated in vacuo. The crude material was purified by flash chromatography eluting a mixture of 50% ethyl acetate in hexane to give (56 mg, 58%) of (S)-1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol as an white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (1H, s), 7.78 (1H, s), 4.88 (1H, m), 3.95 (m, 1H), 3.82 (2H, m), 2.59 (3H, s), 2.36 (3H, s), 1.13 (3H, d, J=6.3 Hz). m/z 254 (M+H+). C. To a solution of (S)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-6-ol (20 mg, 0.08 mmol) in chloroform (1.0 mL) at 0° C., was added a solution of peracetic acid in acetic acid (51 μL, 0.24 mmol, 32% wt solution). The mixture was allowed to reach RT and stirred for an additional 2.0 h. A saturated solution of ammonium chloride was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL), the organic layers were combined, washed with water (100 mL), brine (100 mL), dried and concentrated in vacuo. The resulting sulfone was used without any purification. D. At −78° C., sodium hydride (60% in oil, 3.1 mg, 0.08 mmol) was added to a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol (13 mg, 0.09 mmol, see Example 4) in dimethyl formamide (1 mL). The mixture was stirred at 0° C. for 30 min. and cooled back down to −78° C. (S)-1-(4-methanesulfonyl-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (22 mg, 0.08 mmol) was then added and the mixture was stirred at RT for 2 h, quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was purified by preparative HPLC to yield (10 mg, 36%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J=9.3 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.61 (1H, t, J=3.1 Hz), 6.59 (1H, dd, J=1.98, 3.3 Hz), 4.01-3.97 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J=6.3 Hz). m/z 358 (M+H+). The tube was sealed The mixture was cooled to RT concentrated in vacuo The crude material was purified by flash chromatography eluting a mixture of 50% ethyl acetate in hexane

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

Procedure: To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 30.0 mg, 0.0613 mmol) and (S)-(−)-methyloxirane (8.56 μL, 0.122 mmol) in isopropyl alcohol (2 mL)/N,N-dimethylformamide (0.5 mL), triethylamine (17.1 μL, 0.122 mmol) was added at ambient temperature. The reaction mixture was then warmed up to 90° C. After 2 hours, the volatiles were removed and the residue was dissolved in methanol (2 mL). Potassium carbonate (16.9 mg, 0.122 mmol) was added and the reaction mixture was warmed up to 60° C. After 30 minutes, the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.8 mg) as its TFA salt. LCMS calculated for C22H26N5O3 (M+H)+: m/z=408.2. Found: 408.2. the volatiles were removed the residue was dissolved in methanol (2 mL) the reaction mixture was warmed up to 60° C After 30 minutes the crude mixture was purified on RP-HPLC (XBridge C18 column eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min)

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

Procedure: 150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.

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

Procedure: 150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.

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

Procedure: 86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+

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

Procedure: 86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+

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

Procedure: To a solution of 2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 375B) (50 mg, 0.110 mmol) and DIPEA (0.031 mL, 0.221 mmol) in MeOH (0.5 mL)/DCM (0.5 ml) was added (S)-2-methyloxirane (64.1 mg, 1.104 mmol). The reaction was stirred for 16 hours. The solvents were removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 10-55% B over 25 minutes, then a 8-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(((S)-2-hydroxypropyl)amino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (14.5 mg). The solvents were removed the crude material was purified via preparative LC/MS with the following conditions Gradient: 10-55% B over 25 minutes a 8-minute hold Fractions containing the desired product dried via centrifugal evaporation

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

Procedure: A suspension of 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 367)(16 mg, 0.041 mmol) and (S)-(−)-propylene oxide (0.085 mL, 1.22 mmol) in a mixture of NMP (0.8 mL) and MeOH (0.2 mL) was stirred at 50° C. for 4.5 hr. The solvent was removed and the product was purified by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound (6.1 mg). This was converted to the mono HCl salt. The solvent was removed the product was purified by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles Gradient: 15-55% B over 20 minutes a 5-minute hold