ethyl (2S)-2-(trifluoromethylsulfonyloxy)propanoate

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

Procedure: A suspension of bis(2-chloroethyl)amine hydrochloride (0.392 g; 2.1 mmol) in 5N aqueous sodium hydroxide (3 mL) is extracted with ether (2×10 mL) and the combined extracts are washed with a minimum amount of water and saturated brine. The ethereal solution is dried quickly over magnesium sulfate and filtered. Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating. The residue is mixed with a solution of ethyl (S)-2-[(trifluoromethylsulfonyl)oxy]-propionate (0.5 g; 2 mmol) in tetrahydrofuran (1 mL). After stirring the reaction mixture for 24 hrs at room temperature, there is no visible precipitate. The volatiles are removed under reduced pressure and the remaining viscous oil is dissolved in ether (8 mL), and the slightly turbid solution is filtered after 60 minutes. The filtrate is treated dropwise with n-heptane to induce crystallization; the final ratio of n-heptane/ether is 1:3. The crystalline salt is collected by filtration and washed quickly with a small portion of ether. There is obtained 0.653 g (yield 83.3%) of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester, trifluoromethanesulfonate; mp 73–74.5° C.; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J=7.1 Hz, 3H), 1.76 (d, J=7.2 Hz, 3H), 3.87 (m, 2H), 4.00 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.57 (q, J=7.2 Hz, 1H), 9.02 (b, 1H). is extracted with ether (2×10 mL) the combined extracts are washed with a minimum amount of water and saturated brine The ethereal solution is dried quickly over magnesium sulfate filtered Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating The volatiles are removed under reduced pressure the remaining viscous oil is dissolved in ether (8 mL) the slightly turbid solution is filtered after 60 minutes The filtrate is treated dropwise with n-heptane crystallization The crystalline salt is collected by filtration washed quickly with a small portion of ether

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

Procedure: A suspension of bis(2-chloroethyl)amine hydrochloride (0.392 g; 2.1 mmol) in 5N aqueous sodium hydroxide (3 mL) is extracted with ether (2×10 mL) and the combined extracts are washed with a minimum amount of water and saturated brine. The ethereal solution is dried quickly over magnesium sulfate and filtered. Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating. The residue is mixed with a solution of ethyl (S)-2-[(trifluoromethylsulfonyl)oxy]-propionate (0.5 g; 2 mmol) in tetrahydrofuran (1 mL). After stirring the reaction mixture for 24 hrs at room temperature, there is no visible precipitate. The volatiles are removed under reduced pressure and the remaining viscous oil is dissolved in ether (8 mL), and the slightly turbid solution is filtered after 60 minutes. The filtrate is treated dropwise with n-heptane to induce crystallization; the final ratio of n-heptane/ether is 1:3. The crystalline salt is collected by filtration and washed quickly with a small portion of ether. There is obtained 0.653 g (yield 83.3%) of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester, trifluoromethanesulfonate; mp 73–74.5° C.; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J=7.1 Hz, 3H), 1.76 (d, J=7.2 Hz, 3H), 3.87 (m, 2H), 4.00 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.57 (q, J=7.2 Hz, 1H), 9.02 (b, 1H). is extracted with ether (2×10 mL) the combined extracts are washed with a minimum amount of water and saturated brine The ethereal solution is dried quickly over magnesium sulfate filtered Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating The volatiles are removed under reduced pressure the remaining viscous oil is dissolved in ether (8 mL) the slightly turbid solution is filtered after 60 minutes The filtrate is treated dropwise with n-heptane crystallization The crystalline salt is collected by filtration washed quickly with a small portion of ether

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

Procedure: To a mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 259 mmol) in anhydrous THF (800 mL) was added KHMDS solution (1M in THF, 259 mL, 259 mmol) drop-wise at 0° C. and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 117 g, 466 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (1000 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (4×500 mL). The combined organic phase was washed with brine (1 L), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 97%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 2H), 4.67-4.58 (d, J=14.8 Hz, 2H), 4.26-4.20 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). SFC (Table 1, Method 29) Rt=4.146 min.; [α]D20=31.45 (C=0.002 g/mL in methanol). was added The reaction mixture was quenched by the addition of water (1000 mL) The organic phase was separated the aqueous solution was extracted with EtOAc (4×500 mL) The combined organic phase was washed with brine (1 L) dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether)

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

Procedure: To a 0° C. suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (Preparation #2, Step A, 55 g, 283 mmol) in THF (1.1 L) was added drop-wise KHMDS (1M solution in THF, 283 mL, 283 mmol) and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 142 g, 567 mmol) was added drop-wise and the reaction mixture was stirred for 30 min. Water (1 L) was added and the aqueous solution was extracted with EtOAc (3×1 L). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give (R)-2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80.0 g, 96%) as an oil. 1H NMR (CDCl3, 400 MHz): δ 7.96 (dd, J=2.4, 8.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 5.34 (q, J=7.2 Hz, 1H), 4.81-4.66 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H). SFC (Table 2, Method 3) Rt=5.39 min. was added drop-wise the aqueous solution was extracted with EtOAc (3×1 L) The combined organic phase was dried over anhydrous Na2SO4 filtered The filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether)

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

Procedure: N-(3-Chloro-2-fluorophenyl)-6-[(isopropylamino)methyl]-7-methoxyquinazolin-4-amine (prepared as described in Example 56) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-isopropyl-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 6H); 1.31 (d, 3H); 3.10 (m, 1H); 3.63 (q, 1H); 3.98 (s, 3H); 4.02 (s, 2H); 7.20 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.59 (m, 1H); 8.42 (s, 2H); 9.68 (brs, 1H); Mass Spectrum: (M+H)+ 447.

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

Procedure: N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-({[(1S)-2-methoxy-1-methylethyl]amino}methyl)quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 3H); 1.32 (d, 3H); 3.04 (m, 1H); 3.14 (s, 3H); 3.22 (dd, 1H); 3.43 (dd, 1H); 3.69 (q, 1H); 3.96 (m, 4H); 4.05 (d, 1H); 7.19 (s, 1H); 7.29 (t, 1H); 7.49 (t, 1H); 7.60 (t, 1H); 8.43 (m, 2H); 9.64 (brs, 1H); 12.01 (brs, 1H); Mass Spectrum: (M+H)+ 477.

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

Procedure: N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine (prepared as described in Example 50) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-methoxyethyl)-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.28 (d, 3H); 2.85 (t, 2H); 3.13 (s, 3H); 3.34 (m, 2H); 3.56 (q, 1H); 3.93 (m, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.57 (m, 1H); 8.41 (m, 2H); 9.70 (brs, 1H); Mass Spectrum: (M+H)+ 463.

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

Procedure: N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-pyrrolidin-1-ylethyl)amino]methyl}quinazolin-4-amine (prepared as described in Example 47) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-pyrrolidin-1-ylethyl)-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.27 (d, 3H); 1.83 (m, 4H); 2.86 (m, 8H); 3.44 (q, 1H); 3.84 (d, 1H); 3.94 (d, 1H); 4.01 (s, 3H); 7.25 (s, 1H); 7.33 (t, 1H); 7.53 (m, 1H); 7.63 (m, 1H); 8.42 (s, 1H); 8.48 (s, 1H); 9.78 (brs, 1H); Mass Spectrum: (M+H)+ 502.

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

Procedure: Analogously to Example 35c, 0.32 ml of ethyl 2(S)-trifluoromethanesulphonyloxypropionate and 0.734 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are reacted. The title compound is obtained as a colourless oil. Rf=0.19 (1:3 EtOAc-heptane); Rt=5.93.

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

Procedure: A suspension of bis(2-chloroethyl)amine hydrochloride (0.392 g; 2.1 mmol) in 5N aqueous sodium hydroxide (3 mL) is extracted with ether (2×10 mL) and the combined extracts are washed with a minimum amount of water and saturated brine. The ethereal solution is dried quickly over magnesium sulfate and filtered. Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating. The residue is mixed with a solution of ethyl (S)-2-[(trifluoromethylsulfonyl)oxy]-propionate (0.5 g; 2 mmol) in tetrahydrofuran (1 mL). After stirring the reaction mixture for 24 hrs at room temperature, there is no visible precipitate. The volatiles are removed under reduced pressure and the remaining viscous oil is dissolved in ether (8 mL), and the slightly turbid solution is filtered after 60 minutes. The filtrate is treated dropwise with n-heptane to induce crystallization; the final ratio of n-heptane/ether is 1:3. The crystalline salt is collected by filtration and washed quickly with a small portion of ether. There is obtained 0.653 g (yield 83.3%) of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester, trifluoromethanesulfonate; mp 73–74.5° C.; 1H NMR (300 MHz, CDCl3) δ 1.35 (t, J=7.1 Hz, 3H), 1.76 (d, J=7.2 Hz, 3H), 3.87 (m, 2H), 4.00 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.57 (q, J=7.2 Hz, 1H), 9.02 (b, 1H). is extracted with ether (2×10 mL) the combined extracts are washed with a minimum amount of water and saturated brine The ethereal solution is dried quickly over magnesium sulfate filtered Tetrahydrofuran (2 mL) is added to the filtrate, and ether is carefully removed under reduced pressure on a rotavapor unit without heating The volatiles are removed under reduced pressure the remaining viscous oil is dissolved in ether (8 mL) the slightly turbid solution is filtered after 60 minutes The filtrate is treated dropwise with n-heptane crystallization The crystalline salt is collected by filtration washed quickly with a small portion of ether

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

Procedure: To a mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 259 mmol) in anhydrous THF (800 mL) was added KHMDS solution (1M in THF, 259 mL, 259 mmol) drop-wise at 0° C. and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 117 g, 466 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (1000 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (4×500 mL). The combined organic phase was washed with brine (1 L), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 97%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 2H), 4.67-4.58 (d, J=14.8 Hz, 2H), 4.26-4.20 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). SFC (Table 1, Method 29) Rt=4.146 min.; [α]D20=31.45 (C=0.002 g/mL in methanol). was added The reaction mixture was quenched by the addition of water (1000 mL) The organic phase was separated the aqueous solution was extracted with EtOAc (4×500 mL) The combined organic phase was washed with brine (1 L) dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether)

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

Procedure: To a 0° C. suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (Preparation #2, Step A, 55 g, 283 mmol) in THF (1.1 L) was added drop-wise KHMDS (1M solution in THF, 283 mL, 283 mmol) and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 142 g, 567 mmol) was added drop-wise and the reaction mixture was stirred for 30 min. Water (1 L) was added and the aqueous solution was extracted with EtOAc (3×1 L). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give (R)-2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80.0 g, 96%) as an oil. 1H NMR (CDCl3, 400 MHz): δ 7.96 (dd, J=2.4, 8.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 5.34 (q, J=7.2 Hz, 1H), 4.81-4.66 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H). SFC (Table 2, Method 3) Rt=5.39 min. was added drop-wise the aqueous solution was extracted with EtOAc (3×1 L) The combined organic phase was dried over anhydrous Na2SO4 filtered The filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether)