4-methoxybut-2-ynoic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Isobutyl chloroformate (0.432 g, 3.2 mmol) and N-methylmorpholine (0.959 g, 9.48 mmol) were added to an ice cold solution of 0.720 g (6.32 mmol) of 4-methoxy-but-2-ynoic acid in 30 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 0.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 8 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.270 g of 4-Methoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 411. the mixture was stirred for 2 hr at 0° C The reaction was then quenched with ice water poured into saturated sodium bicarbonate the product was extracted with ethyl acetate Chromatography of the extract on silica gel eluting with methanol/ethyl acetate (15:85)

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

Procedure: This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-methoxybut-2-ynoic acid (Intermediate 50), to afford the title compound (9.1 mg, 24.7%). Data: UPLC (C) Rt: 1.44 min; m/z 496.2 (M+H)+. This compound was prepared, in an analogous manner

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

Procedure: Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.). the mixture was stirred at 0° C. for 2 hr The reaction was quenched with ice water poured into saturated sodium bicarbonate and brine extracted with ethyl acetate The ethyl acetate layer was concentrated purified by thin-layer chromatography eluted with 5% methanol in chlorform The product was collected dried in vacuo

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

Procedure: Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.). the mixture was stirred at 0° C. for 2 hr The reaction was quenched with ice water poured into saturated sodium bicarbonate and brine extracted with ethyl acetate The ethyl acetate layer was concentrated purified by thin-layer chromatography eluted with 5% methanol in chlorform The product was collected dried in vacuo

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

Procedure: Isobutyl chloroformate(0.410 g, 3.0 mmol) and N-methylmorpholine(0.910 g, 9.0 mmol) were added to an ice cold solution of 0.680 g (6.0 mmol) of 4-methoxy-2-butynoic acid in 20 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.500 g (01.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water, and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.200 g (35%) of yellow solid; ESMS m/z 435.1 (M+H+); mp 198-202° C.(dec). the mixture was stirred at 0° C. for 2 h The reaction was quenched with ice water poured into saturated sodium bicarbonate and brine The product was collected washed with ethyl acetate dried in vacuo

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

Procedure: Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.). the mixture was stirred at 0° C. for 2 hr The reaction was quenched with ice water poured into saturated sodium bicarbonate and brine extracted with ethyl acetate The ethyl acetate layer was concentrated purified by thin-layer chromatography eluted with 5% methanol in chlorform The product was collected dried in vacuo

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

Procedure: Isobutyl chloroformate (0.410 g, 3.0 mmol) and N-methylmorpholine (0.910 g, 9.0 mmol) were added to an ice cold solution of 0.680 g (6.0 mmol) of 4-methoxy-2-butynoic acid in 20 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.500 g (01.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water, and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.200 g (35%) of yellow solid; ESMS m/z 435.1 (M+H+); mp 198-202° C. (dec). the mixture was stirred at 0° C. for 2 h The reaction was quenched with ice water poured into saturated sodium bicarbonate and brine The product was collected washed with ethyl acetate dried in vacuo

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

Procedure: Isobutyl chloroformate (0.432 g, 3.2 mmol) and N-methylmorpholine (0.959 g, 9.48 mmol) were added to an ice cold solution of 0.720 g (6.32 mmol) of 4-methoxy-but-2-ynoic acid in 30 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 0.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 8 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.270 g of 4-Methoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 411. the mixture was stirred for 2 hr at 0° C The reaction was then quenched with ice water poured into saturated sodium bicarbonate the product was extracted with ethyl acetate Chromatography of the extract on silica gel eluting with methanol/ethyl acetate (15:85)

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

Procedure: This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-methoxybut-2-ynoic acid (Intermediate 50), to afford the title compound (9.1 mg, 24.7%). Data: UPLC (C) Rt: 1.44 min; m/z 496.2 (M+H)+. This compound was prepared, in an analogous manner

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

Procedure: Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.). the mixture was stirred at 0° C. for 2 hr The reaction was quenched with ice water poured into saturated sodium bicarbonate and brine extracted with ethyl acetate The ethyl acetate layer was concentrated purified by thin-layer chromatography eluted with 5% methanol in chlorform The product was collected dried in vacuo