methyl 5-(bromomethyl)-2-fluorobenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compounds were prepared from 6-fluoro-1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 6-fluoroquinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using procedures similar to those of compounds of Examples 1 and 2), and the corresponding substituted piperazine using a procedure similar to those described for the synthesis of compound of Example 3.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compounds were prepared from 1-(3-carboxy-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione (prepared from 6-methylquinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those for compounds of Example 1 and 2), and the corresponding substituted piperazine using a procedure similar to those described for the synthesis of compound of Example 3.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The following compounds were prepared from 1-(3-carboxy-4-fluorobenzyl)-6-methylquinazoline-2,4(1H,3H)-dione (prepared from 6-methylquinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those for compounds of Example 1 and 2), and the corresponding substituted piperazine using a procedure similar to those described for the synthesis of compound of Example 3.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared from quinazoline-2,4(1H,3H)-dione and methyl 5-(bromomethyl)-2-fluorobenzoate using a procedure similar to those described for the synthesis of compound of Example 1. 1H NMR (DMSO-d6): 11.75 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.67-7.55 (m, 2H), 7.32-7.21 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H). MS: m/z 329.1 [M+H]+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)quinazoline with a substituted alkyl 3-(halomethyl)benzoate, such as methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-cyclopentylcarbonylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione. Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)quinazoline with a substituted alkyl 3-(halomethyl)benzoate, such as methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxy-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-cyclopentylcarbonylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione. Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)-5,6,7,8-tetrahydroquinazoline with methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazol ine-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(4-fluoro-3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(4-fluoro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)-5,6,7,8-tetrahydroquinazoline with methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazol ine-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(4-fluoro-3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(4-fluoro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 5-bromomethyl-2-fluorobenzoate (12.49 g, 50.6 mmol) in methylene chloride (150 mL) at 0° C. is added BBr3 (5.26 mL, 55.62 mmol) slowly, via syringe. The solution is then warmed to room temperature over 2.5 hours, and then is cooled back down to 0° C., and allyl alcohol (103 mL, 1.52 mol) is added dropwise. The solution is then stirred overnight, after which time it is diluted with CH2Cl2 (250 mL), then washed with sat'd aq. NaHCO3 (2×300 mL), brine (150 ml), and dried over MgSO4. Evaporation of solvent yields allyl 5-bromomethyl-2-fluorobenzoate. is added dropwise washed with sat'd aq. NaHCO3 (2×300 mL), brine (150 ml) dried over MgSO4 Evaporation of solvent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 5-bromomethyl-2-fluorobenzoate (12.49 g, 50.6 mmol) in methylene chloride (150 mL) at 0° C. is added BBr3 (5.26 mL, 55.62 mmol) slowly, via syringe. The solution is then warmed to room temperature over 2.5 hours, and then is cooled back down to 0° C., and allyl alcohol (103 mL, 1.52 mol) is added dropwise. The solution is then stirred overnight, after which time it is diluted with CH2Cl2 (250 mL), then washed with sat'd aq. NaHCO3 (2×300 mL), brine (150 ml), and dried over MgSO4. Evaporation of solvent yields allyl 5-bromomethyl-2-fluorobenzoate. is added dropwise washed with sat'd aq. NaHCO3 (2×300 mL), brine (150 ml) dried over MgSO4 Evaporation of solvent