2-phenylmethoxyisoindole-1,3-dione

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: When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.

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

Procedure: When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.

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

Procedure: When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.

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: The title compound was prepared from 2-(benzyloxy)isoindoline-1,3-dione and hydrazine monohydrate in 64% yield using the same procedure as described in the synthesis of intermediate G. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37 (m, 5H), 6.70 (s, 2H).

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

Procedure: The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and (bromomethyl)benzene in 64% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method A): [MH]+=254, tR=5.19 min.

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

Procedure: To a solution of 2-hydroxyisoindoline-1,3-dione (1.0 g, 6.13 mmol) in DMSO (10 mL) was added Cs2CO3 (1.997 g, 6.13 mmol). The resulting mixture was stirred at it for 30 min. 1-bromomethyl 4-methoxy-benzene (0.88 mL, 6.13 mmol) was then added dropwise. After stirring at 50° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give 2-(benzyloxy)isoindoline-1,3-dione as a white solid (0.9 g, 49%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.85 (s, 4H), 7.42 (d, 2H), 6.94 (d, 2H), 5.08 (s, 2H), 3.75 (s, 3H). After stirring at 50° C. overnight the reaction mixture was quenched with NH4Cl (aq) extracted with EtOAc washed with NH4Cl (aq) dried over Na2SO4 filtered concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes

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

Procedure: The title compound was prepared from 2-(benzyloxy)isoindoline-1,3-dione and hydrazine monohydrate in 64% yield using the same procedure as described in the synthesis of intermediate G. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37 (m, 5H), 6.70 (s, 2H).

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

Procedure: The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and (bromomethyl)benzene in 64% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method A): [MH]+=254, tR=5.19 min.