1,4-dioxane-2,3-diol

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-4,5-diamino-2-methylpyrimidine (317 mg, 2.0 mmol) and 1,4-dioxane-2,3-diol (240 mg, 2.0 mmol) in EtOH (15 mL) was stirred at 25° C. for 1 h. TLC analysis (1:1 hexane/EtOAc on SiO2) indicated complete consumption of starting material. 1-(4-Methoxyphenyl)-ethylamine (332 mg, 2.2 mmol) and triethylamine (Et3N, 0.3 mL, 2.2 mmol) were added, and the reaction was stirred overnight. The majority of solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over SiO2, eluting with 2:1 EtOAc/hexane, then 100% EtOAc to afford [1-(4-methoxyphenyl)ethyl]-2-methylpteridin-4-yl-amine (126 mg) as a brown oil. consumption of starting material the reaction was stirred overnight The majority of solvent was removed in vacuo the residue was partitioned between EtOAc and H2O The organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over SiO2 eluting with 2:1 EtOAc/hexane

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

Procedure: A solution of (S)-3-benzo[1,2,5]thiadiazol-5-yl-2-methyl-propan-1-ol (5 g, 24 mmol) in EtOH (60 ml) is cooled to 0° and then treated with half concentrated HCl (40 ml, ca. 200 mmol). Zn dust (8.5 g, 130 mmol) is added in 1 g portions at 0°, one portion every 5 minutes. After the last addition, the mixture is stirred at 10° to 15° for 45 minutes. Under ice cooling, half concentrated NH4OH (40 ml, ca. 290 mmol) is added dropwise. The mixture is filtered over Hyflo, the filtrate concentrated under reduced pressure and the remaining aqueous phase twice extracted with EtOAc (150 ml, 50 ml). Drying over Na2SO4 and evaporation give the diamnino intermediate as a brownish, clear oil which tends to darken upon exposure to light and air. This intermediate is dissolved in absolute EtOH (60 ml) and cooled to 0°. 1,4dioxane-2,3-diol (3.75 g, 31.2 mmol) is added at once and the solution stirred at room temperature for 2 h. The mixture is evaporated to dryness, the residue distributed between brine (50 ml) and DCM (50 ml), the organic phase washed with brine (25 ml), dried over Na2SO4 and evaporated to afford (S)-2-methyl-3-quinoxalin-6-yl-propan-1-ol as a brownish, clear, viscous oil of sufficient purity for the next step. ee=91% (HPLC on chiral stat. phase). TLC (silicagel, DCM/MeOH/NH4OH 85:15:1): rf 0.68. every 5 minutes After the last addition The mixture is filtered over Hyflo the filtrate concentrated under reduced pressure the remaining aqueous phase twice extracted with EtOAc (150 ml, 50 ml) Drying over Na2SO4 and evaporation give the diamnino intermediate as a brownish, clear oil which cooled to 0° stirred at room temperature for 2 h The mixture is evaporated to dryness the organic phase washed with brine (25 ml) dried over Na2SO4 evaporated

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

Procedure: A solution of (S)-3-benzo[1,2,5]thiadiazol-5-yl-2-methyl-propan-1-ol (5 g, 24 mmol) in EtOH (60 ml) is cooled to 0° and then treated with half concentrated HCl (40 ml, ca. 200 mmol). Zn dust (8.5 g, 130 mmol) is added in 1 g portions at 0°, one portion every 5 minutes. After the last addition, the mixture is stirred at 10° to 15° for 45 minutes. Under ice cooling, half concentrated NH4OH (40 ml, ca. 290 mmol) is added dropwise. The mixture is filtered over Hyflo, the filtrate concentrated under reduced pressure and the remaining aqueous phase twice extracted with EtOAc (150 ml, 50 ml). Drying over Na2SO4 and evaporation give the diamnino intermediate as a brownish, clear oil which tends to darken upon exposure to light and air. This intermediate is dissolved in absolute EtOH (60 ml) and cooled to 0°. 1,4dioxane-2,3-diol (3.75 g, 31.2 mmol) is added at once and the solution stirred at room temperature for 2 h. The mixture is evaporated to dryness, the residue distributed between brine (50 ml) and DCM (50 ml), the organic phase washed with brine (25 ml), dried over Na2SO4 and evaporated to afford (S)-2-methyl-3-quinoxalin-6-yl-propan-1-ol as a brownish, clear, viscous oil of sufficient purity for the next step. ee=91% (HPLC on chiral stat. phase). TLC (silicagel, DCM/MeOH/NH4OH 85:15:1): rf 0.68. every 5 minutes After the last addition The mixture is filtered over Hyflo the filtrate concentrated under reduced pressure the remaining aqueous phase twice extracted with EtOAc (150 ml, 50 ml) Drying over Na2SO4 and evaporation give the diamnino intermediate as a brownish, clear oil which cooled to 0° stirred at room temperature for 2 h The mixture is evaporated to dryness the organic phase washed with brine (25 ml) dried over Na2SO4 evaporated

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

Procedure: Charts A1-A3 summarise the routes used in the synthesis of a series of pyrido[3,2-d]pyrimidin-4-ol derivatives. The preparation of the derivatives of [1,7]naphthyridin-8-ol is described in Charts B1-B2. Compound B1 was prepared following the literature method2 for the synthesis of a similar compound. The synthesis of the pyrido[2,3-d]pyridazin-8-ol itself and derivatives C1 and C2 followed the method previously described3 by Brzezinski and coworkers. Further derivatives in this series were prepared following the routes summarised in Charts C1-C4. Charts D1-D2 show the routes to a series of [1,6]naphthyridin-8-ol derivatives. The synthesis of compound D1 used the method4 of Blanco and coworkers. Other members in this series have been prepared following the routes shown in Charts D1-D2. Chart E1 describes the route to a series of pyrido[3,4-b]pyrazin-5-ol derivatives. Condensation of 1,2,3-triaminopyridine with 2,3-dihydroxy-1,4-dioxan gave pyrido[3,4-b]pyrazin-5-ol (E1), the parent compound in this series; the same reaction employing 2,3,4-triaminopyridine as starting material (Chart F1) gave pyrido[3,4-b]pyrazin-8-ol (F1). Further derivatives in the pyrido[3,4-b]pyrazin-5-ol and pyrido[3,4-b]pyrazin-8-ol classes were prepared using the routes shown in Charts E1 and F1. Charts G1-G2 show the routes employed in the synthesis of a range of [1,5]naphthyridin-4,8-diol and [1,5]naphthyridin-8-ol derivatives. The synthesis of compound G1, the precursor to the parent compound, [1,5]naphthyridin-4,8-diol, followed the route described5 by Brown and Dewar. Pyrido[4,3-d]pyrimidin-8-ol (H1) was prepared4 following the route shown in Chart H1, employing 4,5-pyrimidinedicarboxylic acid as starting material. Further derivatives in this class were prepared using routes as shown in Charts H1 and H2. for the synthesis of a similar compound were prepared Other members in this series have been prepared

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

Procedure: Charts A1-A3 summarise the routes used in the synthesis of a series of pyrido[3,2-d]pyrimidin-4-ol derivatives. The preparation of the derivatives of [1,7]naphthyridin-8-ol is described in Charts B1-B2. Compound B1 was prepared following the literature method2 for the synthesis of a similar compound. The synthesis of the pyrido[2,3-d]pyridazin-8-ol itself and derivatives C1 and C2 followed the method previously described3 by Brzezinski and coworkers. Further derivatives in this series were prepared following the routes summarised in Charts C1-C4. Charts D1-D2 show the routes to a series of [1,6]naphthyridin-8-ol derivatives. The synthesis of compound D1 used the method4 of Blanco and coworkers. Other members in this series have been prepared following the routes shown in Charts D1-D2. Chart E1 describes the route to a series of pyrido[3,4-b]pyrazin-5-ol derivatives. Condensation of 1,2,3-triaminopyridine with 2,3-dihydroxy-1,4-dioxan gave pyrido[3,4-b]pyrazin-5-ol (E1), the parent compound in this series; the same reaction employing 2,3,4-triaminopyridine as starting material (Chart F1) gave pyrido[3,4-b]pyrazin-8-ol (F1). Further derivatives in the pyrido[3,4-b]pyrazin-5-ol and pyrido[3,4-b]pyrazin-8-ol classes were prepared using the routes shown in Charts E1 and F1. Charts G1-G2 show the routes employed in the synthesis of a range of [1,5]naphthyridin-4,8-diol and [1,5]naphthyridin-8-ol derivatives. The synthesis of compound G1, the precursor to the parent compound, [1,5]naphthyridin-4,8-diol, followed the route described5 by Brown and Dewar. Pyrido[4,3-d]pyrimidin-8-ol (H1) was prepared4 following the route shown in Chart H1, employing 4,5-pyrimidinedicarboxylic acid as starting material. Further derivatives in this class were prepared using routes as shown in Charts H1 and H2. for the synthesis of a similar compound were prepared Other members in this series have been prepared

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

Procedure: 200 mg (0.598 mmol) of the compound from example 43A were initially charged in ethanol (10 ml), then 144 mg (1.20 mmol) of 2,3-dihydroxy-1,4-dioxane were added and the reaction mixture was stirred at RT for 5 h. The solid formed was filtered off, washed with ethanol and dried under high vacuum. This gave 90 mg (41% of theory) of the title compound in solid form. The solid formed was filtered off washed with ethanol dried under high vacuum

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-4,5-diamino-2-methylpyrimidine (317 mg, 2.0 mmol) and 1,4-dioxane-2,3-diol (240 mg, 2.0 mmol) in EtOH (15 mL) was stirred at 25° C. for 1 h. TLC analysis (1:1 hexane/EtOAc on SiO2) indicated complete consumption of starting material. 1-(4-Methoxyphenyl)-ethylamine (332 mg, 2.2 mmol) and triethylamine (Et3N, 0.3 mL, 2.2 mmol) were added, and the reaction was stirred overnight. The majority of solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over SiO2, eluting with 2:1 EtOAc/hexane, then 100% EtOAc to afford [1-(4-methoxyphenyl)ethyl]-2-methylpteridin-4-yl-amine (126 mg) as a brown oil. consumption of starting material the reaction was stirred overnight The majority of solvent was removed in vacuo the residue was partitioned between EtOAc and H2O The organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over SiO2 eluting with 2:1 EtOAc/hexane

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-4,5-diamino-2-methylpyrimidine (317 mg, 2.0 mmol) and 1,4-dioxane-2,3-diol (240 mg, 2.0 mmol) in EtOH (15 mL) was stirred at 25° C. for 1 h. TLC analysis (1:1 hexane/EtOAc on SiO2) indicated complete consumption of starting material. 1-(4-Methoxyphenyl)-ethylamine (332 mg, 2.2 mmol) and triethylamine (Et3N, 0.3 mL, 2.2 mmol) were added, and the reaction was stirred overnight. The majority of solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over SiO2, eluting with 2:1 EtOAc/hexane, then 100% EtOAc to afford [1-(4-methoxyphenyl)ethyl]-2-methylpteridin-4-yl-amine (126 mg) as a brown oil. consumption of starting material the reaction was stirred overnight The majority of solvent was removed in vacuo the residue was partitioned between EtOAc and H2O The organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over SiO2 eluting with 2:1 EtOAc/hexane

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

Procedure: 4-Chloro-2-methyl-pteridine. A mixture of 6-chloro-2-methyl-pyrimidine-4,5-diamine (37 mg, 0.233 mmol) and 1,4-dioxane-2,3-diol (32 mg, 0.266 mmol) in 0.8 mL of absolute ethanol was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography (50% ethyl acetate/hexane) to give the title compound (41 mg, 0.227 mmol, 97%). 1H NMR (CDCl3): 9.24 (d, J=1.8, 1H), 9.05 (d, J=1.5, 1H), 2.99 (s, 3H). The reaction mixture was evaporated to dryness the residue was purified by column chromatography (50% ethyl acetate/hexane)

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

Procedure: The same synthesis procedures as in Example 1 were conducted except for using 2-chloro-5-cyanopyridine and 1,4-dioxane-2,3-diol in place of 4-cyanopyridine and a 40% glyoxal aqueous solution, respectively, and, after completion of the reaction, the organic layer was distilled under reduced pressure of 3.0 to 3.1 Torr to obtain a 150 to 152° C. fraction. Thus, there was obtained 151.0 g (yield: 82.5%) of the end product as pale yellow crystals. HPLC analysis revealed that purity of the product was 99.1%. The same synthesis procedures as in Example 1 the organic layer was distilled under reduced pressure of 3.0 to 3.1 Torr to obtain a 150 to 152° C. fraction

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

Procedure: A mixture of 4-(3-bromoanilino)-6,7-diaminoquinazoline (90 mg, 0.27 mmol) and 1,4-dioxane-2,3-diol (0.2 g, 1.6 mmol) [Venuti, M. C.; Synthesis, 1982, 61-63] in MeOH (20 mL) is stirred at room temperature overnight to give a precipitate of 4-(3-bromoanilino)pyrazino[2,3-g]quinazoline (80 mg, 83%). 1H NMR (DMSO) δ10.45 (1H, brs), 9.52 (1H, s), 9.09 (1H, d, J=1.6 Hz), 9.06 (1H, d, J=1.6 Hz), 8.71 (1H, s), 8.44 (1H, s), 8.32 (1H, brs), 7.99 (1H, m), 7.45-7.34 (2H, m). ##STR24##

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

Procedure: 4-Chloro-2-methyl-pteridine. A mixture of 6-chloro-2-methyl-pyrimidine-4,5-diamine (37 mg, 0.233 mmol) and 1,4-dioxane-2,3-diol (32 mg, 0.266 mmol) in 0.8 mL of absolute ethanol was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography (50% ethyl acetate/hexane) to give the title compound (41 mg, 0.227 mmol, 97%). 1H NMR (CDCl3): 9.24 (d, J=1.8, 1H), 9.05 (d, J=1.5, 1H), 2.99 (s, 3H). The reaction mixture was evaporated to dryness the residue was purified by column chromatography (50% ethyl acetate/hexane)