3,3-dimethyloxolan-2-one

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

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

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

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

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of dihydro-3,3-dimethyl-2(3H)-furanone (10 mmol; 1.14 g), aqueous 1 M KOH solution (10 mmol) and one drop of phenolphthalein indicator (0.5% w/v in EtOH/water (1:1)) is stirred at 105° C. for 3.5 hours. The mixture is cooled to ambient temperature and concentration under reduced pressure. To the residue is added 10 mL of EtOH. To the solution is added 50 ml of Et2O, and the solid isolated by filtration and dried under 100 mbar at 50° C. to give potassium 4-hydroxy-2,2-dimethylbutyrate (1.21 g, 71%). The mixture is cooled to ambient temperature concentration under reduced pressure To the residue is added 10 mL of EtOH To the solution is added 50 ml of Et2O the solid isolated by filtration dried under 100 mbar at 50° C.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.05 g (18.0 mmol) of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Eur. Pat. application EPO 178,189), 4.52 g (21.6 mmol) of methyl 4-bromo-2,2dimethylbutyrate (prepared by treatment of 2,2-dimethylbutyrolactone with gaseous HBr, conversion to the acid chloride with oxalyl chloride, and treatment with methanol and triethylamine), and 2.99 g (21.6 mmol) of anhydrous K2CO3 in 40 ml of DMF is heated at 100° C. for 4 hrs under N2. The DMF is removed under vacuum, the residue taken up in 300 ml of 50:50 waterEtOAc, the organic phase washed with cold 5% NaOH (50 ml), then water (50 ml), and dried (MgSO4). The solvent is removed under vacuum to give an oily residue The oil is crystallized by the addition of 50 ml of ethyl ether to give 4.75 g of 6-[4-(3-carbomethoxy3,3-dimethylpropyloxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a white crystalline solid, m.p. 109°-110° C. Yield, 75%. The DMF is removed under vacuum the organic phase washed with cold 5% NaOH (50 ml) water (50 ml), and dried (MgSO4) The solvent is removed under vacuum to give an oily residue The oil is crystallized by the addition of 50 ml of ethyl ether

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

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 500 mg, 1.299 mmol) and 3,3-dimethyldihydrofuran-2(3H)-one (222 mg, 1.948 mmol) in THF (10 mL) was treated with trimethylaluminum (2 M in toluene, 562 mg, 7.79 mmol) dropwise at rt. The mixture was heated at 50° C. for 1.5 h, cooled to rt and treated with water. The mixture was filtered through Celite and the solids were washed thoroughly with DCM and methanol. The filtrate was washed with water, dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from DCM to 10% ammonia-methanol-DCM) to provide 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide as a yellow solid (250 mg, 46%). Mass spectrum m/z 418, 420 (M+H)+. cooled to rt The mixture was filtered through Celite the solids were washed thoroughly with DCM and methanol The filtrate was washed with water dried concentrated the residue was purified by column chromatography ( eluting with a gradient from DCM to 10% ammonia-methanol-DCM)

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

Procedure: To a solution of 3,3-dimethyl-dihydrofuran-2(3H)-one (2.04 g, 17.9 mmol) in THF (15 mL) were added 2-chlorobenzylamine (2.4 mL, 19.9 mmol, 1.1 equiv.) and AlMe3 (2M in toluene, 4.5 mL, 9 mmol, 0.5 equiv.). The reaction mixture was stirred for 3 days. The reaction mixture was saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated to give N-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide as a white solid (3.8 g, 83%), which was used without further purification. LRMS (M+H+) m/z 256.0. extracted with EtOAc The organic layer was washed with saturated NaHCO3, H2O and brine dried over Na2SO4 concentrated

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

Procedure: To a solution of 3,3-dimethyl-dihydrofuran-2(3H)-one (2.04 g, 17.9 mmol) in THF (15 mL) were added 2-chlorobenzylamine (2.4 mL, 19.9 mmol, 1.1 equiv.) and AlMe3 (2M in toluene, 4.5 mL, 9 mmol, 0.5 equiv.). The reaction mixture was stirred for 3 days. The reaction mixture was saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated to give N-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide as a white solid (3.8 g, 83%), which was used without further purification. LRMS (M+H+) m/z 256.0. extracted with EtOAc The organic layer was washed with saturated NaHCO3, H2O and brine dried over Na2SO4 concentrated

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

Procedure: A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H2O (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and acidified to pH 5 with aqueous HCl solution. The mixture was then extracted with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl-butanoic acid compound 54-B (4 g). was heated at reflux for 2 h The mixture was then extracted with ethyl acetate 3 times The combined organic layers were washed with brine dried over Na2SO4 concentrated under reduced pressure