2,2-dimethyl-5-propan-2-ylidene-1,3-dioxane-4,6-dione

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

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 2,2-dimethyl-5-(1-methylethylidene)-1,3-dioxane-4,6-dione and potassium cyanide. This compound was prepared

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from acetone and 2,2-dimethyl-1,3-dioxane-4,6-dione. This compound was prepared

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

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

Procedure: Meldrum's acid (100.0 g) was charged to a dry, nitrogen flushed reactor. Acetone (632.1 mL) was then charged to the reactor and the mixture was agitated for about 5 minutes at 20° C.-25° C. until a solution was obtained. Acetic acid (0.791 mL) was then charged to the reactor, followed by 1.215 mL of morpholine, and the solution was agitated at 20° C.-25° C. for about 48 hours. An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which may be monitored by either GC or 1H-NMR. If the ratio of the area % of 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione to Meldrum's acid is ≧80:20, proceed to the next step; if it is not, the batch should be aged for an additional 3 hours before repeating the check. The acetone was distilled at about 40° C. and 150-200 mmHg. After approximately two-thirds of the reaction volume was distilled out, 563 mL of methylcyclohexane was charged and the distillation continued until the acetone stopped distilling over. A total of 645 mL (508 g) of distillate was collected for this run. MTBE (500 mL) was charged to the batch at 40° C. and the batch was cooled to 20° C.-25° C. The solution was observed to make sure a cloudy solution was obtained (no solids). If there is solid present, additional MTBE may be charged to effect dissolution. The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water). The MTBE was distilled out at 40° C.-45° C. and 150-200 mmHg. A total of 400 mL (300 g) distillate was collected for this run. As distillation proceeds, a white slurry formed. The internal temperature was ramped to 0° C.-5° C. over 1 hour and then held at this temperature for at least 1 hour. The slurry was filtered, the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane, and the solid was dried at 20° C.-35° C. and 25-50 mmHg for no less than 4 hours. 2,2-Dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione was obtained as a white solid (93.7 g, 70.4% yield, 96.0 wt. % purity by assay). was obtained the solution was agitated at 20° C.-25° C. for about 48 hours An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which the batch should be aged for an additional 3 hours The acetone was distilled at about 40° C. After approximately two-thirds of the reaction volume was distilled out 563 mL of methylcyclohexane was charged the distillation stopped distilling over A total of 645 mL (508 g) of distillate was collected for this run MTBE (500 mL) was charged to the batch at 40° C. the batch was cooled to 20° C.-25° C was obtained (no solids) may be charged dissolution The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water) The MTBE was distilled out at 40° C.-45° C. A total of 400 mL (300 g) distillate was collected for this run As distillation proceeds a white slurry formed The internal temperature was ramped to 0° C.-5° C. over 1 hour held at this temperature for at least 1 hour The slurry was filtered the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane the solid was dried at 20° C.-35° C. 25-50 mmHg for no less than 4 hours

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

Procedure: Meldrum's acid (100.0 g) was charged to a dry, nitrogen flushed reactor. Acetone (632.1 mL) was then charged to the reactor and the mixture was agitated for about 5 minutes at 20° C.-25° C. until a solution was obtained. Acetic acid (0.791 mL) was then charged to the reactor, followed by 1.215 mL of morpholine, and the solution was agitated at 20° C.-25° C. for about 48 hours. An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which may be monitored by either GC or 1H-NMR. If the ratio of the area % of 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione to Meldrum's acid is ≧80:20, proceed to the next step; if it is not, the batch should be aged for an additional 3 hours before repeating the check. The acetone was distilled at about 40° C. and 150-200 mmHg. After approximately two-thirds of the reaction volume was distilled out, 563 mL of methylcyclohexane was charged and the distillation continued until the acetone stopped distilling over. A total of 645 mL (508 g) of distillate was collected for this run. MTBE (500 mL) was charged to the batch at 40° C. and the batch was cooled to 20° C.-25° C. The solution was observed to make sure a cloudy solution was obtained (no solids). If there is solid present, additional MTBE may be charged to effect dissolution. The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water). The MTBE was distilled out at 40° C.-45° C. and 150-200 mmHg. A total of 400 mL (300 g) distillate was collected for this run. As distillation proceeds, a white slurry formed. The internal temperature was ramped to 0° C.-5° C. over 1 hour and then held at this temperature for at least 1 hour. The slurry was filtered, the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane, and the solid was dried at 20° C.-35° C. and 25-50 mmHg for no less than 4 hours. 2,2-Dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione was obtained as a white solid (93.7 g, 70.4% yield, 96.0 wt. % purity by assay). was obtained the solution was agitated at 20° C.-25° C. for about 48 hours An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which the batch should be aged for an additional 3 hours The acetone was distilled at about 40° C. After approximately two-thirds of the reaction volume was distilled out 563 mL of methylcyclohexane was charged the distillation stopped distilling over A total of 645 mL (508 g) of distillate was collected for this run MTBE (500 mL) was charged to the batch at 40° C. the batch was cooled to 20° C.-25° C was obtained (no solids) may be charged dissolution The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water) The MTBE was distilled out at 40° C.-45° C. A total of 400 mL (300 g) distillate was collected for this run As distillation proceeds a white slurry formed The internal temperature was ramped to 0° C.-5° C. over 1 hour held at this temperature for at least 1 hour The slurry was filtered the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane the solid was dried at 20° C.-35° C. 25-50 mmHg for no less than 4 hours

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

Procedure: Meldrum's acid (100.0 g) was charged to a dry, nitrogen flushed reactor. Acetone (632.1 mL) was then charged to the reactor and the mixture was agitated for about 5 minutes at 20° C.-25° C. until a solution was obtained. Acetic acid (0.791 mL) was then charged to the reactor, followed by 1.215 mL of morpholine, and the solution was agitated at 20° C.-25° C. for about 48 hours. An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which may be monitored by either GC or 1H-NMR. If the ratio of the area % of 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione to Meldrum's acid is ≧80:20, proceed to the next step; if it is not, the batch should be aged for an additional 3 hours before repeating the check. The acetone was distilled at about 40° C. and 150-200 mmHg. After approximately two-thirds of the reaction volume was distilled out, 563 mL of methylcyclohexane was charged and the distillation continued until the acetone stopped distilling over. A total of 645 mL (508 g) of distillate was collected for this run. MTBE (500 mL) was charged to the batch at 40° C. and the batch was cooled to 20° C.-25° C. The solution was observed to make sure a cloudy solution was obtained (no solids). If there is solid present, additional MTBE may be charged to effect dissolution. The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water). The MTBE was distilled out at 40° C.-45° C. and 150-200 mmHg. A total of 400 mL (300 g) distillate was collected for this run. As distillation proceeds, a white slurry formed. The internal temperature was ramped to 0° C.-5° C. over 1 hour and then held at this temperature for at least 1 hour. The slurry was filtered, the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane, and the solid was dried at 20° C.-35° C. and 25-50 mmHg for no less than 4 hours. 2,2-Dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione was obtained as a white solid (93.7 g, 70.4% yield, 96.0 wt. % purity by assay). was obtained the solution was agitated at 20° C.-25° C. for about 48 hours An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which the batch should be aged for an additional 3 hours The acetone was distilled at about 40° C. After approximately two-thirds of the reaction volume was distilled out 563 mL of methylcyclohexane was charged the distillation stopped distilling over A total of 645 mL (508 g) of distillate was collected for this run MTBE (500 mL) was charged to the batch at 40° C. the batch was cooled to 20° C.-25° C was obtained (no solids) may be charged dissolution The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water) The MTBE was distilled out at 40° C.-45° C. A total of 400 mL (300 g) distillate was collected for this run As distillation proceeds a white slurry formed The internal temperature was ramped to 0° C.-5° C. over 1 hour held at this temperature for at least 1 hour The slurry was filtered the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane the solid was dried at 20° C.-35° C. 25-50 mmHg for no less than 4 hours

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution (183 mL, 182.79 mmol) of 1M isopropylmagnesium chloride in THF was added dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene (50.0 g, 166.17 mmol) in anhydrous THF (96 mL) over 20 min at −20° C. under argon atmosphere. The reaction mixture was stirred at −20° C. for 30 min, and added dropwise to a solution of 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene (84 mL) over 20 min at −20° C., and then the used container was washed with THF (24 mL). The reaction mixture was stirred at 0° C. for 3 hr, 10% aqueous citric acid solution (200 mL) was added thereto at 0° C., and the mixture was extracted with toluene (200 mL). The organic layer was concentrated under reduced pressure to give 5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale-yellow oil. the used container was washed with THF (24 mL) The reaction mixture was stirred at 0° C. for 3 hr 10% aqueous citric acid solution (200 mL) was added at 0° C., and the mixture was extracted with toluene (200 mL) The organic layer was concentrated under reduced pressure

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

Procedure: Morpholine (261 mg, 261 μL, 2.99 mmol) and acetic acid (200 mg, 191 μL, 3.32 mmol) were added to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (24.0 g, 166.17 mmol) in acetone (120 g) at room temperature under argon atmosphere, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogencarbonate solution (200 mL), and the mixture was extracted with toluene (200 mL). The organic layer was washed with 10% brine (200 mL), and the solvent was evaporated under reduced pressure to give 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione as a white solid. The obtained white solid was subjected to azeotropy with toluene (100 mL) (×2). The reaction mixture was concentrated under reduced pressure To the obtained residue was added saturated aqueous sodium hydrogencarbonate solution (200 mL) the mixture was extracted with toluene (200 mL) The organic layer was washed with 10% brine (200 mL) the solvent was evaporated under reduced pressure

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

Procedure: The 5-(2-(3-methoxyphenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (85.C) was prepared via the procedure described in Huang, X.; et. al.; Tetrahedron Letters; 1982, (1); pp. 75-76. from (3-methoxyphenyl)magnesium bromide (1.0 M in THF solution from Aldrich) and 85.B. 1H NMR (400 MHz, CDCl3) ppm 7.26 (1H, t, J=8.0 Hz), 6.94 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=2.2 Hz), 6.79 (1H, dd, J=8.2, 2.3 Hz), 3.81 (3H, s), 3.62 (1H, s), 1.67 (6H, s), 1.66 (3H, s), 1.34 (3H, s).

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

Procedure: The 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione (85.B) was prepared from 2,2-dimethyl-1,3-dioxane-4,6-dione 85.A (commercially available from Aldrich) via the same procedure described in Vogt, P. F.; et. al.; Synthetic Communications; 2001, (5); pp. 679-684.

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 2,2-dimethyl-5-(1-methylethylidene)-1,3-dioxane-4,6-dione and potassium cyanide. This compound was prepared