1,3,5-trioxane

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slow stream of hydrogen chloride gas is passed into a mixture of 1-chloro-3-octanol (35.5 g., 0.218 mole) and s-trioxane (6.55 g., 0.073 mole) in a conical flask cooled to 0° C. and protected from atmospheric moisture. The process requires about 31/2 hours. The resulting two-phase mixture is treated with anhydrous calcium chloride at 25° C. for 64 hours. The upper aqueous phase is removed by this action. The solid material is removed by filtration and the filtrate distilled to give the 3-chloromethoxy-1-chlorooctane as a colorless liquid (28.2 g., 61%), b.p. 128°-130°/15 mm.; pmr (CDCl3) δ 0.88 (3H,t), 1.98 (2H,q), 3.61 (2H,t), 3.92 (H,m), and 5.51 (2H,s). 2 hours The upper aqueous phase is removed by this action The solid material is removed by filtration the filtrate distilled

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Intermediate (2a) (14.5 g, 46.3 mmol) was dissolved in DCM (151 mL, 2.4 mol) and stirred at 0° C. under nitrogen. 1 M titanium tetrachloride in DCM (48.6 mL) was added and stirred for 15 minutes. DIPEA (8.9 mL, 51.0 mmol) was added dropwise at 0° C. and the mixture was stirred for 75 minutes. 1,3,5-Trioxane (4.6 g, 51.0 mmol) in DCM (30 mL) was then added. After 10 minutes a second equivalent of 1 M titanium tetrachloride in DCM (48.6 mL) was added and the mixture stirred at 0° C. for 5 hours. The reaction was then quenched with 250 mL of saturated ammonium chloride. Water and DCM were added, and the aqueous phase was extracted twice more with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to provide intermediate (2b) (13.9 g). stirred for 15 minutes the mixture was stirred for 75 minutes the mixture stirred at 0° C. for 5 hours The reaction was then quenched with 250 mL of saturated ammonium chloride Water and DCM were added the aqueous phase was extracted twice more with DCM dried over MgSO4 filtered concentrated The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes)

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

Procedure: 10.0 g of 2-thiopheneethanol, 3.5 g of 1,3,5-trioxane, and 862 mg of indium(III) chloride were added to 1,500 mL of butyronitrile, and the resulting mixture was refluxed for 6 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to obtain 6.6 g (yield of 60%) of the title compound, of which analysis data were the same as obtained in Example 14. the resulting mixture was refluxed for 6 hours concentrated by evaporation under reduced pressure The residue was distilled under reduced pressure

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

Procedure: 10.0 g of 2-thiopheneethanol, 3.5 g of 1,3,5-trioxane, and 862 mg of indium(III) chloride were added to 1,500 mL of butyronitrile, and the resulting mixture was refluxed for 6 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to obtain 6.6 g (yield of 60%) of the title compound, of which analysis data were the same as obtained in Example 14. the resulting mixture was refluxed for 6 hours concentrated by evaporation under reduced pressure The residue was distilled under reduced pressure

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

Procedure: In the first process stage, dimethyl α-fluoromalonate is subjected to hydroxymethylation with formaldehyde. (Dimethyl α-fluoromalonate is a known compound; see Journal of Fluorine Chemistry 25 (1984), 203-212.) The formaldehyde is preferably employed in the form of an aqueous solution having a formaldehyde content of 30 to 40% by weight. The formaldehyde is employed in an amount of 1 to 10 mot, preferably 1.1 to 3 mot (relative to 1 mol of dimethyl α-fluoromalonate). It is also possible to use paraformaldehyde, hexamethylenetetramine or 1,3,5-trioxane instead of formaldehyde. It is advantagous to carry out the reaction in the presence of a basic catalyst, which is then used in an amount of 2 to 50, preferably 5 to 15, mol % (relative to the dimethyl α-fluoromalonate). The catalyst used is, in particular, an alkali metal bicarbonate, for example potassium bicarbonate and sodium bicarbonate. The reaction is carried out at a temperature of 5° to 40° C., preferably 15° to 30° C. The dimethyl α -hydroxymethyl-α-fluoromalonate formed is then isolated from the reaction mixture, preferably by salting out or extraction by means of a water-immiscible organic solvent. A suitable solvent is, above all, an aliphatic chlorinated hydrocarbon having 1 to 4 carbon atoms, for example methylene dichloride, chloroform, carbon tetrachloride, 1,1-dichloroethane or 1,2-dichloroethane. A combination of salting out and extraction is particularly advantageous; a saturated salt solution (ammonium sulfate or sodium chloride) is then first added to the reaction mixture, and this mixture is then extracted. Dimethyl α-hydroxymethyl-α-fluoromalonate is obtained in the form of a colorless solid by evaporating the solvent. the reaction in the presence of a basic catalyst, which is carried out at a temperature of 5° to 40° C., preferably 15° to 30° C

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

Procedure: In the first process stage, dimethyl α-fluoromalonate is subjected to hydroxymethylation with formaldehyde. (Dimethyl α-fluoromalonate is a known compound; see Journal of Fluorine Chemistry 25 (1984), 203-212.) The formaldehyde is preferably employed in the form of an aqueous solution having a formaldehyde content of 30 to 40% by weight. The formaldehyde is employed in an amount of 1 to 10 mot, preferably 1.1 to 3 mot (relative to 1 mol of dimethyl α-fluoromalonate). It is also possible to use paraformaldehyde, hexamethylenetetramine or 1,3,5-trioxane instead of formaldehyde. It is advantagous to carry out the reaction in the presence of a basic catalyst, which is then used in an amount of 2 to 50, preferably 5 to 15, mol % (relative to the dimethyl α-fluoromalonate). The catalyst used is, in particular, an alkali metal bicarbonate, for example potassium bicarbonate and sodium bicarbonate. The reaction is carried out at a temperature of 5° to 40° C., preferably 15° to 30° C. The dimethyl α -hydroxymethyl-α-fluoromalonate formed is then isolated from the reaction mixture, preferably by salting out or extraction by means of a water-immiscible organic solvent. A suitable solvent is, above all, an aliphatic chlorinated hydrocarbon having 1 to 4 carbon atoms, for example methylene dichloride, chloroform, carbon tetrachloride, 1,1-dichloroethane or 1,2-dichloroethane. A combination of salting out and extraction is particularly advantageous; a saturated salt solution (ammonium sulfate or sodium chloride) is then first added to the reaction mixture, and this mixture is then extracted. Dimethyl α-hydroxymethyl-α-fluoromalonate is obtained in the form of a colorless solid by evaporating the solvent. the reaction in the presence of a basic catalyst, which is carried out at a temperature of 5° to 40° C., preferably 15° to 30° C

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 200 g of glacial acetic-acid, 200 g of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene and 35.4 g of 1,3,5-trioxane, a catalytic quantity (4.0 g) of concentrated sulfuric acid was added and the batch was heated to 106°-110° C. for 11/4 hours. The mixture was then cooled to 30° C. and partitioned between 100 ml of water and 200 ml of heptane. The bottom layer was discarded and to the remaining solution 100 ml of methanol was added. A solution of 96 g of 85% potassium hydroxide in 100 ml of water was then added and the reaction mixture was heated to 68°-72° C. for 13/4 hours. The batch was then cooled to 30° C. and the phases were allowed to separate. The bottom layer was discarded and the top layer was concentrated in vacuo until 25% of the total volume was distilled off. The remaining solution was diluted with 100 ml of heptane and 182 g of triethylamine. To the resulting mixture, a solution of 324 g of sulfur trioxide/pyridine complex in 535 g of dimethyl sulfoxide and 78.3 g of triethylamine was added at 30°-35° C. The batch was stirred at 30°-35° C. for 1/2 hour, then cooled to about 20° C. and quenched with 600 g of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was diluted with 100 ml of methanol and 50% sodium hydroxide solution (90 g) was added. The reaction mixture was stirred for 11/2 hours at 30°-34° C. Water (100 ml) was added and the phases were allowed to separate at room temperature. The bottom layer was discarded and the top solution was concentrated in vacuo to remove the solvent. The residue was dissolved in 200 ml of ethanol, the solution was cooled to about 3° C., seeded and the product was allowed to crystallize overnight. The solids were filtered off, washed with 80 ml of cold ethanol and dried to constant weight. Yield: 100 g of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C. the batch was heated to 106°-110° C. for 11/4 hours partitioned between 100 ml of water and 200 ml of heptane was added A solution of 96 g of 85% potassium hydroxide in 100 ml of water was then added the reaction mixture was heated to 68°-72° C. for 13/4 hours The batch was then cooled to 30° C. to separate the top layer was concentrated in vacuo until 25% of the total volume was distilled off The remaining solution was diluted with 100 ml of heptane and 182 g of triethylamine To the resulting mixture, a solution of 324 g of sulfur trioxide/pyridine complex in 535 g of dimethyl sulfoxide and 78.3 g of triethylamine was added at 30°-35° C cooled to about 20° C. quenched with 600 g of iced water to separate The top layer was diluted with 100 ml of methanol and 50% sodium hydroxide solution (90 g) was added The reaction mixture was stirred for 11/2 hours at 30°-34° C Water (100 ml) was added to separate at room temperature the top solution was concentrated in vacuo to remove the solvent The residue was dissolved in 200 ml of ethanol the solution was cooled to about 3° C. to crystallize overnight The solids were filtered off washed with 80 ml of cold ethanol dried to constant weight

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 200 g of glacial acetic-acid, 200 g of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene and 35.4 g of 1,3,5-trioxane, a catalytic quantity (4.0 g) of concentrated sulfuric acid was added and the batch was heated to 106°-110° C. for 11/4 hours. The mixture was then cooled to 30° C. and partitioned between 100 ml of water and 200 ml of heptane. The bottom layer was discarded and to the remaining solution 100 ml of methanol was added. A solution of 96 g of 85% potassium hydroxide in 100 ml of water was then added and the reaction mixture was heated to 68°-72° C. for 13/4 hours. The batch was then cooled to 30° C. and the phases were allowed to separate. The bottom layer was discarded and the top layer was concentrated in vacuo until 25% of the total volume was distilled off. The remaining solution was diluted with 100 ml of heptane and 182 g of triethylamine. To the resulting mixture, a solution of 324 g of sulfur trioxide/pyridine complex in 535 g of dimethyl sulfoxide and 78.3 g of triethylamine was added at 30°-35° C. The batch was stirred at 30°-35° C. for 1/2 hour, then cooled to about 20° C. and quenched with 600 g of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was diluted with 100 ml of methanol and 50% sodium hydroxide solution (90 g) was added. The reaction mixture was stirred for 11/2 hours at 30°-34° C. Water (100 ml) was added and the phases were allowed to separate at room temperature. The bottom layer was discarded and the top solution was concentrated in vacuo to remove the solvent. The residue was dissolved in 200 ml of ethanol, the solution was cooled to about 3° C., seeded and the product was allowed to crystallize overnight. The solids were filtered off, washed with 80 ml of cold ethanol and dried to constant weight. Yield: 100 g of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C. the batch was heated to 106°-110° C. for 11/4 hours partitioned between 100 ml of water and 200 ml of heptane was added A solution of 96 g of 85% potassium hydroxide in 100 ml of water was then added the reaction mixture was heated to 68°-72° C. for 13/4 hours The batch was then cooled to 30° C. to separate the top layer was concentrated in vacuo until 25% of the total volume was distilled off The remaining solution was diluted with 100 ml of heptane and 182 g of triethylamine To the resulting mixture, a solution of 324 g of sulfur trioxide/pyridine complex in 535 g of dimethyl sulfoxide and 78.3 g of triethylamine was added at 30°-35° C cooled to about 20° C. quenched with 600 g of iced water to separate The top layer was diluted with 100 ml of methanol and 50% sodium hydroxide solution (90 g) was added The reaction mixture was stirred for 11/2 hours at 30°-34° C Water (100 ml) was added to separate at room temperature the top solution was concentrated in vacuo to remove the solvent The residue was dissolved in 200 ml of ethanol the solution was cooled to about 3° C. to crystallize overnight The solids were filtered off washed with 80 ml of cold ethanol dried to constant weight

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

Procedure: To a mixture of 20 kg of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene, 72 kg of 96% formic acid and 3.6 kg of 1,3,5-trioxane, 96 g of 70% benzoyl peroxide catalyst was added and the bath was heated to reflux for about 3 hours. The mixture was then cooled to room temperature and 48 kg of heptane was added with stirring. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with water, then 48 kg of methanol and 7.2 kg of 50% aqueous sodium hydroxide were added. The mixture was stirred for about 10 minutes, washed with water and dried with 10 kg of anhydrous sodium sulfate. The sodium sulfate was filtered off and the filter cake was washed with 10 kg of heptane. To the combined filtrates, 96 kg of dimethyl sulfoxide and 28 kg of triethylamine were added. Sulfur trioxide/pyridine complex (36 kg) was then charged portionwise at 30°-35° C. The batch was agitated for 15 minutes and the reaction was quenched with 96 kg of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with dilute hydrochloric acid and with brine. Methanol (48 kg) and 50% sodium hydroxide (4.8 kg) were added and the batch was stirred at 21°-25° C. for one hour. Ice (0.6 kg) was added and the mixture was stirred for 15 minutes. The phases were allowed to separate and the bottom layer was discarded. The top solution was washed with brine and concentrated in vacuo to remove the volatiles. The residue was dissolved in 22 kg of isopropanol and 2.8 kg of water. The mixture was then cooled to about -10° C., seeded and stirred for 16 hours. The crystallized product was filtered off, washed with cold aqueous isopropanol and dried to constant weight. Yield: 8.5 kg of 2-(4-fluoro-3-methylphenyl)- 4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C. was added the bath was heated to reflux for about 3 hours to separate The top layer was washed with water 48 kg of methanol and 7.2 kg of 50% aqueous sodium hydroxide were added The mixture was stirred for about 10 minutes washed with water dried with 10 kg of anhydrous sodium sulfate The sodium sulfate was filtered off the filter cake was washed with 10 kg of heptane To the combined filtrates, 96 kg of dimethyl sulfoxide and 28 kg of triethylamine were added Sulfur trioxide/pyridine complex (36 kg) was then charged portionwise at 30°-35° C The batch was agitated for 15 minutes the reaction was quenched with 96 kg of iced water to separate The top layer was washed with dilute hydrochloric acid and with brine Methanol (48 kg) and 50% sodium hydroxide (4.8 kg) were added the batch was stirred at 21°-25° C. for one hour Ice (0.6 kg) was added the mixture was stirred for 15 minutes to separate The top solution was washed with brine concentrated in vacuo to remove the volatiles The residue was dissolved in 22 kg of isopropanol The mixture was then cooled to about -10° C. stirred for 16 hours The crystallized product was filtered off washed with cold aqueous isopropanol dried to constant weight

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

Procedure: To a mixture of 20 kg of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene, 72 kg of 96% formic acid and 3.6 kg of 1,3,5-trioxane, 96 g of 70% benzoyl peroxide catalyst was added and the bath was heated to reflux for about 3 hours. The mixture was then cooled to room temperature and 48 kg of heptane was added with stirring. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with water, then 48 kg of methanol and 7.2 kg of 50% aqueous sodium hydroxide were added. The mixture was stirred for about 10 minutes, washed with water and dried with 10 kg of anhydrous sodium sulfate. The sodium sulfate was filtered off and the filter cake was washed with 10 kg of heptane. To the combined filtrates, 96 kg of dimethyl sulfoxide and 28 kg of triethylamine were added. Sulfur trioxide/pyridine complex (36 kg) was then charged portionwise at 30°-35° C. The batch was agitated for 15 minutes and the reaction was quenched with 96 kg of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with dilute hydrochloric acid and with brine. Methanol (48 kg) and 50% sodium hydroxide (4.8 kg) were added and the batch was stirred at 21°-25° C. for one hour. Ice (0.6 kg) was added and the mixture was stirred for 15 minutes. The phases were allowed to separate and the bottom layer was discarded. The top solution was washed with brine and concentrated in vacuo to remove the volatiles. The residue was dissolved in 22 kg of isopropanol and 2.8 kg of water. The mixture was then cooled to about -10° C., seeded and stirred for 16 hours. The crystallized product was filtered off, washed with cold aqueous isopropanol and dried to constant weight. Yield: 8.5 kg of 2-(4-fluoro-3-methylphenyl)- 4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C. was added the bath was heated to reflux for about 3 hours to separate The top layer was washed with water 48 kg of methanol and 7.2 kg of 50% aqueous sodium hydroxide were added The mixture was stirred for about 10 minutes washed with water dried with 10 kg of anhydrous sodium sulfate The sodium sulfate was filtered off the filter cake was washed with 10 kg of heptane To the combined filtrates, 96 kg of dimethyl sulfoxide and 28 kg of triethylamine were added Sulfur trioxide/pyridine complex (36 kg) was then charged portionwise at 30°-35° C The batch was agitated for 15 minutes the reaction was quenched with 96 kg of iced water to separate The top layer was washed with dilute hydrochloric acid and with brine Methanol (48 kg) and 50% sodium hydroxide (4.8 kg) were added the batch was stirred at 21°-25° C. for one hour Ice (0.6 kg) was added the mixture was stirred for 15 minutes to separate The top solution was washed with brine concentrated in vacuo to remove the volatiles The residue was dissolved in 22 kg of isopropanol The mixture was then cooled to about -10° C. stirred for 16 hours The crystallized product was filtered off washed with cold aqueous isopropanol dried to constant weight