tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate

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

Procedure: To a solution of (4R-cis)-6-[(benzoyloxy)methyl]-2,2-dimethyl-1,3 -dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (a) above (30.00 g, 82.4 mmole) in methanol (275 ml) was added granular anhydrous potassium carbonate (5.68 g, 41.2 mmole) in one portion. The resulting heterogeneous solution was stirred vigorously for 2 hours to complete the hydrolysis. The progress of the reaction was followed by TLC analysis. (TLC: Rf =0.31 for the benzoyloxy starting material, Rf =0.17 for the title compound (silica gel, Ether:Hexane, 1:1, visualized by Ce(SO4)2 spray). the hydrolysis

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

Procedure: Solid tetrabutylammonium benzoate obtained as above (126.47 g, 0.348 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared as in step (d) of Example 1 above (32.3 g, 0.116 mole) in HPLC grade 1-methyl-2-pyrrolidinone (465 ml) under argon. The resulting solution was stirred at 100° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis (TLC: Rf =0.47 for the chloride starting material; Rf =0.35 for the title compound (silica gel, Ether: Hexane, 4:6, visualization by Ce (SO4 )2 spray). After 6.5 hours the reaction was completed.

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

Procedure: To a solution of (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester obtained in step (a) above (22.65 g, 75 mmole) in methanol (250 ml) was added powdered anhydrous potassium carbonate (5.17 g, 37.5 mmole) in one portion. The resulting heterogeneous solution was stirred vigorously for 30 minutes to complete the hydrolysis. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf=0.54 for acetyloxy starting material; Rf=0.26 for the title compound (silica gel, Ethyl acetate:Hexane, 1:1, visualized by Ce(SO4)2 spray). the hydrolysis

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Solid tetra-n-butylammonium acetate prepared in step (e) (i) of Example 1 above (106.2 g, 0,352 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (d) of Example 1 above (32.7 g, 0. 117 mole) in HPLC grade 1-methyl-2-pyrrolidinone (471 ml) under argon. The resulting solution was stirred at 85° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf =0.54 for the title compound; Rf =0.63 for the chloride starting material (silica gel, Ethyl acetate: Hexane, 1:1, visualization by Ce(SO4)2 spray).) After 9 hours the reaction was completed.

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

Procedure: In 100 mL of methanol was dissolved 10 g (33.1 mmol) of tert-butyl 2-{(4R,6S)-2,2-dimethyl-6-[(methylcarbonyloxy)methyl]-1,3-dioxan-4-yl}acetate [synthesized by the process described in Example 8], and under ice-cooling and stirring, 0.46 g (3.3 mmol) of potassium carbonate was added. The mixture was further stirred under ice-cooling for 4 hours. From this reaction mixture, the reaction solvent was distilled off by heating under reduced pressure, and the residue was diluted with 50 mL of water and neutralized with 0.1 N-hydrochloric acid. This solution was extracted with ethyl acetate and the resulting organic layer was washed with water and dehydrated over anhydrous sodium sulfate. The solvent was then distilled off by heating under reduced pressure. The oily residue was decompressed to 1 Torr or less with a vacuum pump to remove the solvent almost thoroughly. As a result, 8.6 g of tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (colorless oil) was obtained in a yield of 100%. synthesized by the process cooling The mixture was further stirred under ice- cooling for 4 hours From this reaction mixture, the reaction solvent was distilled off by heating under reduced pressure the residue was diluted with 50 mL of water and neutralized with 0.1 N-hydrochloric acid This solution was extracted with ethyl acetate the resulting organic layer was washed with water The solvent was then distilled off by heating under reduced pressure to remove the solvent almost thoroughly

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

Procedure: In 100 mL of methanol was dissolved 10 g (33.1 mmol) of tert-butyl 2-{(4R,6S)-2,2-dimethyl-6-[(methylcarbonyloxy)methyl]-1,3-dioxan-4-yl}acetate [synthesized by the process described in Example 8], and under ice-cooling and stirring, 0.46 g (3.3 mmol) of potassium carbonate was added. The mixture was further stirred under ice-cooling for 4 hours. From this reaction mixture, the reaction solvent was distilled off by heating under reduced pressure, and the residue was diluted with 50 mL of water and neutralized with 0.1 N-hydrochloric acid. This solution was extracted with ethyl acetate and the resulting organic layer was washed with water and dehydrated over anhydrous sodium sulfate. The solvent was then distilled off by heating under reduced pressure. The oily residue was decompressed to 1 Torr or less with a vacuum pump to remove the solvent almost thoroughly. As a result, 8.6 g of tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (colorless oil) was obtained in a yield of 100%. synthesized by the process cooling The mixture was further stirred under ice- cooling for 4 hours From this reaction mixture, the reaction solvent was distilled off by heating under reduced pressure the residue was diluted with 50 mL of water and neutralized with 0.1 N-hydrochloric acid This solution was extracted with ethyl acetate the resulting organic layer was washed with water The solvent was then distilled off by heating under reduced pressure to remove the solvent almost thoroughly

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 grams), methanol (1 L), n-butyl amine (200 ml) and sodium, tertiary butoxide (74 grams) was heated to 40-45° C. and stirred up to completion of the reaction. Distilled off the reaction mixture completely under reduced pressure and water (300 ml) was added to it at 25-30° C. The reaction mixture was cooled and acidified with aqueous acetic acid. The reaction mixture washed with cyclohexane and product from aqueous layer was extracted into methylene chloride. The organic layer was washed with saturated sodium chloride solution and the solvent from it was distilled off under reduced pressure to get the title compound. Distilled off the reaction mixture completely under reduced pressure and water (300 ml) was added to it at 25-30° C The reaction mixture was cooled The reaction mixture washed with cyclohexane and product from aqueous layer was extracted into methylene chloride The organic layer was washed with saturated sodium chloride solution the solvent from it was distilled off under reduced pressure

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 grams), methanol (1 L), n-butyl amine (200 ml) and sodium, tertiary butoxide (74 grams) was heated to 40-45° C. and stirred up to completion of the reaction. Distilled off the reaction mixture completely under reduced pressure and water (300 ml) was added to it at 25-30° C. The reaction mixture was cooled and acidified with aqueous acetic acid. The reaction mixture washed with cyclohexane and product from aqueous layer was extracted into methylene chloride. The organic layer was washed with saturated sodium chloride solution and the solvent from it was distilled off under reduced pressure to get the title compound. Distilled off the reaction mixture completely under reduced pressure and water (300 ml) was added to it at 25-30° C The reaction mixture was cooled The reaction mixture washed with cyclohexane and product from aqueous layer was extracted into methylene chloride The organic layer was washed with saturated sodium chloride solution the solvent from it was distilled off under reduced pressure

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

Procedure: To the −15° C. to −5° C. pre-cooled reaction mixture of AZADO (0.002 g), potassium bromide (0.22 g) and methylene chloride (30 ml) added 5 g of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate. Stirred the reaction mixture for 15 minutes at −15° C. to −5° C. 19 ml of sodium hypochlorite solution was added to the reaction mixture at same temperature. Stirred the reaction mixture for 15 minutes. Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution. 20 ml of water was added and separated the both aqueous and organic layers. Washed the organic layer with water followed by brine solution. Distilled off the solvent completely to get the title compound as a solid. To the −15° C. to −5° C. pre-cooled Stirred the reaction mixture for 15 minutes Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution 20 ml of water was added separated the both aqueous and organic layers Washed the organic layer with water Distilled off the solvent completely

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 grams), methanol (80 ml), n-butyl amine (20 ml) and potassium carbonate (10.6 grams) was heated to 40-45° C. and stirred up to completion of the reaction. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (32 ml) and a mixture of AZADO (0.002 grams), potassium bromide (0.44 grams) in methylene chloride (48 ml) was added to it and stirred for 15 minutes. Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. and stirred for an hour. After completion of the reaction, the reaction mixture was quenched with sodium thio sulfate solution at below 10° C. Both organic and aqueous layers were separated and aqueous layer extracted with methylene chloride. The solvent from organic layer was distilled off under reduced pressure to get the title compound. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. stirred for 15 minutes The unwanted solid was filtered off the filtrate was distilled off under reduced pressure The obtained residue was dissolved in methylene chloride (32 ml) a mixture of AZADO (0.002 grams), potassium bromide (0.44 grams) in methylene chloride (48 ml) was added to it stirred for 15 minutes Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. stirred for an hour After completion of the reaction the reaction mixture was quenched with sodium thio sulfate solution at below 10° C Both organic and aqueous layers were separated aqueous layer extracted with methylene chloride The solvent from organic layer was distilled off under reduced pressure

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 grams), methanol (80 ml), n-butyl amine (20 ml) and potassium carbonate (10.6 grams) was heated to 40-45° C. and stirred up to completion of the reaction. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (32 ml) and a mixture of AZADO (0.002 grams), potassium bromide (0.44 grams) in methylene chloride (48 ml) was added to it and stirred for 15 minutes. Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. and stirred for an hour. After completion of the reaction, the reaction mixture was quenched with sodium thio sulfate solution at below 10° C. Both organic and aqueous layers were separated and aqueous layer extracted with methylene chloride. The solvent from organic layer was distilled off under reduced pressure to get the title compound. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. stirred for 15 minutes The unwanted solid was filtered off the filtrate was distilled off under reduced pressure The obtained residue was dissolved in methylene chloride (32 ml) a mixture of AZADO (0.002 grams), potassium bromide (0.44 grams) in methylene chloride (48 ml) was added to it stirred for 15 minutes Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. stirred for an hour After completion of the reaction the reaction mixture was quenched with sodium thio sulfate solution at below 10° C Both organic and aqueous layers were separated aqueous layer extracted with methylene chloride The solvent from organic layer was distilled off under reduced pressure

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 grams), methanol (80 ml), n-butyl amine (20 ml) and potassium carbonate (10.6 grams) was heated to 40-45° C. and stirred up to completion of the reaction. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (32 ml) and a mixture of TEMPO (0.015 grams), potassium bromide (0.36 grams) in methylene chloride (48 ml) was added to it and stirred for 15 minutes. Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. and stirred for an hour. After completion of the reaction, the reaction mixture was quenched with sodium thio sulfate solution at below 10° C. Both organic and aqueous layers were separated and aqueous layer extracted with methylene chloride. The solvent from organic layer was distilled off under reduced pressure to get the title compound. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. stirred for 15 minutes The unwanted solid was filtered off the filtrate was distilled off under reduced pressure The obtained residue was dissolved in methylene chloride (32 ml) a mixture of TEMPO (0.015 grams), potassium bromide (0.36 grams) in methylene chloride (48 ml) was added to it stirred for 15 minutes Sodium hypochlorite solution (20.8 ml) was added to the reaction mixture at −15 to 15° C. stirred for an hour After completion of the reaction the reaction mixture was quenched with sodium thio sulfate solution at below 10° C Both organic and aqueous layers were separated aqueous layer extracted with methylene chloride The solvent from organic layer was distilled off under reduced pressure