2-Tert-butylpropanedioic acid

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

Procedure: Thus, the optically active compounds are prepared from the known isoasborbic acid using the methodology described by Volante R. P. et al, in U.S. Pat. No. 4,611,067 but in that case starting with ascorbic acid. This establishes the optically active centers desired in Formula XXVa and Formula XXIIIa as R. Thus, the (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of Formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0° C. to -40° C., preferably -20° C., warmed to 25° C. and the activated acid derivative is not isolated but the solution is added to a suspension of a salt of 1,1-dimethylethyl malonic acid such as, for example, the potassium salt of 1,1-dimethylethyl malonic acid (half ester, half salt) anhydrous magnesium chloride, and an amine such as, for example, diisopropylethylamine in acetonitrile at -10° C. to 20° C. preferably at 5° C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to afford the (R)-1,1-dimethylethyl 6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of Formula XXVIII. The ketone of Formula XXVIII is treated with fluoride ion at 0° C. to 65° C., preferably 25° C. to afford the (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate of Formula XXVII. The ketone of Formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofuran at -78° C. to -110° C., preferably -100° C. to afford [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-hydroxyhexanoate of Formula XXVI. The diol of Formula XXVI is treated with a ketal forming reagent such as, for example, acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like, in the presence of an acid such as, for example, camphorsulfonic acid, para-toluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent such as, for example, dichloromethane, and the like, at 0° C. to the reflux temperature of the reagent or solvent to afford a compound of Formula XXVa wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as --(CH2)n --, wherein n is 4 or 5. Thus, the optically active compounds are prepared from the known isoasborbic acid the activated acid derivative is not isolated at -10° C. to 20° C. preferably at 5° C

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

Procedure: 2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reacted to obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which in turn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanol to obtain the compound 17. The solvents used in Mitsunobu reaction are the anhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethane or the like, and the anhydrous tetrahydrofuran is preferable. The reaction temperature is between −10-100° C., and the room temperature is preferable. The reaction time is between 0.1-72 hours, and 24 hours are preferable.

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

Procedure: 2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reacted to obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which in turn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanol to obtain the compound 17. The solvents used in Mitsunobu reaction are the anhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethane or the like, and the anhydrous tetrahydrofuran is preferable. The reaction temperature is between −10-100° C., and the room temperature is preferable. The reaction time is between 0.1-72 hours, and 24 hours are preferable.

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

Procedure: Thus, the optically active compounds are prepared from the known isoascorbic acid using the methodology described by Volante R. P. et al, in U.S. Pat. No. 611,067 but in that case starting with ascorbic acid. This establishes the optically active centers desired in Formula XXVa and Formula XXIIIa as R. Thus, the (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of Formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0° C. to -40° C., preferably -20° C., warmed to 25° C. and the activated acid derivative is not isolated but the solution is added to a suspension of a salt of 1,1-dimethylethyl malonic acid such as, for example, the potassium salt of 1,1-dimethylethyl malonic acid (half ester, half salt) anhydrous magnesium chloride, and an amine such as, for example, diisopropylethylamine in acetonitrile at -10° C. to 20° C. preferably at 5° C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to afford the (R)-1,1-dimethylethyl 6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of Formula XXVIII. The ketone of Formula XXVIII is treated with fluoride ion at 0° C. to 65° C., preferably 25° C. to afford the (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate of Formula XXVII. The ketone of Formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofuran at -78° C. to -110° C., preferably -100° C. to afford [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-hydroxyhexanoate of Formula XXVI. The diol of Formula XXVI is treated with a ketal forming reagent such as, for example, acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like, in the presence of an acid such as, for example, camphorsulfonic acid, para-toluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent such as, for example, dichloromethane, and the like, at 0° C. to the reflux temperature of the reagent or solvent to afford a compound of Formula XXVa wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as --(CH2)n --, wherein n is 4 or 5. the activated acid derivative is not isolated at -10° C. to 20° C. preferably at 5° C

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

Procedure: Thus, the optically active compounds are prepared from the known isoasborbic acid using the methodology described by Volante R. P. et al, in U.S. Pat. No. 4,611,067 but in that case starting with ascorbic acid. This establishes the optically active centers desired in Formula XXVa and Formula XXIIIa as R. Thus, the (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of Formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0° C. to -40° C., preferably -20° C., warmed to 25° C. and the activated acid derivative is not isolated but the solution is added to a suspension of a salt of 1,1-dimethylethyl malonic acid such as, for example, the potassium salt of 1,1-dimethylethyl malonic acid (half ester, half salt) anhydrous magnesium chloride, and an amine such as, for example, diisopropylethylamine in acetonitrile at -10° C. to 20° C. preferably at 5° C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to afford the (R)-1,1-dimethylethyl 6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of Formula XXVIII. The ketone of Formula XXVIII is treated with fluoride ion at 0° C. to 65° C., preferably 25° C. to afford the (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate of Formula XXVII. The ketone of Formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofuran at -78° C. to -110° C., preferably -100° C. to afford [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-hydroxyhexanoate of Formula XXVI. The diol of Formula XXVI is treated with a ketal forming reagent such as, for example, acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like, in the presence of an acid such as, for example, camphorsulfonic acid, para-toluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent such as, for example, dichloromethane, and the like, at 0° C. to the reflux temperature of the reagent or solvent to afford a compound of Formula XXVa wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as --(CH2)n --, wherein n is 4 or 5. Thus, the optically active compounds are prepared from the known isoasborbic acid the activated acid derivative is not isolated at -10° C. to 20° C. preferably at 5° C

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

Procedure: Thus, the optically active compounds are prepared from the known isoasborbic acid using the methodology described by Volante R. P. et al, in U.S. Pat. No. 4,611,067 but in that case starting with ascorbic acid. This establishes the optically active centers desired in Formula XXVa and Formula XXIIIa as R. Thus, the (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of Formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0° C. to -40° C., preferably -20° C., warmed to 25° C. and the activated acid derivative is not isolated but the solution is added to a suspension of a salt of 1,1-dimethylethyl malonic acid such as, for example, the potassium salt of 1,1-dimethylethyl malonic acid (half ester, half salt) anhydrous magnesium chloride, and an amine such as, for example, diisopropylethylamine in acetonitrile at -10° C. to 20° C. preferably at 5° C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to afford the (R)-1,1-dimethylethyl 6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of Formula XXVIII. The ketone of Formula XXVIII is treated with fluoride ion at 0° C. to 65° C., preferably 25° C. to afford the (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate of Formula XXVII. The ketone of Formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofuran at -78° C. to -110° C., preferably -100° C. to afford [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-hydroxyhexanoate of Formula XXVI. The diol of Formula XXVI is treated with a ketal forming reagent such as, for example, acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like, in the presence of an acid such as, for example, camphorsulfonic acid, para-toluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent such as, for example, dichloromethane, and the like, at 0° C. to the reflux temperature of the reagent or solvent to afford a compound of Formula XXVa wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as --(CH2)n --, wherein n is 4 or 5. Thus, the optically active compounds are prepared from the known isoasborbic acid the activated acid derivative is not isolated at -10° C. to 20° C. preferably at 5° C

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

Procedure: 2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reacted to obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which in turn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanol to obtain the compound 17. The solvents used in Mitsunobu reaction are the anhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethane or the like, and the anhydrous tetrahydrofuran is preferable. The reaction temperature is between −10-100° C., and the room temperature is preferable. The reaction time is between 0.1-72 hours, and 24 hours are preferable.

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

Procedure: 2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reacted to obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which in turn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanol to obtain the compound 17. The solvents used in Mitsunobu reaction are the anhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethane or the like, and the anhydrous tetrahydrofuran is preferable. The reaction temperature is between −10-100° C., and the room temperature is preferable. The reaction time is between 0.1-72 hours, and 24 hours are preferable.

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

Procedure: The title compound was synthesized from 2-(6-methoxy-pyridin-2-yl)-2-methyl-propionic acid and mono-tert-butyl malonic acid according to the method used for the synthesis of Compound PR4. The resultant was used for the next step without further purification. used for the synthesis of Compound PR4 The resultant was used for the next step without further purification

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

Procedure: Mono-tert-butyl malonic acid (72.5 g) was dissolved in DME (360 ml), added with TEA (189 ml) and magnesium chloride (29.63 g) and the mixture was stirred for 2 hrs. In a separate vessel, CDI (52.75 g) was added to the DME (360 ml) solution of 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (90 g) and stirred at room temperature for 1 hr to prepare a solution. This solution was then added dropwise to the aforementioned mixture, and the resulting solution was washed with DME (90 ml) and stirred at 70° C. for 3 hrs. The reaction mixture was diluted with isopropyl acetate (225 ml) and heptane (225 ml), and the organic layer was washed with 2 N hydrochloric acid (684 ml), 0.17 N hydrochloric acid (540 ml), 15% aqueous solution of ammonium chloride (540 ml), 1 N aqueous solution of sodium hydroxide (540 ml) and 15% brine (540 ml) in order. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product, which was used for the next step without further purification. stirred at room temperature for 1 hr to prepare a solution This solution was then added dropwise to the aforementioned mixture the resulting solution was washed with DME (90 ml) stirred at 70° C. for 3 hrs The reaction mixture was diluted with isopropyl acetate (225 ml) and heptane (225 ml) the organic layer was washed with 2 N hydrochloric acid (684 ml), 0.17 N hydrochloric acid (540 ml), 15% aqueous solution of ammonium chloride (540 ml), 1 N aqueous solution of sodium hydroxide (540 ml) and 15% brine (540 ml) in order The organic layer was concentrated under reduced pressure

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

Procedure: Thus, the optically active compounds are prepared from the known isoascorbic acid using the methodology described by Volante R. P. et al., in U.S. Pat. No. 4,611,067 but in that case starting with ascorbic acid. This establishes the optically active centers desired in Formula XXVa and Formula XXIIIa as R. Thus, the (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of Formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0° C. to -40° C., preferably -20° C., warmed to 25° C. and the activated acid derivative is not isolated but the solution is added to a suspension of a salt of 1,1-dimethylethyl malonic acid such as, for example, the potassium salt of 1,1-dimethylethyl malonic acid (half ester, half salt) anhydrous magnesium chloride, and an amine such as, for example, diisopropylethylamine in acetonitrile at -10° C. to 20° C. preferably at 5° C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to afford the (R)-1,1-dimethylethyl 6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of Formula XXVIII. The ketone of Formula XXVIII is treated with fluoride ion at 0° C. to 65° C., preferably 25° C. to afford the (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate of Formula XXVII. The ketone of Formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofruan at -78° C. to -110° C., preferably -100° C. to afford [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-hydroxyhexanoate of Formula XXVI. The diol of Formula XXVI is treated with a ketal forming reagent as such as, for example, acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like, in the presence of an acid such as, for example, camphorsulfonic acid, para-toluenesulfonic acid, and the like, in the presence of excess reagent or in an inert solvent such as, for example, dichloromethane, and the like, at 0° C. to the reflux temperature of the reagent or solvent to afford a compound of Formula XXVa wherein R7 and R8 are independently hydrogen, alkyl of from one to three carbon atoms, phenyl or R7 and R8 are taken together as --(CH2)n --, wherein n is 4 or 5. the activated acid derivative is not isolated at -10° C. to 20° C. preferably at 5° C

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

Procedure: The title compound was synthesized from 2-(6-methoxy-pyridin-2-yl)-2-methyl-propionic acid and mono-tert-butyl malonic acid according to the method used for the synthesis of Compound PR4. The resultant was used for the next step without further purification. used for the synthesis of Compound PR4 The resultant was used for the next step without further purification