Process for production of piperidine derivatives

1. A process for preparing the piperidine derivative compound 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid of formula

comprising the sequential steps of:

(1) reacting 4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene with 4-chlorobutyryl chloride to provide 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene;

(2) hydrolyzing said 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene to provide 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid;

(3) reacting said 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid with methanol to provide methyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate;

(4) reacting said methyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate with 4-(α,α-diphenyl)piperidinemethanol to provide methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate;

(5) reducing said methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate to provide methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate; and

(6) hydrolyzing said methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate to provide said 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.

2. The process of claim 1 , wherein during the first step, prior to reacting 4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene with 4-chlorobutyryl chloride, 4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene is cooled to about −78° C.

3. The process of claim 2 , wherein n-butyllithium is added to bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene, the mixture is stirred for about 30 minutes, and 4-chlorobutyryl chloride is subsequently added to the mixture while keeping the temperature of the reaction below about −75° C.

4. The process of claim 3 , wherein after the addition of 4-chlorobutyryl chloride the mixture is stirred for about 30 minutes, warmed to about −15° C., quenched with water, and the product is extracted.

5. The process of claim 1 , wherein during the second step, said hydrolyzing step includes mixing 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene with concentrated hydrochloric acid and 1,4-dioxane, and bringing the mixture to reflux for about 18 hours.

6. The process of claim 5 , wherein said mixture is extracted with ethyl acetate, the organics are washed with a sodium chloride solution, dried, and concentrated.

7. The process of claim 1 , wherein during the third step, said 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid is mixed with hydrochloric acid-saturated methanol for about one hour, the mixture is concentrated to dryness and partitioned between ethyl acetate and water.

8. The process of claim 7 , wherein said mixture is again extracted with ethyl acetate, the organic phases are dried, and concentrated to an oil.

9. The process of claim 1 , wherein during the fourth step, said methyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate is mixed with toluene, 4-(α,α-diphenyl)piperidinemethanol, potassium carbonate, and the mixture is refluxed for about seven hours.

10. The process of claim 9 , wherein said reaction mixture is cooled, filtered and concentrated, and the residue is dissolved in Et 2 O and treated with excess ethereal hydrochloric acid.

11. The process of claim 1 , wherein during the fifth step, said reducing step includes mixing said methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate with methanol and sodium borohydride.

12. The process of claim 11 , wherein the mixture is concentrated to a solid, the residue is partitioned, the aqueous portion is extracted with EtOAc, the combined organics are washed with sodium chloride, dried, filtered, and concentrated to provide methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate.

13. The process of claim 1 , wherein during the sixth step, said hydrolyzing step includes mixing said methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate with methanol and water, sodium hydroxide is then added, and the mixture is refluxed for about one hour.

14. The process of claim 13 , wherein said mixture is cooled, methanol is removed, the concentrate is diluted with water and CHCl3, and the pH is adjusted to approximately 5.5 to 6.0.

15. The process of claim 14 , wherein the phases are then separated, the aqueous phase is extracted, the combined organics are dried, filtered and stripped to provide crude 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.