Wisconsin Alumni Research Foundation

James Thoden

Hector Floyd Deluca

Hazel Holden

Agnieszka Flores

Lori A Plum

Pawel Grzywacz

Margaret Clagett-Dame

Rafal R Sicinski

Rafal Barycki

Agnieszka Glebocka

Sumithra Gowlugari

Hector F Deluca

Disclosed are methods of purifying the compound (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dto obtain the compound in crystalline form. The methods typically include the steps of dissolving (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Din a solvent comprising ethyl acetate and hexane to form a solution, allowing crystals of (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dto form and precipitate from the solution, and recovering the crystals of (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dfrom the solution.

Procedure for crystallization of (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24-25-trihydroxy-19-nor-vitamin D

Disclosed are 1&#x3b1;,25-dihydroxy-24,24-difluoro-2-methylene-19-nor-vitamin D analogs and their pharmaceutical uses. These new vitamin D analogs are 19-nor-vitamin D analogs having two fluorine atom substitutions at the 24 position (C-24) in the side chain and optionally having a 2-methylene substituent.

(20S)-1-&#x3b1;,25-dihydroxy-24,24-difluoro-19-nor-vitamin Danalogs and their pharmaceutical uses

Disclosed are methods of purifying the compound (20R,22R)-2-methylene-19-nor-22-methyl-1&#x3b1;,25-dihydroxyvitamin Dto obtain the compound in crystalline form. The methods typically include the steps of dissolving a product containing the compound in a solvent comprising hexane and 2-propanol, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals. Certain diol precursors formed during the synthesis of the compound and its diasteromers also may be obtained in crystalline form using ethyl acetate as a solvent.

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Disclosed are methods of purifying the compound (20R)-19-nor-24-difluoro-1&#x3b1;,25-dihydroxyvitamin Dto obtain the compound in crystalline form. The methods typically include the steps of dissolving a product containing the compound in a solvent comprising hexane and 2-propanol, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals.

Disclosed are methods of purifying the compound (20R)-2-methylene-19-nor-24-difluoro-1&#x3b1;,25-dihydroxyvitamin Dto obtain the compound in crystalline form. The methods typically include the steps of dissolving a product containing the compound in a solvent comprising hexane and 2-propanol, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals.

Crystallization of (20R)-2-methylene-19-nor-24-difluoro-1&#x3b1;,25-dihydroxyvitamin D3

Disclosed are methods of purifying (20R) and (20S) analogs of 2-methylene-19-nor-22-dimethyl-1&#x3b1;,25-dihydroxyvitamin Dto obtain the (20R) and (20S) analogs in crystalline form. The method includes the steps of preparing a solvent of either diethyl ether or a mixture of 2-propanol and hexane, dissolving a product containing the (20R) and (20S) analog to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals.

Compounds of formula I are provided where X, X, and Xare independently selected from H or hydroxy protecting groups. Such compounds may be used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions. 

A method of purifying 1&#x3b1;-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin Dto obtain 1&#x3b1;-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin Din crystalline form. The method includes the steps of preparing a solvent of either ethyl formate or a mixture of ethyl formate and hexane, dissolving a product containing 1&#x3b1;-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin Dto be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1&#x3b1;-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin Dcrystals, and recovering the 1&#x3b1;-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin Dcrystals.

Crystallization a 1alpha-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D3

A method of purifying 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol to obtain 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in crystalline form using precipitation with hexane from ethyl acetate. A method of preparing 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals acceptable for X-ray experiment using precipitation with hexane from benzene by diffusive exchange of the solvents is also described.

Crystallization of 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol

A method of purifying (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dto obtain (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Din crystalline form. The method includes the steps of preparing a solvent of methanol and water, dissolving a product containing (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dto be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dcrystals, and recovering the (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dcrystals.

A method of purifying 2-methylene-19-nor-20(S)-1&agr;-hydroxy-bis-homo-pregnacaciferol to obtain 2-methylene-19-nor-20(S)-1&agr;-hydroxy-bis-homo-pregnacalciferol in crystalline form. The method includes the steps of boiling a solvent such as acetone under inert atmosphere, dissolving a product containing 2-methylene-19-nor-20(S)-1&agr;-hydroxy-bis-homo-pregnacalciferol to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 2-methylene-19-nor-20(S)-1&agr;-hydroxy-bis-homo-pregnacalciferol crystals, and recovering the 2-methylene-19-nor-20(S)-1&agr;-hydroxy-bis-homo-pregnacalciferol crystals.

2-methylene-19-nor-20(S)-1&agr;-hydroxy-bis-homo-pregnacalciferol in crystalline form

A method of purifying 1&agr;-hydroxyvitamin D to obtain 1&agr;-hydroxyvitamin D in crystalline form. The method includes the steps of boiling a solvent selected from the group consisting of ethyl formate, ethyl acetate and a 2-propanol-hexane mixture under inert atmosphere, dissolving a product containing 1&agr;-hydroxyvitamin D to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1&agr;-hydroxyvitamin D crystals, and recovering the 1&agr;-hydroxyvitamin D crystals. Petroleum ether is also added to the solvent after dissolving the product to be purified in the solvent.

Crystalline 1&agr;-hydroxyvitamin D2 and method of purification thereof

A method of purifying 1&agr;-hydroxyvitamin D to obtain 1&agr;-hydroxyvitamin D in crystalline form. The method includes the steps of boiling a solvent selected from the group consisting of ethyl formate, ethyl acetate and a 2-propanol-hexane mixture under inert atmosphere, dissolving a product containing 1&agr;-hydroxyvitamin D to be purified in the. solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1&agr;-hydroxyvitamin D crystals, and recovering the 1&agr;-hydroxyvitamin D crystals. Optionally, petroleum ether may be added to the solvent after dissolving the product to be purified in the solvent.

A method of purifying 1&agr;,24(S)-dihydroxyvitamin D to obtain 1&agr;,24(S)-dihydroxyvitamin D in crystalline form. The method includes the steps of boiling a solvent under inert atmosphere, dissolving a product containing 1&agr;,24(S)-dihydroxyvitamin D to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1&agr;,24(S)-dihydroxyvitamin D crystals, and recovering the 1&agr;,24(S)-dihydroxyvitamin D crystals. The purification technique involves using one of several binary solvent systems, namely, acetone and hexane, 2-propanol and hexane, or ethyl formate and petroleum ether.

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Madison, WI, United States of America

James Thoden