# US 9,040,728 B2 · Crystallization of (20R) 19-nor-24-difluoro-1α,25-dihydroxyvitamin D3

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- Number: US 9,040,728 B2
- Document ID: US9040728B2
- Status: Granted
- Kind: B2
- Application number: 13/828,223
- Filed: 2013-03-14
- Published: 2013-12-05
- Granted: 2015-05-26
- Earliest claimed: 2012-05-30
- Assignees: Wisconsin Alumni Research Foundation
- Applicants: Wisconsin Alumni Research Foundation
- Inventors: Hector F. DeLuca; Agnieszka Flores; James B. Thoden; Hazel M. Holden
- Web page: https://patentgrep.com/patent/US9040728B2

## CPC

- C07C 401/00: Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07C 2601/14: The ring being saturated
- C07C 2602/24: the ring system containing nine carbon atoms, e.g. perhydroindane
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed are methods of purifying the compound (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D3 to 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.

## Claims

### Claim 1

A compound having the formula
in crystalline form, and named (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D3,
wherein the crystalline form has a molecular packing arrangement defined by space group C2 and unit cell dimensions a=23.88 Å, b=6.16 Å, c=19.63 Å, α=90°, β=121.83° and γ=90°.

### Claim 2 (depends on 1)

A three dimensional structure for (20R)-9-nor-24-diafluoro-1α,25-dihydroxyvitamin D as defined by the molecular packing arrangement set forth in claim 1.

### Claim 3

A method of purifying (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D3, comprising the steps of:
(a) preparing a solvent comprising hexane;
(b) adding a product containing (20R)-9-nor-24-difluoro-1α,25-dihydroxyvitamin D3 to be purified to said hexane to form a suspension of the product in the hexane;
(c) adding 2-propanol dropwise to the suspension to form a mixture of the product in the hexane and 2-propanol;
(d) heating the mixture to dissolve the product containing (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D- to be purified in said mixture;
(e) cooling said mixture and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D crystals; and
(f) separating the (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D3 crystals from the solvent.

### Claim 4 (depends on 3)

The method of claim 3 including the further step of allowing said solvent and dissolved product to cool to ambient temperature prior to cooling below ambient temperature.

### Claim 5 (depends on 3)

The method of claim 3 wherein the step of separating comprises filtering the mixture and precipitate to obtain the crystals.

### Claim 6 (depends on 3)

The method of claim 3 including, a further step (g) comprising repeating steps (a) through (f) using the recovered crystals from step (f) as the product of step (b).

### Claim 7 (depends on 3)

The method of claim 3 wherein said mixture comprises about 15% 2-propanol and about 85% hexane by volume.