Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-12-15
2002-10-08
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S167000, C552S653000
Reexamination Certificate
active
06462031
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
The present invention relates to purification of organic compounds, and more particularly to the purification of 1&agr;-hydroxyvitamin D
2
(1&agr;-OH-D
2
) by preparing it in crystalline form.
Purification of organic compounds, especially those designated for pharmaceutical use, is of considerable importance for chemists synthesizing such compounds. Preparation of the compound usually requires many synthetic steps and, therefore, the final product can be contaminated not only with side-products derived from the last synthetic step of the procedure but also with compounds that were formed in previous steps. Even chromatographic purification, which is a very efficient but relatively time-consuming process, does not usually provide compounds which are sufficiently pure to be used as drugs.
Depending on the method used to synthesize 1&agr;-hydroxyvitamin D compounds, different minor undesirable compounds can accompany the final product. Thus, for example, if direct C-1 hydroxylation of 5,6-trans geometric isomer of vitamin D is performed, followed by SeO
2
/NMO oxidation and photochemical irradiation [see Andrews et al.,
J. Org. Chem.
51, 1635 (1986); Calverley et al.,
Tetrahedron
43, 4609 (1987); Choudry et al.,
J. Org. Chem.
58, 1496 (1993)], the final 1&agr;-hydroxyvitamin D product can be contaminated with 1&agr;-hydroxy- as well as 5,6-trans isomers. If the method consists of C-1 allylic oxidation of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct of the previtamin D compound, followed by cycloreversion of the modified adduct under basic conditions [Nevinckx et al.,
Tetrahedron
47, 9419 (1991); Vanmaele et al.,
Tetrahedron
41, 141 (1985) and 40, 1179 (1991); Vanmaele et al.,
Tetrahedron Lett.
23, 995 (1982)], one can expect that the desired 1&agr;-hydroxyvitamin can be contaminated with the previtamin 5(10),6,8-triene and 1 P-hydroxy isomer. One of the most useful C-1 hydroxylation methods, of very broad scope and numerous applications, is the experimentally simple procedure elaborated by Paaren et al. [see
J Org. Chem.
45, 3253 (1980) and
Proc. Natl. Acad. Sci. U.S.A.
75, 2080 (1978)]. This method consists of allylic oxidation of 3,5-cyclovitamin D derivatives, readily obtained from the buffered solvolysis of vitamin D tosylates, with SeO
2
/ t-BuOOH and subsequent acid-catalyzed cycloreversion to the desired 1&agr;-hydroxy compounds. Taking into account this synthetic path it is reasonable to assume that the final product can be contaminated with 1&bgr;-hydroxy epimer, 5,6-trans isomer and the previtamin D form. 1&agr;-hydroxyvitamin D
4
is another undesirable contaminant found in 1&agr;-hydroxyvitamin D
2
synthesized from vitamin D
2
or from ergosterol. 1&agr;-hydroxyvitamin D
4
results from C-1 oxidation of vitamin D
4,
which in turn is derived from contamination of the commercial ergosterol material. Typically, the final product may contain up to about 1.5% by weight 1&agr;-hydroxyvitamin D
4.
Thus, a purification technique that would eliminate or substantially reduce the amount of 1&agr;-hydroxyvitamin D
4
in the final product to less than about 01.-0.2% would be highly desirable.
The vitamin D conjugated triene system is not only heat- and light-sensitive but it is also prone to oxidation, leading to the complex mixture of very polar compounds. Oxidation usually happens when a vitamin D compound has been stored for a prolonged time. Other types of processes that can lead to a partial decomposition of vitamin D compounds consist of the some water-elimination reactions; their driving force is allylic (1&agr;-) and homoallylic (3&bgr;-) position of the hydroxy groups. The presence of such above-mentioned oxidation and elimination products can be easily detected by thin-layer chromatography. Thus, for example, using precoated aluminum silica sheets [with UV indicator; from EM Science (Cherry Hill, N.J.)] and solvent system hexane-ethyl acetate (4:6), the spot of 1&agr;-OH-D
2
(R
f
0.27) and its elimination products (R
f
's ca. 0.7-0.9) are visible in ultraviolet light. Also, after spraying with sulfuric acid and heating, an additional spot can be visualized (R
f
0), derived from oxidation products.
Usually, all 1&agr;-hydroxylation procedures require at least one chromatographic purification. However, even chromatographically purified 1&agr;-hydroxyvitamin D
2
, although showing consistent spectroscopic data, suggesting its homogeneity, does not meet the purity criteria required for therapeutic agents that can be orally, parenterally or transdermally administered. Therefore, it was evident that a suitable method of purification of 1&agr;-hydroxyvitamin D
2
is required.
Since it is well known that the simplest procedure that can be used for compound purification is a crystallization process, it was decided to investigate purification of 1&agr;-OH-D
2
by means of crystallization. The solvent plays a crucial role in the crystallization process, and is typically an individual liquid substance or a suitable mixture of different liquids. For crystallizing 1&agr;-hydroxyvitamin D
2
, the most appropriate solvent and/or solvent system is characterized by the following factors:
(1) low toxicity;
(2) low boiling point;
(3) significant dependence of solubility properties with regard to temperature (condition necessary for providing satisfactory crystallization yield); and
(4) relatively low cost.
It was found that highly apolar solvents (e.g. hydrocarbons) were not suitable due to the low solubility of 1&agr;-OH-D
2
in them. Quite the reverse situation occurred in highly polar solvent media (e.g. alcohols), in which 1&agr;-OH-D
2
showed too high solubility. Therefore, it was concluded that for the successful crystallization of 1&agr;-OH-D
2
, a solvent of medium polarity is required or, alternatively, a solvent mixture consisting of two (or more) solvents differing considerably in polarity. Interestingly, hexane, so frequently used for crystallization purposes with co-solvents like acetone, ethyl acetate or diethyl ether, was found less suitable for crystallization of 1&agr;-OH-D
2
. Unusually low yields of crystallization were obtained when hexane-containing solvent systems were used. However, it was discovered that replacement of the hexane in such solvent mixtures with petroleum ether increased significantly the yield of crystals. After numerous experiments it was found that an individual solvent, namely ethyl formate, was most useful for the crystallization of 1&agr;-OH-D
2
. In addition, binary and ternary solvent systems namely: ethyl acetate-petroleum ether and 2-propanol-hexane-petroleum ether, respectively, also performed well. These solvents are all characterized by low toxicity, and they are very easy to remove by evaporation or other well known methods. In all cases the crystallization process occurred easily and efficiently; and the precipitated crystals were sufficiently large to assure their recovery by filtration.
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Solvay Product Information, 1 alpha-Hydroxyergocalciferol, Vitamin D Workshop, Orlando, Florida, 1994.*
Solvay Product Information, Ercalcidal, 10th Vitamin D Workshop, Strasbourg, France, May 24-29, 1997.*
Solvay Product Information Bulletin and Certificate of Analysis, 1 alpha Hydroxyergocalciferol, May 6, 1998.*
Strungell et al. 1&agr;,24(S)-Dihydroxyvitamin D2: a biologically active product of 1&agr;hydroxyvitamin D2made in the human hepatoma, Hep3B, abstract of Biochemical Journal, 1995, 310, 233-241.
Calbiochem, Vitam
DeLuca Hector F.
Holden Hazel
Sicinski Rafal R.
Thoden James Brian
Andrus, Sceals, Starke & Sawall, LLP
Qazi Sabiha
Wisconsin Alumni Research Foundation
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