Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus containing
Reexamination Certificate
2002-07-25
2004-01-27
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus containing
C568S626000, C568S660000, C568S014000, C556S405000
Reexamination Certificate
active
06683219
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to vitamin D compounds, and more particularly to the synthesis of an A-ring synthon used in the preparation of 19-nor vitamin D compounds, and to novel synthetic intermediates formed during the synthesis.
The natural hormone, 1&agr;,25-dihydroxyvitamin D
3
and its analog in ergosterol series, i.e. 1&agr;,25-dihydroxyvitamin D
2
are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1&agr;-hydroxyvitamin D
3
, 1&agr;-hydroxyvitamin D
2
, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases.
The discovery of the hormonally active form of vitamin D
3
, 1&agr;,25-dihydroxyvitamin D
3
(1&agr;,25-(OH)
2
D
3
or calcitriol) has greatly stimulated research into its physiology and chemistry. As previously noted, it has been established that 1&agr;,25-(OH)
2
D
3
not only regulates the mineral metabolism in animals and humans, but also exerts potent effects upon cell proliferation and cellular differentiation. Therefore, the chemistry of vitamin D has been recently focused on the design and synthesis of analogs that can exert selective biological actions.
Recently, a class of vitamin D analogs has been discovered, i.e. the so called 19-nor-vitamin D compounds, which are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1&agr;,25-dihydroxy-19-nor-vitamin D
3
) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Different methods of synthesis of such 19-nor-vitamin D analogs have been described. See for example Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), DeLuca et al., U.S. Pat. No. 5,086,191, and DeLuca et al U.S. Pat. No. 5,936,133.
In one particularly advantageous method, the preparation of various 19-nor-vitamin D compounds can be accomplished by the condensation of a bicyclic Windaus-Grundmann type ketone having the desired side chain structure with an A-ring phosphine oxide to the corresponding 19-nor vitamin D analog followed by deprotection, particularly at C-1 and C-3 in the latter compounds. One method of preparing the required A-ring phosphine oxides is to transform a methyl ester obtained from quinic acid into the desired A-ring synthon in accordance with the synthesis set forth in DeLuca et al U.S. Pat. No. 5,936,133. It is, however, desirable to provide an alternate method for preparing such A-ring phosphine oxides.
SUMMARY OF THE INVENTION
The present invention provides a new method for the synthesis of an A-ring synthon phosphine oxide used in the preparation of 19-nor vitamin D compounds, and to novel synthetic intermediates formed during the synthesis. The new method prepares the phosphine oxide from (D)-glucose.
The A-ring synthon phosphine oxide to be prepared is represented by the following structure
where the wavy line indicates a stereochemical center so that the phosphine oxide substituent may have either the R or S configuration, and may thus be obtained as a mixture of two isomers. Each of R
3
, R
4
and R
5
may independently be selected from a hydroxy protecting group, but preferably R
3
and R
5
are both a t-butyldimethylsilyl hydroxy protecting group (abbreviated “TBS”) and R
4
is a trimethylsilyl hydroxy protecting group (abbreviated “TMS”).
Preferably, the method of making the phosphine oxide comprises the steps of:
converting D-glucose having the structure
to a 2-deoxy-glucose derivative having the structure
where R
1
is an alkyl group;
iodinating the 2-deoxy-glucose derivative to form a 5-iodinated derivative having the structure
eliminating the iodine substituent of said 5-iodinated derivative to form a 1-ether derivative having the structure
reducing the 1-ether derivative to form a 1-alcohol derivative having the structure
converting the 1-alcohol derivative to a 1-protected derivative having the structure
where R
2
is a hydroxy protecting group;
reducing the 1-protected derivative with a metal hydride to form a 5-alcohol derivative having the structure
benzylating the 5-alcohol derivative to form a benzylated derivative having the structure
hydrolyzing the benzyl derivative to form a 1-hydroxyl derivative having the structure
oxidizing the 1-hydroxyl derivative to form a 1-ketone derivative having the structure
converting the 1-ketone derivative to a 3,4,5-protected derivative having the structure
where R
3
, R
4
and R
5
are each independently a hydroxy-protecting group;
condensing the 3,4,5-protected derivative to an ester derivative having the structure
where R
6
is an alkyl group;
reducing the ester derivative with a metal hydride to form a 3,4,5-protected-1-alcohol derivative having the structure
and converting the 3,4,5-protected-1-alcohol to a phosphine oxide having the structure
Alternate methods of converting D-glucose to the 2-deoxy-glucose derivative are illustrated in FIGS.
1
and
2
.
REFERENCES:
patent: 5086191 (1992-02-01), DeLuca et al.
patent: 5581006 (1996-12-01), DeLuca et al.
patent: 5936133 (1999-08-01), Deluca et al.
CA:122:81736 abs of Journal of Medicinal Chemistry 37(22) pp 3730-8 by Sicinski et al 1994.*
CA:115:92747 abs of Journal of the Chemical Soc. Chem. Communications (5) pp 298-3000 by Baker et al 1991.*
CA:127:359017 abs of Tetrahedron by Kozikowski et al 53(44) pp 14903-14914 1997.*
CA:114:7016 abs of Australian Journal of Chemistry by Cambie et l 43(9) pp1597-1602 1990.*
CA:115:92747 abs of Journal of Chem Society, Chem. Commun. by Baker (5) pp 298-300 1991.*
CA:130:263914 abs of Bioscience, Biotechnology and Biochemistry by Iwase et al 62(12) pp 2396-2407 1998.*
CA:96:163704 abs of Heterocycles by Yoshikawa et al 17 pp 209-14 1982.*
Sicinski et al, “New 1&agr;,25-Dihydroxy-19-Norvitamin D3Compounds of High Biological Activity: Synthesis and Biological Evaluation of 2-Hydroxymethyl, 2-Methyl, and 2-Methylene Analogues,” J. Med. Chem., 1998, 41, 4662-4674.
Posner et al, “Stereocontrolled Synthesis of a Trihydroxylated A Ring as an Immediate Precursor to 1&agr;,2&agr;,25-Trihydroxyvitamin D3,” J. Org. Chem., 1991, 56, 4339-4341.
Perlman et al, “1&agr;,25-Dihydroxy-19-Nor-Vitamin D3, A Novel Vitamin D-Related Compound with Potential Therapeutic Activity,” Tetrahedron Letters, 1990, vol. 31, No. 13, 1823-1824.
Perlman et al, “Novel Synthesis of 19-Nor-Vitamin D Compounds,” Tetrahedron Letters, vol. 32, No. 52, 7663-7666 (1990).
DeLuca Hector F.
Shimizu Masato
Yamada Sachiko
Andrus Sceales Starke & Sawall LLP
Vollano Jean F.
Wisconsin Alumni Research Foundation
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