Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Reexamination Certificate
2002-09-25
2004-06-22
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
C558S054000
Reexamination Certificate
active
06753435
ABSTRACT:
TECHNICAL FIELD
The present invention relates to intermediates for the synthesis of vitamin D derivatives useful as drugs and processes for the preparation of the same. More particularly it relates to intermediates for the synthesis of 1&agr;-hydroxyvitamin D derivatives useful as drugs such as osteogenesis promoters, tumorous cell growth inhibitors, immunosuppressants, anti-hypercalcemia drugs, therapeutic agents for inflammatory respiratory diseases and the like and processes for the preparation of the same.
BACKGROUND ART
It has hitherto been disclosed that vitamin D compounds and metabolites thereof play a highly important role as control substances of metabolism of in vivo calcium or phosphates in patent publications and general literature. Processes according to JP-B (hereinafter JP-B refers to Japanese Examined Patent Publication) No. 2-24268 and Tetrahedron Letters, 1992, 33, 105 are known as processes for the preparation of the vitamin D compounds.
Robert Henry Hesse et al. disclose processes for the preparation of vitamin D derivatives represented by the formula (5) from vitamin D
2
in nine steps:
(JP-B No. 2-24268); however, it may be scarcely said that the processes are industrial processes for the preparation because toxic selenium dioxide (SeO
2
) is used in steps of introducing a hydroxy group in the course of the processes.
On the other hand, Mercedes Torneiro, L. Castedo, W. H. Okamura et al. disclose processes for the preparation of vitamin D derivatives represented by the formula:
by a coupling reaction of compounds represented by the general formula (4):
with compounds represented by the following general formula (6).
For example, Tetrahedron Letters, 1992, 33, 105 describes an example of protecting a tertiary hydroxy group at the side chain terminal of a substituent Y with methoxymethyl group (MOM: —CH
2
OCH
3
) and reacting the protected compound.
Further, Tetrahedron Letters, 1998, 29, 1203 and Tetrahedron 1991, 47, 3485 describe an example of ketalizing and protecting the carbonyl group in the side chain of the substituent Y and reacting the protected compound.
In addition, Journal of American Chemical Society (J. Am. Chem. Soc.), 1991, 113, 6958 describes an example of reaction with a compound having a tertiary hydroxy group at the side chain terminal of the substituent Y.
However, nothing is known about an example of coupling reaction with a compound having a primary hydroxy group at the side chain terminal of the substituent Y or a compound having the primary hydroxy group protected with a protecting group.
By the way, coupling reaction of an acetylene compound with a triflate derivative (R-OTf) is known as the Stille reaction [for example, Stille et al., Journal of Organic Chemistry (J. Org. Chem.), 1985, 50, 2302]. The reaction is carried out by heating the acetylene compound and the triflate derivative in the presence of a palladium catalyst [Pd(0) or Pd(II)] and an additive [for example, triethylamine or lithium chloride (LiCl)] in a solvent (for example, tetrahydrofuran, ethanol, dimethylformamide or dimethyl sulfoxide) to prepare the objective coupling product.
An example of preparing vitamin D
3
derivatives utilizing the reaction conditions has been reported by Okamura et al. [for example, Journal of American Chemical Society (J. Am. Chem. Soc.), 1991, 113, 6958].
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide novel intermediates for the synthesis of 1&agr;-hydroxyvitamin D derivatives.
Another object of the present invention is to provide novel processes for the preparation of intermediates for the synthesis of the 1&agr;-hydroxyvitamin D derivatives.
As a result of intensive studies made on the objects, the inventors have achieved the following invention. Namely, the present invention is a process for the preparation of a compound represented by the formula (2):
wherein, R
1
and R
2
are each the same as in the formula (4), which comprises reacting a compound represented by the formula (1):
wherein, Tf represents SO
2
CF
3
, with a compound represented by the formula (4):
wherein, R
1
and R
2
are each the same or different and represent each a hydrogen atom, a tri(C
1
-C
7
hydrocarbon)silyl group, a diphenyl(C
1-C
7
hydrocarbon)silyl group or a group forming an acetal bond or an ester bond with an oxygen atom to which each of R
1
and R
2
is bound, in the presence of a palladium catalyst and an additive.
In addition, the present invention is a process for the preparation of a compound represented by the formula (3):
wherein, R
1
and R
2
are each the same as in the above formula (4), which comprises, if necessary, adding a basic compound in order to lower the activity of a Lindlar catalyst in the presence of the Lindlar catalyst and hydrogen gas, then catalytically reducing the compound represented by the formula (2):
wherein, R
1
and R
2
are each the same as in the above formula (4), and further heating the obtained product.
Furthermore, the present invention is a process for the preparation of a compound represented by the formula (5):
wherein, R
1
and R
2
are each the same as in the above formula (4), which comprises oxidizing the compound represented by the formula (3):
wherein, R
1
and R
2
are each the same as in the formula (4), with an oxidizing agent.
In addition, the present invention is the compound represented by the formula (1):
wherein, Tf represents SO
2
CF
3
, the compound represented by the formula (2):
wherein, R
1
and R
2
are each the same as in the above formula (4) and the compound represented by the formula (3):
wherein, R
1
and R
2
are each the same as in the above formula (4), which are the intermediates for the synthesis of the vitamin D derivatives used in the processes for the preparation mentioned above.
BEST MODE FOR CARRYING OUT THE INVENTION
The compound which is represented by the formula (1) and used as a raw material in the processes of the present invention is prepared from vitamin D
2
through the following synthetic route:
The preparation of the diol derivative from the vitamin D
2
is realized by ozone oxidation reaction of the vitamin D
2
by referring to known processes (J. Org. Chem., 1986, 51,1264 and the like).
The next preparation of a protected substance of the primary hydroxy group can be realized by introducing, for example t-butyldimethylsilyl group into the primary hydroxy group. In the process, the introduction of the protecting group can be realized by stirring t-butyldimethylsilyl chloride and the diol derivative in the presence of a basic compound such as imidazole in a solvent such as DMF, THF or methylene chloride at about normal temperature. The t-butyldimethylsilyl chloride or the like is used in an amount within the range of 1 to 1.5 equivalents based on 1 equivalent of the primary hydroxyl group.
The next preparation of the ketone derivative can be carried out by oxidation reaction of the secondary hydroxy group which is the protected derivative of the primary hydroxy group under various oxidizing conditions by using an oxidizing agent, for example MnO2 in acetone solvent or an Ru catalyst and NMO (N-methylmorpholine N-oxide), oxalyl chloride, DMSO and triethylamine in acetone solvent.
The next preparation of the triflate derivative can be realized by reacting, for example the ketone derivative with N-phenyltrifluoromethanesulfonimide (PhN(CF
3
SO
2
)
2
) and LDA (lithium diisopropylamide) in THF solvent. The preparation of the triflate derivative can be carried out by referring to the conditions for preparing the triflate derivative described in, for example Journal of American Chemical Society (J. Am. Chem. Soc.), 1991, 113, 6958.
The protecting group of the primary hydroxy group can subsequently be eliminated to prepare the compound represented by the formula (1). The elimination of the protecting group, i.e. silyl group can be realized by reaction in a solution of Bu
4
NF in THF or a solution of HF-pyridine in acetonitrile. An amount of the Bu
4
NF or HF-pyrid
Koga Masahiro
Minoshima Toru
Badio Barbara P.
Sughrue & Mion, PLLC
Teijin Limited
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