Process for producing phosphineoxide vitamin D precursors

Details Process for producing phosphineoxide vitamin D precursors Process for producing phosphineoxide vitamin D precursors

2000-03-29

2003-08-05

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C552S653000

Reexamination Certificate

active

06603030

ABSTRACT:

BACKGROUND OF THE INVENTION
Vitamin D analogs, such as 1&agr;-fluoro-25-hydroxy-16-23E-diene-26,27-bishomo-20-epi-cholecalciferol, 1,25-dihydroxy-16-ene-23-yne-26,27-bishomo-19-nor-20-epi-cholecalciferol, 1&agr;, 25-dihydroxy-18-norvitamin D3, 1&agr;, 25-dihydroxy-18,19-dinorvitamin D3, 1&agr;-fluoro-25-hydroxycholecalciferol, and 1&agr;-fluoro-25-hydroxyergocalciferol, are known to have pharmaceutical activity and are useful for treating various conditions, such as psoriasis and neoplastic disease.
A key phosphine oxide compound of formula 1 below is used in the efficient synthesis of such vitamin D analogues and provides the A ring of the vitamin. Certain species of Compound 1 are known to be valuable intermediates in the synthesis of the mentioned pharmacologically active vitamin D analogues (see for example EP Publication No. 0 808 833). The remaining species of Compound 1 can be modified to be useful in the above processes or can be used for producing other vitamin D analogues. Known processes for making this intermediate of Compound 1 typically result in low yields. However, the subject invention provides a process to produce the desired intermediate in high yield.
SUMMARY OF THE INVENTION
The subject invention provides a process for producing a compound of the formula:
where Ph is phenyl, X
1
and X
2
are both hydrogen or X
1
and X
2
taken together are CH
2
, R
1
is a protecting group, R
2
is fluorine, hydrogen, or OR
3
, where R
3
is a protecting group, and the squiggly line represents a bond that results in the adjacent double bond being in either the E or Z configuration. This process comprises chlorinating a compound of the formula:
where X
1
, X
2
, R
1
, R
2
, and the squiggly line are as above, using triphosgene in the presence of an organic base to obtain the compound of the formula:
where X
1
, X
2
, R
1
, R
2
, and the squiggly line are as above. The compound of formula 3 is then reacted with a salt of diphenyl phosphine oxide to obtain the compound of formula 1.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention is an improved process for producing a compound of formula 1 (“Compound 1”). This process involves chlorinating a compound of formula 2 (“Compound 2”) using triphosgene as the chlorine source in the presence of an organic base to obtain the compound of formula 3 (“Compound 3”). The chlorine in Compound 3 is replaced by phosphine oxide using a salt of diphenyl phosphine oxide that can be formed in situ, to obtain Compound 1. The structures of Compounds 1-3 are set forth below.
Compound 1 is a compound of the formula:
where Ph is phenyl, X
1
and X
2
are both hydrogen or X
1
and X
2
taken together are CH
2
, R
1
is a protecting group, R
2
is fluorine, hydrogen, or OR
3
, where R
3
is a protecting group, and the squiggly line represents a bond that results in the adjacent double bond being in either the E or Z configuration. For clarity, the squiggly line is shorthand for the following two configurations:
Since Compound 1 can be used in numerous synthetic pathways for producing vitamin D analogs, the bonds between the ring carbons and the OR
1
substituent and R
2
can be in either the &agr; or &bgr; configuration as needed for the final synthesis.
Compound 1 is produced by chlorinating Compound 2 of the formula:
where X
1
and X
2
, R
1
and R
2
, and the squiggly line are as defined for Compound 1. Compound 2 is reacted with triphosgene in the presence of an organic base to obtain Compound 3 where Ph, X
1
and X
2
, R
1
and R
2
, and the squiggly line are as defined for Compound 1.
Many species of Compound 2 are known. See for example, Perlman et al.,
Novel synthesis of
19-
nor
-
vitamin D compounds, Tetrahedron Lett
., 32(52): 7663-6 (1991), Courtney et al.,
Asymmetric synthesis of a key ring A synthon for
1&agr;-
hydroxy
-19-
nor vitamin D, Tetrahedron Lett
., 39(21): 3363-3366 (1998), Shiuey et al.
Total synthesis of
1&agr;-
fluoro
-25-
hydroxycholecalciferol and
-
ergocalciferol., J. Org. Chem.
55(1): 243-7 (1990), Reddy,
Synthesis and activity of
3-
epi vitamin
D3
compounds for use in treatment of disorders involving aberrant activity of hyperproliferative skin, parathyroid, and bone cells
., PCT Publication No. WO 9851663, Sotojima,
Preparation of cyclohexylideneethanol derivatives as intermediates for
1&agr;-
hydroxy
- and 1&agr;, 25-
dihydroxyvitamin
D3, JP Kokai No. 05279283, Baggiolini et al.,
Stereoselective total synthesis of
1&agr;, 25-
dihydroxycholecalciferoL, J. Am. Chem. Soc
., 104(10): 2945-8 (1982). The remaining species of Compound 2 can be produced from these known compounds using procedures known in the art. Such production is well within the skill of the artisan.
Compound 3 has the formula:
where X
1
and X
2
, R
1
and R
2
, and the squiggly line are as defined for Compound 1. Compound 3 is then reacted with a salt of diphenyl phosphine oxide, to obtain Compound 1.
In any of the above processes of this invention, R
1
can be any appropriate protecting group. The choice of an appropriate protecting group is within the skill of the artisan. By hydroxy protecting group is meant any standard compound for protecting a hydroxy group during a chemical reaction (such that the hydroxy group is easily reinstated), specifically during acidic or basic hydrolysis. However, a silyl protecting group, such as tert-butyl dimethyl silyl (“TBS”) is preferred.
R
2
can be fluorine, hydrogen, or a protected hydroxy group. A protected hydroxy group is a group in which oxygen binds to the ring and is protected by a protecting group. As above, the choice of an appropriate protecting group is within the skill of the artisan. Preferred protected hydroxy groups include silyl protected hydroxy groups, such as hydroxy protected by TBS. The use of a TBS protected hydroxy group results in R
2
being tert-butyl dimethyl silyl oxide (“TBSO”). For any compound of this invention, R
1
and R
2
may use the same or different hydroxy protecting groups.
The salts of diphenyl phosphine oxide that can be used in the inventive process include the sodium, lithium, and potassium salts. However, the sodium salt is preferred. In a preferred process, R
1
is TBS and R
2
is fluorine or TBSO. For the chlorination of Compound 2, a preferred amount of triphosgene is about one-half (½) mole relative to one (1) mole of Compound 2. Either pyridine or triethylamine may be added to the reaction. For either one, the preferred amount is 2 equivalents.
In preferred processes of this invention, R
1
is TBS, R
2
is OR
3
, and R
3
is TBS. In other preferred processes, R
1
is TBS and R
2
is fluorine. In yet other preferred processes, R
1
is TBS and R
2
is hydrogen. In the subject invention, Compounds 1, 2, and 3 can have the P(O)(Ph)
2
, OH, and Cl, respectively, in either the cis or trans position. In any of these compounds, R
1
and R
2
may be present above (
)or below (
) the plane of the cyclohexane ring to which they are attached. Both may be above, both may be below, or one may be above and the other may be below.
Compound 3 is obtained from Compound 2 by chlorinating the allylic alcohol of Compound 2 to the allylic chloride in Compound 3. This chlorinating is performed in and organic solvent, preferably an aprotic solvent such as hexane. For each mole of Compound 2, one-half (½) mole or more of triphosgene is used as the chlorine source. At least 2 equivalents of an organic base, preferably an aprotic amine base such as pyridine, or preferably triethylamine, should be included. Temperature is not critical and may range between −30° C. and 50° C. However, a temperature around 0° C. is preferred.
Compound 1 is obtained from Compound 3 by replacing the chlorine with phosphine oxide. Results are obtained by using an alkali metal salt of diphenylphosphine oxide, preferably the sodium salt. Other acceptable alkali metal salts include lithiu

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