Intermediates for the synthesis of vitamin D and steroid...

Details Intermediates for the synthesis of vitamin D and steroid... Intermediates for the synthesis of vitamin D and steroid...

2000-05-22

2002-06-04

Badio, Barbara P. (Department: 1616)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S512000, C549S513000, C549S516000, C549S522000, C552S653000

Reexamination Certificate

active

06399767

ABSTRACT:

Throughout this application, various publications are referred to. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
Vitamin D and its derivatives have important physiological functions. For example, 1&agr;,25-dihydroxy vitamin D
3
exhibits a broad range of physiological functions such as calcium metabolism-controlling activity, growth-inhibiting activity, differentiation-inducing activity on cells such as tumor cells, and immune-controlling activity. However, vitamin D
3
derivatives exhibit undesirable side effects such as hypercalcemia.
Novel vitamin D derivatives have been developed to retain effectiveness in the treatment of specific diseases while reducing associated side effects.
For example, Japanese Patent No. 61-267550 (issued Nov. 27, 1986) discloses a 9,10-seco-5,7,10(19)-pregnatriene derivative which exhibits an immune-controlling activity and a differentiation-inducing activity on tumor cells. In addition, Japanese Patent No. 61-267550 (issued Nov. 27, 1986) also discloses two processes for preparing the final product, one using pregnenorone and the other dehydroepiandorosterone as the starting material.
1&agr;,25-dihydroxy-22-oxavitamin D
3
(OCT), the 22-oxa analogue of 1&agr;,25-dihydroxyvitamin D
3
has potent in vitro differentiation-inducing activities with low in vivo calcemic liability. OCT is being clinically investigated as a candidate for treatment of secondary hyperparathyroidism and psoriasis.
Japanese Patent No. 6-072994 (issued Mar. 15, 1994) discloses a 22-oxacholecalciferol derivative and a process for the preparation thereof. It discloses a process for preparing an oxacholecalciferol derivative which comprises reacting a pregnene derivative having a hydroxyl group at the 20-position with a dialkylacrylamide compound to give an ether compound and then reacting the thus-obtained ether compound with an organometal compound to give the desired compound.
Japanese Patent No. 6-080626 (issued Mar. 22, 1994) discloses a 22-oxavitamin D derivative. It also discloses a process which comprises reacting 1&agr;,3&bgr;-bis(tert-butyldimethylsilyloxy)-pregne-5,7-diene-20(S or R)-ol as a starting compound with an epoxide in the presence of a base to give a compound having an ether bond at the 20-position.
In addition, Japanese Patent No. 6-256300 (issued Sep. 13, 1994) and Kubodera et al. (Bioorganic & Medicinal Chemistry Letters, 4(5): 753-756, 1994) disclose a process for stereospecifically preparing an epoxy compound which comprises reacting 1&agr;,3&bgr;-bis(tert-butyldimethylsilyloxy)-pregna-5,7-diene-20(S)-ol with 4-(tetrahydropyran-2-yloxy)-3-methyl-2-butene-1-bromide to give an ether compound, deprotecting it, and subjecting the deprotected ether compound to Sharpless oxidation. However, the above processes require more than one step for introducing an ether bond and an epoxy group into a side chain of a steroid group and therefore, result in low yield of the desired compound.
Furthermore, none of the above references disclose a synthesis method in which an alcohol compound is reacted with an epoxy hydrocarbon compound having an eliminating group at its end, thereby forming an ether bond. Also, the above references do not disclose a bicyclo[4.3.0]nonane structure (hereinafter referred to as a CD ring structure), a steroid structure, or a vitamin D structure, each having an ether bond and an epoxy group at a side chain.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing a compound having the structure of the following formula I:
wherein n is an integer from 1-5; each of R
1
and R
2
independently is optionally substituted C
1
-C
6
alkyl; each of W and X is independently hydrogen or C
1
-C
6
alkyl; Y is O, S or NR
3
where R
3
is hydrogen, C
1
-C
6
alkyl or a protective group; and Z is:
where each of R
4
, R
5
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R
6
and R
7
independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond; which comprises:
(a) reacting a compound having the following formula IV:
 wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure, of the following formula V or V′:
 wherein n, R
1
and R
2
are as defined above, and E is an eliminating group, to produce the compound of formula I; and
(b) recovering the compound so produced.
The present invention also provides a compound having the structure of the formula I:
wherein n is an integer from 1-5; each of R
1
and R
2
independently is optionally substituted C
1
-C
6
alkyl; each of W and X is independently hydrogen or C
1
-C
6
alkyl; Y is O, S or NR
3
where R
3
is hydrogen, C
1
-C
6
alkyl or a protective group; and Z is:
where each of R
4
, R
5
; R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R
6
and R
7
independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond.
The present invention further provides a process for preparing a compound having the structure of the following formula VI:
wherein n is an integer from 1-5; each of R
1
and R
2
independently is optionally substituted C
1
-C
6
alkyl; each of W and X is independently hydrogen or C
1
-C
6
alkyl; Y is O, S or NR
3
where R
3
is hydrogen, C
1
-C
6
alkyl or a protective group; and Z is:
where each of R
4
, R
5
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R
6
and R
7
independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond; which comprises:
(a) reacting a compound having the following formula IV:
 wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure of the following formula V or formula V′:
 wherein n, R
1
and R
2
are as defined above, and E is an eliminating group, to produce an epoxide compound having the structure of formula I:
(b) treating the epoxide compound with a reducing agent to produce the compound of formula VI; and
(c) recovering the compound so produced.
The present invention further provides a process for preparing a compound having the structure:
wherein n is an integer from 1-5; each of R
1
and R
2
independently is optionally substituted C
1
-C
6
alkyl; each of W and X is independently hydrogen or C
1
-C
6
alkyl; Y is O, S or NR
3
where R
3
is hydrogen, C
1
-C
6
alkyl or a protective group; and Z′ is a vitamin D structure optionally having one or more protected or unprotected substituents and/or one or more protective groups, wherein Z′ is preferably:
where each of R
10
, R
11
, R
12
, and R
13
independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl;
which comprises:
(a) reacting a compound having the structure:
 wherein W, X, and Y are as defined above and Z″ represents a steroid structure optionally having one or more protected or unprotected substituents and/or one or more protective groups, Z″ most preferably being:
 where each of R
4
, R
5
, R
8
, and R
9
independently is hydrogen, a substituted

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