Processes for the preparation of steroid derivatives,...

Details Processes for the preparation of steroid derivatives,... Processes for the preparation of steroid derivatives,...

2000-11-20

2001-10-30

Badio, Barbara P. (Department: 1616)

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

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S583000, C552S606000, C552S608000, C540S051000

Reexamination Certificate

active

06310225

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing steroid derivatives, intermediates thereof and processes for producing the intermediates. The steroid derivatives provided by the present invention are useful as intermediates for the synthesis of vitamin D derivatives, such as 1&agr;,25-dihydroxyvitamin D
3
and 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxyvitamin D
3
, which have calcium metabolism modulating activity and differentiation inducing activity and are useful as therapeutic agents for diseases caused by calcium metabolism disorder, such as osteoporosis and osteomalacia, or as antitumor agents.
BACKGROUND ART
Known as the processes for producing vitamin D derivatives, such as 1&agr;,25-dihydroxyvitamin D
3
and 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxyvitamin D
3
, and intermediates for the synthesis thereof are, among others, (1) the process for producing pregnane derivatives which comprises epoxidizing 21-hydroxy-20-methyl-pregna-1,4,6-trien-3-one and reductively cleaving the resulting 1,2-epoxide (cf. JP Kokoku S62-14558), (2) the process for producing 1&agr;,25-dihydroxy-7-dehydrocholesterol which comprises oxidizing 25-hydroxycholesterol with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), protecting the hydroxy group at position 25 of the thus-obtained 25-hydroxycholesta-1,4,6-trien-3-one, enol-acetylating the position 3 of the protected compound and reducing the resulting compound (cf. U.S. Pat. No. 4,287,129), (3) the process for producing pregnane derivatives which comprises reducing 1&agr;,2&agr;-epoxy-20-methyl-4,6-pregnadien-3-on-21-ol at the position 3 thereof, then converting the resulting compound to the corresponding diepoxy alcohol by 4,5-epoxidization, oxidizing the hydroxy group at position 3 of the diepoxy alcohol, then reducing the oxidation product for simultaneous steric inversion, cleaving by reduction the epoxy moieties of the resulting compound, causing the resulting hydroxy group to rearrange and then eliminating it to thereby construct the 5,7-diene structure (cf. JP 2,731,543), (4) the process for producing steroid derivatives which comprises protecting the hydroxy group at position 22 or 24 of 22-hydroxy-23,24-dinorchola-1,4,6-trien-3-one or 24-hydroxy-chola-1,4,6-trien-3-one, then enol-acetylating the protected compound at position 3 and reducing the resulting compound (cf. JP 2,750,175) and (5) the process for producing 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxyvitamin D
3
which comprises using the steroid derivative obtained by the method described in Japanese Patent Specification No. 2,750,175 (cf. JP Kokai H07-112998). Among these, the process (2) uses a starting material having the side chain skeleton. On the other hand, the processes (1), (3), (4) and (5) use starting materials with a functional group introduced therein at position 22 and introduce the side chain after modifying the ring A and ring B moieties.
As mentioned above, several processes for producing vitamin D derivatives, such as 1&agr;,25-dihydroxyvitamin D
3
and 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxyvitamin D
3
, and intermediates for the synthesis thereof are already known.
However, no example is known of the production of vitamin D derivatives using a starting material having a halogen atom, which is a reactive substituent, as the functional group at position 22 and carrying out side chain introduction after modification of the ring A and ring B moieties.
On the other hand, an example of the synthesis of 7,8-didehydrodemosterol has been reported (cf. Schoenauer et al., Liebigs Ann. Chem., vol. 6, pages 1031-1042 (1983)). In that example, a complicated process was used; namely a steroid derivative having a chlorine atom at position 22 was used as the starting material, the ring A and ring B moieties were first modified, then the chlorine atom at position 22 was converted to an acetoxy group by treatment with tetrabutylammonium acetate, then a tosylate compound was derived from the acetoxy compound by hydrolysis and tosylation, the thus-obtained tosylate compound was converted to the corresponding aldehyde by Pfitzner-Moffat oxidation and then the side chain was introduced utilizing the Wittig reaction. Further, a steroid derivative having a chlorine atom at position 22 was used as the starting material and, after modification of the ring A and ring B moieties, the chlorine atom was converted to a more reactive iodine atom and an attempt was made, but unsuccessfully, to directly introduce the side chain basic skeleton of 7,8-didehydrodemosterol into the iodide by reacting with prenyl bromide-&pgr;-allylnickel complex.
Thus, it is an object of the present invention to provide steroid derivatives useful as intermediates for the production of vitamin D derivatives, such as 1&agr;,25-dihydroxyvitamin D
3
and 2&bgr;-(3-hydroxypropoxy)-1&agr;,25-dihydroxyvitamin D
3
, and a process for producing the steroid derivatives.
Intensive investigations made by the present inventors with the expectation that if it becomes possible to introduce various side chains into a steroid derivative having a halogen atom at position 22, which is used as the starting material, by utilizing the reactivity of that moiety, the complicated reaction steps for protection and deprotection required for protecting such a functional group as a hydroxy group prior to modification of the ring A and ring B moieties will become unnecessary, hence it will become possible to produce various vitamin D derivatives as well as intermediates for the synthesis thereof by a simplified process as compared with the prior art processes for producing vitamin D derivatives and intermediates for the synthesis thereof which comprise side chain introduction following modification of the ring A and ring B moieties, have now led to the present invention.
DISCLOSURE OF INVENTION
According to the present invention, the above object can be accomplished by providing:
(1) A halide compound represented by the general formula (II) (hereinafter referred to as “halide compound(II)” for short):
wherein X represents a bromine atom or an iodine atom;
(2) A 1,4,6-trien-3-one compound represented by the general formula (III) (hereinafter referred to as “1,4,6-trien-3-one compound (III)” for short):
wherein X is as defined above;
(3) A 1,3,5,7-tetraene compound represented by the general formula (IV) (hereinafter referred to as “1,3,5,7-tetraene compound (IV)” for short):
wherein X is as defined above and R
1
represents an acyl group;
(4) A 1,5,7-triene compound represented by the general formula (V):
wherein X is as defined above and R
2
represents a hydrogen atom or a hydroxy-protecting group;
(5) A process for producing 3&bgr;-hydroxy-1,5,7-triene compounds represented by the general formula (V-1) (hereinafter referred to as “3&bgr;-hydroxy-1,5,7-triene compounds (V-1)” for short):
wherein X is as defined above, which comprises reducing a 1,3,5,7-tetraene compound (IV);
(6) A process for producing 1,3,5,7-tetraene compounds (IV) which comprises subjecting a 1,4,6-trien-3-one compound (III) to enol esterification;
(7) A process for producing 1,4,6-trien-3-one compounds (III) which comprises dehydrating the hydroxy group at position 7 of a halide compound (II);
(8) A process for producing halide compounds (II) which comprises reacting a sulfonate compound represented by the general formula (I) (hereinafter referred to as “sulfonate compound (I)” for short):
wherein R represents an organic sulfonyloxy group, with a brominating agent or an iodinating agent;
(9) A process for producing diene adducts represented by the general formula (X) (hereinafter referred to as “diene adducts (X)” for short):
wherein R
22
represents a hydroxy-protecting group, R
3
, R
4
, R
5
and R
6
each represents a hydrogen atom or an alkyl group, R
7
, R
8
, R
9
and R
10
each represents a hydrogen atom, a fluorine atom, a protected hydroxy group or an alkyl group, R
3
and R
5
, R
4
and R
6
or R
5
and R
7
may combinedly represent a single bond, R
11
represents a hydrogen atom, a trifluoromethyl group, a cycl

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