JPH0853411A - Vitamin d3 derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new 1alpha-hydroxyvitamin D3 derivative useful as a medicine such as a bone formation promoter, an immunosuppressor, a tumor cell proliferation suppressor or an agent for hypercalcemia agent. CONSTITUTION:This vitamin D3 derivative is expressed by formula I, e.g. 1alpha hydroxy-22-[(1-hydroxy-1-methyl)-2-cyclopentene-4-yl]-23, 24, 25, 26, 27-pentanoyl- vitamin D3. This vitamin D3 derivative of formula I is obtained by reacting a new cyclopentene derivative of formula II with a compound of formula III [R2 and R3 are each H, a tri(1-7C hydrocarbon)silyl, a 2-7C acyl or a group forming an acetal bond together with O of OH] in the presence of Pd catalyst to afford a vitamin D3 derivative of formula IV and subjecting the resultant derivative to deprotecting reaction except when R<1>, R<2> and R<3> are simultaneously H. Cyclopentene derivative) of formula V (R<12> is same as R<2> and R<3>) and formula VI (R<12> is same as R<2> and R<3>) are new substances.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a vitamin D ₃ derivative useful as a medicine. More specifically, the present invention relates to a 1α-hydroxyvitamin D ₃ derivative useful as a drug such as an osteogenesis promoter, an immunosuppressant, a tumor cell growth inhibitor, and a hypercalcemia agent, a method for producing the same, and an intermediate for producing the same.

[0002]

2. Description of the Related Art The fact that vitamin D ₃ metabolites play an extremely important role as regulators of substance metabolism of calcium and phosphate in the living body has hitherto been reported in many patent publications and general documents. It is well recognized through disclosure. In addition, recently, many substances having the ability of inducing differentiation of neoplastic bone marrow cells have been found, and clinical use as a therapeutic drug for various diseases is increasing. On the other hand, recently, a novel vitamin D ₃ active metabolite having an α-hydroxy lactone ring as a steroid side chain was found [Archives of Biochemistry &.
Biophysics <Arch.Bio-chem.Biophys., 204,339-
391 (1980)〉; FEBS LETTERS 134,
207-211 (1981)]. This compound is 1α, 25-dihydroxy-vitamin D ₃ -26,23-lactone and is represented by the structural formula shown below.

[0003]

[Chemical 7]

This compound has a calcium concentration-decreasing action in serum (JP-A-58-118516), a tumor cell growth-inhibiting action (JP-A-58-210011), and an osteogenic action promoting action (JP-A-58-210011). It has been reported that there is an action such as 60-185715).

[0005]

The problem to be solved by the present invention is to find a novel vitamin D ₃ derivative having osteogenesis promoting activity and the like.

[0006]

Means for Solving the Problems The inventors of the present invention have made extensive studies for this purpose and, as a result, have reached the novel vitamin D ₃ derivative of the present invention.

That is, the present invention provides the following formula (1)

[0008]

Embedded image

It is a vitamin D ₃ derivative represented by:
In the above formula (1), the C-1 position of the cyclopentene ring and C
The configuration of the asymmetric center at the -4 position may be either (R) configuration or (S) configuration. Further, the present invention also includes a mixture of these four stereoisomers in any ratio. Among them, the asymmetric center at the C-1 position has the (R) configuration, the asymmetric center at the C-4 position has the (S) configuration, and the asymmetric center at the C-1 position has the (S) configuration. It is preferable that the asymmetric center at the C-4 position has the (S) configuration.

Specific examples of the preferred vitamin D ₃ derivative of the present invention are as follows. 1) 1α-hydroxy-22-[(1-hydroxy-1
-Methyl) -2-cyclopenten-4-yl] -23,
24,25,26,27- Pentanoru - vitamin _{D 3 2) (1R, 4S} ) -1α- hydroxy -22 - [(1-
Hydroxy-1-methyl) -2-cyclopentene-4-
Ill] -23, 24, 25, 26, 27-pentanol-
Vitamin D ₃ 3) (1R, 4R) -1α-hydroxy-22-[(1-
Hydroxy-1-methyl) -2-cyclopentene-4-
Ill] -23, 24, 25, 26, 27-pentanol-
Vitamin _{D 3 4) (1S, 4R} ) -1α- hydroxy -22 - [(1-
Hydroxy-1-methyl) -2-cyclopentene-4-
Ill] -23, 24, 25, 26, 27-pentanol-
Vitamin _{D 3 5) (1S, 4S} ) -1α- hydroxy -22 - [(1-
Hydroxy-1-methyl) -2-cyclopentene-4-
Ill] -23, 24, 25, 26, 27-pentanol-
Vitamin D ₃ Further, the present invention includes a method for producing a vitamin D ₃ derivative represented by the above formula (1). That is, the following formula (2)

[0011]

[Chemical 9]

(In the formula, R ¹ is a hydrogen atom and tri (C1 to C
7 hydrocarbon) silyl group, C2 to C7 acyl group, or a group that forms an acetal bond with an oxygen atom of a hydroxyl group, and X represents a bromine atom or an iodine atom. ) A cyclopentene derivative represented by the following formula (3)

[0013]

[Chemical 10]

(Wherein R ² and R ³ are the same or different,
Hydrogen atom, tri (C1-C7 hydrocarbon) silyl group, C2
~ C7 represents an acyl group or a group that forms an acetal bond together with an oxygen atom of a hydroxyl group. ) In the presence of a palladium catalyst, the compound represented by the following formula (4)

[0015]

[Chemical 11]

(Wherein R ¹ , R ² and R ³ are the same as defined above), a vitamin D ₃ derivative is produced, and then R ¹ , R ² and R ³ are all hydrogen atoms. The method for producing a vitamin D ₃ derivative represented by the above formula (1) is characterized by carrying out a deprotection reaction except when

In the method for producing a vitamin D ₃ derivative of the present invention, the C-1 position and C of the cyclopentene ring of the cyclopentene derivative represented by the above formula (2), which is the starting material, are used.
The configuration of the asymmetric center at the -4 position may be either (R) configuration or (S) configuration. It may also be a mixture of those stereoisomers at any ratio. For example, when the cyclopentene derivative represented by the above formula (2) in which the asymmetric center at the C-1 position of the cyclopentene ring has the (R) configuration and the asymmetric center at the C-4 position has the (S) configuration The configuration of these sites is preserved during the reaction, and the asymmetric center at the C-1 position of the cyclopentene ring is (R).
The vitamin D ₃ derivative represented by the above formula (1), which has the configuration and the asymmetric center at the C-4 position has the (S) configuration, is obtained.

Similarly, the cyclopentene derivative represented by the above formula (1) in which the asymmetric center at the C-1 position of the cyclopentene ring has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration. Is used, C- of the cyclopentene ring
A vitamin D ₃ derivative represented by the above formula (1) in which the asymmetric center at the 1-position has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration is obtained.

Where R ¹ , R ² or R ³ is tri (C
1 to C7 hydrocarbon) silyl group, specific examples thereof include trimethylsilyl, triethylsilyl,
Preferred examples include a tri (C1-C4 alkyl) silyl group such as a t-butyldimethylsilyl group and a diphenyl (C1-C4 alkyl) silyl group such as a t-butyldiphenylsilyl group. In addition, R ¹ , R ² ,
Alternatively, when R ³ represents a C1 to C7 acyl group, specific examples thereof include acetyl, propionyl, n-butyryl, pivaloyl, benzoyl, methoxycarbonyl,
Ethoxycarbonyl, benzyloxycarbonyl and the like can be mentioned as preferable ones. further,
When R ¹ , R ² or R ³ represents a group that forms an acetal bond with an oxygen atom of a hydroxyl group, specific examples thereof include methoxymethyl, (2-methoxyethoxy) methyl, 2-methoxy-2-propyl, 2-Tetrahydrofuranyl, 2-tetrahydropyranyl group and the like can be mentioned as preferable ones.

The vitamin D ₃ derivative represented by the above formula (4) is produced by reacting the cyclopentene derivative represented by the above formula (2) with the compound represented by the above formula (3) in the presence of a palladium catalyst. . The palladium catalyst used here is a zero-valent or divalent organic palladium compound and a tri-substituted phosphorus compound (molar ratio 1: 1 to 1
1:10). Examples of such organic palladium compounds include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) palladium chloroform, palladium acetate and the like. Examples of phosphorus compounds include triphenylphosphine and tributylphosphine. Among these, tris (dibenzylideneacetone) palladium and triphenylphosphine, tris (dibenzylideneacetone) palladium chloroform and triphenylphosphine (1: 1 to 1:10) are preferable as the palladium catalyst.

Here, the cyclopentene derivative represented by the above formula (2) and the compound represented by the above formula (3) undergo stoichiometric equimolar reaction, but a small excess of a readily available compound is used. Is desirable. The palladium catalyst is used in the range of 0.1 to 100 mol%, preferably 1 to 20 mol% based on the cyclopentene derivative represented by the above formula (2). Further, the tri-substituted phosphorus compound is usually used in an amount of 1 to 10 times the amount of the organopalladium compound in order to produce active palladium.

The reaction solvent used in this reaction is a hydrocarbon solvent such as hexane or toluene, diethyl ether,
Examples thereof include ether solvents such as tetrahydrofuran, dioxane and dimethoxyethane, water-soluble solvents such as N, N-dimethylformamide and acetonitrile, and mixed solvents thereof. It is desirable to use them after sufficiently degassing.

The reaction temperature used is in the range of room temperature to the boiling point of the solvent. The reaction time varies depending on the reaction temperature, and is usually carried out using an analytical means such as thin layer chromatography until either the cyclopentene derivative represented by the above formula (2) or the compound represented by the above formula (3) disappears. Is desirable.

In order to capture an acid such as hydrogen halide produced in the reaction system, it is preferable to add a base such as triethylamine or diisopropylethylamine for the reaction. The amount of the base is preferably 1 equivalent or more with respect to the cyclopentene derivative represented by the above formula (2), and it can also be used as a solvent. Thus, vitamin D ₃ represented by the above formula (4)
Although the derivative is produced in the reaction system, the vitamin D ₃ derivative represented by the above formula (1) can be obtained by further subjecting it to a deprotection reaction.

As a method for such deprotection reaction, a well-known method (eg, Calveley, MJ, Tetrahedron, 2
0,4609-4619, 1987), and the deprotecting agent in that case includes, for example, tetrabutylammonium fluoride, pyridinium-p-toluenesulfonate and the like.

The present invention also includes the cyclopentene derivative represented by the above formula (2). In the above formula (2), the configurations of the asymmetric centers at the C-1 position and the C-4 position of the cyclopentene ring may be either the (R) configuration or the (S) configuration. Further, the present invention also includes a mixture of these four stereoisomers in any ratio. Among them, the asymmetric center at the C-1 position has the (R) configuration, the asymmetric center at the C-4 position has the (S) configuration, and the asymmetric center at the C-1 position has the (S) configuration. It is preferable that the asymmetric center at the C-4 position has the (S) configuration.

Preferred specific examples of the cyclopentene derivative of the present invention represented by the above formula (2) are as follows. 1) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 2) (1R, 4S) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 3) (1S, 4R) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 4) (1S, 4S) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 5) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-
Methyl-2-cyclopentene 6) (1R, 4S) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-
Methyl-2-cyclopentene 7) (1S, 4R) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-
Methyl-2-cyclopentene 8) (1S, 4S) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-
Methyl-2-cyclopentene 9) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 10) (1R, 4S)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 11) (1S, 4R ) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 12) (1S, 4S ) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 13) (1R, 4R ) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 14) (1R, 4S) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 15) (1S, 4R) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 16) (1S, 4S) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyloxy} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 17) (1R, 4R) -4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 18) (1R, 4S)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 19) (1S, 4R)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 20) (1S, 4S)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 21) (1R, 4R)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 22) (1R, 4S)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 23) (1S, 4R)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 24) (1S, 4S)- 4-{(2R) -2-[(1
R, 7aR) (4E) -Octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol

The cyclopentene derivative represented by the above formula (2) can be synthesized according to the following scheme.

[0029]

[Chemical 12]

(In the above scheme, R ¹ , R ⁴ , and R
¹² are the same or different, and each is a hydrogen atom, tri (C
1 to C7 hydrocarbon) silyl group, C2 to C7 acyl group,
Alternatively, it represents a group that forms an acetal bond with the oxygen atom of the hydroxyl group. ) Here, preferred specific examples of R ⁴ and R ¹² are the above R 4
^The same as those mentioned for ¹ , R ² and R ³ can be mentioned.

Cyclopentene derivatives represented by the following formula (5) are also included in the present invention.

[0032]

[Chemical 13]

(In the formula, R ^{11 and} R ⁴ are the same or different,
It represents a tri (C1-C7 hydrocarbon) silyl group, a C2-C7 acyl group, or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. )

In the above formula (5), C- of the cyclopentene ring is
The configurations of the asymmetric centers at the 1-position and C-4 position are as follows:
Either (R) arrangement or (S) arrangement may be adopted. Further, the present invention also includes a mixture of these four stereoisomers in any ratio. Among them, the asymmetric center at the C-1 position has the (R) configuration, the asymmetric center at the C-4 position has the (S) configuration, and the asymmetric center at the C-1 position has the (S) configuration. It is preferable that the asymmetric center at the C-4 position has the (S) configuration. This compound can be led to a cyclopentene derivative represented by the above formula (2) as shown in the above scheme.

Preferred specific examples of the cyclopentene derivative of the present invention represented by the above formula (5) are shown below. 1) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 2) (1R, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 3) (1S, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 4) (1S, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-
Cyclopentene 5) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4- (t-butyldimethylsilyloxy) -7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 6) (1R, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4- (t-butyldimethylsilyloxy) -7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 7) (1S, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4- (t-butyldimethylsilyloxy) -7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 8) (1S, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4- (t-butyldimethylsilyloxy) -7a-methyl-1H-inden-1-yl] -propyl} -1- (t-butyldimethylsilyloxy) -1-methyl-2-cyclopentene 9) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol 10) (1R, 4S) -4-{(2R) -2-[(1
R, 7aR) -octahydro-4-hydroxy-7a-
Methyl-1H-inden-1-yl] -propyl} -1
-Methyl-2-cyclopenten-1-ol 11) (1S, 4R) -4-{(2R) -2-[(1
R, 7aR) -octahydro-4-hydroxy-7a-
Methyl-1H-inden-1-yl] -propyl} -1
-Methyl-2-cyclopenten-1-ol 12) (1S, 4S) -4-{(2R) -2-[(1
R, 7aR) -octahydro-4-hydroxy-7a-
Methyl-1H-inden-1-yl] -propyl} -1
-Methyl-2-cyclopenten-1-ol Further, the cyclopentene derivative represented by the above formula (6) is also included in the present invention.

[0036]

Embedded image

(In the formula, R ¹² is a hydrogen atom and tri (C1 to C
7 hydrocarbon) silyl group, C2 to C7 acyl group, or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. )

In the above formula (6), C- of the cyclopentene ring is
The configurations of the asymmetric centers at the 1-position and C-4 position are as follows:
Either (R) arrangement or (S) arrangement may be adopted. Further, the present invention also includes a mixture of these four stereoisomers in any ratio. Among them, the asymmetric center at the C-1 position has the (R) configuration, the asymmetric center at the C-4 position has the (S) configuration, and the asymmetric center at the C-1 position has the (S) configuration. It is preferable that the asymmetric center at the C-4 position has the (S) configuration. This compound can be converted into the cyclopentene derivative represented by the above formula (2) as shown in the above scheme.

Preferred specific examples of the cyclopentene derivative of the present invention represented by the above formula (6) are shown below. 1) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 2) (1R, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 3) (1S, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 4) (1S, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1-trimethylsilyloxy-1-methyl-2-cyclopentene 5) (1R, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1- (t-
Butyldimethylsilyloxy) -1-methyl-2-cyclopentene 6) (1R, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1- (t-
Butyldimethylsilyloxy) -1-methyl-2-cyclopentene 7) (1S, 4R) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1- (t-
Butyldimethylsilyloxy) -1-methyl-2-cyclopentene 8) (1S, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-oxo-7a-methyl-
1H-inden-1-yl] -propyl} -1- (t-
Butyldimethylsilyloxy) -1-methyl-2-cyclopentene

[0040]

EXAMPLES The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention.

Example 1 (2R) -2-[(1R, 7aR) -octahydro-4
-Trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl-p-toluenesulfonate

[0042]

[Chemical 15]

Compound (7) was added to a 100 ml eggplant flask.
2.0 g of (2R) -2-[(1R, 7aR) (4E) -octahydro-4-hydroxy-7a-methyl-1-H-inden-1-yl] -propanol and p-toluenesulfonyl chloride.2. 3 g was added, dissolved in 10 ml of dried dichloromethane, and stirred under ice cooling. 4 ml of pyridine was added thereto, and the mixture was stirred for 6 hours under ice cooling. The reaction solution was poured into 100 ml of ethyl acetate-20 ml of water and extracted. The organic layer was washed twice with saturated aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to obtain 4.2 g of a crude product. This was placed in a 100 ml round-bottomed flask, 2.04 g of imidazole was added, and 20 ml of dried dichloromethane was added thereto and stirred under ice cooling. Trimethylsilyl chloride (1.91 ml) was added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was ethyl acetate 100 ml-water 2
It was poured into 0 ml and extracted. The extract was washed twice with saturated saline and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to obtain 4.07 g of a crude product. This was purified with a silica gel column (IR-60, 200 g, hexane / ethyl acetate = 9/1) to obtain the desired product (8), (2R) -2-[(1R, 7aR) -octahydro-4-trimethylsilyloxy. -7a-methyl-1
3.27 g (yield 87%) of H-inden-1-yl] -propyl-p-toluenesulfonate was obtained.

¹ H-NMR (CDCl ₃ δppm) 7.78 (d 2H J = 18Hz) 7.34 (d 2H J = 18Hz) 3.9 to 4.0
(m 1H) 3.95 (dd 1H J = 3 & 9.2Hz) 3.79 (dd 1H J = 4.3 & 9.2H
z) 2.45 (s 3H) 1.00 to 2.00 (m 13H) 0.89 (d 3H J = 18Hz) 0.83 (s 3
H) 0.03 (s 9H)

Example 2 (2R) -2-[(1R, 7aR) -octahydro-4
-Trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -iodopropane

[0046]

Embedded image

Compound (8) was added to a 500 ml eggplant flask.
(2R) -2-[(1R, 7aR) -octahydro-4
3.27 g of -trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl-p-toluenesulfonate was dissolved in 200 ml of acetone, 5 g of sodium iodide was added thereto, and the mixture was heated under reflux overnight. After allowing the reaction solution to cool, the precipitate was filtered and the solvent was distilled off under reduced pressure. 300 ml of ether and 200 ml of water were added to the residue for liquid separation, and the aqueous layer was extracted with 200 ml of ether, and the organic layer was washed twice with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain 4.5 g of a crude product. This is a silica gel column (I
R-60, 80 g, hexane,) and the desired product (9), (2R) -2-[(1R, 7aR) -octahydro-4-trimethylsilyloxy-7a-methyl-1.
2.72 g (yield 94%) of H-inden-1-yl] -iodopropane was obtained.

¹ H-NMR (CDCl ₃ δppm) 3.99 (m 1H) 3.33 (dd 1H J = 2 & 5Hz) 3.17 (dd 1H
J = 5 & 9Hz) 1.00 ~ 2.00 (m 13H) 0.99 (d 3H J = 5.6Hz) 0.92 (s
3H) 0.05 (s 9H)

Example 3 (4S) -4-{(2R) -2-[(1R, 7aR)-
Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -2-
Production of cyclopenten-1-one

[0050]

[Chemical 17]

10 ml of ether was placed in a 100 ml round-bottomed flask, cooled to -78 ° C., and 14.3 ml of a hexane solution of t-butyllithium (1.54 mol / L) was added thereto. Compound (9),
(2R) -2-[(1R, 7aR) -octahydro-4
-Trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -iodopropane 3.94 g in ether 10
It was dissolved in ml, added to the above solution, and stirred at -78 ° C for 1 hour. Copper iodide 2.1 g, tri (n-butyl) phosphine 5.5
Dissolve ml in 10 ml THF and add to the above reaction mixture -78
The mixture was stirred at ° C for 1 hour. Here, (4S) -4- (t-butyldimethylsilyloxy) -2-cyclopentene-1
-ON 2.54 g dissolved in 10 ml THF and added, then -40
Stirred for 2 hours at ℃. This was poured into 30 ml of a saturated aqueous solution of ammonium chloride and extracted with 50 ml of ether and 30 ml. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain 11.7 g of a crude product. Dichloromethane 15
This was dissolved in 0 ml, 1,8-diazabicyclo [5.4.0] undecene (2 ml) was added, and the mixture was stirred overnight at room temperature. To this, 400 ml of ether was added, and washed with saturated potassium hydrogen sulfate aqueous solution, saturated sodium hydrogen carbonate aqueous solution, and saturated saline respectively,
It was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to obtain 10.9 g of a crude product. This was purified with a silica gel column (IR-60, 400 g, hexane / ethyl acetate = 40/1, 19/1, 9/1) to obtain the desired product (10), (4S) -4-{(2R)-. 2-[(1
R, 7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -2-cyclopenten-1-one (1.76 g, yield 50%) was obtained.

¹ H-NMR (CD ₃ Cl δppm) 7.57 (dd 1H J = 2.3 & 5.6Hz) 6.10 (dd 1H J = 2 & 5.6H
z) 3.99 (m 1H) 2.80 ~ 3.10 (m 1H) 2.50 (dd 1H J = 6.3 & 18.8Hz)
1.00 ~ 2.00 (m 16H) 0.97 (d 3H J = 6.3Hz) 0.90 (s 3H) 0.05 (s 9H)

Example 4 (1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-trimethylsilyloxy-7
a-Methyl-1H-inden-1-yl] -propyl}
-1-Methyl-2-cyclopenten-1-ol and (1S, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-trimethylsilyloxy-7
a-Methyl-1H-inden-1-yl] -propyl}
Production of -1-methyl-2-cyclopenten-1-ol

[0054]

Embedded image

Compound (10) was added to a 300 ml eggplant flask.
(4S) -4-{(2R) -2-[(1R, 7aR)-
Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -2-
Take 1.76 g of cyclopenten-1-one and take 150 m of THF
1 was added and stirred, and the mixture was cooled to -78 ° C. To this, 6.5 ml of methyllithium ether solution (1.16mol / L) was added, and 1
Stir for 5 minutes. 50 ml of saturated saline was added to decompose excess methyllithium, 100 ml of ether was added, and the layers were separated. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure,
The crude product is purified by a silica gel column (Merck gel; 300 g, hexane / ethyl acetate = 15/1 to 9/1),
Target (11), (1R, 4S) -4-{(2R) -2-
[(1R, 7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopentene-
1.55 g of 1-ol (yield 84%), and the target product (1
2), (1S, 4S) -4-{(2R) -2-[(1
R, 7aR) -Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol (0.27 g, yield 14%) was obtained. .

¹ H-NMR (D ₆ -acetone δppm) of compound (11) 5.40 to 5.60 (m 2H) 4.00 (brs 1H) 2.50 to 2.70 (m 1H)
) 0.90 to 2.20 (m 18H) 1.18 (s 3H) 0.88 (d 3H J = 5Hz)
0.87 (s 3H) 0.03 (s 9H) ¹ H-NMR of compound (12) (D ₆ -acetone δppm) 5.54 (s 2H) 3.90 to 4.00 (m 1H) 2.80 to 3.00 (m 1H
) 0.90 ~ 2.10 (m 18H) 1.26 (s 3H) 0.87 (d 3H J = 6.3
Hz) 0.87 (s 3H) 0.03 (s 9H)

[Embodiment 5] (1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-hydroxy-7a-methyl-
Preparation of 1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol

[0058]

[Chemical 19]

Compound (11) was added to a 100 ml eggplant flask.
(1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-trimethylsilyloxy-7
a-Methyl-1H-inden-1-yl] -propyl}
Add -1-methyl-2-cyclopenten-1-ol to 1.55
Then, 20 ml of THF was added and the mixture was stirred under ice cooling. To this, 5.1 ml of a THF solution (1 mol / L) of tetra-n-butylammonium fluoride was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into 100 ml of ether-30 ml of water and extracted. The organic layer was washed 4 times with saturated saline and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to obtain 1.29 g of a crude product. This was a silica gel column (IR-60, 150 g, hexane / ethyl acetate = 1).
Purification is carried out at 5/1 to 1/1) to obtain the desired product (13), (1
R, 4S) -4-{(2R) -2-[(1R, 7aR)-
Octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl] -propyl} -1-
1.21 g (yield 97%) of methyl-2-cyclopenten-1-ol was obtained.

Similarly, the compounds (12), (1S, 4S)-
4-{(2R) -2-[(1R, 7aR) -octahydro-4-trimethylsilyloxy-7a-methyl-1H
-Inden-1-yl] -propyl} -1-methyl-2
260 mg of cyclopentene-1-carboxylic acid ol was treated to obtain the desired product (14), (1S, 4S) -4-{(2
R) -2-[(1R, 7aR) -octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]
-Propyl} -1-methyl-2-cyclopentene-1-
174 mg of all was obtained (84% yield).

¹ H-NMR (D ₆ -acetone δppm) of compound (13) 5.50 to 5.70 (m 2H) 4.08 (brs 1H) 2.60 to 2.80 (m 1
H) 1.00 to 2.20 (m 19H) 1.32 (s 3H) 1.06 (s 3H) 1.
03 (d 3H J = 9.3Hz) ¹ H-NMR of compound (14) (D ₆ -acetone δpp
m) 5.59 (s 2H) 4.08 (brs 1H) 2.80 ~ 3.00 (m 1H)
1.00 to 2.30 (m 19H) 1.32 (s 3H) 0.98 (s 3H) 0.93 (d 3H J = 9.6Hz)

Example 6 (1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-oxo-7a-methyl-1H
-Inden-1-yl] -propyl} -1-methyl-2
-Production of cyclopenten-1-ol

[0063]

Embedded image

Compound (13) in a 100 ml round-bottomed flask,
(1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-hydroxy-7a-methyl-
277 mg of 1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol was dissolved in 25 ml of toluene and stirred under a nitrogen atmosphere. Tetrakistriphenylphosphine ruthenium dihydride (115 mg) and allyl methyl carbonate (5 ml) were added to the mixture to give 80-1.
The mixture was stirred at 00 ° C for 1 day. The reaction solution was filtered through Celite, the solvent was evaporated under reduced pressure, and the residue was filtered through a silica gel column (IR-6
0, 80 g, hexane / ethyl acetate = 3/1, 1/1)
The desired product (15), (1R, 4S) -4-
{(2R) -2-[(1R, 7aR) -octahydro-
221 mg (yield 79%) of 4-oxo-7a-methyl-1H-inden-1-yl] -propyloxy} -1-methyl-2-cyclopenten-1-ol was obtained.

Similarly, the compounds (14), (1S, 4S)-
4-{(2R) -2-[(1R, 7aR) -octahydro-4-hydroxy-7a-methyl-1H-indene-
62 mg of 1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol was treated to obtain the desired product (16), (1
S, 4S) -4-{(2R) -2-[(1R, 7aR)-
52 mg (yield 84%) of octahydro-4-oxo-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol were obtained.

¹ H-NMR (CD ₃ Cl δppm) of compound (15) 5.60 to 5.70 (m 2H) 2.60 to 2.80 (m 1H) 1.20 to 2.50
(m 18H) 1.35 (s 3H) 0.99 (d 3H J = 9.3Hz) 0.65 (s 3H) ¹ H-NMR (CD ₃ Cl δppm) of compound (16) 5.60 to 5.70 (m 2H) 2.80 to 3.00 (m 1H) 1.00 to 2.50 (m
18H) 1.43 (s 3H) 0.99 (d 3H J = 9.3Hz) 0.66 (s 3H)

[Embodiment 7] (1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-oxo-7a-methyl-1H
-Inden-1-yl] -propyl} -1-methyl-1
-Trimethylsilyloxy-2-cyclopentene production

[0068]

[Chemical 21]

Compound (15) was added to a 100 ml eggplant flask.
(1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-oxo-7a-methyl-1H
177 mg of -inden-1-yl] -propyloxy} -1-methyl-2-cyclopenten-1-ol and 128 mg of imidazole were added. Next, 20 ml of dried dichloromethane was added and stirred, 120 μl of trimethylsilyl chloride was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into 50 ml of ether-30 ml of water and extracted.
The organic layer was washed twice with saturated saline and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to a silica gel column (IR-60, 8).
Purification was performed with 0 g of hexane / ethyl acetate = 19/1, 4/1) to obtain the desired product (17), (1R, 4S) -4-.
{(2R) -2-[(1R, 7aR) -Octadehydro-4-oxo-7a-methyl-1H-inden-1-yl] -propyloxy} -1-methyl-1-trimethylsilyloxy-2-cyclopentene 188 mg (yield 8
5%) was obtained.

Similarly, the compounds (16), (1S, 4S)-
4-{(2R) -2-[(1R, 7aR) -octahydro-4-oxo-7a-methyl-1H-indene-1-
52 mg of yl] -propyl} -1-methyl-2-cyclopenten-1-ol was treated to obtain the desired product (18), (1S,
4S) -4-{(2R) -2-[(1R, 7aR) -octahydro-4-oxo-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopentene-1 -All 49 mg (75% yield) was obtained.

¹ H-NMR (CD ₃ Cl δppm) of compound (17) 5.71 (dd 1H J = 2 & 5.6Hz) 5.56 (dd 1H J = 1.65 & 5.
6Hz) 2.60 to 2.80 (m 1H) 1.10 to 2.50 (m 17H) 1.31 (s 3H
) 0.98 (d 3H J = 9.3Hz) 0.65 (s 3H) 0.12 (s 9H) ¹ H-NMR (CD ₃ Cl δppm) 5.50-5.65 (m 2H) 2.80-2.90 (m 1H) 1.10 of compound (18) ~ 2.5
0 (m 17H) 1.31 (s 3H) 0.98 (d 3H J = 9.3Hz) 0.56 (s 3H)
0.07 (s 9H)

[Embodiment 8] (1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol.

[0073]

[Chemical formula 22]

5.30 g of bromomethylenetriphenylphosphonium bromide was placed in a 200 ml round-bottomed flask, 30 ml of dry THF was added, and the mixture was stirred and cooled in a -65 ° C. bath. Next, 12.2 ml of a 1 M solution of sodium bistrimethylsilylamide in THF was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Compound (17), (1R, 4S) -4-{(2
R) -2-[(1R, 7aR) -octahydro-4-oxo-7a-methyl-1H-inden-1-yl] -propyloxy} -1-methyl-1-trimethylsilyloxy-2-cyclopentene 882 mg THF 10 ml The solution was added dropwise, the cooling bath was removed, and the mixture was stirred at room temperature for 30 minutes.
Hexane was further added to the reaction solution and the mixture was stirred. The precipitate was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 10 ml of THF and stirred with ice cooling, and a solution of tetra (n-butyl) ammonium fluoride in THF (1 mol / L) 5
After adding ml, the mixture was stirred under ice cooling for 1 hour. The reaction mixture was poured into 100 ml of ethyl acetate and 30 ml of water, and after liquid separation, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was purified with a silica gel column (IR-60, 200 g, hexane / ethyl acetate = 19/1 to 2/1) to obtain the desired product ( 1
9), (1R, 4S) -4-{(2R) -2-[(1R,
7aR) -Octahydro-4-bromomethylene-7a-
Methyl-1H-inden-1-yl] -propyl} -1
-Methyl-2-cyclopenten-1-ol 422 mg
(Yield 47%) was obtained.

¹ H-NMR (CDCl ₃ δppm) 5.50-5.70 (br 3H) 2.80-2.90 (m 1H) 2.60-2.
80 (m 1H) 2.10 ~ 2.25 (m 1H) 1.20 ~ 2.00 (m 16H) 1.35 (s 3
H) 0.96 (d 3H J = 6.3Hz) 0.57 (s 3H)

[Embodiment 9] (1R, 4S) -4-{(2R) -2-[(1R, 7a
R) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-
Production of methyl-1-trimethylsilyloxy-2-cyclopentene

[0077]

[Chemical formula 23]

Compound (19) was added to a 100 ml eggplant flask.
(1R, 4S) -4-{(2R) -2-[(1R, 7a
(R) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol (422 mg) and imidazole (158 mg) were added. Next, 5 ml of dried dichloromethane was added and stirred, and 175 μl of trimethylsilyl chloride was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into 50 ml of ether-20 ml of water and extracted.
The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, the solvent was evaporated under reduced pressure, and the resulting residue was filtered through a silica gel column (IR-60, 150).
g, hexane / ethyl acetate = 50/1 to 19/1) for purification, and the desired product (20), (1R, 4S) -4-
{(2R) -2-[(1R, 7aR) -octahydro-
4-Bromomethylene-7a-methyl-1H-indene-
422 mg (yield 84%) of 1-yl] -propyl} -1-methyl-2-cyclopenten-1-ol was obtained.

¹ H-NMR (CDCl ₃ δppm) 5.50 to 5.70 (m 2H) 5.53 (s 1H) 1.10 to 3.00 (m 1
8) 1.35 (s 3H) 0.94 (d 3H J = 6.3Hz) 0.56 (s 3H) 0.11 (s 9H)

Example 10 1α, 3-bistrimethylsilyloxy-22-[(1
R, 4S) -1-Trimethylsilyloxy-1-methyl-2-cyclopenten-4-yl] -3-deoxy-2
3,24,25,26,27-Pentanol-Vitamin D
Manufacturing ₃

[0081]

[Chemical formula 24]

63.7 mg of triphenylphosphine was placed in a dry eggplant flask and deaerated. Tris (dibenzylideneacetone) dipalladium chloroform 20
After further adding mg, the mixture was degassed, and 7.2 ml of a mixed solvent of toluene / diisopropylethylamine = 1/1 that had been distilled under a nitrogen atmosphere was added, and the mixture was stirred at room temperature for 20 minutes. Next, the compound (20), (1R, 4S) -4-{(2R) -2-
[(1R, 7aR) -Octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl] -propyl} -1-methyl-1-trimethylsilyloxy-2
-88 mg of cyclopentene, compound (21), (3S,
5R) -bistrimethylsilyloxy-1-octene-
57 mg of 7-yne was dissolved in 2 ml of a mixed solvent of distilled toluene / diisopropylethylamine = 1/1 and added dropwise to the above reaction solution. After heating under reflux for 1.5 hours, the temperature was returned to room temperature, the reaction solution was poured into 50 ml of ethyl acetate-10 ml of a saturated aqueous solution of potassium hydrogen sulfate, and extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to obtain 300 mg of a crude product. This was purified with a silica gel column (Merck gel, 200 g, hexane / ethyl acetate = 100/1 to 20/1) to obtain the desired product (22), 1α, 3-bistrimethylsilyloxy-22-[(1R, 4S)-. 1-Trimethylsilyloxy-1-methyl-2-cyclopenten-4-yl]-
3-deoxy -23,24,25,26,27- Pentanoru - vitamin D ₃ and 58.8 mg (46% yield).

¹ H-NMR (CDCl ₃ δppm) 6.27 (d like 1H) 6.04 (d like 1H) 5.50 to 5.60 (m
2H) 5.20 (s 1H) 4.90 (brs 1H) 4.30 ~ 4.40 (m 1H) 4.10 ~ 4.20 (m 1H
) 1.10 ~ 3.00 (m 22H) 1.32 (s 3H) 0.94 (d 3H J = 6.3Hz) 0.55 (s 3H)
0.00 to 0.20 (m 18H)

Example 11 1α-Hydroxy-22-[(1R, 4S) -1-hydroxy-1-methyl-2-cyclopenten-4-yl]-
23,24,25,26,27- Pentanoru - production of vitamin D ₃

[0085]

[Chemical 25]

Compound (22), 1 in a 25 ml eggplant flask.
α, 3-bistrimethylsilyloxy-22-[(1R,
4S) -1-Trimethylsilyloxy-1-methyl-2
-Cyclopenten-4-yl] -3-deoxy-23,
Vitamin D ₃ - 24,25,26,27- Pentanoru
After taking 58.8 mg, 5 ml of dry THF was added and stirred, and 0.5 ml of a 1M tetrabutylammonium fluoride THF solution was added under ice cooling, and the mixture was stirred under ice cooling for 3 hours.
50 ml of ethyl acetate-saturated aqueous potassium hydrogen sulfate solution
It was poured into 10 ml and extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the obtained crude product was subjected to a silica gel column (IR-60 Merck gel, 250
g, hexane / ethyl acetate = 1/1 to 1/3) to give the desired product (23), 1α-hydroxy-22-
[(1R, 4S) -1-hydroxy-1-methyl-2-
Cyclopenten-4-yl] -23, 24, 25, 2
22.1 mg of 6,27-pentanor-vitamin D ₃ (yield 5
7%).

¹ H-NMR (CDCl ₃ δppm) 6.38 (d 1H J = 11.2Hz) 6.01 (d 1H J = 11.2Hz) 5.64
(s 2H) 5.33 (s 1H) 5.00 (s 1H) 4.40 to 4.50 (m 1H) 4.15 to 4.30 (m
1H) 1.20 to 2.90 (m 25H) 1.32 (s 3H) 0.96 (d 3H J = 6.3H
z) 0.55 (s 3H)

[Example 12] Intracytoplasmic 1α, 25-dihydroxybi of chicken small intestinal mucosa
The compound of the present invention for the tamin D ₃ receptor (VDR)
The binding affinity of chick small intestine mucosa cytoplasmic 1α, 25-dihydroxyvitamin D ₃ receptor is isolated and the receptor binding affinity is measured by a known method [Steroids, 3
7, 33-43 (1981)]. Ie 12
20 pg [2 mm x 75 mm polypropylene tube
6,27- methyl ^- 3 H] ^1α, 25- dihydroxyvitamin _{D 3 (158 Ci / mmol,} 16800dp
m) and the test compound are dissolved in 50 μl of ethanol and added to 1 ml of phosphate buffer (pH 7.4), 0.2 mg of 1α, 25-dihydroxyvitamin D ₃ receptor protein 1α, 25-dihydroxyvitamin D ₃ receptor protein in chicken small intestinal mucosa and 1 mg of gelatin. What was melt | dissolved was added and it was made to react at 25 degreeC for 1 hour. After the reaction, 1 ml of 40% polyethylene glycol 6000 solution was added to each tube, and after vigorous stirring, 2260 × at 4 ° C.
Centrifuge at 60 g for 60 minutes. The tube in the precipitation portion was cut with a cutter knife, placed in a vial for liquid scintillation, 10 ml of dioxane scintillator was added, and its radioactivity was measured with a liquid scintillation counter. The results are shown in the table below. It can be seen that the compound of the present invention does not easily bind to this receptor.

[Embodiment 13]The present invention for vitamin D binding protein in fetal bovine serum
Compound binding affinity 25-Human to Vitamin D Binding Protein in Fetal Bovine Serum
Droxy vitamin D₃ And the binding affinity of the compound of the present invention
The Journal Steroid Biochemistry
Regular Biology (J.Steroid Biochem. Mole
c. Biol. 41, 109-112 (1992)).
went. That is, in a glass tube of 12 × 105 mm
200 pg of [26,27-methyl-³H] 25-Hide
Roxy vitamin D₃(28 Ci / mmol, 3100
0% dpm) 0.01% Triton X-100
The solution and test compound were dissolved in 10 μl of ethanol and added.
It was It contains 0.9% sodium chloride in fetal bovine serum.
Solution diluted 2500 times with phosphate buffer (pH 7.0)
Add 0.2 ml and react at 4 ° C for 24 hours, then 0.5 ml
Of 0.5% charcoal, 0.075% dextran
And 0.5% bovine serum albumin solution was added. At 4 ° C
After reacting for 15 minutes, centrifuge at 2260 xg for 10 minutes,
Transfer 0.5 ml of the supernatant of
, Liquid vitamin sc in a liquid scintillation counter
Bound to a protein [26,27-methyl-³H] 2
5-hydroxyvitamin D₃Was measured. So
The results are shown below together with the results of Example 12. Departure
A bright compound easily binds to vitamin D binding protein
I understand. This suggests a long blood half-life
There is.

[0090]

[Table 1]

[Example 14] Collagen synthesis and non-collagen protein in osteoblasts
A synthetic mouse osteoblast cell line (MCJT cell) was dispersed in α-MEM medium containing 10% fetal calf serum (FCS) (1 × 10 6).
⁴ cells / ml medium), 2 ml each of this 35
The cells were seeded on a mm culture dish and cultured at 37 ° C. under 5% CO ₂ . Four days later, after reaching confluence, the medium was replaced with the same medium, and the test compound was then added to an ethanol solution (1 × 10 ^−4).
M and 1 × 10 ⁻⁵ M) were added in 2 μl aliquots. 2 μl of ethanol alone was added to the control group. These 3
It was cultured at 7 ° C. under 5% CO ₂ . After 45 hours of culture, the medium was exchanged with an α-MEM medium containing 0.1% bovine serum albumin (BSA), 0.1 mM ascorbic acid, and 0.5 mM fumaric acid-β-aminopropionitrile, and the ethanol of the test compound was again used. After the solution or ethanol was added in the same amount as the previous time and cultured for 30 minutes, 4 μCi of [ ³ H] proline was added to each petri dish and incorporated into osteoblasts for 3 hours.

The amount of collagen and the amount of non-collagen protein synthesized were determined by the method of Perterkofsky et al. [Biochemistry 10, 988-994 (197).
1)]. The results are shown in the table below.

[0093]

[Table 2]

[0094]

INDUSTRIAL APPLICABILITY The vitamin D ₃ derivative of the present invention is used as a drug such as an osteogenesis promoter, an immunosuppressant, a tumor cell growth inhibitor, a hypercalcemia agent and the like. The cyclopentene derivative of the present invention is used as its synthetic intermediate, and the method of the present invention provides its synthetic method.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/59 ADT ADU C07C 29/44 35/21 35/52 43/30 49/737 // C07C 69/145 C07F 7/18 A (72) Inventor Yuko Tanaka 4-3, Asahigaoka, Hino-shi, Tokyo Inside Teijin Research Center, Tokyo (72) Seiichi Ishizuka 4-3.2 Asahigaoka, Hino-shi, Tokyo No. Teijin Limited Tokyo Research Center

Claims (14)

[Claims] 1. The following formula (1): Vitamin D ₃ derivative represented by. 2. The C- of the cyclopentene ring of the above formula (1)
The vitamin D ₃ derivative according to claim 1, wherein the asymmetric center at the 1-position has the (R) configuration and the asymmetric center at the C-4 position has the (S) configuration. 3. The C- of the cyclopentene ring of the above formula (1)
The vitamin D ₃ derivative according to claim 1, wherein the asymmetric center at the 1-position has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration. 4. The following formula (2): (In the formula, R ¹ is a hydrogen atom, tri (C1-C7 hydrocarbon))
It represents a silyl group, a C2-C7 acyl group, or a group forming an acetal bond together with an oxygen atom of a hydroxyl group, and X represents a bromine atom or an iodine atom. ) A cyclopentene derivative represented by: 5. The C— of the cyclopentene ring of the above formula (2)
The cyclopentene derivative according to claim 4, wherein the asymmetric center at the 1-position has the (R) configuration and the asymmetric center at the C-4 position has the (S) configuration. 6. The C- of the cyclopentene ring of the above formula (2)
The cyclopentene derivative according to claim 4, wherein the asymmetric center at the 1-position has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration. 7. A cyclopentene derivative represented by the above formula (2) and the following formula (3): (In the formula, R ² and R ³ are the same or different and are a hydrogen atom,
It represents a tri (C1-C7 hydrocarbon) silyl group, a C2-C7 acyl group, or a group that forms an acetal bond together with an oxygen atom of a hydroxyl group. ) Is reacted with a compound represented by the formula (1) in the presence of a palladium catalyst to give a compound represented by the following formula (4): (In the formula, R ¹ , R ² , and R ³ are the same as the above definition.)
A vitamin D ₃ derivative represented by
^A method for producing a vitamin D ₃ derivative represented by the above formula (1), characterized in that deprotection reaction is carried out except when ¹ , R ² and R ³ are all hydrogen atoms. 8. The following formula (5): (In the formula, R ¹¹ and R ⁴ are the same or different,
It represents a tri (C1-C7 hydrocarbon) silyl group, a C2-C7 acyl group, or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. ) A cyclopentene derivative represented by: 9. The C- of the cyclopentene ring of the above formula (5)
The cyclopentene derivative according to claim 8, wherein the asymmetric center at the 1-position has the (R) configuration and the asymmetric center at the C-4 position has the (S) configuration. 10. The C of the cyclopentene ring of the above formula (5)
The cyclopentene derivative according to claim 8, wherein the asymmetric center at the -1 position has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration. 11. The following formula (6): (In the formula, R ¹² is a hydrogen atom, tri (C1-C7 hydrocarbon))
A silyl group, a C2-C7 acyl group, or a group that forms an acetal bond together with an oxygen atom of a hydroxyl group. ) A cyclopentene derivative represented by: 12. The C of the cyclopentene ring of the above formula (6)
The cyclopentene derivative according to claim 11, wherein the asymmetric center at the -1 position has the (R) configuration and the asymmetric center at the C-4 position has the (S) configuration. 13. The C of the cyclopentene ring of the above formula (6)
The cyclopentene derivative according to claim 11, wherein the asymmetric center at the -1 position has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration. 14. A process for producing a cyclopentene derivative represented by the above formula (2), which comprises reacting the cyclopentene derivative represented by the above formula (6) with bromomethylenetriphenylphosphonium bromide in the presence of a base.