VITAMIN D3 DERIVATIVE AND PRODUCTION PROCESS THEREOF

DERIVE DE LA VITAMINE D3 ET PROCEDE DE FABRICATION CONNEXE

English Abstract

A vitamin D, derivative represented by the following
formula:

(see formula I)
wherein, R is, independently, a hydrogen atom, tri(C1 to
C7 hydrocarbon) silyl group, C2 to C8 acyl group, or group
forming an acetal bond together with an oxygen atom of a
hydroxyl group, A is

(see formula II) (see formula III) or (see formula IV)
where, R1 is a methyl group or methylene group, and when
R1 is a methylene group, the bond between the R1 and the
3-position of the lactone ring is a double bond, R2 is a
hydrogen atom or C1 to C3 alkyl group, R3 is a hydrogen
atom, or R2 and R3 together indicate a substitutable
single methylene group.

French Abstract

Dérivé de la vitamine D3 représenté par la formule générale (I), dans laquelle les R représentent chacun indépendamment hydrogène, tri(hydrocarbyle C1-C7)silyle, acyle C2-C8 ou un groupe formant une liaison acétal avec l'atome d'oxygène ou un groupe hydroxyle; A représente les groupes (a), (b) ou (c); R<1> représente méthyle ou méthylène, à condition que lorsque R<1> est méthylène, la liaison entre ce composé et la position 3 du noyau lactone soit une double liaison; R<2> représente hydrogène ou alkyle C1-C3; et R<3> représente hydrogène, ou R<2> et R<3> peuvent se combiner pour représenter un groupe méthylène éventuellement substitué.

Claims

-119-

CLAIMS:
1. A vitamin D3 derivative represented by the
following formula (I):

Image
wherein, R is, independently, a hydrogen atom, tri(C1 to C7
hydrocarbon) silyl group, C2 to CB acyl group, or a group
forming an acetal bond together with an oxygen atom of a
hydroxyl group, A is

Image
where, R1 is a methyl group or methylene group and when R1 is
a methylene group, the bond between the R1 and the 3-position
of the lactone ring is a double bond, R2 is a hydrogen atom
or C1 to C3 alkyl group, R3 is a hydrogen atom, or R2 and R3
together indicate a single methylene group, which is
substitutable with a t-butyl group, phenyl group or methyl
group.


-120-

2. A vitamin D3 derivative as claimed in claim 1
represented by the following formula (1-1):

Image
wherein the asymmetric center of the C-1 position of the
cyclopentene ring of the formula (1-1) is the (S)
configuration and the asymmetric center of the C-4 position
is the (S) configuration.
3. A cyclopentene derivative represented by the
following formula (1-2):

Image
wherein R~ is a hydrogen atom, a tri(C1 to C7 hydrocarbon)
silyl group, a C2 to C7 acyl group, or a group forming an
acetal bond together with an oxygen atom of a hydroxyl
group, and X1 is a bromine atom or iodine atom.

Description

TN-C847/PCT
- 1 -

DESCRIPTION 2168728
Vitamin D3 Derivative and Production Process Thereof
TECHNICAL FIELD
The present invention relates to a vitamin D3
derivative useful as a pharmaceutical. More specifically,
it relates to a la-hydroxy vitamin D3 derivative useful
as a pharmaceutical such as an agent for promoting bone
formation, an agent for suppressing proliferation of
tumor cells, an agent for high calcium blood diseases,
and an immunosuppression agent, a production process
thereof, and a production intermediate.
BACKGROUND ART
It is fully recognized through disclosures in patent
publications and a large number of general references
that vitamin D3 metabolites play an extremely important
role as substances controlling the metabolism of calcium
and phosphates in the body. Recently, further, an
increase has been seen in clinical application as drugs
for the treatment of various diseases such as with the
numerous vitamin D3 metabolites found to have the
function of inducing differentiation of tumorous bone
marrow cells. On the other hand, recently, a novel
vitamin D3 active metabolite having an a-hydroxyl ac tone
ring at the steroid side chain has been found. [Arch.
Bio-chem. Biophys., 204, 339-391 (1980); FEBS LETTERS,
134, 207-211 (1981)]. This compound is
la,25-dihydroxy-vitamin D3-26,23-lactone and is
represented by the following structural formula:


- 2 - 2168728
O 0 H
0
H

H0 OH

This compound has been reported to have an action
for reducing the concentration of calcium in blood serum
(Japanese Unexamined Patent Publication (Kokai) No.
58-118516), an action for suppressing the proliferation
of tumor cells (Japanese Unexamined Patent Publication
(Kokai) No. 58-210011), an action for promoting bone
formation (Japanese Unexamined Patent Publication (Kokai)
No. 60-185715), etc.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a
novel vitamin D3 derivative having activity to promote
bone formation, a production process therefor, and
production intermediates.
In accordance with the present invention, there is
provided a vitamin D, derivative having the following
formula (I):

A
F-{
~ (I)
O R

wherein, R is, independently, a hydrogen atom, tri(C, to


CA 02168728 2006-10-18
- 3 -

C-, hydrocarbon) silyl group, C2 to C8 acyl group, or a group
forming an acetal bond together with an oxygen atom of a
hydroxyl group, A is
R
, , 2 S
4

OH or OR, y:: 0 0 C00R2

where, R1 is a methyl group or methylene group, and when R'
is a methylene group, the bond between R' and the 3-position
of the lactone ring is a double bond, R 2 is a hydrogen atom
or C1 to C3 alkyl group, R3 is a hydrogen atom, or R'` and R3
together are a single methylene group, which is
substitutable with a t-butyl group, phenyl group or methyl
group.
In accordance with another embodiment of the present
invention, there is provided a lactone compound represented
by the following formula (2-2):

R l%.. 5 .
0-----
O ( 2 - 2 )
+ H
X2
wherein, RZ is a methyl group or methylene group, provided
that when R2 is a methylene group, the bond between R2 and
the 3-position of the lactone ring is a double bond,

and X2 is a bromine atom or iodine atom.
Yet another embodiment of the present invention
provides a heptanoic acid derivative represented by the
following formula (3-2):


CA 02168728 2006-10-18
- 3a -
Z
I 0 R
COzR;
~ ~,
e~

~ 2
wherein, R~ is a hydrogen atom or C1 to C3 alkyl group and R3
is a hydrogen atom or R3 and R; together are a single
methylene group which is substitutable with a t-butyl group,
phenyl group or methyl group.

BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will now be explained in further
detail with reference to the drawings.

Figure 1 and Fig. 2 are respectively figures showing
the results of synthesis of collagen and synthesis of
noncollagen protein in the following Examples.

BEST MODE FOR WORKING THE INVENTION
That is, according to the first aspect of the present
invention, there is provided a vitamin D3 derivative
represented by the following formula (1-1):

!-~
C 1 - 1 )
HO OH

In the above formula (1-1), the configurations of the
asymmetric centers of the C-1 position and C-4 position of
the cyclopentene ring may be either of the (R)


- 4 - 2168728

configuration or (S) configuration, respectively.
Further, the present invention includes mixtures of any
proportions of these four types of stereo isomers: Among
them, ones where the asymmetric center of the C-1
position is the (R) configuration, ones where the
asymmetric center of the C-4 position is the (S)
configuration, and ones where the asymmetric center of
the C-1 position is the (S) configuration and the
asymmetric center of the C-4 position is the (S)
configuration are preferred.
Specific examples of the preferred vitamin D3
derivative of the first aspect of the present invention
are as follows:
1) 23,24,25,26,27-pentanol-la-hydroxy-22-[(1-
hydroxy-l-methyl)-2-cyclopenten-4-yl]-vitamin D3
2) 23,24,25,26,27-pentanol-la-hydroxy-22-[(1R,4S)-
(1-hydroxy-l-methyl)-2-cyclopenten-4-yl]-vitamin D3
3) 23,24,25,26,27-pentanol-la-hydroxy-22-[(1R,4R)-
(1-hydroxy-l-methyl)-2-cyclopenten-4-yl]-vitamin D;
4) 23,24,25,26,27-pentanol-la-hydroxy-22-[(lS,4R)-
(1-hydroxy-l-methyl)-2-cyclopenten-4-yl]-vitamin D3
5) 23,24,25,26,27-pentanol-la-hydroxy-22-[(1S,4S)-
(1-hydroxy-l-methyl)-2-cyclopenten-4-yl]-vitamin D3
Further, the present invention includes a production
process of the vitamin D, derivative represented by the
above formula (1-1).
That is, it includes a production process of a
vitamin D3 derivative represented by the above formula
(1-1) characterized by reacting a cyclopentene derivative
represented by the following formula (1-2):


216$728
-S-

-~`OR
(1 Z)
H
X, .
wherein R; is a hydrogen atom, a tri (C, to C7
hydrocarbon) silyl group, a C2 to C7 acyl group, or a group
forming an acetal bond with an oxygen atom of a hydroxyl
group, and X, is a bromine atom or iodine atom
and an enyne derivative represented by the following
formula (1-3)

1 - 3 )
R;0 OR"
wherein R; and R; are a hydrogen atom, tri (C, to C7
hydrocarbon) silyl group, C2 to C7 acyl group, or a group
forming an acetal bond with an oxygen atom of a hydroxyl
group
in the presence of a palladium catalyst to obtain a
vitamin D, derivative represented by the following
formula (1-4):

OR~
tH

1 4 35 R,O ORz


2168728
- 6 -

wherein, Ri, Ri, and Ri are the same as defined above and
optionally performing a deblocking reaction.
In the production process of a vitamin D3 derivative
according to the first aspect of the present invention,
the configurations of the asymmetric centers of the C-1
position and C-4 position of the cyclopentene ring of the
starting material, that is, the cyclopentene derivative
represented by the above formula (1-2), may respectively
be either of the (R) configuration or (S) configuration.
Further, the derivative may be a mixture of any ratio of
these stereo isomers. For example, when a cyclopentene
derivative represented by the above formula (1-2) wherein
the asymmetric center of the C-1 position of the
cyclopentene ring is the (R) configuration and the
asymmetric center of the C-4 position is the (S)
configuration is used, the configurations of these
portions are preserved during the reaction and a vitamin
D3 derivative represented by the above formula (1-1)
wherein the asymmetric center of the C-1 position of the
cyclopentene ring is.the (R) configuration and the
asymmetric center of the C-4 position is the (S)
configuration is obtained.
In the same way, when a cyclopentene derivative
represented by the above formula (1-1) where the
asymmetric center of the C-1 position of the cyclopentene
ring is the (S) configuration and the asymmetric center
of the C-4 position is the (S) configuration is used, a
vitamin D3 derivative represented by the above formula
(1-1) wherein the asymmetric center of the C-1 position
of the cyclopentene ring is the (S) configuration and the
asymmetric center of the C-4 position is (S)
configuration is obtained.
Here, when Ri, R;, or R' is a tri(C, to C,
hydrocarbon)silyl group, specific examples are preferably
a tri(C1 to C4 alkyl)silyl group such as a trimethylsilyl,
triethylsilyl, or t-butyldimethylsilyl group, a phenyl(C1


2168728
- 7 -

to C4 alkyl)silyl group such as a t-butyldiphenylsilyl
group, etc. Further, when Ri, Ri, or Ri is a C1 to C7 acyl
group, the specific examples are preferably an acetyl,
propionyl, n-butyryl, pivaloyl, benzoyl, methoxycarbonyl,
ethoxycarbonyl, benzyloxycarbonyl group, etc. Further,
when Ri, Ri, or Ri is a group forming an acetal bond with
an oxygen atom of a hydroxyl group, specific examples are
preferably, a methoxymethyl, (2-methoxyethoxy)methyl,
2-methoxy-2-propyl, 2-tetrahydrofuranyl,
2-tetrahydropyranyl group, etc.
The vitamin D3 derivative represented by the above
formula (1-4) is produced by reacting the cyclopentene
derivative represented by the above formula (1-2) with an
enyne derivative represented by the above formula (1-3)
in the presence of a palladium catalyst. Here, the
palladium catalyst used is a zero-valent or bivalent
organopalladium compound. Examples of such a palladium
compound, are tetrakis(triphenylphosphine) palladium or
any mixture of a tris(dibenzylideneacetone) palladium,
tris(dibenzylideneacetone)palladium chloroform, palladium
acetate, etc. with a phosphorus compound such as
triphenylphosphine or tributylphosphine (molar ratio of
1:1 to 1:10). As the palladium catalyst among these, a
combination of tris(dibenzylideneacetone) palladium and
triphenylphosphine (1:1 to 1:10) or
tris(dibenzylideneacetone)palladium chloroform and
triphenylphosphine (1:1 to 1:10) is preferred.
Here, the cyclopentene derivative represented by
the above formula (1-2) and the enyne derivative
represented by the above formula (1-3) stoichiometrically
react equimolarly, but it is preferable to use a slight
excess of the more readily available compound. Further,
the palladium catalyst is used in a range of 0.1 to
100 molar %, preferably 1 to 20 molar %, with respect to
the cyclopentene derivative of the above formula (1-2).
Examples of the reaction solvent used in this


2168728
- 8 -

reaction are a hydrocarbon type solvent such as hexane
and toluene, an ether type solvent such as diethyl ether,
tetrahydrofuran, dioxane, and dimethoxyethane, a
water-soluble solvent such as N,N-dimethylformamide and
acetonitrile, and mixed solvents of the same. All of
these are preferably used after sufficient deaeration.
As the reaction temperature, a range of from room
temperature to the boiling point of the solvent is used.
The reaction time differs depending on the reaction
temperature. Usually, the reaction is preferably
continued until one of the cyclopentene derivative
represented by the above formula (1-2) or the enyne
derivative represented by the above formula (1-3) is
found to be consumed by an analytical means such as thin
layer chromatography.
Further, to trap the acids such as the hydrogen
halides in the reaction system, it is preferable to
perform the reaction added with a base such as
triethylamine or diisopropylethylamine. As the amount of
the base, it is preferable to use at least one equivalent
of the cyclopentene derivative represented by the above
formula (1-2). It may also be used together as a solvent.
Therefore, the vitamin D3 derivative represented by the
above formula (1-4) is produced in the reaction system,
but it is possible to effect a deprotection reaction when
necessary to obtain the vitamin D3 derivative represented
by the above formula (1-1).
As the method of the deblocking reaction, when
deblocking for example the silyl groups, it is possible
to use a known method (for example, Calveley, M. J.,
Tetrahedron, 20, 4609-4619, 1987). Examples of the
deprotection agent in this case are tetrabutylammonium
fluoride, pyridinium-p-toluene sulfonate, etc.
Further, in the process of the present.invention,
the compound represented by the above formula (1-2) which
is used as a starting material may be synthesized in


2168728
- 9 -

accordance with the following scheme:
OH OTs
Nal 1) t6ULi
1) TsCI
_ -~- --~-
2)TMSCI etc. 2)TBS0~0
OH R0 RiO 3) OBU

O
Deprotection of
O H hydroxyl group
MeLi

R i 0 R i O One example of (1 - 5)
Protection
of
OH OH hydroxyl !ORl 2
Oxidation qroup
1.5
HO O O
Example of (1 - 6) Example of (1 - 6)
Example of (1 - 5)
Protection
of
OH hydroxyl ',
1) Halomethylation group 0 R 1
-~--
2 0 2} Deprotection of
hydroxyl group
X X
wherein, in the above scheme, R;, R;, and R;Z are a
hydrogen atom, tri(C, to C7 hydrocarbon) silyl group,_C2 to
25 C7 acyl group, or group forming an acetal bond with an
oxygen atom of a hydroxyl group.
Here, preferable specific examples of R'; and R;Z are
those as mentioned for the above R;, R;, and. R;.

30 ORI
(1 5)
R~0 H

35 wherein, R; and R; may be the same or different and
represent a hydrogen atom, tri(C, to C7 hydrocarbon) silyl


2168728
- 10 -

group, CI to C7 acyl group, or group forming an acetal
bond with an oxygen atom of a hydroxyl group.
Preferable specific examples of the cyclopentene
derivative of the present invention of the above formula
(1-5) are as follows:
1) (1R,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
2) (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
3) (1S,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
4) (1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
5) (1R,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-(t-
butyldimethylsilyloxy)-7a-methyl-lH-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-lH-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-lH-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-lH-inden-1-yl]-propyl}-
1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene
9) (1R,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-2-
cyclopenten-l-ol
10) (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-2-
cyclopenten-l-ol
11) (1S,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-


2168728
- 11 -

hydroxy-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-2-
cyclopenten-l-ol
12) (1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-ylJ-propyl}-1-methyl-2-
cyclopenten-l-ol

ORy
(1-6)
p H

wherein, R; is a hydrogen atom, tri(C, to C7
hydrocarbon) silyl group, C1 to C7 acyl group, or group
forming an acetal bond with an oxygen atom of a hydroxyl
group.
Further, preferable specific examples of the
cyclopentene derivative of the present invention of the
above formula (1-6) are as follows:
1) (1R,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-1-trimethylsilyloxy-l-
methyl-2-cyclopentene
2) (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-1-yl]-propyl}-1-trimethylsilyloxy-l-
methyl-2-cyclopentene
3) (1S,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-1-trimethylsilyloxy-l-
methyl-2-cyclopentene
4) (1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-1-trimethylsilyloxy-l-
methyl-2-cyclopentene
5) (1R,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-1-yl]-propyl}-1-(t-butyldimethyl-
silyloxy)-1-methyl-2-cyclopentene
6) (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-1-(t-butyldimethyl-
silyloxy)-1-methyl-2-cyclopentene


2168728
- 12 -

7) (1S,4R)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-1-(t-butyldimethyl-
silyloxy)-1-methyl-2-cyclopentene
8) (1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-1-(t-butyldimethyl-
silyloxy)-1-methyl-2-cyclopentene
Further, in the above scheme, preferable specific
examples of the cyclopentene derivative of the present
invention of the above formula (1-2) are as follows:
1) (1R,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
2) (1R,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
3) (1S,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
4) (1S,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
5) (1R,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-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-lH-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-lH-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-lH-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-lH-inden-1-yl]-propyloxy}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
10) (1R,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-


13 - 2168728
-

iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
11) (1S,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
12) (1S,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-
trimethylsilyloxy-l-methyl-2-cyclopentene
13) (1R,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-(t-
butyldimethylsilyloxy)-1-methyl-2-cyclopentene
14) (1R,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-(t-
butyldimethylsilyloxy)-1-methyl-2-cyclopentene
15) (1S,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-(t-
butyldimethylsilyloxy)-1-methyl-2-cyclopentene
16) (1S,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyloxy}-1-(t-
butyldimethylsilyloxy)-1-methyl-2-cyclopentene
17) (1R,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-
2-cyclopenten-l-ol
18) (1R,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-
2-cyclopenten-l-ol
19) (1S,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-
2-cyclopenten-l-ol
20) (1S,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-
2-cyclopenten-l-ol
21) (1R,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-l-yl]-propyl}-1-methyl-
2-cyclopenten-l-ol
22) (1R,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-


2168728
- 14 -

2-cyclopenten-l-ol
23) (1S,4R)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-ylJ-propyl}-1-methyl-
2-cyclopenten-l-ol
24) (1S,4S)-4-{(2R)-2-[(1R,7aR)(4E)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-l-yl]-propyl}-1-methyl-
2-cyclopenten-l-ol
According to the second aspect of the present
invention, there is provided a vitamin D, derivative
represented by the following formula (2-1):

5 3 R 12
O
H
( 2 - 1 )
RZ~OV' 0R2

In the above formula (2-1), RZ may be either of a methyl
group or methylene group. Note that when Rz is a
methylene group, the bond between R; and the 3-position
of the lactone ring is a double bond (same below).
Further, when RZ is a methyl group, the configuration of
the asymmetric center of the 3-position of the lactone
ring is the (S) configuration and the configuration of
the asymmetric center of the 5-position may be either of
the (S) or (R) configuration. Further, the derivative may
be a mixture of any ratio of (S) and (R). Further, when
RZ is a methylene group, the configuration of the
asymmetric center of the 5-position of the lactone ring
may be either of the (S) or (R) configuration. Further,
the derivative may be a mixture of any of (S) or (R).
Among these, those where the asymmetric center of the


2168723
- 15 -

5-position is an (S) configuration are preferred.
In the above formula [1], RZ and RZ may be the same
or different and represent a hydrogen atom, tri(C1 to C7
hydrocarbon) silyl group, or C2 to C. acyl group.
Here, when RZ or Rz is a tri ( C1 to C7
hydrocarbon)silyl group, examples of specific examples
are preferably a tri(C, to C4 alkyl)silyl group such as a
trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl
group, a phenyl(C1 to C4 alkyl)silyl group such as a
t-butyldiphenylsilyl group, and a tribenzylsilyl group.
Further, a dimethyl(2,4,6-tri-t-butylphenoxy)silyl group
may be used.
Further, when Rz or RZ is a C2 to C8 acyl group, the
specific examples are preferably an acetyl, propionyl,
n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, caproyl,
enanthyl, benzoyl, methoxycarbonyl, ethoxycarbonyl,
benzyloxycarbonyl group, etc. Among these, a C2 to C6 acyl
group, for example, an n-butyryl, iso-butyryl,
methoxycarbonyl, ethoxycarbonyl group, and benzoyl group
are preferred.
Preferable specific examples of the vitamin D3
derivative represented by the above formula (2-1) of the
second aspect of the present invention are as follows:
1) la-hydroxyvitamin D3-26,23-lactone
2) 23(S),25(S)-l(x-hydroxyvitamin D3-26,23-lactone
3) 23(R),25(S)-la-hydroxyvitamin D3-26,23-lactone
4) la-hydroxy- 2 5, 2 7 -dehydro -vitamin D3-26,23-
lactone
5) 23(S)-la-hydroxy-25,27-dehydro-vitamin D3-
26,23-lactone
6) 23(R)-la-hydroxy-25,27-dehydro-vitamin D3 -
26,23-lactone
The present invention further includes a process of
production of the vitamin D3 derivative of t-he above
formula (2-1). That is, it provides a production process
of the vitamin D3 derivative represented by the above


- 16 - 2168728

formula (2-1), characterized by reacting of a lactone
compound represented by the following formula (2-2)

3 R Z
5
O ( 2 _ 2 )
H
2
wherein X2 is a bromine atom or iodine atom, RZ is a
methyl group or methylene group
with an enyne compound represented by the following
formula (2-10)


( 2 -10)
R Z 0 0R,

wherein, R; and R; are the same as defined above
in the presence of a palladium catalyst.
This vitamin D, derivative can be made the vitamin D;
derivative represented by the fnl 1 n~.r; r~n fnrm>> 1 a r 2-11 )

5 3 R i
z
0
IH
I ( 2 -li)

HO'PJ OH

wherein, R; is the same as defined above
optionally by effecting a deprotection reaction.
In the production process of the vitamin D3


2168 728
- 17 -

derivative according to the present invention, for the
configurations of the 3-position and 5-position of the
lactone ring of the lactone compound represented by the
above formulas (2-2), (2-1), and (2-11), when Rz is a
methyl group, the 3-position is the (S) configuration,
but the 5-position may be either of the (S) or (R)
configuration. The derivative may also be any mixture
thereof.
Further, when RZ is a methylene group, the
configuration of the 5-position of the lactone ring may
be either of the (S) or (R) configuration. The derivative
may also be any mixture thereof. For example, when a
compound represented by the above formula (2-2) wherein
the asymmetric center of the 3-position of the lactone
ring is the (S) configuration and the asymmetric center
of the 5-position is the (S) configuration is used, the
configurations of these positions are preserved during
the reaction and a lactone compound represented by the
above formula (2-1) where the asymmetric center of the
3-position of the lactone ring is the (S) configuration
and the asymmetric center of the 5-position is the (S)
configuration is obtained.
In the same way, when a compound represented by the
above formula (2-2) wherein the asymmetric center of the
3-position of the lactone ring is the (S) configuration
and the asymmetric center of the 5-position is the (R)
configuration is used, a lactone compound represented by
the above formula (2-1) where the asymmetric center of
the 3-position of the lactone ring is the (S)
configuration and the asymmetric center of the 5-position
is the (R) configuration is obtained.
The vitamin D3 derivative represented by the above
formula (2-11) is produced by reacting the lactone
compound represented by the above formula (2-2) with an
enyne compound represented by the above formula (2-10) in
the presence of a palladium catalyst. Here, the palladium


2168728
- 18 -

catalyst means, for example, a zero-valent or bivalent
organopalladium. Examples of such a palladium compound
are tetrakis(triphenylphosphine)palladium or a mixture of
tris(dibenzylideneacetone)palladium,
tris(dibenzylideneacetone)palladium chloroform, and
palladium acetate with a phosphorus compound such as
triphenylphosphine or tributylphosphine (molar ratio of
1:1 to 1:10). Among these, as the palladium catalyst, a
combination of tris(dibenzylideneacetone)palladium and
triphenylphosphine (1:1 to 1:10) or tris(dibenzylidene-
acetone)palladium chloroform and triphenylphosphine (1:1
to 1:10) is preferred.
Here, the lactone compound represented by the above
formula (2-2) and the enyne compound represented by the
above formula (2-10) stoichiometrically react
equimolarly, but to ensure the reaction is reliably
completed, it is usually preferable to use a slightly
excess amount of either one of the two reactants,
whichever is more readily available.
Further, the palladium catalyst is used in a range
of 1 to 100 molar %, preferably 5 to 30 molar %, with
respect to the lactone compound represented by the above
formula (2-2).
Examples of the organic solvent used in the process
of production, are a hydrocarbon type solvent such as
hexane or toluene, an ether type solvent such as
tetrahydrofuran or dioxane, a water-soluble solvent such
as N,N-dimethylformamide or acetonitrile, and mixed
solvents thereof. For all of these, it is important to
sufficiently deaerate them before use.
As the reaction temperature, in general a range of
from room temperature to the boiling point of the solvent
is used. The reaction time differs according to the
reaction solvent used and the reaction temperature, but
usually the reaction is preferably performed until either
of the lactone compound represented by the above formula
(2-2) or the enyne compound represented by the above


- 19 - 2168728

formula (2-10) is consumed as determined using an
analytical means such as thin layer chromatography.
Further, in addition to the palladium catalyst, to
trap the hydrogen halide, the reaction is preferably
performed in the presence of a base such as, for example,
triethylamine or diisopropylethylamine.
As the amount of the base, at least one equivalent
of the lactone compound of the above formula (2-2) is
preferable. The combined use as a solvent is also
possible, if necessary.
Further, the vitamin D3 derivative represented by
the above formula (2-1) of the present invention may if
necessary be made the vitamin D3 derivative represented
by the above formula (2-11) by deblocking.
As the deblocking reaction, for example, when
deblocking the silyl groups, a known method (for example,
Calvely, M. J., Tetrahedoron, 20, 4609 to 4619, 1987) may
be used. Examples of the deblocking agent in this case
are tetrabutylammonium fluoride, pyridinium-p-toluene
sulfonate, etc.
The compound represented by the above formula (2-2)
used as a starting material in the process of the present
invention may, for example, be synthesized in accordance
with the following scheme. When X is an iodine atom, the
configuration differs in the same way.


2168728
- 20 -

(Synthesis scheme)

~~ OH
Known method
Vitamin D2
(J.O.C. 1 986, 51,1264 etc.) _
H
HO
,,,,
qOTS CN CHO
TsCi KCN DISaL-H
HO H HO H HO H

(Starting Material of Scheme 1)
PDC

T
''~,.
OT
s
H
0
(Starting Material of Scheme 2)


21 2168728
- -

[Scheme 1]

OH ~O2Me

O H

'''=. ] ). Br"jCOMe 7. Example of (2 - 6)
CHO

2).Zn
R 0 3). Sat.NH4Claq.
OH C02V-e
Wherein Rz0 is the same as defined above
R20 H
Example of (2 - 6)

`'== . /\ ~~~~
~~, ~',=
~ r 1
qOHcO2Me O
O O
LiOH
N HCI H PDC H
0
HO FIO Example of (2 - 6) Example of (2 - 5) Example of (2 - 3)

~,,, ~,.,, "=.
OH COZMe p I O
LiOH O O
HCI PDC II N
HO HO O
Example of (2 - 6) Example of (2 - 5) Example of (2 - 3).

O H2 O
O Pd/C 0
>--
H
Example of (2 - 3) O Example of (2 - 3)
~,= 1 ).BrCH2 P(C6H5)3Br

0 Z).((CH3)3Si]ZNNa O
O O
H I H
0
Example of (2 - 3) gr=
Example of (Z - 2) or (2 - 9)


2168728
- 22 -

[Scheme 2]

OTs CN
OTs
1).BrCHZP(C6H5)36r
2).((CH3)3Si)2NNa KNIBAL H
H
Br Br Sf
Exam le of
Example of (2 - 7) p (2 - 7)

~~ .

OH COZMe
CHO
H Example of (2 - 4)
1). Br~COzMe Br

2).Zn ~''-=
H 3). Sat.NH4CIaq. OH
8 r COzMe
Example of (2 - 7)

I H Example of (2 - 4)
Br

OH CO2Me O
LiOH
H "~ H
B~
Br Example of (2 - 4) Example of (2 - 2)
~.,. %-.
OH COzMe O
LiOH ~
IH HCI
"
Br > Br
Example of (2 - 4) Example of (2 - 2)


23 - 2168728
-

That is, the lactone compound represented by the
above formula (2-2) is obtained by halomethylation of the
lactone compound represented by the above formula (2-3).
Further, the compound represented by the above formula
(2-3) is obtained by deblocking, if necessary, and then
oxidizing the lactone compound represented by the above
formula (2-5). Further, the lactone compound represented
by the above formula (2-5) may be synthesized from the
heptanoic acid derivative represented by the above
formula (2-6). On the other hand, the lactone compound
represented by the above formula (2-2) may be derived
from the heptanoic acid derivative represented by the
above formula (2-4). Further, the heptanoic acid
derivative represented by the above formula (2-4) may be
synthesized from the compound represented by the above
formula (2-7). These reactions will be shown more
specifically in the Examples:

5 H
2 20

p 2 3
0O
~
O H
wherein R; is a methyl group or methylene group, when R'z
is a methylene group, the bond between RZ and the
3-position of the lactone ring being a double bond.

OH C02Me 2 - 4)

OH
X
wherein X is a bromine atom or iodine atom.


2168728
- 24 -

0 ( 2 - 5 )
R40 R
2
wherein R'; is a hydrogen atom, tri ( C, to C7
hydrocarbon)silyl group, C, to C7 acyl group, or group
forming an acetal group together with an oxygen atom of a
hydroxyl group.

OH CO2Me ( 2 - 6 )
R2 O H

wherein Rz is the same as defined above.
(2- 7)
IH
X
wherein X is a bromine atom or iodine atom, Y is a cyano
group, formyl group, tosyl group, mesyl group,
phenylsulfonyloxy group, tri(C, to C7 hydrocarbon)silyl
group, C, to C7 acyl group, or hydroxyl group which may be
blocked by an acetal group together with the oxygen atom
of a hydroxyl group.
The present invention includes compounds represented
by the above formulas (2-2), (2-3), (2-4), (2-5), (2-6),
and (2-7) serving as intermediates for the synthesis of
the vitamin D3 derivative represented by the above
formula (2-1).
Here, when the R' of the lactone compound
represented by the above formula (2-3) and (2-5) is a
methyl group, the asymmetric center of the 3-position of
the lactone ring is the (S) configuration and the


2168728
- 25 -

asymmetric center of the 5-position may be either of the
(R) configuration or (S) configuration. The derivative
may also be any mixture thereof at any ratio.
Further, in the heptanoic acid derivative
represented by the above formula (2-4) or (2-6), the
asymmetric center of the 4-position may be either of the
(R) configuration or (S) configuration. The derivative
may also be a mixture of any ratio of the two.
Preferable specific examples of the compound
represented by the above formula (2-2) according to the
present invention are as follows:
1) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
2) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
3) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]propyl}-3-methyl-
dehydro-2(3H)-furanon
4) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-methyl-
dehydro-2(3H)-furanon
5) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
6) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
7) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-methyl-
dehydro-2(3H)-furanon
8) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-methyl-
dehydro-2(3H)-furanon
Preferable specific examples of the compound
represented by the above formula (2-3) according to the


2168728
- 26 -

present invention are as follows:
1) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-ir.den-1-yl]propyl}-3-methylene-dehydro-2(3H)-
furanon
2) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-
furanon
3) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-
furanon
4) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-l-yl]propyl}-3-methyl-dehydro-2(3H)-
furanon
Preferable specific examples of the compound
represented by the above formula (2-4) according to the
present invention are as follows:
1) (4S,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl
-4-hydroxy-l-heptene
2) (4R,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl
-4-hydroxy-l-heptene
3) (4S,6R)-6-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-
4-hydroxy-l-heptene
4) (4R,6R)-6-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-
4-hydroxy-l-heptene
Preferable specific examples of the compound
represented by the above formula (2-5) according to the
present invention are as follows:
1) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]propyl}-3-methylene-
dehydro-2(3H)-furanon
2) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]propyl}-3-methylene-
dehydro-2(3H)-furanon


27 - 2168728
-

3) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]propyl}-3-methyl-dehydro-
2(3H)-furanon
4) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-l-yl]propyl}-3-methyl-dehydro-
2(3H)-furanon
5) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
6) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
7) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4--
rimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3-
methyl-dehydro-2(3H)-furanon
8) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3-
methyl-dehydro-2(3H)-furanon
9) (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-t-
butyldimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon
10) (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
t-butyldimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3
-methylene-dehydro-2(3H)-furanon
11) (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
t-butyldimethylsilyloxy-7a-methyl-lH-inden-1-yl]propyl}-3
-methyl-dehydro-2(3H)-furanon
12) (3S,5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
t-butyldimethylsilyloxy-7a-methyl-lH-inden-l-yl]propyl}-3
-methyl-dehydro-2(3H)-furanon
Preferable specific examples of the compound
represented by the above formula (2-6) according to the
present invention are as follows:
1) (4S,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-
7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-l-
heptene
2) (4R,6R)-6-[(1R,7aR)-octahydro-4-hydroxy-7a-


2168728
- 28 -

methyl-lH-inden-1-ylJ-2-methoxycarbonyl-4-hydroxy-l-
heptene
3) (4S,6R)-6-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-2-
methoxycarbonyl-4-hydroxy-l-heptene
4) (4R,6R)-6-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-2-
methoxycarbonyl-4-hydroxy-l-heptene
5) (4S,6R)-6-[(1R,7aR)-octahydro-4-t-
butyldimethylsilyloxy-7a-methyl-lH-inden-1-y1J-2-
methoxycarbonyl-4-hydroxy-l-heptene
6) (4R,6R)-6-[(1R,7aR)-octahydro-4-t-
butyldimethylsilyloxy-7a-methyl-lH-inden-l-ylJ-2-
methoxycarbonyl-4-hydroxy-l-heptene
Preferable specific examples of the compound
represented by the above formula (2-7) according to the
present invention are as follows:
1) (2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]propylparatoluenes
ulfonate
2) (3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]butyronitrile
3) (3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]butanal
4) (2R)-2-[(1R,7aR)-octahydro-4-iodomethylene-
7a-methyl-lH-inden-1-yljpropylparatoluene-sulfonate
5) (3R)-3-[(1R,7aR)-octahydro-4-iodomethylene-
7a-methyl-lH-inden-1-yl]butyronitrile
6) (3R)-3-[(1R,7aR)-octahydro-4-iodomethylene-
7a-methyl-lH-inden-1-yl]butanal
The vitamin D3 derivative represented by the above
formula (2-1) may be used as an agent for promoting bone
growth. Further, the compounds represented by the above
formulas (2-2), (2-3), (2-4), (2-5), (2-6),.and (2-7) may
be used as intermediates for the synthesis thereof.
That is, according to the third aspect of the


2168728
- 29 -

present invention, there is provided a vitamin D3
derivative represented by the following formula (3-1):
5 OR;
COZR
~ H
I ( 3 - 1 )
:R; OR;
wherein R' is a hydrogen atom or C, to C, alkyl group, R;
is a hydrogen atom, or R; and R; together indicate a
substitutable single methylene group. R; is a hydrogen
atom, tri ( C, to C7 hydrocarbon) silyl group, C2 to C,, acyl
group, or a group forming an acetal bond together with an
oxygen atom of a hydroxyl group.
alkyl group, specific
Here, when R; is a C, to C3
examples are preferably methyl, ethyl, and propyl.
Further, examples of the substituent, when R; and R2
3
together represent a substitutable single methylene
group, are preferably a t-butyl group, phenyl group, or
methyl group. When R; is a tri(C, to C7 hydrocarbon) silyl
group, a tri(C, to C4 alkyl)silyl group such as a
trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl
group or a phenyl(C,-Ca alkyl)silyl group such as a
t-butyldiphenylsilyl groiln are preferable.
Further, when R; is a C2 to CH acyl group, an acetyl,
propionyl, N-butyryl, pivaloyl, benzoyl, methoxycarbonyl,
ethoxycarbonyl, or benzyloxycarbonyl group are
preferable. Further, when R; is a group forming an acetal
bond with an oxygen atom of a hydroxyl group, a
methoxymethyl, 2-methoxy-ethoxymethyl,
2-methoxy-2-propyl, 2-tetrahydrofuranyl, or
2-tetrahydropyranyl group are preferable.
Here, the configuration of the 25-position of the
vitamin D, derivative of the present invention may be


2168728
- 30 -

either of the (R) configuration or (S) configuration. The
derivative may also be any mixture thereof at any ratio
of the two components. Specific examples of the vitamin
D3 derivative according to the third aspect of the
present invention are given below:
1) la,25(R)-dihydroxyvitamin D3-26-carboxylic acid
2) la,25(S)-dihydroxyvitamin D3-26-carboxylic acid
3) la,25(R)-dihydroxyvitamin D3-26-carboxylic acid
methylester
4) la,25(S)-dihydroxyvitamin D3-26-carboxylic acid
methylester
5) la,25(R)-dihydroxyvitamin D3-26-carboxylic acid
ethylester
6) la,25(S)-dihydroxyvitamin D3-26-carboxylic acid
ethylester
7) la,25(R)-dihydroxyvitamin D3-26-carboxylic acid
methylester-1,3-bistrimethylsilylether
8) la,25(S)-dihydroxyvitamin D3-26-carboxylic acid
methylester-1,3-bistrimethylsilylether
9) la,25(R)-dihydroxyvitamin D3-26-carboxylic acid
ethylester-1,3-bistrimethylsilylether
10) la,25(S)-dihydroxyvitamin D3-26-carboxylic acid
ethylester-1,3-bistrimethylsilylether
11) 25,26,27-trinol-la-hydroxy-24-[(2S,5R)-2-t-
butyl-5-methyl-1,3-dioxolan-4-one-5-yl]-vitamin D3
12) 25,26,27-trino].-la-hydroxy-24-[(2S,5R)-2-t-
butyl-5-methyl-1,3-dioxolan-4-one-5-yl]-vitamin D3-1,3-
bistrimethylsilylether
13) 25,26,27-trinol-la-hydroxy-24-[(2S,5R)-2-t-
butyl-5-methyl-1, 3-dioxolan-4-one-5-yl ]-vitamin D3-1,3-
bis(t-butyldimethylsilylether)
Further, the present invention includes a production
process of a vitamin D3 derivative represented by the
above formula (3-1).
That is, it provides a production process of a
vitamin D3 derivative represented by the above formula


2168728
- 31 -

(3-1) characterized by reacting a heptanoic acid
derivative represented by the followina for-i= (3-2)-
2
0R;
CO2R3 ( 3 - 2 )
H
Br
wherein R:; and R; are the same as defined above
with an enyne compound represented by the following
formula (3-5):

------------------ ~ 3 - 5 )
; OR;

wherein R; is the same as defined above
in the presence of a palladium catalyst.
In the production process of the vitamin D3
derivative according to the present invention, the
configuration of the asymmetric center of the 2-position
of the starting material, that is, the heptanoic acid
derivative represented by the above formula (3-2), may be
either of the (R) configuration or (S) configuration.
Further, the derivative may be any mixture of these
stereo isomers at any ratio.
For example, when a heptanoic acid derivative
represented by the above formula (3-2) where the
asymmetric center of the 2-position is the (R)
configuration is used, the configuration is preserved
during the reaction and a vitamin D3 derivative
represented by the above formula (3-1) where the
asymmetric center of the 25-position is the (R)
configuration is obtained.
In the same way, when a heptanoic acid derivative
represented by the above formula (3-2) where the
asymmetric center of the 2-position is an (S)
configuration is used, a vitamin D3 derivative


2168728
- 32 -

represented by the above formula (3-1) where the
asymmetric center of the 25-position is the (R)
configuration is obtained.
The vitamin D3 derivative represented by the above
formula (3-1) is produced by reacting the heptanoic acid
derivative represented by the above formula (3-2) with
the enyne compound represented by above formula (3-5) in
the presence of a palladium catalyst. Here, as the
palladium catalyst used, mention may be made for example
of a zero-valent or bivalent organopalladium compound.
Examples of such a palladium compound are
tetrakis(triphenyl phosphine)palladium or a mixture of a
tris(dibenzylidene-acetone palladium,
tris(dibenzylideneacetone)palladium chloroform, palladium
acetate, etc. with a phosphorus compound such as
triphenylphosphine or tributylphosphine (molar ratio of
1:1 to 1:10). Among these, as the palladium catalyst, the
combination of tris(dibenzyli-deneacetone)palladium and
triphenylphosphine (1:1 to 1:10) or
tris(dibenzylideneacetone)palladium chloroform and
triphenylphosphine (1:1 to 1:10) is preferred.
Here, the heptanoic acid derivative represented by
the above formula (3-2) and the enyne compound
represented by the above formula (3-5) stoichiometrically
react equimolarly, but it is desirable to use a slight
excess of the more readily available compound. Further,
the palladium catalyst is used in the range of 0.1 to 100
molar %, preferably 1 to 20 molar %, with respect to the.
heptanoic acid derivative represented by the above
formula (3-2).
Examples of the reaction solvent used in this
reaction are a hydrocarbon type solvent such as hexane or
toluene, an ether type solvent such as ether,
tetrahydrofuran, dioxane, or dimethoxyethane, a water
soluble solvent such as N,N -dimethylformamide or
acetonitrile, or any mixed solvents thereof. All of these


2168728
- 33 -

are preferably used after sufficient deaeration.
As the reaction temperature, a range of from room
temperature to the boiling point is used. The reaction
time differs according to the reaction temperature, but
usually it is preferable that the reaction be performed
until one of the heptanoic acid derivative represented by
the above formula (3-2) or enyne compound represented by
the above formula (3-5) is consumed as determined using
an analytical means such as thin layer chromatography.
Further, to trap the acids such as the hydrogen
halides produced during the reaction, it is preferable to
add a base such as, for example, triethylamine or
diisopropylethylamine and cause a reaction. As the amount
of the base, at least one equivalent of the heptanoic
acid derivative represented by the above formula (3-2) is
preferably used. It is also possible to use together as a
solvent. Therefore, the vitamin D3 derivative represented
by the above formula (3-1) is produced in the reaction
system, but it is further possible to effect a deblocking
reaction, if necessary.
As the method of the deblocking reaction, it is
possible to use a known method in the case of deblocking,
for example, the silyl groups (for example, Calveley,
M.J., Tetrahedron, 20, 4609 to 4619, 1987). Examples of
the deblocking agent in this case are tetrabutylammonium
fluoride and pyridinium-p-toluene sulfonate.
An example of the synthesis method of a heptanoic
acid derivative represented by the above formula (3-2)
used as a starting material in the process of the present
invention is shown in the following scheme. The same
applies when R3 and R~ are other groups.


2168728
- 34 -

OH CHO
OH
1)'BuCOCt Oxidation wiCCig
Protection of
2)secondary H
HO H hydroxyl group R' 10 H R"O
3) 0H'

COZMe OH CHO
0
~eu
DIBAL Oxidation 0 0

RaiO H RatO fi RaiO
HO MeO2CO
0 1 ) Pd(OAc)2.Bu3P
O
>.....'eu >...., 8u
MeOCOCI o o NH^-HCOO-
0
0
2) HZ 10%- Pd/C
H R aiO
R 'lO

O O
.....'su >....,'Bu
O 1)Deprotection O Bromomethylation

A"O H 2) Oxidation H
O
Example of (3 - 4) Example of (3 - 3)
O
~....='E~u
O O

H
Br '
Exainple of (3 - 2)

wherein, in ttie above scheme, R4' is a hydrogen atom,
tri(C, to C. hydrocarbon)silyl group, or a group forming
an acetal bond with an oxygen atom of a hydroxyl group.


2168728
- 35 -

2
OR3
C02R3 (33)

H
wherein, R; is a hydrogen atom or C, to C; alkyl group, R;
is a hydrogen atom, or R; and R; together represent a
substitutable single methylene group (examples of the
substituent at this time are a C, to C. alkyl group such
as methyl, t-butyl, or phenyl).

~''= OR3
t
C02R3 ( 3 4 )
R3 H

wherein, R~ and R; are the same as defined above, and R;
is a hydrogen atom, tri(C, to C7 hydrocarbon) silyl group,
C, to C7 acyl group, or represent an acetal group together
with the oxygen atom of the hydroxyl group.
That is, the heptanoic acid derivative represented
by the above formula (3-2) is obtained by
bromomethylation of the heptanoic acid derivative
represented by the above formula (3-3). Further, the
heptanoic acid derivative represented by the above
formula (3-3) is obtained by deprotecting the heptanoic
acid derivative represented by the above (3-4) when
necessary. Specific examples of these reactions are shown
in the Examples. Here, the configuration of the
2-position of the heptanoic acid derivatives represented
by the above formula (3-2), (3-3), or (3-4) may be either
of the (R) configuration or (S) configuration. The
derivative may also be any mixture thereof at any ratio.
The present invention includes intermediates for
synthesis of the vitamin D3 derivative according to the


2168728
- 36 -

present invention represented by the above formulas
(3-2), (3-3), or (3-4).
Preferable examples of the heptanoic acid derivative
represented by the above formula (3-2) of the present
invention are as follows:
1) (2S,5R)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]pentyl}-2-t-butyl-
5-methyl-l,3-dioxolan-4-one
2) (2R,5S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]pentyl}-2-t-butyl-
5-methyl-1, 3-dioxolan-4-one
3) (2S,5R)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]pentyl}-2-phenyl-
5-methyl-l,3-dioxolan-4-one
4) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl}-2-hydroxy-2-
methylheptanoic acid
5) (2S,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl}-2-hydroxy-2-
methylheptanoic acid
6) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl}-2-hydroxy-2-
methylheptanoic acid methylester
7) (2S,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl}-2-hydroxy-2-
methylheptanoic acid ethylester
8) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl}-2-
trimethylsilyloxy-2-methylheptanoic acid methylester
9) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl}-2-t-
butyldimethylsilyloxy-2-methylheptanoic acid methylester
10) (2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl}-2-acetoxy-2-
methylheptanoic acid methylester
11) (2R,6R)-6-{(iR,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl}-2-


2168728
- 37 -

methoxymethyloxy-2-methylheptanoic acid methylester
Further, preferable examples represented by the
heptanoic acid derivative of the above (3-3) according to
the present invention are as follows:
1) (2R,5S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-
oxo-7a-methyl-lH-inden-1-yl]pentyl}-2-t-butyl-5-methyl-
1,3-dioxolan-4-one
2) (2R,5S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-1-yl]pentyl}-2-t-butyl-5-methyl-l,3-
dioxolan-4-one
3) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl] pentyl}-2-phenyl-5-methyl-l,3-
dioxolan-4-one
4) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-
1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
5) (2S,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
6) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-
1H-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
methylester
7) (2S,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
ethylester
8) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl}-2-trimethylsilyloxy-2-
methylheptanoic acid methylester
9) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl}-2-t-butyldimethylsilyloxy-2-
methylheptanoic acid methylester
10) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-
1H-inden-1-yl}-2-acetoxy-2-methylheptanoic acid
methylester
11) (2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-
1H-inden-1-yl}-2-methoxymethyloxy-2-methylheptanoic acid
methylester
Further, preferable examples of the heptanoic acid
derivative represented by the above (3-4) according to


38 - 2168728
-

the present invention are as follows:
1) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-1-yl]pentyl}-2-t-butyl-5-
methyl-l,3-dioxolan-4-one
2) (2R,5S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]pentyl}-2-t-butyl-5-
methyl-l,3-dioxolan-4-one
3) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]pentyl}-
2-phenyl-5-methyl-1,3-dioxolan-4-one
4) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-
acetoxy-7a-methyl-lH-inden-l-yl]pentyl}-2-phenyl-5-
methyl-l,3-dioxolan-4-one
5) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-
benzyloxy-7a-methyl-lH-inden-1-yl]pentyl}-2-phenyl-5-
methyl-l,3-dioxolan-4-one
6) (2S,5R)-5-{(4R)-4-[(1R,7aR)-octahydro-4-
methoxymethyloxy-7a-methyl-lH-inden-l-yl] pentyl}-2-
phenyl-5-methyl-1,3-dioxolan-4-one
7) (2R,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-
methyl-lH-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
8) (2S,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-
methyl-lH-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
9) (2R,6R)-6-{(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-l-yl}-2-hydroxy-2-
methylheptanoic acid
10) (2S,6R)-6-{(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-l-yl}-2-hydroxy-2-
methylheptanoic acid
11) (2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-
methyl-lH-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
12) (2R,6R)-6-{(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl}-2-hydroxy-2-
methylheptanoic acid methylester
13) (2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-
methyl-lH-inden-1-yl}-2-hydroxy-2-methylheptanoic acid
methylester


39 - 2168728
-

14) (2R,6R)-6-{(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl}-2-hydroxy-2-
methylheptanoic acid ethylester
15) (2R,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-
methyl-lH-inden-1-yl}-2-trimethylsilyloxy-2-
methylheptanoic acid methylester
16) (2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-
methyl-lH-inden-1-yl}-2-trimethylsilyloxy-2-
methylheptanoic acid methylester
17) (2R,6R)-6-{(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl}-2-acetoxy-2-
methylheptanoic acid methylester
18) (2R, 6R)-6-{(1R, 7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl}-2-
methoxymethyloxy-2-methylheptanoic acid methylester
The vitamin D3 derivative represented by the above
formula (3-1) may be used as an agent for promoting bone
formation. Further, the heptanoic acid derivatives
represented by the above formulas (3-2), (3-3), and (3-4)
may be used as intermediates for the synthesis thereof.
According to the present invention, as a
manufacturing intermediate for the vitamin D3 derivative
according to the present invention, there is the
exomethylene derivative represented by the following
formula (4-1):

s J

4 - 1 )
.U }-I
X¾

wherein R; is a hydrogen atom, tri ( C, to C7
hydrocarbon) silyl group, C2 to C7 acyl group, or group
forming an acetal bond with an oxygen atom of a hydroxyl
group, and X4 is a bromine atom or iodine atom.


2168728
- 40 -

In the present invention, in the compound
represented by the above formula (4-1), the
configurations of the asymmetric centers of the C-3
position and C-5 position of the 2(3H)-furanon ring may
respectively be either of the (R) configuration or (S)
configuration. Further, the present invention includes
mixtures of these four types of stereo isomers at any
ratio. Among these, those where the asymmetric center of
the C-3 position is the (R) configuration and the
asymmetric center of the C-5 position is the (R)
configuration and ones where the asymmetric center of the
C-3 position is the (R) configuration and the asymmetric
center of the C-5 position is the (S) configuration are
preferred. Further, the configuration of the
carbon-carbon double bond of the halomethylene portion is
the (E) configuration.
Specific examples of the exomethylene derivative of
the above formula (4-1) of the present invention are
given below:
1) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-hydroxy-2(3H)-furanon
2) (3R,5S)-5-{(3R)-3-[(1R, 7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-hydroxy-2(3H)-furanon
3) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-hydroxy-2(3H)-furanon
4) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-hydroxy-2(3H)-furanon
5) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-trimethylsilyloxy-2(3H)-furanon
6) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-trimethylsilyloxy-2(3H)-furanon


41 - 2168728
-

7) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-trimethylsilyloxy-2(3H)-furanon
8) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-trimethylsilyloxy-2(3H)-furanon
9) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-(t-butyldimethylsilyloxy)-2(3H)-furanon
10) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-(t-butyldimethylsilyloxy)-2(3H)-furanon
11) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-(t-butyldimethylsilyloxy)-2(3H)-furanon
12) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-(t-butyldimethylsilyloxy)-2(3H)-furanon
13) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-acetoxy-2(3H)-furanon
14) (3R,.5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3
-acetoxy-2(3H)-furanon
15) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-acetoxy-2(3H)-furanon
16) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-acetoxy-2(3H)-furanon
17) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-ethoxycarbonyloxy-2(3H)-furanon
18) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-ethoxycarbonyloxy-2(3H)-furanon
19) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-


2168728
- 42 -

bromomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3
-ethoxycarbonyloxy-2(3H)-furanon
20) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3
-ethoxycarbonyloxy-2(3H)-furanon
21) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3
-methoxymethyloxy-2(3H)-furanon
22) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3
-methoxymethyloxy-2(3H)-furanon
23) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3
-methoxymethyloxy-2(3H)-furanon
24) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-methoxymethyloxy-2(3H)-furanon
25) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-tetrahydropyranyloxy-2(3H)-furanon
26) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-tetrahydropyranyloxy-2(3H)-furanon
27) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-tetrahydropyranyloxy-2(3H)-furanon
28) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-tetrahydropyranyloxy-2(3H)-furanon
29) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-
hydroxy-2(3H)-furanon
30) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-
hydroxy-2(3H)-furanon
31) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-


2168728
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hydroxy-2(3H)-furanon
32) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-
hydroxy-2(3H)-furanon
33) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3-
trimethylsilyloxy-2(3H)-furanon
34) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3-
trimethylsilyloxy-2(3H)-furanon
35) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-
trimethylsilyloxy-2(3H)-furanon
36) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
iodomethylene-7a-methyl-lH-inden-l-yl]-butyl}-3-methyl-3-
trimethylsilyloxy-2(3H)-furanon
Further, the present invention provides a process
for producing the exomethylene derivative represented by
the above formula (4-1).
That is, it provides a process causing a reaction of
a 2(3H)-furanon derivative represented by the following
formula (4-2)

oj oOR"
(4 - 2)
O H

wherein R', is a hydrogen atom, tri ( C, to C7
hydrocarbon) silyl group, C2 to C7 acyl group, or group
forming an acetal bond together with an oxygen atom of a
hydroxyl group
with a halogenated methylenetriphenylphosphonium halide
in the presence of a base so as to produce an
exomethylene derivative represented by the following
formula (4-1):


2168728
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0RA

4-1)
FI
X
wherein, R4 and X are the same as defined above.
In the production process of an exomethylene
derivative according to the present invention, the
configurations of the asymmetric center of the C-3
position and C-S position of the 2(3)H-furanon ring of
the starting material, that is, the 2(3)H-furanon
derivative represented by the above formula (4-2), may
respectively be either of the (R) configuration or (S)
configuration. Further, the derivative may be any mixture
of these stereo isomers at any ratio.
For example, when a 2(3H)-furanon derivative of the
above formula (4-2) wherein the asymmetric center of the
C-3 position of the 2(3H)-furanon ring is the (R)
configuration and the asymmetric center of the C-5
position is the (R) configuration, the configuration of
these portions are preserved during the reaction and an
exomethylene derivative represented by the above formula
(4-1) wherein the asymmetric center of the C-3 position
of the 2(3H)-furanon ring is the (R) configuration and
the asymmetric center of the C-5 position is the (R)
configuration is obtained.
In the same way, when a 2(3H)-furanon derivative
represented by the above formula (4-2) where the
asymmetric center of the C-3 position of the
2(3H)-furanon ring is the (R) configuration and the
asymmetric center of the C-5 position is the (S)
configuration is used, an exomethylene derivative
represented by the above formula (4-1) where the
asymmetric center of the C-3 position of the
2(3H)-furanon ring is the (R) configuration and the
asymmetric center of the C-S position is the (S)


2168728
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configuration is obtained.
Here, when R`i is a tri(C1 to C7 hydrocarbon) silyl
group, specific examples are preferably a tri(CI to C4
alkyl)silyl group such as a trimethylsilyl,
triethylsilyl, or t-butyldimethylsilyl group or a
phenyl(Cl to C4 alkyl)silyl group such as a
t-butyldiphenylsilyl group.
Further, when Ra is a C2 to C. acyl group, specific
examples are preferably an acetyl, propionyl, N-butyryl,
pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl,
benzyloxycarbonyl group. Further, when R~ is a group
forming an acetal bond together with an oxygen atom of a
hydroxyl group, specific examples are preferably a
methoxymethyl, (2-methoxyethoxy)-methyl,
2-methoxy-2-propyl, 2-tetrahydrofuranyl, or
2-tetrahydropyranyl group.
The exomethylene derivative represented by the above
formula (4-1) is produced by reacting the 2(3H)-furanon
derivative represented by the above formula (4-2) with a
halogenated methylenetriphenylphosphonium halide in the
presence of a base. Here, as the halogenated
methylenetriphenylphosphonium halide which is used,
bromomethylenetriphenylphosphonium bromide etc. are
preferred. Further, as the base used, lithium
diisopropylamide, lithium bistrimethylsilyl-amide, sodium
bistrimethylsilylamide, etc. may be exemplified as
preferable examples. Further, as the amount of the base
used, 1 to 10 times the amount of the 2(3H)-furanon
derivative is preferable.
Here, as the amount of the halogenated
methylenetriphenylphosphonium halide for reacting with
the 2(3H)-furanon derivative of the above formula (4-2),
1 to 10 times the amount of the 2(3H)-furanon derivative
is preferably used.
Examples of the reaction solvent used in this
reaction are an ether type solvent such as diethyl ether,


2168728
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tetrahydrofuran, and dimethoxyethane. As the reaction
temperature, a range of from -60 C to room temperature is
used. The reaction time differs according to the reaction
temperature, but usually that the reaction be continued
until the 2(3H)-furanon derivative of the above formula
(4-2) is consumed as determined using an analytical means
such as thin layer chromatography.
The compound represented by the above formula (4-2)
used as a starting material in the present invention may
be synthesized, for example, in accordance with the
following scheme:

CHO Ce2"'''-
\~~0; i OFi f
DiZ;,L
Protection
of
O:-i hydroxyl "'0 R,0
group

])2uOK :i0 0, 1:7J17 ~J=~~~C:^G

R 0 RO O

I U5O T,-,SO ~^+ Q
O Or

c'~Cridd(i0n I
R`0 n10 O

0--~ O
O -H O -G
I OR"
~ Protection of
Qn rlydroxyl grouP
O
0
wherein, in the above scheme, R' and R'2 are a hydrogen
atom, tri(C, to C7 hydrocarbon)silyl group, C2 to C7 acyl
group, or group forming an acetal bond with an oxygen


2168728
- 47 -

atom of a hydroxyl group.
Specific examples of the 2(3H)-furanon derivative
represented by the chemical formula (4-2) preferred in
the present invention are as follows:
1) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-hydroxy-2(3H)-
furanon
2) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]-butyl}-3-methyl-3-hydroxy-2(3H)-
furanon
3) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]-butyl}-3-methyl-3-hydroxy-2(3H)-
furanon
4) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]-butyl}-3-methyl-3-hydroxy-2(3H)-
furanon
5) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]-butyl}-3-methyl-3-trimethylsilyl-
oxy-2(3H)-furanon
6) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethylsilyl-
oxy-2(3H)-furanon
7) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethylsilyl-
oxy-2(3H)-furanon
8) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethylsilyl-
oxy-2(3H)-furanon
9) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-(t-butyl-
dimethylsilyloxy)-2(3H)-furanon
10) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-(t-butyl-
dimethylsilyloxy)-2(3H)-furanon
11) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-(t-butyl-
dimethylsilyloxy)-2(3H)-furanon


2168728
- 48 -

12) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-(t-butyl-
dimethylsilyloxy)-2(3H)-furanon
13) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-acetoxy-2(3H)-
furanon
14) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-acetoxy-2(3H)-
furanon
15) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-acetoxy-2(3H)-
furanon
16) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-acetoxy-2(3H)-
furanon
17) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]-butyl}-3-methyl-3-ethoxycarbonyl-
oxy-2(3H)-furanon
18) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-ethoxycarbonyl-
oxy-2(3H)-furanon
19) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-ethoxycarbonyl-
oxy-2(3H)-furanon
20) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-ethoxycarbonyl-
oxy-2(3H)-furanon
21) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-methoxymethyl-
oxy-2(3H)-furanon
22) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-methoxymethyl-
oxy-2(3H)-furanon
23) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-methoxymethyl-
oxy-2(3H)-furanon
24) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-


2168728
- 49 -

methyl-lH-inden-1-yl]-butyl}-3-methyl-3-methoxymethyl-
oxy-2(3H)-furanon
25) (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-tetrahydro-
pyranyloxy-2(3H)-furanon
26) (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-tetrahydro-
pyranyloxy-2(3H)-furanon
27) (3S,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-tetrahydro-
pyranyloxy-2(3H)-furanon
28) (3S,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]-butyl}-3-methyl-3-tetrahydro-
pyranyloxy-2(3H)-furanon
EXAMPLES
The present invention will now be explained in
further detail by way of Examples, which, however, do not
restrict the present invention in any way.
Example 1-1
Production of (2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl-p-
toluenestiI. fonate

i~ 0 H 0 T s
2 5 I~ I 1) T s C: I
'~./-- -
I H 2) T M S C I
OH TMSO
Compound ( 1- i) Compound ( 1_ - 3)

A 2.0 g amount of the compound (1-7), (2R)-2-[(1R,
7aR)(4E)-octahydro-4-hydroxy-7a-methyl-l-H-inden-1-yl]
-propanol, and 2.3 g of p-toluenesulfonyl chloride were
placed into a 100 ml eggplant-shaped flask. These were
dissolved in 10 ml of dried dichloromethane, then the
solution was stirred under ice-cooling. A 4 ml amount of
pyridine was added thereto, then the solution was stirred
under ice cooling for 6 hours.


2168728
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The reaction solution was poured into 100 ml of
ethyl acetate and 20 ml of water and extracted. The
organic layer was washed 2 times with a saturated aqueous
solution of potassium hydrogensulfate, a saturated
aqueous solution of sodium bicarbonate, and saturated
saline, then was dried over anhydrous magnesium sulfate.
The desiccant was filtered out, then the solvent was
distilled off under reduced pressure to obtain a crude
product in an amount of 4.2 g. This was placed in a 100
ml eggplant-shaped flask, then 2.04 g of imidazole was
added. Thereto 20 ml of dried dichloromethane was added.
The solution was then stirred under ice-cooling. Next,
1.91 ml of trimethylsilyl chloride was added thereto and
the solution was stirred at room temperature over night.
The reaction solution was poured into 100 ml of ethyl
acetate and 20 ml of water and extracted. The organic
layer was then washed 2 times with saturated saline, then
was dried over anhydrous magnesium sulfate. The desiccant
was filtered out and the solvent was distilled off under
reduced pressure to obtain a crude product in an amount
of 4.07 g. This was purified by a silica gel column
(IR-60, 200 g, hexane/ethyl acetate = 9/1) to obtain the
desired product (1-8), (2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-propyl-p-
toluenesulfonate in an amount of 3.27 g (yield 87%).
'H-NMR (CDC13, S ppm)
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 & 9.2Hz), 2.45(s, 3H), 1.00 to 2.00 (m, 13H), 0.89
(d, 3H J=18Hz), 0.83 (s, 3H), 0.03 (s, 9H)
Example 1-2
Process of production of (2R)-2-[(1R,7aR)-octahydro-
4-trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-iodopropane


2168728
- 51 -

~ o T s

TH
TiM SO TNISO
Compound (1 - 8) Compound ( ~ - 9)

A 3.27 g amount of the compound (1-8), (2R)-2-[(1R,
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-1-y
1]-propyl-p-toluenesulfonate, was dissolved in 200 ml of
acetone in a 500 ml eggplant-shaped flask. To this was
added 5 g of sodium iodide. The solution was then heated
and refluxed over night.
The reaction solution was allowed to cool, then the
precipitate was filtered out and the solvent was
distilled off under reduced pressure. A 300 ml amount of
ether and 200 ml of water were added to the residue and
separation performed. Extraction was performed from the
aqueous layer by 200 ml of ether, then the organic layer
was washed 2 times with a saturated aqueous solution of
sodium hydrogencarbonate and saturated saline. The result
was dried over anhydrous magnesium sulfate, the desiccant
was filtered out, then the solvent was distilled off
under reduced pressure to obtain a crude product in an
amount of 4.5 g. This was purified by a silica gel column
(IR-60, 80 g, hexane) to obtain the desired product
(1-9), (2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-
7a-methyl-lH-inden-l-yl]-iodopropane, in an amount of
2.72 g (yield 94%).
'H-NMR (CDC13, S ppm)
3.99 (m, 1H), 3.33 (dd, 1H J=2 & 5Hz), 3.17 (dd, 1H
J=5 & 9Hz), 1.00 to 2.00 (m, 13H), 0.99 (d, 3H, J=5.6Hz),
0.92 (s, 3H), 0.05 (s, 9H)
Example 1-3


2168728
_ 52 -

Production of (4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl}-2-
cyclopenten-l-one

I I 8u Li 0
( 2)TBSO
H 3) D B U G H
Til/iSO TMSO
Compound ( 1- 9) Compound (1- 10)
A 10 ml amount of ether was placed into a 100 ml
eggplant-shaped flask and cooled to -78 C, followed by
adding 14.3 ml of a hexane solution of t-butyllithium
(1.54 mol/liter). A 3.94 g amount of the compound (1-9),
(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-l-yl]-iodopropane was dissolved in 10 ml of
ether and then added to the above solution which was then
stirred at -78 C for 1 hour. A 2.1 g amount of copper
iodide and 5.5 ml of tri(N-butyl)phosphine were dissolved
in 10 ml of tetrahydrofuran, the solution was then added
to the above reaction solution, then this was stirred at
-78 C for 1 hour. Thereto 2.54 g of (4S)-4-(t-
butyldimethylsilyloxy)-2-cyclopenten-l-one dissolved in
10 ml of tetrahydrofuran was added. The solution was then
stirred at -40 C for 2 hours. This was poured into 30 ml
of a saturated aqueous solution of ammonium chloride,
then extraction was performed by 50 ml, 30 ml of ether.
The organic layer was washed 2 times with saturated
saline, then was dried over anhydrous sodium sulfate, the
desiccant was filtered out, and the solvent was distilled
off under reduced pressure to obtain a crude product in
an amount of 11.7 g. This was dissolved in 150 ml of
dichloromethane, 2 ml of 1,8-diazabicyclo[5.4.0]undecene
was added, then the solution was stirred at room
temperature over night. Thereto 400 ml of ether was
added. This was then washed by a saturated aqueous
solution of potassium hydrogensulfate, a saturated


2168728
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aqueous solution of sodium hydrogencarbonate, and
saturated saline and was dried over anhydrous magnesium
sulfate. The desiccant was filtered out, then the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 10.9 g. This was purified
by a silica gel column (IR-60, 400 g, hexane/ethyl
acetate = 40/1, 19/1, 9/1) to obtain the desired product
(1-10), (4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-propyl}-2-
cyclopenten-l-one in an amount of 1.76 g (yield 50%).
'H-NMR (CD3Cl1 S ppm)
7.57 (dd, 1H, J=2.3 & 5.6Hz), 6.10 (dd, 1H J=2 &
5.6Hz), 3.99 (m, 1H), 2.80 to 3.10 (m, 1H), 2.50 (dd, 1H,
J=6.3 & 18.8Hz), 1.00 to 2.00 (m, 16H), 0.97 (d, 3H
J=6.3Hz), 0.90 (s, 3H), 0.05 (s, 9H)
Example 1-4
Production of (1R, 4S)-4-{(2R)-2-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-ylJ-
propyl}-1-methyl-2-cyclopenten-l-ol and (1S,4S)-4-
{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl
-1H-inden-l-yl]-propyl}-1-methyl-2-cyclopenten-l-ol
O
~.~~ ' =....~ ~ ~
j 1 \~ I ~ I ~I o ri ~~='o h
ttit e L i (\ ~J ~
~ /:
IH H H
TMSO TNiSO T lSO
Compound (1 _ 1 0) Compound (1 - 1 1) Compound (1 - 12 )
A 1.76 g amount of the compound (1-10), (4S)-4-
{(2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-1-yl]-propyl}-2-cyclopenten-l-one was
placed into a 300 ml eggplant-shaped flask. A 150 ml
amount of tetrahydrofuran was added and the solution
stirred and cooled to -78 C, and then, 6.5 ml of an ether
solution of methyllithium (1.16 mol/liter) was added,


2168728
- 54 -

followed by stirring for 15 minutes. A 50 ml amount of
saturated saline was added, the excess methyllithium was
broken down, then 100 ml of ether was added for
separation. The organic layer was washed with saturated
saline, then was dried over anhydrous magnesium sulfate.
The desiccant was filtered out, the solvent was distilled
off under reduced pressure, and the crude product was
purified by a silica gel column (Merck gel: 300 g,
hexane/ethyl acetate = 15/1 to 9/1) to obtain the desired
product (1-11), (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propyl}-1-
methyl-2-cyclopenten-l-ol in an amount of 1.55 g (yield
84%) and the desired product (1-12), (1S,4S)-4-{(2R)-2-
[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-
inden-1-yl]-propyl}-1-methyl-2-cyclopenten-l-ol, in an
amount of 0.27 g (yield 14%).
Compound (1-11) IH-NMR (D6-acetone, S ppm)
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)
Compound (1-12) 'H-NMR (D,-acetone, 8 ppm)
5.54 (s, 2H), 3.90 to 4.00 (m, 1H), 2.80 to 3.00 (m,
1H), 0.90 to 2.10 (m, 18H), 1.26 (s, 3H), 0.87 (d, 3H,
J=6.3Hz), 0.87 (s, 3H), 0.03 (s, 9H)
Example 1-5
Production of (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-l-yl]-propyl}-i-methyl-2-
cyclopenten-l-ol

CL; O H
n
au4 IN F
H > u
TNtSO H O
Compound (1 - 1 1) Compound (1 - 13)


2168728
- 55 -

A 1.55 g amount of the compound (1-11), (1R,4S)-4-
{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-l-ol
was taken in a 100 ml eggplant-shaped flask, then 20 ml
of THF was added and the solution stirred under
ice-cooling. Then, 5.1 ml of a tetrahydrofuran solution
(1 mol/liter) of tetra-n-butylammonium fluoride was added
thereto and, then the solution was stirred for 1 hour.
The reaction solution was poured in 100 ml of ether and
30 ml of water and extracted. The organic layer was
washed 4 times with saturated saline, then was dried over
anhydrous magnesium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 1.29
g. This was purified by a silica gel column (IR-60, 150
g, hexane/ethyl acetate =15/1 to 1/1) to obtain the
desired product (1-13), (1R,4S)-4-{(2R)-2-
[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-l-ol in an
amount of 1.21 g (yield 97%).

OH Bu~NF_ cOH
TMSO H HO H
Compound ( 1- 1 2) Compound ( 1- 1 4)
Similarly, 260 mg of the compound (1-12),
(1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy
-7a-methyl-lH-inden-1-yl]-propyl}-1-methyl-2-
cyclopenten-l-ol was treated in the same way to obtain
the desired product (1-14), (1S,4S)-4-{(2R)-2-[(1R,7aR)-
octahydro-4-hydroxy-7a-methyl-lH-inden-l-yl]-propyl}-1-
methyl-2-cyclopenten-l-ol in an amount of 174 mg (yield
840).


2168728
- 56 -

Compound (1-13) 'H-NMR (D6-acetone, S ppm)
5.50 to 5.70 (m, 2H), 4.08 (brs, 1H), 2.60 to 2.80
(m, 1H), 1.00 to 2.20 (m, 19H), 1.32 (s, 3H), 1.06 (s,
3H), 1.03 (d, 3H, J=9.3Hz)
Compound (1-14) 'H-NMR (D,,-acetone, S ppm)
5.59 (s, 2H), 4.08 (brs, 1H), 2.80 to 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 1-6
Production of (1R,4S)-4-{(2R)-2-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-1-yl]-propyl}-1-
methyl-2-cyclopenten-l-ol

H
o
(phj p) 4 t?~l H 2 ~
--=- ,
;-{
H 0 Methyl allylcarbonate O
Compound (1 - 15 )
Compound (1 - 13)

A 277 mg amount of the compound (1-13), (1R,4S)-4-
{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-lH-inden-
1-yl]-propyl}-1-methyl-2-cyclopenten-l-ol was dissolved
in 25 ml of toluene in a 100 ml eggplant-shaped flask,
then the solution was stirred under a nitrogen
atmosphere. Thereafter, 115 mg of tetrakis-
triphenylphosphine ruthenium dihydride and 5 ml of
methylallyl carbonate was added thereto, and then the
solution was stirred at 80 to 100 C for 1 day. The
reaction solution was filtered by Celite, the solvent was
distilled off under reduced pressure, and the residue was
purified by a silica gel column (IR-60, 80 g,
hexane/ethyl acetate = 3/1, 1/1) to obtain the desired
product (1-15), (1R,4S)-4-{(2R)-2-
[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-inden-l-yl]-
propyloxy}-1-methyl-2-cyclopenten-l-ol, in an amount of


- 57 - 2168728
221 mg (yield 79%).

,,.. ..
'*OH (Ph3P)4RuH2 OH
Methyl allylcarbonate
HO H 0 H
Compound (1- 4) Compound (11- 1 6)
A 62 mg amount of the compound (1-14), (1S,4S)-4-
{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-lH-inden-
1-yl]-propyl}-1-methyl-2-cyclopenten-l-ol, was treated in
the same way to obtain the desired product (1-16),
(1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-propyl}-l-methyl-2-cyclopenten-l-ol
in an amount of 52 mg (yield 84%).
Compound (1-15) 'H-NMR (CDjCl, S ppm)
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)
Compound (1-16) 'H-NMR (CD3C1, S ppm)
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)
Example 1-7
Production of (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-
4-oxo-7a-methyl-lH-inden-l-yl]-propyl}-l-methyl-l-
trimethylsilyloxy-2-cyclopentene

OH OT~~iS
T NI S C I
H - ' I H
O O
Compound (1- 15) Compound (1- 17)
A 177 mg amount of the compound (1-15), (lR,4S)-


2168728
- 58 -

4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-inden-l-
yl]-propyloxy}-1-methyl-2-cyclopenten-l-ol, and 128 mg of
imidazole were placed in a 100 ml eggplant-shaped flask.
Next, 20 ml of dried dichloromethane was added and the
solution was stirred. A 120 l amount of trimethylsilyl
chloride was added under ice cooling, then the solution
was stirred at the same temperature for 30 minutes. The
reaction solution was poured in 50 ml of ether and 30 ml
of water and extracted. The organic layer was washed 2
times with saturated saline, then was dried over
anhydrous magnesium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure. The obtained residue was purified by a silica
gel column (IR-60, 80 g, hexane/ethyl acetate =19/1, 4/1)
to obtain the desired product (1-17), (1R,
4S)-4-{(2R)-2-[(1R,7aR)-octadehydro-4-oxo-7a-methyl-lH-
inden-1-yl]-propyloxy}-1-methyl-l-trimethylsilyloxy-2-
cyclopentene in an amount of 188 mg (yield 85%).

~-=.
ry` ON 'i Ivi S CI qfl<OTMS
O H y
Compound (. 1- 1 G) Compound g)
A 52 mg amount of the compound (1-16), (1S,4S)-4-
{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-inden-l-
yl]-propyl}-1-methyl-2-cyclopenten-l-ol, was treated in
the same way to obtain the desired product (1-18),
(1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-
inden-1-yl]-propyl}-1-methyl-2-cyclopenten-l-ol in an
amount of 49 mg (yield 75%).
Compound (1-17) 'H-NMR (CD;Cl, 6 ppm)
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,


2168728
- 59 -

9H)
Compound (1-18) 'H-NMR (CD3C1, S ppm)
5.50 to 5.65 (m, 2H), 2.80 to 2.90 (m, 1H), 1.10 to
2.50 (m, 17H), 1.31 (s, 3H), 0.98 (d, 3H J=9.3Hz), 0.56
(s, 3H), 0.07 (s, 9H)
Example 1-8
Production of (1R,4S)-4-{(2R)-2-[(1R,7aR)-
octahydro-4-bromomethylene-7a-methyl-lH-inden-1-yl]-
propyl}-1-methyl-2.-cyclopenten-l-ol
OH
OTiti1S

~ E' P h, P C H Br Br IH H

0 Br
Compound (1 - 17) Compound (1 - 19 )
A 5.30 g amount of bromomethylene-
triphenylphosphonium bromide was taken in a 200 ml
.eggplant-shaped flask, 30 ml of dried tetrahydrofuran was
added, and the solution was stirred and cooled by a-65 C
bath. Next, 12.2 ml of a 1M solution of sodium
bistrimethylsilylamide in tetrahydrofuran was added
dropwise and the solution stirred at the same temperature
for 1 hour. Thereafter, 10 ml of a tetrahydrofuran
solution of 882 mg of the compound (1-17),
(1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-
inden-1-yl]-propyloxy}-1-methyl-l-trimethylsilyloxy-
2-cyclopentene was added dropwise, the cooling bath was
removed, then the solution was stirred at room
temperature for 30 minutes. Further, hexane was added to
the reaction solution which was then further stirred. The
precipitate was filtered out and the solvent was
distilled off under reduced pressure. The obtained
residue was dissolved in 10 ml of tetrahydrofuran and the
solution stirred while cooling by ice. To this was added
5 ml of a tetrahydrofuran solution (1 mol/liter) of


2168723
- 60 -

tetra(n-butyl)ammonium fluoride, then the solution was
stirred under ice cooling for 1 hour. The reaction
solution was poured in 100 ml of ethyl acetate and 30 ml
of water and separated. The organic layer was washed with
saline, then was dried over anhydrous magnesium sulfate.
The desiccant was filtered out, then the solvent was
distilled off under reduced pressure and the obtained
residue was purified by a silica gel column (IR-60, 200
g, hexane/ethyl acetate = 19/1 to 2/1) to obtain the
desired product (1-19), (1R, 4S)-4-{(2R)-2-[(1R,7aR)-
octahydro-4-bromomethylene-7a-methyl-lH-inden-l-yl]-
propyl}-1-methyl-2-cyclopenten-l-ol in an amount of 422
mg (yield 47%).
'H-NMR (CDC13, 8 ppm)
5.50 to 5.70 (br, 3H), 2.80 to 2.90 (m, 1H), 2.60 to
2.80 (m, 1H), 2.10 to 2.25 (m, 1H), 1.20 to 2.00 (m,
16H), 1.35 (s, 3H), 0.96 (d, 3H J=6.3Hz), 0.57 (s, 3H)
Example 1-9
Production of (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-
4-bromomethylene-7a-methyl-lH-inden-1-yl]-propyl}-1-
methyl-l-trimethylsilyloxy-2-cyclopentene

J ~ I OH ~ I - OTi-vtS
TNI S C 1 ~
H
B r B Y
Compound (1 - j g) Compound ( 1- 20)
A 422 mg amount of the compound (1-19),
(1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a
-methyl-lH-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-
1-ol and 158 mg of imidazole were added to a 100 ml
eggplant-shaped flask. Next, 5 ml of dried
dichloromethane was added and stirred in, then 175 l f
trimethylsilyl chloride was added under ice cooling and


- 61 - 2168(28
the solution stirred at the same temperature for 30
minutes. The reaction solution was poured into 50 ml of
ether and 20 ml of water and extracted. The organic layer
was washed 2 times with saturated saline, then was dried
over anhydrous magnesium sulfate, the desiccant was
filtered out, the solvent was distilled off under reduced
pressure, and the obtained residue was purified by a
silica gel column (IR-60, 150 g, hexane/ethyl acetate =
50/1 to 19/1) to obtain the desired product (1-20),
(1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-
7a-methyl-lH-inden-1-yl]-propyl}-l-methyl-2-cyclopenten
-1-ol in an amount of 422 mg (yield 84%).
IH-NMR (CDC13, S ppm)
5.50 to 5.70 (m, 2H), 5.53 (s, 1H), 1.10 to 3.00 (m,
18), 1.35 (s, 3H), 0.94 (d, 3H, J=6.3Hz), 0.56 (s, 3H),
0.11 (s, 9H)
Example 1-10
Production of 23,24,25,26,27-pentanol-la-hydroxy-22-
[(1R,4S)-1-trimethylsilyloxy-l-methyl-2-cyclopenten-4-
yl]-vitamin D3-la,3-bistrimethylsilylether

O T H
H
OTm S

,
;{
5 1 - T,f S 0 O T Y S , Compound
Compound (1 - 2 0 ) Compound (1 - 21) (1 - 22)
T;fSO OT~!S

A 63.7 mg amount of triphenylphosphine was taken in
a dried eggplant-shaped flask and deaerated. To this was
added 20 mg of tris(dibenzylideneacetone)dipalladium
chloroform, followed by further deaeration. A 7.2 ml
amount of a mixed solvent of distilled
toluene/diisopropylethylamine = 1/1 was added under a
nitrogen atmosphere, then the solution was stirred at
room temperature for 20 minutes. Next, 88 mg of the


2168728
- 62 -

compound (1-20), (1R,4S)-4-{(2R)-2-[(1R,7aR)-
octahydro-4-bromomethylene-7a-methyl-lH-inden-1-yl]
-propyl}-1-methyl-l-trimethylsilyloxy-2-cyclopentene and
57 mg of the compound (1-21), (3S,5R)-bistrimethylsilyl-
oxy-l-octen-7-yne were dissolved in 2 ml of a mixed
solvent of distilled toluene/diisopropylethylamine = 1/1
and then added dropwise to the above reaction solution.
The solution was heated and refluxed for 1.5 hours, then
returned to room temperature. The reaction solution was
poured into 50 ml of ethyl acetate and 10 ml of a
saturated aqueous solution of potassium hydrogensulfate
and extracted. The organic layer was washed by a
saturated aqueous solution of sodium hydrogencarbonate
and saturated saline, then was dried over anhydrous
magnesium sulfate. The desiccant was filtered out and the
solvent was distilled off under reduced pressure to
obtain a crude product in an amount of 300 mg. This was
purified by a silica gel column (Merck gel, 200 g,
hexane/ethyl acetate = 100 /1 to 20/1) to obtain the
desired product (1-22), 23,24,25,26,27-pentanol-la,
3-hydroxy-22-[(1R,4S)-1-trimethylsilyloxy-l-methyl-2-
cyclopenten-4-yl]-vitamin D3-la,3-bistrimethylsilyl-ether
in an amount of 58.8 mg (yield 46%).
1H-NMR (CDC13, 8 ppm)
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 to 4.40 (m,
1H), 4.10 to 4.20 (m, 1H), 1.10 to 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 1-11
Production of 23,24,25,26,27-pentanol-la-
hydroxy-22-[(1R, 4S)-l-hydroxy-l-methyl-2-cyclopenten-
4-yl]-vitamin D3


2168728
- 63 -

J T iv1S 7 !-I OH f H J H


TM SO OTN(S HO~ OH
Compound ( j - 22) Compound ( j - 23)
A 58.8 mg amount of the compound (1-22),
23,24,25,26,27-pentanol-la-hydroxy-22-[(1R,4S)-l-
trimethylsilyloxy-l-methyl-2-cyclopenten-4-yl]-vitamin
D3-la,3-bistrimethylsilylether, was taken in a 25 ml
eggplant-shaped flask, then 5 ml of dried tetrahydrofuran
was added and the solution stirred. A 0.5 ml amount of a
1M solution of tetrabutylammoniumfluoride in
tetrahydrofuran was added and the solution stirred under
ice cooling for 3 hours. The reaction solution was poured
in 50 ml of ethyl acetate and 10 ml of a saturated
aqueous solution of potassium hydrogensulfate and
extracted. The organic layer was washed with a saturated
aqueous solution of sodium bicarbonate and saturated
saline, then was dried over anhydrous magnesium sulfate.
The desiccant was filtered out, the solvent was distilled
off under reduced pressure, and the obtained crude
product was purified by a silica gel column (IR-60 Merck
gel, 250 g, hexane/ethyl acetate = 1/1 to 1/3) to obtain
the desired product (1-23),23,24,25,26,27-pentanol-la-
hydroxy-22-[(1R, 4S)-1-hydroxy-l-methyl-2-cyclopenten-4-
yl]-vitamin D3 in an amount of 22.1 mg (yield 57%).
'H-NMR (CDC13, S ppm)
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=6.3Hz), 0.55 (s, 3H)
Example 2-1


2168728
- 64 -

Production of (4S,6R)-6-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-l-yl]-2-methoxycarbonyl-4-
hydroxy-l-heptene and (4R,6R)-6-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-4-
hydroxy-l-heptene

OH CO2Me
=
H
HO

CHO COzMe
2). Zn

=
H 3). Sat.NHQCIaq. r
HO I OH CO2Me
H
HO
A 3.0 g amount of (3R)-3-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]butanal was placed in a
500 ml eggplant-shaped flask, 100 ml of tetrahydrofuran
was added, and the solution was stirred and cooled by an
ice-cooled bath. A 3.2 ml amount of methyl-2-
bromomethylacrylate was added dropwise to this. Next,
1.37 g of zinc powder and 390 ml of a saturated aqueous
solution of ammonium chloride were added and the solution
was stirred at the same temperature for 45 minutes.
A 150 ml amount of ethyl acetate was added to the
reaction solution for extraction. The organic layer was
washed 2 times with saturated saline, then was dried over
anhydrous magnesium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 5.0 g.
This was purified by a silica gel column (Merck gel, 250
g, hexane/ethyl acetate = 9/1 to 3/1) to obtain (4S,6R)-


2168728
- 65 -

6-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-lH-inden-1-yl]-
2-methoxycarbonyl-4-hydroxy-l-heptene (more polar) in an
amount of 2.03 g and (4R,6R)-6-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-4-
hydroxy-l-heptene (less polar) in an amount of 1.522 g
(yield 81%).
'H-NMR (CDC13, S ppm)
6.25 (d, 1H, J=2Hz), 5.66 (d, 1H, J=2Hz), 4.07 (br,
1H), 3.82 to 3.88 (br, 1H), 3 .77 (s, 3H), 2.51 (dd, 1H,
J1=1Hz, J2=9Hz), 2.36 (dd, 1H, J1=8Hz, J2=14Hz), 0.96 (s,
1H), 0.94 (d, 3H, J=6Hz), 6.27 (d, 1H, J=1Hz), 5.69 (d,
1H, J=lHz), 4.07 (br, 1H), 3.80 to 3.86 (br, 1H), 3.77
(s, 3H), 2.69 (dd, 1H, J1=1Hz, J2=lOHz), 2.18 (dd, 1H,
J1=9Hz, J2=14Hz), 0.98 (d, 3H, J=7Hz), 0.95 (s, 3H).
Example 2-2
Production of (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-1-yl]propyl}-3-methylene-
dehydro-2(3H)-furanon

OH C02Me
LiOH
-~
HCI
-T.
OH
OH
A 1.00 g amount of (4S,6R)-6-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-4-
hydroxy-l-heptene was taken in a 100 ml eggplant-shaped
flask, then 15 ml of tetrahydrofuran was added to
dissolve it. Further, 15 ml of water was added and the
solution was stirred and cooled by an ice-cooled bath. To
this was added 6 ml of a 4N aqueous solution of lithium
hydroxide, then the solution was stirred at the same
temperature for 1 hour. Next, at the same temperature,
concentrated hydrochloric acid was dropwise added to
adjust the pH to 2, then the solution was stirred at room


66 - 2168728
-

temperature for 3 hours. To the reaction solution were
added 50 ml of water and 200 ml of ethyl acetate for
extraction. The organic layer was further washed 3 times
with water and was washed 2 times with saturated saline,
then was dried over anhydrous magnesium sulfate. The
desiccant was filtered out and the solvent was distilled
off under reduced pressure to obtain (5S)-5-{(2R)-2-
[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-
1-yl]propyl}-3-methylene-dehydro-2(3H)-furanon in an
amount of 880 mg.
'H-NMR (CDC13, 6 ppm)
6.22 (t, 1H, J=3Hz), 5.62 (t, 1H, J=2Hz), 4.58 (dd,
1H, Jl=7Hz, J2=14Hz), 4.08 (d, 1H, J=3Hz), 3.01 to 3.10
(m, 1H), 2.56 to 2.6 (m, 1H), 1.00 (d, 3H, J=7Hz), 0.95
(s, 3H).
Example 2-3
Production of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-l-yl]propyl}-3-methylene-
dehydro-2(3H)-furanon

OH C02Me O
LiOH O
HCI
OH OH
A 570 mg amount of (4R,6R)-6-[(1R,7aR)-octahydro-4-
hydroxy-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl-4-
hydroxy-l-heptene was taken in a 100 ml eggplant-shaped
flask, then 5 ml of tetrahydrofuran was added to dissolve
it. Further, 5 ml of water was added and the solution
stirred and cooled by an ice-cooled bath. To this was
added 3 ml of a 4N aqueous solution of lithium hydroxide.
The solution was stirred at the same temperature for 1
hour. Next, under the same temperature, concentrated


2168728
- 67 -

hydrochloric acid was added dropwise to adjust the pH to
2, then the solution was stirred at room temperature for
3 hours. To the reaction solution were added 50 ml of
water and 200 ml of ethyl acetate for extraction. The
organic layer was further washed 3 times with water and 2
times with saturated saline, then was dried over
anhydrous magnesium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure to obtain (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-1-yl]propyl}-3-methylene-
dehydro-2(3H)-furanon in an amount of 451 mg.
Example 2-4
Production of (5S)-5-{(2R)-2-[(1R,7R)-octahydro-
4-oxo-7a-methyl-lH-inden-l-yl]propyl}-3-methylene-
dehydro-2(3H)-furanon

0
o 0
0

f
PDC HO H O

A 2.38 g amount of pyridinium bichromate was taken
in a 200 ml eggplant-shaped flask, 50 ml of dimethyl
formamide was added, then the solution was cooled by an
ice-cooled bath. Thereafter, a solution of 880 mg of
(5S)-5-{(2R)-2-[(1R,7R)-octahydro-4-hydroxy-
7a-methyl-lH-inden-l-yl]propyl}-3-methylene-dehydro-
2(3H)-furanon dissolved in 20 ml of dimethyl formamide
was dropwise added and the solution was stirred at room
temperature for 3 hours. A 200 ml amount of ether was
added to the reaction solution, the insolubles were
filtered out, then the result was washed with water and
then saturated saline, then was dried over anhydrous
magnesium sulfate. The desiccant was filtered out and the
solvent was distilled off under reduced pressure to


2168728
- 68 -

obtain a crude product in an amount of 1.02 g. This was
purified by a silica gel column (Daiso gel IR-60, 150 g,
hexane/ethyl acetate = 3/1 to 2/1) to obtain
(5S)-{(2R)-2-[(1R,7aR)-octahydro-4-
oxo-7a-methyl-lH-inden-l-yl]propyl}-3-methylene-dehydro-2
(3H)-furanon in an amount of 700 mg (yield 69%).
'H-NMR (CDC131 S ppm)
6.23 (t, 1H, J=3Hz), 5.63 (t, 1H, J=2Hz), 4.6 to 4.7
(m, 1H), 3.0 to 3.13 (m,1H), 2.4 to 2.6 (m,1H), 1.05 (d,
3H, J=7Hz), 0.67 (s, 3H).
Example 2-5
Production of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
oxo-7a-methyl-lH-inden-1-yl]propyl}-3-methylene-dehydro-2
(3H)-furanon

O
0
O 0
= PDC
H H
HO 0
A 648 mg amount of pyridinium bichromate was taken
in a 200 ml eggplant-shaped flask, 10 ml of dimethyl
formamide was added, and the solution was cooled by an
ice-cooled bath. Thereafter a solution of 240 mg of
(5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-hydroxy-
7a-methyl-lH-inden-l-yl]propyl}-3-methylene-dehydro-
2(3H)-furanon dissolved in 10 ml of dimethyl formamide
was dropwise added and the solution was stirred at room
temperature for 3 hours. A 100 ml amount of ether was
added to the reaction solution, the insolubles were
filtered out, then the result was washed with water and
saturated saline, then was dried over anhydrous magnesium
sulfate. The desiccant was filtered out and the solvent
was distilled off under reduced pressure to obtain a


2168728
- 69 -

crude product in an amount of 600 mg. This was purified
by a silica gel column (Daiso gel IR-60, 100 g,
hexane/ethyl acetate = 3/1 to 2/1) to obtain
(5R)-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-
furanon in an amount of 327 mg.
'H-NMR (CDC13, S ppm)
6.23 (t, 1H, J=3Hz), 5.63 (t, 1H, J=2Hz), 4.59 (t,
1H, J=7Hz), 3.0 to 3.10 (m, 1H), 2.4 to 2.6 (m, 1H), 1.07
(d, 3H, J=6Hz), 0.66 (s, 3H).
Example 2-6
Production of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-
4-oxo-7a-methyl-lH-inden-1-yl]propyl}-3-methyl-dehydro-
2(3H)-furanon

o H2 o
o Pd/C

O H 0

A 200 mg amount of (5S)-5-{(2R)-2-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon was taken in a 100 ml
eggplant-shaped flask, 50 ml of ethanol was added, and
the solution was stirred for dissolution. A 50 mg amount
of 10% Pd/carbon was added under a nitrogen atmosphere,
the atmosphere was replaced with hydrogen (balloon), then
the solution was stirred at room temperature for 3 hours.
The atmosphere was replaced with nitrogen, then the
catalyst was filtered out and the solvent was distilled
off under reduced pressure to obtain
(3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-1-yl]propyl}-3-methyl-dehydro-2(3H)-
furanon in an amount of 185 mg.


2168728
- 70 -

'H-NMR (CDC13, S ppm)
4.40 to 4.51 (m, 1H), 2.62 to 2.72 (m, 1H), 2.41 to
2.51 (m, 2H), 2.27 (d, 3H, J=7Hz), 1.03 (d, 3H, J=7Hz),
0.66 (s, 3H).
Example 2-7
Production of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-
4-bromomethylene-7a-methyl-lH-inden-l-yl]propyl}-3-
methyl-dehydro-2(3H)-furanon

1 ).BrCH2P(C6H5)3Br

O 2).L(CH3)3S[12Nh2 0
O 0
O H H
Br
A 1.79 g amount of bromomethylenetriphenyl-
phosphonium bromide was taken in a 100 ml eggplant-shaped
flask, 20 ml of dried tetrahydrofuran was added, and the
solution was stirred and cooled by a-70 C cooling bath.
Thereafter 3.9 ml of a 1M [(CH3)jSi],NNA/tetrahydrofuran
solution was dropwise added, then the solution was
stirred at the same temperature for 1 hour. Next, a
solution of 120 mg of (3S,5S)-5-{(2R)-2-[(lR,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-l-yl]propyl}-
3-methyl-dehydro-2(3H)-furanon dissolved in 5 ml of dried
tetrahydrofuran was dropwise added to this. The cooling
bath was removed, then the solution was stirred for 2
hours. Next, hexane was added and the insolubles filtered
out, then the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 1.2 g.
This was purified by a silica gel column (Daiso gel
IR-60, 80 g, hexane/ethyl acetate = 15/1) to obtain
(3S,5S)-5-{(2R)-2-[(lR,7aR)-octahydro-4-bromomethylene-7a
-methyl-lH-inden-l-yl]propyl}-3-methyl-dehydro-2(3H)-
furanon in an amount of 69 mg (yield 46%).


2168728
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'H-NMR (CDC13, S ppm)
5.65 (d,1H, J=2Hz), 4.40 to 4.50 (m, 1H), 2.85 to
2.90 (m, 1H), 2.62 to 2.72 (m, 1H), 2.41 to 2.50 (m, 1H),
2.67 (d, 3H, J=7Hz), 1.00 (d, 3H, J=7Hz), 0.58 (s, 3H).
Example 2-8
Production of (2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]propylparatoluene
sulfonate

OTs
OTs
1 ).BrCH2P(C6Hs)3Br
2).[(CH3)3Si]2NNa
H H
O
Br
A 2.39 g amount of bromomethylenetriphenyl-
phosphonium bromide was taken in a 100 ml eggplant-shaped
flask, 40 ml of dried tetrahydrofuran was added, and the
solution was stirred and cooled by a-70 C cooling bath.
Thereafter 5.28 ml of a 1M [(CH3)3Si]2 NNa/tetrahydrofuran
solution was dropwise added, then the solution was
stirred at the same temperature for 1 hour. Next, a
solution of 300 mg of (2R)-2-[(1R,7aR)-octahydro-4-oxo-
7a-methyl-lH-inden-1-yl]propylparatoluene sulfonate
dissolved in 10 ml of dried tetrahydrofuran was added
dropwise. The cooling bath was removed and then the
solution was stirred for 1 hour. Next, hexane was added
and the insolubles were filtered out, then the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 2.5 g. This was purified by
a silica gel column (Merck gel, 100 g, hexane/ethyl
acetate = 14/1, 9/1) to obtain {(2R)-2-[(1R,7aR)-
octahydro-4-bromomethylene-7a-methyl-lH-inden-l-
yl]propylparatoluene sulfonate in an amount of 178 mg
(yield 48%).
'H-NMR (CDC13, 8 ppm)


2168723
- 72 -

7.78 (d, 2H, J=8Hz), 7.35 (d, 2H, J=8Hz), 5.64
(s,1H), 3.96 (dd, 1H, J1=3Hz, J2=9Hz), 3.82 (dd, 1H,
J1=6Hz, J2=9Hz), 2.45 (s, 3Hz), 0.99 (d, 3H, J=7Hz), 0.53
(s, 3H).
Example 2-9
Production of (3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]butyronitrile
I KCN

gr Br
A 178 mg amount of (2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]propylparatoluenes
ulfonate was taken in a 50 ml eggplant-shaped flask, then
6 ml of dimethyl formamide was added for dissolution. To
20 this was then charged 215 mg of KCN, then the solution
was stirred in a 50 C bath for 24 hours. To the reaction
solution was added 50 ml of water, then extraction was
performed with ether. The organic layer was washed with
water and saturated saline, then was dried over anhydrous
25 magnesium sull'ate and the desiccant was filtered out. The
solvent was distilled off under reduced pressure to
obtain a crude product in an amount of 110 mg. This was
purified by a silica gel column (Daiso gel, hexane/ethyl
acetate = 14/1) to obtain (3R)-3-[(1R,7aR)-octahydro-4-
30 bromomethylene-7a-methyl-lH-inden-l-yl]butyronitrile in
an amount of 84 mg (yield 69%).
`H-NMR (CDC13, S ppm)
5.67 (s, 1H), 2.86 to 2.91 (m, 1H), 2.21 to 2.35 (m,
2H), 1.18 (d, 3H, J=6Hz), 0.59 (s, 3H).
35 Example 2-10


73 - 2168728
-

Production of (3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]butanol
CN CHO
DIBAL-H
H H
Br Br
A 84 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]butyronitrile was
taken in a 25 ml eggplant-shaped flask, then 5 ml of
dried dichloromethane was then added to dissolve the
same. The solution was cooled by a-70 C bath, then 660
l of a 1.5M [(CH3),CHCH2],A1H/toluene solution was added
dropwise. The solution was stirred at the same
temperature for 1 hour, then 0.5 ml of a saturated
aqueous solution of sodium sulfate, 0.3 ml of methanol,
0.5 ml of 2N hydrochloric acid, and 15 ml of ethyl
acetate were added and the solution stirred for 30
minutes. The reaction solution was filtered by Celite,
then was washed by a saturated solution of ammonium
chloride and saturated saline, then was dried over
anhydrous magnesium sulfate and the desiccant filtered
out. The solvent was distilled off under reduced pressure
to obtain (3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-7a-
methyl-lH-inden-1-yl]butanol in an amount of 85 mg.
Example 2-11
Production of (4S,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl
-4-hydroxy-l-heptene and (4R,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-2-
.methoxycarbonyl-4-hydroxy-l-heptene


74 2168728
- -

~''..

OIHGO2Me
CHO
H
1 ). Br~CO2Me Br

2). Zn ~'''=
H 3). Sat.NH ;Claq. OH CO2M2
. Br

H
6r

A 105 mg amount of (3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]butanol was taken
in a 50 ml eggplant-shaped flask, then 8 ml of dried
tetrahydrofuran was then added to dissolve the same. The
solution was cooled by an ice cooled bath, then 84 l of
methyl-2-bromomethylacrylate was added dropwise. Further,
35 mg of zinc powder and 10 ml of a saturated aqueous
solution of ammonium chloride were added, then the
solution was stirred at the same temperature for 1 hour.
The reaction solution was extracted by ethyl acetate, the
organic layer was washed with saturated saline, then was
dried over anhydrous magnesium sulfate. The desiccant was
filtered out, then the solvent was distilled off under
reduced pressure to obtain a crude product in an amount
of 166 mg. This was purified by a silica gel column
(Merck gel, hexane/ethyl acetate = 9/1) to obtain
(4S,6R)-6-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-
1H-inden-1-yl]-2-methoxycarbonyl-4-hydroxy-l-heptene in
an amount of 43 mg and (4R,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]-2-methoxycarbonyl
-4-hydroxy-l-heptene in an amount of 55 mg.
'H-NMR (CDCl;, 8 ppm)


2168728
- 75 -

6.269 (d, 1H, J=lHz), 5.66 (d, 2H, J=10Hz), 3.77 (s,
3H), 2.84 to 2.93 (m, 1H), 2.65 to 2.72 (m, 1H), 2.13 to
2.27 (m, 1H), 1.02 (d, 3H, J=7Hz), 0.58 (s, 3H), 6.249
(d, 1H, J=1Hz), 5.65 (d, 2H, J=5Hz), 3.77 (s, 3H), 2.84
to 2.90 (m, 1H), 2.53 to 2.55 (m, 1H), 2.31 to 2.39 (m,
1H), 0.97 (d, 3H, J=7Hz), 0.59 (s, 3H)
Example 2-12
Production of (5S)-5-{(2R)-2-[(1R,7aR)-octahydro-
4-bromo~ilethylene-7a-methyl-lH-inden-1-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon

i~,,= ~''~=.
OH COzMe ~
O
LiON
HC! =
y H
Br Br

A 55 mg amount of (4S,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-2-methoxycarbonyl
-4-hydroxy-l-heptene was taken in a 50 ml eggplant-shaped
flask, then 6 ml of tetrahydrofuran was added to dissolve
the same. Further, 6 ml of water was added, the solution
was cooled by an ice-cooled bath, 0.25 ml of 4N lithium
hydroxide was added dropwise, and the solution was
stirred at the same temperature for 1 hour. Next,
concentrated hydrochloric acid was added dropwise under
the same temperature to adjust the pH to 2 and the
solution was stirred at room temperature for 3 hours. To
the reaction solution were added 10 ml of water and 100
ml of ethyl acetate for extraction. The organic layer was
washed 3 times with water and 2 times with saturated
saline, then was dried over anhydrous magnesium sulfate.
The desiccant was filtered out and the solvent was
distilled off under reduced pressure to obtain
(5S)-5-{(2R)-2-[(lR,7aR)-octahydro-4-bromomethylene-7a-


2168728
- 76 -

methyl-lH-inden-1-yl]propyl}-3-methylene-dehydro-2(3H)-
furanon in an amount of 51 mg.
'H-NMR (CDC1,, S ppm)
6.23 (t, 1H, J=3Hz), 5.62 (t, 1H, J=2Hz), 5.65 (d,
1H, J=2Hz), 4.12 (dd, 1H, J1=7Hz, J2=14Hz), 3.00 to 3.11
(m, 1H), 2.85 to 2.9 (m, 1H), 2.47 to 2.57 (m, 1H), 1.03
(d, 3H, J=7Hz), 0.58 (s, 3H).
Example 2-13
Production of (5R)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]propyl}-3-
methylene-dehydro-2(3H)-furanon

//~~' /~~~'= /
OH C02Me
O
LiOH
-;-
HCI
H -~ ' H
Br Br
A 70 mg amount of (4R,6R)-6-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-2-
methoxycarbonyl-4-hydroxy-l-heptene was taken in a 50 ml
eggplant-shaped flask, then 6 ml of tetrahydrofuran was
added for dissolution. Further, 6 ml of water was added,
the solution was cooled by an ice-cooled bath, 0.35 ml of
4N lithium hydroxide was added dropwise, and the solution
was stirred at the same temperature for 1 hour. Next,
concentrated hydrochloric acid was added dropwise under
the same temperature to adjust the pH to 2 and the
solution was stirred at room temperature for 3 hours. To
the reaction solution were added 10 ml of water and 100
ml of ethyl acetate for extraction. The organic layer was
washed 3 times with water and 2 times with saturated
saline, then was dried over anhydrous magnesium sulfate.
The desiccant was filtered out and the solvent was


77 - 2168728
-

distilled off under reduced pressure to obtain (5R)-5-
{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-
1H-inden-l-yl]propyl}-3-methylene-dehydro-2(3H)-furanon
in an amount of 60 mg.
'H-NMR (CDCl31 S ppm)
6.23 (t, 1H, J=3Hz), 5.62 (t, 1H, J=2Hz), 5.65 (d,
1H, J=2Hz), 4.59 to 4.69 (m, 1H), 3.01 to 3.12 (m, 1H),
2.85 to 2.9 (m, 1H), 2.47 to 2.57 (m, 1H), 1.02 (d, 3H,
J=7Hz), 0.59 (s, 3H).
Example 2-14
Production of 23(S),25(S)-la-hydroxyvitamin D3-
26,23-lactone

O
TMSO"" OTMS O
H
O
0
IH
gr TMSO\' OTMS
0
0

PPTs /polymer H
HO" OH

A 28 mg amount of triphenylphosphine was taken in a
dried eggplant-shaped flask and deaerated. Thereafter,
19 mg of tris(dibenzylideneacetone)dipalladium chloroform
was added, followed by further deaeration, then 6 ml of a
mixed solvent of distilled toluene/diisopropylethylamine


2168728
- 78 -

= 1/1 was added under nitrogen and the solution was
stirred at 50 C for 20 minutes. Next, a solution of 65 mg
of (3S,5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]propyl}-3-methyl-
dehydro-2(3H)-furanon and 60 mg of (3S),(5R)-3,5-
bis(trimethylsilyloxy)-l-octen-7-yne dissolved in 3 ml of
a mixed solvent of distilled toluene/diisopropylethyl-
amine = 1/1 was added dropwise. This reaction solution
was stirred at 100 C for 1.5 hours. This was returned to
room temperature, then the reaction solution was poured
into 50 ml of ethyl acetate and 10 ml of a saturated
aqueous solution of potassium hydrogensulfate for
extraction. The organic layer was washed with a saturated
aqueous solution of sodium hydrogencarbonate and
saturated saline, then was dried over anhydrous sodium
sulfate. The desiccant was filtered out and the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 120 mg. This was purified
by a silica gel column (Merck gel, hexane/ethyl acetate =
14/1 to 9/1) to obtain 23(S),25(S)-la-hydroxy-vitamin D3
-26,23-lactone-la,3-bistrimethylsilylether in an amount
of 52 mg (yield 50%). This was placed in a 25 ml
eggplant-shaped flask, then 5 ml of methanol was added to
dissolve it. The solution was cooled by an ice-cooled
bath, then 100 mg of polymer-bonded pyridinium
toluene-4-sulfonate was added and the solution stirred
for 15 hours. The reaction solution was filtered by
Celite, then the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 110
mg. This was purified by a silica gel column (Merck gel,
hexane/ethyl acetate = 2/1 to 1/1) to obtain
23(S),25(S)-la-hydroxyvitamin D,-26,23-lactone in an
amount of 28 mg (yield 72%).
'H-NMR (CDC13, 6 ppm) .
6.37 (d, 1H, J=11Hz), 6.00 (d, 1H, J=11Hz), 5.33 (s,
1H), 5.01 (s, 1H), 4.44 (br, 2H), 4.24 (br, 1H), 1.265


2168728
- 79 -

(d, 3H, J=8Hz), 0.99 (d, 3H, J=6Hz), 0.56 (s, 3H)
Example 2-15
Production of 23(S)-la-hydroxy-25,27-dehydro-vitamin
D,-26,23-lactone
~ '' =..

O
7MSO"" OTMS O
'~=,.
0~ > j H
O
H
Br TMSO"" O T b.1S
%,.

O

4c
PPTs /polymer I Om'-
H_
HO"" OH
A 22 mg amount of triphenylphosphine was taken in a
dried eggplant-shaped flask and then deaearated.
Thereafter, 14 mg of tris(dibenzylideneacetone)
dipalladium chloroform was added, followed by further
deaeration, then 3 ml of a mixed solvent of distilled
toluene/diisopropylethylamine = 1/1 was added under
nitrogen and the solution was stirred at 50 C for 20
minutes. Next, a solution of 51 mg of
(5S)-5-{(2R)-2-[(1R,7aR)-octahydro-4-bromomethylene-
7a-methyl-lH-inden-1-yl]propyl}-3-methylene-dehydro-
2(3H)-furanon and 61 mg of (3S),(5R)-3,5-bis(trimethyl-
silyloxy)-1-octene-7-in dissolved in 4 ml of a mixed
solvent of distilled toluene/diisopropylethylamine = 1/1
was added dropwise. This reaction solution was stirred at
100 C for 1.5 hours, then was returned to room


80 - 2168728
-

temperature. The reaction solution was poured into 50 ml
of ethyl acetate and 10 ml of a saturated aqueous
solution of potassium hydrogensulfate for extraction. The
organic layer was washed with a saturated aqueous
solution of sodium hydrogencarbonate and saturated
saline, then was dried over anhydrous sodium sulfate. The
desiccant was filtered out and the solvent was distilled
off under reduced pressure to obtain a crude product in
an amount of 120 mg. This was purified by a silica
seppack (Waters, hexane/ethyl acetate = 19/1 to 9/1) to
obtain 23(S)-la-hydroxy-25,27-dehydro-vitamin D3
-23,26-lactone-la,3-bistrimethylsilylether in an amount
of 46 mg (yield 50%). This was placed in a 25 ml
eggplant-shaped flask, then 5 ml of methanol was added
for dissolution. The solution was cooled by an ice-cooled
bath, 50 mg of polymer-bonded pyridinium
toluene-4-sulfonate was added, then the solution was
stirred for 15 hours. The reaction solution was filtered
by Celite, then the solvent was distilled off under
reduced pressure to obtain a crude product in an amount
of 110 mg. This was purified by a silica seppack (Waters,
hexane/ethyl acetate = 3/1 to 1/1) to obtain
23(S)-la-hydroxy-25,27-dehydro-vitamin D3-26,23-lactone
in an amount of 12 mg (yield 40%).
'H-NMR (CDC13, S ppm)
6.37 (d, 1H, J=12Hz), 6.22 (t, 1H, J=3Hz), 6.00 (d,
1H, J=11Hz), 5.62 (t, 1H, J=3Hz), 5.323 (d, 1H, J=lHz),
5.00 (s, 1H), 4.59 (t, 1H, J=7Hz), 4.43 to 4.54 (br, 1H),
4.22 to 4.24 (br, 1H), 2.99 to 3.11 (m, 1H), 2.79 to 2.85
(m, 1H), 2.48 to 2.61 (m, 2H), 2.28 to 2.35 (m, 1H), 1.03
(d, 3H, J=6Hz), 0.56 (s, 3H)
Example 2-16
Production of 23(R)-la-hydroxy-25,27-dehydro-vitamin
D3-26,23-lactone


2168728
- 81 -

0
T MSO" OTMS O
O H
O

H
8r TMSO`" OTMS
'~~,.
1 0--~
O
PPTs /polymer ~ H

I
r10l OH

A 26 mg amount of triphenylphosphine was taken in a
dried eggplant-shaped flask and deaerated. To this was
further added 20 mg of tris(dibenzylideneacetone)
dipalladium chloroform followed by further deaeration,
then 3 ml of a mixed solvent of distilled
toluene/diisopropylethylamine = 1/1 was added under
nitrogen and the solution was stirred at 50 C for 20
minutes. Next, a solution of 70 mg of (5R)-5-{(2R)-2-
[(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-lH-inden-1
-yl]propyl}-3-methylene-dehydro-2(3H)-furanon and 84 mg
of (3S),(5R)-3,5-bis(trimethylsilyloxy)-1-octen-7-yne
dissolved in 4 ml of a mixed solvent of distilled
toluene/diisopropylethylamine = 1/1 was added dropwise.
This reaction solution was stirred at 100 C for 1.5
hours, then was returned to room temperature. The
reaction solution was poured into 50 ml of ethyl acetate
and 10 ml of a saturated aqueous solution of potassium
hydrogensulfate for extraction. The organic layer was
washed with a saturated aqueous solution of sodium
hydrogencarbonate and saturated saline, then was dried


2168728
- 82 -

over anhydrous sodium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 190
mg. This was purified by a silica gel seppack (Waters,
hexane/ethyl acetate = 19/1 to 9/1) to obtain
23(R)-la-hydroxy-25,27-dehydro-vitamin D3-26,23-lactone
-la,3-bistrimethylsilylether in an amount of 50 mg (yield
40%). This was placed in a 25 ml eggplant-shaped flask,
then 5 ml of methanol was added to dissolve it. The
solution was cooled by an ice-cooled bath, then 100 mg of
pyridinium toluene-4-sulfonate bonded to a polymer was
added, then the solution was stirred for 15 hours. The
reaction solution was filtered by Celite, then the
solvent was distiiled oif under reduced pressure to
obtain a crude product in an amount of 110 mg. This was
purified by silica seppack (Waters, hexane/ethyl acetate
= 3/1 to 1/1) to obtain 23(R)-la-hydroxy-25,27-
dehydro-vitamin D3 -26,23-lactone in an amount of 14 mg
(yield 43%).
'H-NMR (CDClõ 8 ppm)
6.37 (d, 1H, J=11Hz), 6.225 (t, 1H, J=3Hz), 6.00 (d,
1H, J=llHz), 5.62 (t, 1H, J=2Hz), 5.33 (t, iH, J=2Hz),
5.00 (s, 1H), 4.59 to 4.69 (m, 1H), 4.41 to 4.45 (m, 1H),
4.21 to 4.25 (m, 1H), 3.01 to 3.10 (m, 1H), 2.79 to 2.85
(m, 1H), 2.47 to 2.58 (m, 2H), 2.28 to 2.35 (m, 1H), 1.02
(d, 3H, J=6Hz), 0.58 (s, 3H)
Reference Example 3-1
Production of (2R)-2-[(1R, 7aR)-octahydro-
4-trimethylsilyloxy-7a-methyl-lH-inden-1-yl]propanol
Ott 0
1 )`6uCOCl
~--
Z)TtiiSCi
OH N 3)`Su0'r: TMSO
A 10.78 g amount of (2R)-2-[(1R, 7aR)(4E)-


83 - 2168728
-

octahydro-4-hydroxy-7a-methyl-lH-inden-1-yl]propanol
dissolved in 80 ml of pyridine was added to a 100 ml
eggplant-shaped flask and the solution was stirred under
ice-cooling. Thereafter, 6.57 ml of pivaloyl chloride was
added, then the solution was stirred over night.
To this reaction solution was added 150 ml of water.
The solution was then extracted 3 times by 200 ml of
ether. The organic layer was washed 2 times each by a
saturated aqueous solution of potassium hydrogensulfate,
a saturated aqueous solution of sodium bicarbonate, and
saturated saline, then was dried over anhydrous magnesium
sulfate. The desiccant was filtered out and the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 14.7 g. This was placed in
a 200 ml eggplant-shaped flask, 10.9 g of imidazole was
added, 60 ml of dried dichloromethane was added, and the
solution was stirred under ice-cooling. To this was added
10.2 ml of trimethylsilyl chloride, then the solution was
stirred over night at room temperature. The reaction
solution was poured in 300 ml of ethyl acetate and 100 ml
of water for extraction. The organic layer was washed 2
times each by a saturated aqueous solution of potassium
hydrogensulfate, a saturated aqueous solution of sodium
bicarbonate, and saturated saline, then was dried over
anhydrous magnesium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 18.11
g. A 17.2 g amount of t-butoxy potassium was placed in a
1-liter eggplant-shaped flask, then 440 ml of ether was
added and the solution was stirred under ice-cooling. A
2.1 ml amount of water was added, then a solution of
18.11 g of the above residue dissolved in 120 ml of ether
was added and the solution was stirred over night at room
temperature. A 200 ml amount of water was poured into the
reaction solution for separation, then extraction was
performed with 500 ml of ether. The organic layer was
washed 2 times with saturated saline, then was dried over


84 - 2168728
-

anhydrous magnesium sulfate. The desiccant was filtered
out and the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 15.2
g. This was purified by a silica gel column (IR-60, 1 kg,
hexane/ethyl acetate = 19/1 to 6/1) to obtain
(2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-1-yl]propanol in an amount of 12.6 g
(yield 87%).
'H-NMR (CDC13, 8 ppm)
3.95 (d, 1H, J=3Hz), 3.58 (m, 1H), 3.31 (m, 1H),
1.00 to 2.00 (m, 14H), 0.96 (d, 3H, J=8Hz), 0.85 (s, 3H),
0.03 (s, 9H)
Reference Example 3-2
Production of (2R)-2-[(1R,7aR)-octahydro-4-
trimethylsi.lyloxy-7a-methyl-lH-inden-1-yl]propanal
GHO
OH
PCC
TMSO H TMSO H

A 427 mg amount of cellite, 37 mg of sodium acetate,
and 444 mg of pyridinum chlorochromate were placed in a
50 ml eggplant-shaped flask, then 10 ml of
dichloromethane was added and the solution stirred.
Thereafter, a dichloromethane solution (3 ml) of 426 mg
of (2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-
7a-methyl-lH-inden-1-yl]propanol was added, then the
solution was stirred at room temperature for 3.5 hours.
The reaction solution was filtered by Celite, then
was concentrated and the obtained residue was purified by
a silica gel column to obtain (2R)-2-[(1R, 7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-
yl]propanal in an amount of 254 mg (yield 60%).
'H-NMR (CDC13, S ppm)
9.56 (d, 1H J=3Hz), 3.90 to 4.00 (m, 1H), 2.20 to


2168728
- 85 -

2.50 (m, 1H), 1.00 to 2.00 (m, 12H), 0.92 (d, 3H,
J=6.3Hz), 0.91 (s, 3H), 0.05 (s, 9H)
Reference Example 3-3
Production of methyl(4R)-4-[(1R,7aR)-octahydro-4-
trimethylsilyioxy-7a-methyl-lH-inden-1-yl]-2-pentenoate
C H O CO,Me

wfttig
TMSO N TMSO H

A 3.27 g amount of (2R)-2-[(1R,7aR)-octahydro-
4-trimethylsilyloxy-7a-methyl-lH-inden-1-yl]propanal and
11.9 g of methyl(triphenylphosphoranilidene)acetate were
placed in a 200 ml eggplant-shaped flask, 70 ml of
toluene was added, and the solution was stirred at 80 C
over night. This was cooled to room temperature, then 100
ml of hexane was added, the precipitated deposit was
filtered out, and the filtrate was concentrated under
reduced pressure to obtain a crude product in an amount
of 4.1 g. This was purified by a silica gel column
(IR-60, 200 g, hexane/ethyl acetate = 40/1) to obtain
methyl(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inder.-1-yl]-2-pentenoate in an amount of 3.82 g
(yield 96%).
'H-NMR (CDC13, S ppm)
6.83 (dd, 1H, J=9.9 & 16Hz), 5.73 (d, 1H, 16Hz),
3.99 (brs, 1H), 3.72 (s, 3H), 2.10 to 2.30 (m, 2H), 1.00
to 2.00 (m, 15H), 1.00 (d, 3H, J=6.6Hz), 0.92 (s, 3H),
0.05 (s, 9H)
Reference Example 3-4
Production of (4R)-4-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-penten-l-ol


86 2168728
- -

CO2tite
OH
oIeAL_
-~-

TMSO TMSO H

A 3.66 g amount of inethyl(4R)-4-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-yl]
-2-pentenoate was placed in a 500 ml eggplant-shaped
flask, and 100 ml of hexane and 40 ml of toluene were
then added to dissolve it. The solution was cooled to
-95 C, then 12.2 ml of diisobutylaluminum hydride was
slowly added and the solution stirred at the same
temperature for 1 hour. Next, a further 24 ml of
diisobutylaluminum hydride was added, followed by
stirring for 2 hours. The consumption of the material was
confirmed by thin layer chromatography, then the excess
reducing agent was broken down by methanol and a
saturated aqueous solution of sodium sulfate and then 300
ml of ethyl acetate and 80 ml of a saturated aqueous
solution of ammonia chloride were added for separation.
Extraction was performed from the aqueous layer by 100 ml
of ethyl acetate, then the organic layer was washed with
saturated saline and was dried by anhydrous magnesium
sulfate. The desiccant was filtered out, then the
filtrate was concentrated under reduced pressure to
obtain a crude product in an amount of 3.61 g. This was
purified by a silica column (hexane/ethyl acetate = 19/1
to 4/1) to obtain (4R)-4-[(lR,
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-1-y
1]-2-penten-l-ol in an amount of 3.31 g(980).
`H-NMR (CDC13, 6 ppm)
5.5 to 5.6 (m, 2H), 4.07 (brd, 2H), 3.99 (brs, 1H),
1.0 to 2.2 (m, 14H), 1.00 (d, J=6.6Hz, 3H), 0.90 (s, 3H),
0.05 (s, 9H)
Reference Example 3-5


87 - 216872.8
-

Production of (4R)-4-[(1R,7aR)-octahydro-4-
t-rimethyl.^i1v?oxy-7a-methyl-lH-inden-l-yi]-2-penten-l-al
G HO
OH OX.

`'ASO
TMSO N
A 1.34 g amount o-l' (4R)-4-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-2-penten-l-ol
and 760 mg of N-methylmorpholine-N-oxide were placed in a
100 ml eggplant-shaped flask, then were dissolved in 30
ml of acetone. Thereafter, RuCl, (PPh3)3 was added, then
the solution was stirred at room temperature for 1.5
hours.
To the reaction solution were added 50 ml of hexane
and 1.5 g of Celite, the solution was stirred for 15
minutes, then was filtered and the solvent distilled off
under reduced pressure. The residue was purified by a
silica gel column (hexane/ethyl acetate = 50/1 to 30/1)
to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethyl-
silyloxy-7a-methyl-lH-inden-l-yl]-2-penten-l-al in an
amount of 0.854 g (yield 86%).
'H-NMR (CDC1,, s ppm)
9.51 (d, J=7.9Hz, 1H), 6.71 (dd, J=8.6 & 16Hz, 1H),
6.04 (dd, J=7.9 & 16Hz, 1H), 4.01 (brs, 1H), 2.3 to 2.4
(m, 1H), 1.1 to 2.2 (m, 12H), 1.11 (d, J=6.6Hz, 3H), 0.94
(s, 3H), 0.05 (s, 9H)
Reference Example 3-6
Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-
1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,
3-dioxolan-4-one


88 2168728
- -

HO
CHO O
~ ~..... 16u
O O
H
TMSO H
TMSO
A 15 ml amount of tetrahydrofuran and 910 l of
diisopropylamine were placed in a 100 ml eggplant-shaped
flask, then the solution was cooled to -78 C. Thereafter,
2.52 ml of n-BuLi was added, then the solution was
stirred at the same temperature for 15 minutes, was
stirred at 0 C for 30 minutes, then was again cooled to
-78 C and was stirred for 15 minutes. To this was added a
tetrahydrofuran solution (6 ml) of 627 mg of (5S,2S)-5-
methyl-2-t-butyl-1,3-dioxolan-4-one. The solution was
stirred at the same temperature for 15 minutes, then a
tetrahydrofuran solution (8 ml) of 854 mg of (4R)-4-[(1R,
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-
yl]-2-penten-l-al was added and the solution was reacted
at -78 C for 30 minutes.
To the reaction solution were added a saturated
aqueous solution of ammonium chloride and ether for
separation, then extraction was performed from the
aqueous layer by ethyl acetate. The organic layer was
washed with saturated saline, then was dried over
anhydrous magnesium sulfate and filtered, then the
solvent was distilled off under reduced pressure. The
residue was purified by a silica gel column (hexane/ethyl
acetate = 15/1 to 4/1) to obtain (5R,2S)-5-{(4R)-4-
[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-1-yl]-1-hydroxy-2-penten-1-yl}-5-methyl-
2-t-butyl-1,3-dioxolan-4-one in an amount of 1.24 g
(yield 96%).
'H-NMR (CDCl31 S ppm)
5.0 to 5.7 (m, 3H), 4.1 to 4.2 (m, 1H), 3.99 (brs,
1H), 1.0 to 2.2 (m, 17H), 0.88 to 1.0 (m, 15H), 0.04 (s,
9H)


- 89 - 2168723
Reference Example 3-7
Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-
1-methoxycarbonyloxy-2-penten-l-yl}-5-methyl-2-t-butyl-
1,3-dioxolan-4-one

HO Me02C0
O
0
\ \ \
~...."iou
....,. 'Bu
O p/ . O 0
=
TMSO H TMSO

A 1.24 g amount of (5R,2S)-5-{(4R)-4-[(1R,
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-y
l]-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,
3-dioxolan-4-one and 1.0 g of 4-dimethylaminopyridine
were dissolved in 15 ml of dichloromethane in a 50 ml
eggplant-shaped flask. The solution was stirred under
ice-cooling while slowly adding 315 l of methyl
chloroformate, then was stirred at the same temperature
for 15 minutes and at room temperature for 1.5 hours. A
100 ml amount of ethyl acetate and 30 ml of water were
added for separation, and extraction was performed from
the aqueous layer by 50 ml of ethyl acetate. The organic
layer was washed by a saturated aqueous solution of
potassium hydrogensulfate, a saturated aqueous solution
of sodium hydrogencarbonate, and saturated saline and was
dried over anhydrous magnesium sulfate. The desiccant was
filtered out, then the filtrate was concentrated under
reduced pressure to obtain a crude product in an amount
of 3.61 g. This was purified by a silica column
(hexane/ethyl acetate = 19/1 to 9/1) to obtain (5R,2S)-
5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-l-yl]-l-methoxycarbonyloxy-2-penten-
1-yl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount
of 1.388 g (98%).


- 90 - 216872,8
'H-NMR (CDC13, S ppm)
5.3 to 5.9 (m, 2H), 5.25 (s, 1H), 5.11 (d, J=7Hz,
1H), 3.99 (brs, 1H), 3.78 & 3.75 (s, 3H), 1.0 to 2.2 (m,
16H), 0.8 to 1.0 (m, 15H), 0.05 (s, 9H)
Example 3-1
Production of (5R,2S)-5-{(4R)-4-[(1R,
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-
1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one

i 0 MeOZCO O
O O~ ~...,,,'Bu
) ......' S u
0

H
TMSO H T+n50
Pd(OAc), was placed in a 100 ml eggplant-shaped
flask and dissolved in 50 ml of tetrahydrofuran. Further,
0.54 ml of n-Bu;P was added, the solution stirred at room
temperature for 15 niinutes, 681 mg of ammonium formate
was added, a tetrahydrofuran solution (10 ml) of 1.38 g
of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethyl-
silyloxy-7a-methyl-lH-inder.-1-yl]-1-methoxycarbonyloxy-
2-penten-1-yl}-5-methyl-2-t-butyl-1,3-ciioxolan-4-one was
added, and the solution was reacted at 40 C over night.
To the reaction solution were added 50 rril of hexane
and 50 ml of ether 50 ml, the solution was filtered, then
the solvent was distilled off under reduced pressure to
obtain 920.8 mg of any oily substance. This was subjected
to the following reaction divided into two times without
purification. A 398 mg amount of the oily substance was
dissolved in ethyl acetate, 10% Pd/C was placed in
Microspatel Cup, then this was stirred over night under a
flow of hydrogen. The solution was filtered, then
concentrated to obtain a crude product in an amount of
0.43 g. A 520 mg amount of the remaining oily substance
was treated in the same way to obtain 0.494 g. These were


91 - 2168728
-

combined and purified to obtain 0.867 mg of (5R,2S)-5-
{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-
dioxolan-4-one (yield 73%).
'H-NMR (CDClõ S ppm)
5.19 (s, 1H), 3.99 (brs, 1H), 1.41 (s, 3H), 1.0 to
2.0 (m, 19H), 0.96 (s, 9H), 0.88 (d-like, 3H), 0.87 (s,
3H), 0.05 (s, 9H)
Example 3-2
Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-
4-hydroxy-7a-methyl-lH-inden-1-yl] pentyl}-5-methyl-2-t-
butyl-1,3-dioxolan-4-one

) .....~~0 U
0 ~ ...=. F3U p o /

H H
TMSO rlo
A 913 mg arnount of (5R,2S)-5-{(4R)-4-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-1-yl]
pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one was placed
in a 100 ml eggplant-shaped flask and dissolved in 10 ml
of tetrahydrofuran. A tetrahydrofuran solution (1M, 2.5
ml) of tetrabutylammonium fluoride was added under ice
cooling, then the solution was stirred at the same
temperature for 15 minutes, was returned to room
temperature, then was stirred for 1 hour. Thereafter, 100
ml of ether and 20 ml of water for separation were added,
extraction was performed from the aqueous layer by ether,
then the organic layer was washed with saline and then
was dried over anhydrous magnesium sulfate. Further, this
was concentrated, then purified by a silica column
(hexane/ethyl acetate = 9/1 to 6/1) to obtain (5R,2S)-5-
{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-lH-
inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one
in an amount of 764 mg (99%).


- 92 - 21687-18
'H-NMR ( CDC1;, 5 ppm )
5.19 (s, 1H), 4.08 (brs, 1H), 1.44 (s, 3H), 1.0 to
2.1 (m, 20H), 0.96 (s, 9H), 0.93 (s, 3H), 0.90 (d, 3H,
J=6.6Hz)
Example 3-3
Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-1-yl] pentyl}-
5-methyl-2-t-butyl-1,3-dioxolan-4-one

O 1 O
>......IaU o >.....=a~
PA 104H
HO 0

A 384 mg amount of (5R,2S)-5-{(4R)-4-[(1R,7aR)-
octahydro-4-hydroxy-7a-methyl-lH-inden-1-yl] pentyl}-
5-methyl-2-t-butyl-1,3-dioxolan-4-one and 74 mg of RuH2
(PPh3)4 were placed in a 100 ml two-necked flask and
dissolved in 20 ml of toluene. Thereafter, 8 ml of
methylallyl carbonate was added, then the solution was
stirred at 100 C over night.
The reaction solution was allowed to cool, then the
precipitate was filtered out, the solvent was distilled
off under reduced pressure, and the residue was purified
by a silica gel column (hexane/ethyl acetate = 19/1 to
10/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-
4-oxo-7a-methyl-lH-inden-l-yl]pentyl}-5-methyl-2-t-
butyl-1,3-dioxolan-4-one in an amount of 370 mg (yield
96%).
'H-NMR (CDC13, S ppm)
5.19 (s, 1H), 1.44 (s, 3H), 1.0 to 2.0 (m, 19H),
0.96 (brs, 12H), 0.64 (s, 3H)
Example 3-4
Production of (5R,2S)-5-{(4R)-4-[(1R,7aR)(4E)-
octahydro-4-bromomethylene-7a-methyl-lH-inden-l-yl]
pentyl}-5-methyl-2-t-butyl-l,3-dioxolan-4-one


93 2168728

O O
O
....,,'Bu ....... Bu
O Q 0

O H H
Br
A 5.19 g amount of PPh,CH2Br=Br was placed in a 100
ml eggplant-shaped flask, was suspended in 30 ml of
tetrahydrofuran, and stirred at -78 C. Thereafter, 11.3
ml of TMS,NNa (1M-THF) was added, then the solution was
stirred at room temperature for 1 hour and, then, was
further added a tetrahydrofuran solution (10 ml) of 449
mg of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-l-yl]pentyl}-5-methyl-2-t-butyl-l,3-
dioxolan-4-one, then the solution was returned to room
temperature and stirred for 30 minutes. To the reaction
solution was added ether, the solution was stirred at
room temperature, then the precipitate was filtered out
and the solvent was distilled off under reduced pressure.
The result was purified by a silica gel column
(hexane/ethyl acetate = 100/0 to 100/1 to 4/1) to obtain
(5R, 2S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-l-yl]pentyl}-5-
methyl-2-t-butyl-l,3-dioxolan-4-one in an amount of 242
mg (yield 45%).
1H-NMR (CDCl31 S ppm)
5.65 (s, 1H), 5.19 (s, 1H), 2.80 to 3.00 (m, 1H),
1.44 (s, 3H), 1.0 to 2.1 (m, 18H), 0.96 (s, 9H), 0.93 (d,
3H J=6Hz), 0.56 (s, 3H)
Example 3-5
Production of 25,26,27-trinol-la-hydroxy-24-
{(5R,2S)-5-methyl-2-t-butyl-l,3-dioxolan-4-on-
5-yl}-vitamin D;-la, 3-bistrimethylsilylether


2168728
94

= O
....'Bu
O p0
....'Bu
O O H
s F,

TMSO OTMS

A 17 mg amount of Pd2 (dibenzylideneacetbne)3 =CHC13
and 51.7 mg of PPh3 were placed in a 100 ml two-neck
eggplant-shaped flask and dissolved in 9 ml of toluene
and 9 ml of diisopropylethylamine. Thereafter, 141.5 mg
of (5R,2S)-5-{(4R)-4-[(1R,7aR)(4E)-octahydro-
4-bromomethylene-7a-methyl-lH-inden-1-yl]pentyl}-5-
methyl-2-t-butyl-1,3-dioxolan-4-one dissolved in 2 ml of
toluene and 2 ml of diisopropylethylamine was added, then
the solution was heated and refluxed for 1.5 hours. The
solution was allowed to cool, then 20 ml of hexane was
added, the precipitate filtered out, and the filtrate was
washed with a saturated solution of potassium
hydrogensulfate and saturated saline, then was dried over
anhydrous magnesium sulfate, filtered and concentrated.
The obtained residue was purified by a silica gel column
(hexane/ethyl acetate = 100/1 to 30/1) to obtain
25,26,27-trinol-la-hydroxy-24-{(5R,2S)-5-methyl-
2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D3-la,3-
bistrimethylsilylether in an amount of 118.5 mg (yield
580).
'H-NMR (CDC13, S ppm)
6.27 (d, 1H, J=12Hz), 6.04 (d, 1H, J=12Hz), 5.19
(brs, 2H), 4.90 (brs, 1H), 4.30 to 4.40 (m, 1H), 4.15 to
4.25 (m, 1H), 1.0 to 2.9 (m, 23H), 1.43 (s, 3H), 0.96 (s,
9H), 0.93 (d, 3H, J=6Hz), 0.54 (s, 3H), 0.12 (s, 18H)
Example 3-6


216 728
- 95 -

Production of 25,26,27-trinol-la-hydroxy-24-
{(5R,2S)-5-methyl-2-t-butyl-l,3-dioxolan-4-on-5-yl}
vitamin D3

.....'eu
O O
...' u
O O O
O

H -=.- H
TMsoorMs ;.io oH
A 112 mg amount of 25,26,27-trinol-la-
hydroxy-24-{(5R, 2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-
on-5-yl}-vitamin D3-la,3-bistrimethylsilylether was
placed in a 50 ml eggplant-shaped flask and dissolved in
30 ml of methanol, then 50 mg of pyridinium-para-toluene
sulfonate was added and the solution stirred at room
temperature for 2 hours. The reaction solution was
filtered, the filtrate was concentrated, and the obtained
residue was purified by a silica gel column (hexane/ethyl
acetate = 1/1) to obtain 25,26,27-trinol-la-hydroxy-24-
{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-
vitamin D, in an amount of 40.2 mg (yield 460).
'H-NMR (CDC13, S ppm)
6.38 (d, 1H, J=11Hz), 6.01 (d, 1H, J=11Hz), 5.32 (s,
1H), 5.19 (s, 1H), 5.00 (s, 1H), 4.40 to 4.50 (m, 1H),
4.20 to 4.30 (m, 1H), 1.0 to 2.9 (m, 25H), 1.44 (s, 3H),
0.96 (s, 9H), 0.93 (d, 3H, J=6Hz), 0.54 (s, 3H)
Example 3-7
Production of la,25-dihydroxyvitamin D3-
26-carboxylic acid methylester


96 2168723
- -

0
~.....'3u OH
rO 0 COzMe

H HO " OH HO OH

A 40 mg amount of 25,26,27-trinol-la-hydroxy-24-
{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-
vitamin D3 was placed in a 50 ml eggplant-shaped flask
and dissolved in 5 ml of methanol, then 4N lithium
hydroxide was added and the solution was stirred at room
temperature for 1 hour. The reaction solution was
neutralized, tetrahydrofuran was added, the solution was
washed five times by saturated saline, then was dried
over anhydrous magnesium sulfate. The solution was
filtered and concentrated, the obtained residue was
dissolved in benzene/methanol (4/1), 0.8 ml of a hexane
solution (about 10%) of trimethylsilyldiazomethane was
added, and the solution was stirred at room temperature
for 1 hour. The excess reagent was broken down by formic
acid, then the solution was concentrated. The obtained
residue was purified by a silica gel column (hexane/ethyl
acetate = 2/3 to 1/3) to obtain la,25-dihydroxyvitamin D3
-26-carboxylic acid methylester in an amount of 24.4 mg
(yield 68%).
'H-NMR (CDC13, S ppm)
6.38 (d, 1H, J=11Hz), 6.01 (d, 1H, J=llHz), 5.33 (s,
1H), 5.00 (s, 1H), 4.35 to 4.45 (m, 1H), 4.20 to 4.30 (m,
1H), 3.79 (s, 3H), 1.0 to 3.1 (m, 26H), 1.40 (s, 3H),
0.90 (d, 3H, J=6Hz), 0.53 (s, 3H)
Example 4-1
Production of (2R)-2-[(1R,7aR)-octahydro-
4-trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propanol


- OH 97 - OH 2168728

1
OH 3)`BuOK TMSO
Compound (4-3) Compound (4 - 4)
A 10.78 g amount of the compound (4-3), (2R)-2-[(1R,
7aR)(4E)-octahydro-4-hydroxy-7a-methyl-l-H-inden-l-yl]-
propanol was dissolved in 80 ml of pyridine in a 100 ml
eggplant-shaped flask, then was stirred under ice
cooling. To this was added 6.57 ml of pivaloyl chloride,
then the solution was stirred over night.
Into the reaction solution was placed 150 ml of
water, then extraction was performed 3 times by 200 ml of
ether. The organic layer was washed 2 times each with a
saturated aqueous solution of potassium hydrogensulfate,
saturated aqueous solution of sodium bicarbonate, and
saturated saline, was dried over anhydrous magnesium
sulfate, the desiccant was filtered out, and the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 14.7 g. This was placed in
a 200 ml eggplant-shaped flask, 10.9 g of imidazole was
added, then 60 ml of dried dichloromethane was further
added and the solution stirred under ice-cooling. To this
was added 10.2 ml of trimethylsilyl chloride and the
solution was stirred at room temperature over night. The
reaction solution was poured into 300 ml of methyl
acetate and 100 ml of water for extraction. The organic
layer was washed two times by each of a saturated aqueous
solution of potassium hydrogensulfate, saturated aqueous
solution of sodium bicarbonate, and saturated saline,
then was dried over anhydrous magnesium sulfate. The
desiccant was filtered out and the solvent was distilled
off under reduced pressure to obtain a crude product in
an amount of 18.11 g. A 17.2 g amount of t-butoxy
potassium was placed in a 1-liter eggplant-shaped flask,
440 ml of ether was added, and the solution was stirred
under ice-cooling. A 2.1 ml amount of water was added,
then a solution comprised of 18.11 g of the above residue


21687:2$
- 98 -

dissolved in 120 ml of ether was added and the solution
was stirred at room temperature over night. A 200 ml
amount of water was poured into the reaction solution for
separation, then extraction was performed by 500 ml of
ether. The organic layer was washed 2 times with
saturated saline, then was dried over anhydrous magnesium
sulfate. The desiccant was filtered out and the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 15.2 g. This was purified
by a silica gel column (IR-60, 1 kg, hexane/ethyl acetate
= 19/1 to 6/1) to obtain the desired product (4-4),
(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-l-yl]-propanol in an amount of 12.6 g
(yield 87%).
'H-NMR (CDC13, S ppm)
3.95 (d, 1H, J=3Hz), 3.58 (m, 1H), 3.31 (m, 1H),
1.00 to 2.00 (m, 14H), 0.965 (d, 3H, J=8Hz), 0.85 (s,
3H), 0.03 (s, 9H)
Example 4-2
Production of (2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propanal
OH CHO
PCC

TMSO TMSO
Compound (4 - 4) Compound (4 - 5)

A 427 amount of Celite, 37 mg of sodium acetate, and
444 mg of pyridinium chlorochromate were placed in a 50
ml eggplant-shaped flask, then 10 ml of dichloromethane
was added and the solution stirred. Thereafter, a
dichloromethane solution (3 ml) of 426 mg of the compound
(4-4), that is, (2R)-2-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-propanol was
added and the solution stirred at room temperature for


99 - 2168723
-

3.5 hours.
The reaction solution was filtered by Celite, then
concentrated and the obtained residue was purified by a
silica gel column to obtain the desired product (4-5),
(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-1-yl]-propanol in an amount of 254 mg (yield
60%) .
'H-NMR (CDC13, S ppm)
9.56 (d, 1H, J=3Hz), 3.90 to 4.00 (m, 1H), 2.20 to
2.50 (m, 1H), 1.00 to 2.00 (m, 12H), 0.92 (d, 3H,
J=6.3Hz), 0.91 (s, 3H), 0.05 (s, 9H)
Example 4-3
Production of inethyl(4R)-4-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-heptanoate

CHO COZMe
1)wittig I
2)HZ-Pd/C
TMSO TMSO
Compound ( 4- 5) Compound ( 4- 6)

A 3.27 g amourit of the compound (4-5), (2R)-2-
[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-1-yl]-propanal and 11.9 g of
methyl(triphenylphosphoranilidene)acetate were placed in
a 200 ml eggplant-shaped flask, 70 ml of toluene was
added, and the solution was stirred at 80 C over night.
The solution was cooled to room temperature, then 100 ml
of hexane was added, the precipitated deposit was
filtered out, and the filtrate was concentrated under
reduced pressure to obtain a crude product in an amount
of 4.1 g. This was purified by a silica gel column
(IR-60, 200 g, hexane/ethyl acetate = 40/1 up) to obtain
an oily substance in an amount of 3.82 g. This was
dissolved in 200 ml of ethanol, then 0.5 g of 10% Pd/C
was added, and the solution was stirred under a flow of


- 100 - 2168728

hydrogen at room temperature over night. The Pd/C was
removed by Celite filtration, then the result was
concentrated to obtain 3.66 g of a crude product. This
was purified by a silica gel column (hexane/ethyl acetate
= 20/1) to obtain the desired product methyl(4-6),
(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-1-yl]-heptanoate in an amount of 2.66 g [yield
67%, from compound (4-5)].
'H-NMR (CDClõ S ppm)
4.10 (brs, 1H), 3.66 (s, 3H), 2.10 to 2.30 (m, 2H),
1.00 to 2.00 (m, 15H), 0.93 (s, 3H), 0.90 (d, 3H,
J=6.6Hz), 0.05 (s, 9H)
Example 4-4
Production of (4R)-4-[(1R, 7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-pentanal
C021v1a CHO

D(BAL
Q
TMSO TMSO
Compound ( 4- 6) Compound (4 - 7)
A 3.79 g amount of the compound (4-6),
methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-
methyl-lH-inden-1-yl]-heptanoate was taken in a 300 ml
eggplant-shaped flask, 100 ml of hexane was added, and
the solution was stirred and cooled to -95 C. Thereafter
12.3 ml of a hexane solution (0.93 mol/liter) of
diisobutylaluminum hydride was added and the solution
stirred for 1 hour. A 100 ml amount of methanol was used
to break down the excess reducing agent, then 30 ml of a
saturated aqueous solution of ammonia chloride and 50 ml
of ether were added and the solution was stirred at room
temperature for 1 hour. The insolubles were removed by
filtration by Celite, then the solution was separated and
the aqueous layer was extracted by ether. The organic


2168723
- 101 -

layer was washed two times by saturated saline in an
amount of 50 ml, then was dried over anhydrous magnesium
sulfate. The desiccant was filtered out, then the solvent
was distilled off under reduced pressure to obtain a
crude product in an amount of 4.07 g. This was purified
by a silica gel column (Merck gel: 300 g, hexane/ethyl
acetate = 50/1) to obtain the desired product (4-7),
(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-1-yl]-pentanal in an amount of 3.17 g (yield
92%).
'H-NMR (CDC13, S ppm)
9-.77 (t, 1H, J=2Hz), 3.99 (d-like, 1H), 2.20 to 2.50
(m, 2H), 0.90 to 2.00 (m, 15H), 0.89 (d, 3H, J=7.3Hz),
0.88 (s, 3H), 0.05 (s, 9H)
Example 4-5
Production of (7R)-2-acetoxymethyl-7-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-
octen-4-ol
HO OAc
__~CHO .

TMS ,,~_OAc
7iMSO TMSO
Compound (,I - 7) Compound (4- 8)
A 1.72 g amount of the compound (4-7),
(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-l-yl]-pentanal and 1.10 g of 2-(trimethylsilyl-
methyl)-2-propenyl acetate were taken in a 200 ml
eggplant-shaped flask, then 30 ml of dichloromethane was
added and the solution stirred at -78 C. To this was
added 0.86 ml of BF=EtzO, then the solution stirred at
-78 C for 1 hour. Further, 3 ml of triethylamine was
added to stop the reaction, then the solvent was
distilled off under reduced pressure. The obtained
residue was purified by a silica gel column (IR-60, 150


2.168728
- 102 -

g, hexane/ethyl acetate = 50/1 to 9/1) to obtain the
desired product (4-8), (7R)-2-acetoxymethyl-7-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-
octen-4-ol in an amount of 1.32 g (yield 57%).
'H-NMR (CDC13, S ppm)
5.16 (s, 1H), 5.06 (s, 2H), 4.56 (s, 2H), 3.99 (d-
like, 1H), 3.60 to 3.70 (m, 1H), 2.10 (s, 3H), 1.00 to
2.30 (m, 20H), 0.91 (d, 3H, J=2.3Hz), 0.88 (s, 3H), 0.05
(s, 9H)
Example 4-6
Production of (7R)-2-acetoxymethyl-4-(t-
butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-trimethyl-
silyloxy-7a-met;lyl-lH-inden-1-yl]-octene

OAc
HO OAc TBSO

TBSCI

Compound (4 - 9)
rniSO Compound (4 - TMSO
g)
A 2.18 g amount of the compound (4-8),
(7R)-2-acetoxymethyl-7-[(1R,7aR)-octahydro-4-trimethyl-
silyloxy-7a-methyl-lH-inden-1-yl]-octen-4-ol and 1.06 g
of imidazole were placed in a 100 ml eggplant-shaped
flask and dissolved in 30 ml of dichloromethane, then the
solution stirred under ice-cooling. Thereafter, 1.16 g of
t-butyldimethylsilyl chloride was added, then the
solution was returned to room temperature and stirred
over night. To the reaction solution were added 50 ml of
ether and 20 ml of water for separation, then extraction
was performed from the aqueous layer by ether. The
organic layer was washed by saturated saline and was
dried over anhydrous magnesium sulfate. After filtration
by Celite, the solvent was distilled off under reduced
pressure. The obtained residue was purified by a silica


2168723
- 103 -

gel column (IR-60, 80 g, hexane/ethyl acetate = 3/1, 1/1)
to obtain the desired product (4-9), (7R)-2-
acetoxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-
octene in an amount of 2.59 g (yield 93%).
'H-NMR (CDCl;1 S ppm)
5.09 (s, 1H), 4.96 (s, 2H), 4.54 (s, 2H), 3.98 (brs,
1H), 3.60 to 3.80 (m, 1H), 2.09 (s, 3H), 1.00 to 2.30 (m,
19H), 0.80 to 0.90 (m, 15H), 0.00 to 0.10 (m, 15H)
Example 4-7
Production of (7R)-2-hydroxymethyl-4-(t-
butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-octene

TBSO IOAc TBSO i OH
=
p}{'
1 j

TMSO
Compound (4 9) TMSO Compound ( 4- 10)
A 2.59 g amount of the compound (4-9),
(7R)-2-acetoxymethyl-4-(t-butyldimethylsilyloxy)-7-
[(1R,7aR)-octahyde-4-trimethylsilyloxy-7a-methyl-lH-
inden-1-yl]-octene was placed in a 100 ml eggplant-shaped
flask and dissolved in 20 ml of tetrahydrofuran and 5 ml
of methanol, then the solution was stirred under
ice-cooling. Thereafter, 2 ml of a 4N aqueous solution of
lithium hydroxide was added, then the solution was
stirred under ice cooling for 1 hour. The reaction
solution was placed in 100 ml of ether and 20 ml of water
and was extracted from the aqueous layer by ether. The
organic layer was washed by a saturated aqueous solution
of potassium hydrogensulfate, a saturated aqueous
solution of sodium bicarbonate, and saturated saline and
was dried over anhydrous magnesium sulfate. After


104 - 2168728
-

filtration by Celite, the solvent was distilled off under
reduced pressure to obtain a crude product in an amount
of 2.39. This was purified by a silica gel column (IR-60,
80 g, hexane/ethyl acetate = 19/1, 9/1) to obtain the
desired product (4-10), (7R)-2-hydroxymethyl-4-
(t-butyldimethylsilyloxy)-7-[(1R, 7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-octene in an
amount of 2.15 g (yield 90%).
'H-NMR (CDC13, S ppm)
5.10 (s, 1H), 4.89 (s, 2H), 4.12 (d-like, 2H), 3.99
(brs, 1H), 3.70 to 3.80 (m, 1H), 0.90 to 2.50 (m, 20H),
0.80 to 0.95 (m, 15H), 0.00 to 0.10 (m, 15H)
Example 4-8
Production of (7R,2R)-l, 2-epoxy-2-hydroxymethyl-
4-(t-butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-octane

TBSO OH TBSO OH

sharpless
TMSO epoxidation TMSO
Compound (4- 10) Compound (4 - 1 1)
A 20 ml amount of dichloromethane was placed in a
200 ml eggplant-shaped flask, 1.36 ml of titanium
tetraisopropoxide was added, then the solution was cooled
to -20 C and stirred. Thereafter, 1.05 g of D(-)-diethyl
tartrate dissolved in 5 ml of dichloromethane and the
solution stirred at -25 C for 20 minutes was placed and
then, 2.14 g of the compound (4-10),
(7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R,
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-
yl)-octene, dissolved in 10 ml of dichloromethane, was
added, then the solution was stirred for 30 minutes.
Further, 4.3 ml of t-butyldiperoxide was added and the


216~~~8
- 105 -

solution was stirred at the same temperature for 30
minutes. The reaction solution was poured into 20 ml of a
10% aqueous solution of tartaric acid, the solution was
stirred at that temperature for 30 minutes and at room
temperature for 1 hour, then separation was performed and
extraction performed from the aqueous layer by
dichloromethane. The organic layer was washed by a 10%
aqueous solution of tartaric acid and saturated saline
and was dried over anhydrous magnesium sulfate. After
filtration by Celite, the solvent was distilled off under
reduced pressure, the obtained residue was dissolved in
50 ml of ether, 18 ml of 1N sodium hydroxide was added,
then the solution was stirred under ice cooling for 1
hour. After separation, extraction was performed from the
aqueous layer by ether. The organic layer was washed with
saturated saline, then was dried over anhydrous magnesium
sulfate, then filtered by Celite. The filtrate was
concentrated under reduced pressure to obtain 2.40 g of a
crude product. This was purified by a silica gel column
(IR-60, 200 g, hexane/ethyl acetate = 15/1 to 4/1) to
obtain the desired product (4-11), (7R,
2R)-1,2-epoxy-2-hydroxymethyl-4-
(t-butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-octane in an
amount of 2.08 g (yield 94%).
1H-NMR (CDC13, S ppm)
3.99 (d-like, 1H), 3.50 to 3.80 (m, 3H), 2.50 to
2.90 (m, 2H), 1.00 to 2.00 (m, 20H), 0.80 to 1.00 (m,
15H), 0.00 to 0.10 (m, 15H)
Example 4-9
Production of (7R,2R)-2-hydroxy-2-hydroxymethyl-4-
(t-butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-
trimethylsilyloxy-7a-methyl-lH-inden-1-yl]-octane


106 2168728
- -

OH HO OH
TBSO O ~ON
%

LA H

TN1S0 TMSO
Compound ( 4- 11) Compound (4- 12)
A 2.08 g amount of the compound (4-11), (7R,2R)-1,
2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-
[(1,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-lH-
inden-l-yl]-octane was placed in a 200 ml eggplant-shaped
flask, 50 ml of ether was added, and the solution was
stirred under ice-cooling. Thereafter, 380 mg of lithium
aluminum hydride was added, then the solution was stirred
under ice cooling for 15 minutes, at room temperature for
15 minutes, then was heated and refluxed for 2 hours. The
solution was allowed to cool, then the excess reducing
agent was broken down by a saturated aqueous solution of
mirabilite, 100 ml of ethyl acetate was added, and the
solution was stirred for 30 minutes. This solution was
dried over anhydrous magnesium sulfate and filtered by
cellite, then the solvent was distilled off under reduced
pressure to obtain a crude product in an amount of 1.98
g. This was purified by a silica gel column (IR-60, 200
g, hexane/ethyl acetate = 9/1 to 1/1) to obtain the
desired product (4-12), (7R,2R)-2-hydroxy-2-
hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R,7aR)-
octahydro-4-trimethylsilyloxy-7a-methyl-lH-inden-l-yl]-
octane in an amount of 0.84 g (yield 54%).
'H-NMR (CDC1,, S ppm)
3.99 (d-like, 1H), 3.75 to 3.85 (m, 1H), 3.62 (d, 1H
J=11.2Hz), 3.44 (d, 1H, J=12.4Hz), 0.90 to 2.10 (m, 20H),
1.16 (s, 3H), 0.80 to 0.90 (s, 6H), 0.05 (s,, 9H)
Example 4-10


107 - 2168728
-

Production of (3R,5R)-5-{(3R)-3-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-hydroxy-2(3H)-furanon and (3R,5S)-5-{(3R)-3-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
3-hydroxy-2(3H)-furanon

HO OH O O O O
..OH .,OF { .OFi
Pt -o 2 ~

7MS0 O
Compound ( 4- 12) Compound ( 4- 13) Compound ( 4- 13' )
A 1.06 g amount of platinum oxide was placed in a
500 ml three-necked flask and suspended in 100 ml of
water, and the solution was stirred over night in a
hydrogen atmosphere. The atmosphere was returned to
nitrogen, then 1.03 g of the compound (4-12), (7R,2R)-2-
hydroxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-
[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-
1H-inden-l-yl]-octane and 30 mg of sodium laurate
dissolved in 100 ml of acetone was added, and the
solution was heated and stirred under an oxygen
atmosphere for 3 days at 50 C. After being allowed to
cool, the reaction solution was filtered by Celite, the
filtrate was concentrated under reduced pressure,
extraction was performed from the residue by ethyl
acetate, and the organic layer was washed with saturated
saline, then was dried over anhydrous magnesium sulfate.
The solution was filtered by Celite, then the solvent was
distilled off under reduced pressure to obtain a crude
product in an amount of 1.05 g. This was purified by a
silica gel column (IR-60, 200 g, hexane/ethyl acetate =
3/1 to 1/3) to obtain the desired product (4-13),
(3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-methyl-
1H-inden-l-yl]-butyl}-3-methyl-3-hydroxy-2(3H)-furanon in
an amount of 369 mg (yield 44%) and (4-13'), (3R,5S)-5-


2168728
- 108 -

{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-inder.-l-
yl]-butyl}-3-methyi-3-hydroxy-2(3H)-furanon in an amount
of 350 mg (yield 41%).
Compound (4-13) 'H-NMR (CDC13, S ppm)
4.50 to 4.60 (m, 1H), 1.20 to 2.60 (m, 20H), 1.52
(s, 3H), 0.97 (d, 3H, J=5.6Hz), 0.65 (s, 3H)
Compound (4-13') `H-NMR (CDC131 S ppm)
4.20 to 4.40 (m, 1H), 1.20 to 2.60 (m, 20H), 1.49
(s, 3H), 0.98 (d, 3H, J=5.9Hz), 0.65 (s, 3H)
Example 4-11
Production of (3R,5R)-5-{(3R)-3-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-
.3-trimethylsilyloxy-2(3H)-furanon

O O
O O,y O OTMS
I iMSCI

I I ~
O O
Compound ( =4 - 13 ) Compound (4 1 '-! )

A 383 mg amount of the compound (4-13), (3R,5R)-5-
{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-inden-l-
yl]-butyl}-3-methyl-3-hydroxy-2(3H)-furanon and 250 mg of
imidazole were placed in a 50 ml eggplant-shaped flask.
Next, 10 ml of dried dichloromethane was added and the
solution stirred. Under ice cooling, 0.23 ml of
trimethylsilyl chloride was added, the solution was
stirred at the same temperature for 60 minutes, then the
reaction solution was poured into 50 ml of ether and 30
ml of water for extraction. The organic layer was washed
2 times with saturated saline, then was dried over
anhydrous magnesium sulfate. The desiccant was filtered
out and the solver.t was distilled off under reduced
pressure to obtain a crude product in an amount of 0.64


- 109 - 2168728

g. This was purified by a silica gel column (IR-60, 80 g
hexane/ethyl acetate = 9/1, 4/1) to obtain the desired
product (4-14), (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
oxo-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethyl-
silyloxy-2(3H)-furanon in an amount of 423 mg (yield
90a) .
O O

TMS
O

y OH TMS CI e~Compound
lo

-13' )O H (4-14'
O H ;4

A 301 mg aniount of the compound (4-13'), (3R,
5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-methyl-lH-
inden-1-yl]-butyl}-3-methyl-3-hydroxy-2(3H)-furanon was
treated in the same way to obtain the desired product
(4-14'), (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethylsilyloxy
-2(3H)-furanon in an amount of 358 mg (yield 75%).
Compound (4-14) 'H-NMR (CD3Cl, S ppm)
4.50 to 4.60 (m, 1H), 1.20 to 2.50 (m, 21H), 1.48
(s, 3H), 0.97 (d, 3H, J=5.9Hz), 0.64 (s, 3H), 0.16 (s,
9H)
Compound (4-14') 'H-NMR (CD3C1, S ppm)
4.20 to 4.35 (m, 1H), 1.10 to 2.50 (m, 21H), 1.48
(s, 3H), 0.98 (d, 3H, J=5.9Hz), 0.64 (s, 3H), 0.19 (s,
9H)
Example 4-12
Production of (3R,5R)-5-{(3R)-3-[(1R,7aR)-
octahydro-4-bromomethylene-7a-methyl-lH-inden-1-yl]-
butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon


2163728
- 110 -
0 0

,.OTM S ==,~OTMS
Ph3F~(2Br.Br '"==
NaN(TMS)2
O H N
Br Compound (4 -- 1 5 )
Compound (4- 14)

A 1.03 g aniount of bromomethylenetriphenyl-
phosphonium bromide was taken in a 50 ml eggplant-shaped
flask, 7 ml of dried tetrahydrofuran was added, and the
solution was stirred and cooled by a-65 C bath. Next,
2.35 ml of a 1M solution of sodium bistrimethylsilylamide
in tetrahydrofuran was added dropwise and the solution
stirred at the same temperature for 10 minutes and at
room temperature for 30 minutes. After cooling again to
-65 C, 2 ml of a tetrahydrofuran solution of 186 mg of
the compound (4-14), (3R,5R)-5-{(3R)-3-[(1R,7aR)-
octahydro-4-oxo-7a-methyl-lH-inden-l-yl)-butyl}-3-methyl-
3-trimethylsilyloxy-2(3H)-furanon was dropwise added
thereto. The cooling bath was removed, the solution was
stirred at room temperature for 30 minutes, then hexane
was added to the reaction solution and the solution
stirred. The precipitate was filtered out, the solvent
was distilled off under reduced pressure, and the
resultant residue was purified by a silica gel column
(IR-60, 200 g, hexane/ethyl acetate = 40/1 to 19/1) to
obtain the desired product (4-15),
(3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-bromomethylene-
7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethylsilyl
-oxy-2(3H)-furanon in an amount of 78 mg (yield 35%).


2168728
- 111 -
O
O O
t q=TMS .OiMS

Ph3Fu-i2 Br.Br
NaN( T MS)2

O H 5 Compound (e- 1 a' ) Br H Compound
(- 7 5' )
A 169 mg amount of the compound (4-14'),
(3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-oxo-7a-methyl-
1H-inden-1-yl)-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-
furanon was treated in the same way to obtain the desired
product (4-15'), (3R,5S)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-trimethylsilyloxy-2(3H)-furanon in an amount of 103 mg
(yield 51%).
Compound (4-15) 'H-NMR (CD1Cl, S ppm)
5.65 (s, 1H), 4.40 to 4.50 (m, 1H), 2.80 to 2.90 (m,
1H), 1.20 to 2.40 (m, 21H), 1.48 (s, 3H), 0.94 (d, 3H
J=6.4Hz), 0.57 (s, 3H), 0.16 (s, 9H)
Compound (4-15') 'H-NMR (CD3Cl, S ppm)
5.65 (s, 1H), 4.20 to 4.40 (m, 1H), 2.80 to 2.90 (m,
1H), 1.00 to 2.40 (m, 21H), 1.48 (s, 3H), 0.95 (d, 3H
J=6.3Hz), 0.57 (s, 3H), 0.19 (s, 9H)
Reference Example 4-1
Production of (23R,25R)-22-homo-la-hydroxy-25-
trimethylsilyloxy-vitamin D3-26,23-lactone-la,3-bis-t-
butyldimethylsilylether

/O
O 0
..OTMS
.OTMS

rHiompound
0
Br
TBSO'~ O T BS Compound (ti -17)
Compound (4- 1 0)
TBSO OTBS


2168728
- 112 -

A 51.3 mg amount of triphenylphosphine was taken in
a dried eggplant-shaped flask, then deaerated.
Thereafter, 16.9 mg of tris(dibenzylideneacetone)
dipalladium chloroform was added, followed by further
deaeration, then 6.0 ml of a mixed solvent of distilled
toluene/diisopropylethylamine = 1/1 was added under a
nitrogen atmosphere and the solution stirred at room
temperature for 20 minutes. Next, 77 mg of the compound
(4-15), (3R,5R)-5-{(3R)-3-[(1R,7aR)-octahydro-4-
bromomethylene-7a-methyl-lH-inden-1-yl]-butyl}-3-methyl-3
-trimethylsilyloxy-2(3H)-furanon and 72 mg of the
compound (4-16), (3S,5R)-bis(t-butyldimethylsilyloxy)-
1-octen-7-yne were dissolved in 2 ml of a mixed solvent
of distilled toluene/diisopropylethylamine = 1/1 and
added dropwise into the above reaction solution. The
solution was heated and refluxed for 1.5 hours, then was
returned to room temperature, then the reaction solution
was poured into 50 ml of ethyl acetate and 10 ml of a
saturated aqueous solution of potassium hydrogensulfate
for extraction. The organic layer was washed with a
saturated aqueous solution of sodium hydrogencarbonate
and saturated saline, then was dried over anhydrous
magnesium sulfate. The desiccant was filtered out and the
solvent was distilled off under reduced pressure to
obtain a crude product in an amount of 200 mg. This was
purified by a silica gel column (Merck gel, 200 g,
hexane/ethyl acetate =100/1 to 20/1) to obtain the
desired product (4-17), (23R,25R)-22-homo-la-hydroxy-
25-trimethylsilyloxy-vitamin D3-26,23-lactone-la,3-bis-
t-butyldimethylsilylether in an amount of 86.6 mg (yield
70%).


113 2168728
- -
/0
/0 ~OTMS
OTMS

H ~
Compound
gr Compound
T5S0'~ OTBS (~- ! 1
Compound (4- ! 6)
T BSO OTBS

A 65 mg amount of the coinpound (4-15'), (3R,5S)-
5-{(3R)-3-((1R,7aR)-octahydro-4-bromomethylene-7a-
methyl-lH-inden-1-yl]-butyl}-3-methyl-3-trimethylsilyloxy
-2(3H)-furanon was treated in the same way to obtain the
desired product (4-17'), (23R,25R)-22-homo-la-hydroxy-25-
trimethylsilyloxy-vitamin D3-26,23-lactone-la,3-bis-t-
butyldimethylsilylether in an amount of 78 mg (yield
75%).
Compound (4-17) 'H-NMR (CDC13, S ppm)
6.22 (d, J=11.8Hz), 6.00 (d, J=11.2Hz); 5.18 (brs,
1H), 4.86 (brs, 1H), 4.40 to 4.50 (m, 1H), 4.30 to 4.40
(m, 1H), 4.10 to 4.20 (m, 1H), 1.10 to 3.00 (m, 23H),
1.48 (s, 3H), 0.80 to 1.00 (m, 21H), 0.53 (s, 3H), 0.16
(s, 12H), 0.06 (s, 9H)
Compound (4-17') 'H-NMR (CDC13, S ppm)
6.23 (d-like, 1H), 6.00 (d-like, 1H), 5.18 (brs,
1H), 4.87 (brs, 1H), 4.40 to 4.50 (m, 1H), 4.15 to 4.40
(m, 2H), 1.00 to 2.90 (m, 23H), 1.48 (s, 3H), 0.60 to
0.80 (m, 21H), 0.53 (s, 3H), 0.19 (s, 12H), 0.11 (s, 9H)
Reference Example 4-2
Production of (23R,25R)-22-homo-la, 25-dihydroxy-
vitamin D3-26,23-lactone


114 2168728
- -

O
OTHS 0 0
~ 0 1-1
=.~V~ .
i~ ~ i~ =.
~-: Bud NF
H
Compound( 4- 18 )
: l`~ Compound ( 4 - 17)
rsso orns &
H O" 0 H

A 86 mg amount of the compound (4-17), (23R,25R)-
22-homo-la-hydroxy-25-trimethylsilyloxy-vitamin D3-26,
23-lactone-la,3-bis-t-butyldimethylsilylether, was taken
in a 25 ml eggplant-shaped flask, then 10 ml of
tetrahydrofuran was added and the solution stirred. Under
ice cooling, 2.0 ml of a 1M solution of
tetrabutylammonium fluoride in tetrahydrofuran was added
and the solution stirred at room temperature over night.
Into the reaction solution was placed 5 ml of a saturated
aqueous solution of potassium hydrogensulfate, then the
solution was stirred for 30 minutes at room temperature.
The reaction solution was extracted by ethyl acetate, the
organic layer was washed with a saturated aqueous
solution of sodium bicarbonate and saturated saline, then
was dried over anhydrous magnesium sulfate. The desiccant
was filtered out, the solvent was distilled off under
reduced pressure, and the obtained crude product was
purified by a silica gel column (IR-60, 80 g,
hexane/ethyl acetate = 2/3 to 1/3) to obtain the desired
product (4-18), (23R, 25R)-22-homo-la,25-dihydroxy-
vitamin D;-26,23-lactone in an amount of 23 mg (yield
48%).


115 2168723
- -

f O O
O- p
hr=
i OT~iS ~p~{
BJ4~
Compound Compound
~;-1 7` (4-18r i
TBSO OTBS HO OH
A 77 mg amount of the compound (4-17'), (23S,25R)-
22-homo-la-hydroxy-25-trimethylsilyloxy-vitamin D3-26,23-
lactone-la,3-bis-t-butyldimethylsilylether was treated in
the same way to obtain the desired product (4-18'),
(23S,25R)-22-homo-1a,25-dihydroxy-vitamin D3-26, 23-
lactone in an amount of 11 mg (yield 24%).
Compound (4-18) 'H-NMR (CDC13, 8 ppm)
6.38 (d, 1H, J=11.2Hz), 6.02 (d, 1H, J=11.2Hz), 5.33
(s, 1H), 5.00 (s, iH), 4.50 to 4.65 (m, 1H), 4.40 to 4.20
(m, 2H), 1.00 to 3.00 (m, 23H), 1.49 (s, 3H), 0.95 (d, 3H
J=6.3Hz), 0.55 (s, 3H)
Compound (4-18') 'H-NMR (CDC1;, 8 ppm)
6.38 (d, 1H, J=11.2Hz), 6.01 (d, 1H, J=11.2Hz), 5.33
(s, 1H), 5.00 (s, 1H), 4.40 to 4.50 (m, 1H), 4.30 to 4.40
(m, 1H), 4.10 to 4.20 (m, iH), 1.00 to 3.00 (m, 23H),
1.51 (s, 3H), 0.94 (d, 3H, J=6.3Hz), 0.55 (s, 3H)
Example 5-1
Measurement of Action of Suppression of Formation of
Osteoclasts Induced by 1a,25(OH)zD,
Marrow cells were separated from the femur and tibia
of mice (C57/Black 6, 5 weeks old, male) and incubated
for 7 days in a-MEM containing 10% fetal calf serum in
the presence of 1a,25(OH)2D3 (10-"M) with the addition of
certain concentrations of compounds. The cells were dyed
by tartaric acid resistant acid phosphase (TRAP), and the
nuclei were dyed by Methyl Green. Next, the cells with at


116 - 2168728
-

least 3 nuclei dyed by TRAP (osteoclasts) were counted
under a microscope. The results are shown in the
following Table 5-1.
Table 5-1

Compound TRAP-positive
MNC cell/well
la, 2 5( OH ) ZD3 (VD3) 10-gM 61 . 3 16 . 0
VD3(10-8M + Example 2-15 109M 47.7 9.2
compound 10-$M 34.5 9.9
VD,( 10-RM)+ Example 2-16 10-9M 23.2 10.4
compound 10-8M 24.0 6.9
10-7M 17.5 6.6
Example 5-2
Affinity of compound to la,25-dihydroxyvitamin D3
receptor (VDR) in chicken intestinal membrane cells
The la,25-dihydroxyvitamin D. receptor in chicken
intestinal membrane cells was isolated and evaluated in
receptor affinity by a known method (Steroids, 37, 33-43
(1981). That is, 20 pg of [26,27-methyl- 3 H]1a,25-
dihydroxyvitamin D3 (158 Ci/mmol, 16,800 dpm) and the
test compound dissolved in 50 l of ethanol were added to
12 x 75 mm polypropylene tubes. To these were added 0.2
mg amounts of la,25-dihydroxyvitamin D3 receptor protein
in chicken intestinal membrane cells and 1 mg of gelatin
dissolved in 1 ml of a phosphate buffer (pH 7.4), then
the solutions were reacted at 25 C for one hour. After
the reaction, 1 ml portions of a 40% solution of
polyethylene glycol 6,000 were added to the tubes which
were then shaken vigorously, then were centrifugally
separated at 4 C and 2,260 x g for 60 minutes. The tubes
of the sediment portions were cut off by a cutter knife
and placed in liquid sintillation vials, a dioxane
sintillator was added in amounts of 10 ml, and the
radioactivity was measured by a liquid sintillation
counter. The results are shown in the later given Table
5-2.
Example 5-3


117 - 2168728
-

Affinity of compounds to vitamin D bonded proteins
in fetal calf serum
The affinity of 25-hydroxyvitamin D3 and a test
compound to the vitamin D bonded proteins in fetal calf
serum was determined by the method of J. Steroid Biochem.
Molec. Biol. 41, 109-112 (1992). That is, 200 pg amounts
of [26,27-methyl-3 H]25-hydroxyvitamin D3 (28 Ci/mmol,
31,000 dpm) dissolved in a 0.01% Triton X-100 solution
and the test compound dissolved in 10 l of ethanol were
added to 12 x 105 mm gas tubes. To these were added 0.2
ml amounts of a solution of fetal calf serum diluted
2500-fold by a 0.9% sodium chloride-containing phosphate
buffer (pH 7.0), the solutions were reacted at 4 C for 24
hours, then 0.5 ml of 0.5% charcoal, 0.075% dextrin and
0.5% bovine serum albumin solution were added, the
solutions reacted at 4 C for 15 minutes, then
centrifugally separated at 2,260 x g for 10 minutes. 0.5
ml amounts of the supernatent were taken in liquid
sintillation vials and the radioactivity of the
[26,27-methyl-3 H]25-hydroxyvitamin D3 bonded to the
vitamin D bonded protein was measured by a liquid
sintillation counter.
The results are shown in the following Table 5-2.
Table 5-2

Compound la,25-(OH)2 Vitamin
D3 receptor D-bonded
(molar protein (molar
ratio) ratio)

la, 2 5- ( OH ),D3 1 1
Example 1-11 compound (23) 104 1.2
Example 2-14 compound 207 41.8
Example 2-15 compound 9.8 10.7
Example 2-16 compound 13.8 39.4
Example 3-17 compound 3.6 >500
Example 5-4
Synthesis of Collagen and Noncollagen Protein by
osteoblasts
A murine osteoblast cell strain (MCJT cells) was


118 - 2168728
-

dispersed in an a-MEM medium containing 10% fetal calf
serum (FCS) (1 x 104 cells/ml medium). This was sown in 2
ml amounts in 35 mm incubation dishes, then incubated at
37 C under 5% COZ. After 4 days, after confluent was
reached, the incubation solution was replaced by the same
solution, then an ethanol solution of the test compound
( 1 x 10"4 M and 1 x 10"SM) was added in 2 l amounts. The
control group had only ethanol added in an amount of 2
l. The specimens were incubated at 37 C under 5% C02.
After 45 hours incubation, the medium was replaced by an
a-MEM medium containing 0.1% bovine serum albumin (BSA),
0.1 mM ascorbic acid, and 0.5 mM fumaric acid-p-
aminopropionitrile, the same amount of the ethanol
solution of the test compound or ethanol as the previous
time was added again, then incubation performed for 30
minutes, then 4 Ci of [;H) proline were added to petri
dishes and were allowed to be taken up by the osteoblasts
for 3 hours. The amounts of the synthesized collagen and
noncollagen protein were measured by the method of
Perterkofsky et al. (Biochemistry, 10, 988-994 (1971)).
The results are shown in Fig. 1 and Fig. 2.
INDUSTRIAL APPLICABILITY
As explained above, the vitamin D3 derivative
according to the present invention is useful as an agent
for the promotion of bone formation.

Representative Drawing