JP2988253B2 - Novel fluorinated vitamin D3 analog - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a low calcemic action, on the usefulness of novel vitamin D ₃ analogs as anticancer drugs because of high differentiation inducing effect of tumor cells.

[0002]

BACKGROUND OF THE INVENTION Vitamin D ₃ is a metabolite in vivo,
1α, known as active-form vitamin D _3, 25-dihydroxyvitamin D ₃ has a calcium absorption promoting action from the intestine, is known to be effective for the treatment of such bone lesions. Recently, this active form of vitamin D ₃ and its analogs have a differentiation-inducing effect of returning cancerous cells to normal cells (Hirofumi Tanaka et al .: Biochemistry 55, 1323,
1983), and in fact, some of them have the effect of inhibiting the progression of cancer (KW Colton
n) et al., Lancet , Jan. 28 , 188, 1989.
Years) are allowed. However, active vitamin D ₃ compounds have strong effect on calcium metabolism, because it causes hypercalcemia, can not be used at high doses. Thus, such compounds are not satisfactory for use as a drug, for example, in therapies that require a relatively high dose of the drug, such as the treatment of leukemia.

The general formula:

Embedded image (Wherein, R represents a hydrogen atom or a hydroxyl group) A novel vitamin D derivative having a vitamin D _3- like activity represented by the following formula is described in JP-A-3-68528.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have conducted research for the purpose of creating a novel vitamin D ₃ analog having an excellent effect on calcium metabolism and cell differentiation induction. By introducing a fluorine atom into the vitamin D ₃ derivative, the cell differentiation inducing action is enhanced and side effects on calcium metabolism
(Blood calcium increasing effect) was found to be low, and the present invention was completed. It is another object of the present invention to provide a method for producing the vitamin D ₃ analog. These objects and the advantages provided by the present invention will be apparent to those skilled in the art from the following description.

[0005]

The novel vitamin D ₃ analog provided by the present invention has the general formula [I]:

Embedded image Wherein R ³ , R ⁴ and R ⁵ are each a hydrogen atom or a protecting group for a hydroxyl group, and 23, 24 and 24-
One of the methylene groups of homo-position is substituted with -OR ⁶ (R ⁶ is a hydrogen atom or a protecting group for a hydroxyl group)]
Is a fluorine-containing vitamin D ₃ analog represented by
General formula [IA]:

Embedded image General formula [IB]:

Embedded image And the general formula [IC]:

Embedded image Wherein R ¹ is OR ⁶ and R ² are hydrogen atoms, or R ¹ is a hydrogen atom and R ² is OR ⁶ ; R ³ , R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a hydroxyl group. Which is a group]. Here, as the protecting group for the hydroxyl group, there may be mentioned acetal-based protecting groups such as methoxymethyl, ethoxyethyl, methoxyethoxymethyl, and tetrahydropyranyl; And acyl groups such as acetyl.

Specific examples of the compound represented by the general formula [IA] include: 1) 26,26,26,27,27,27-hexafluoro-
24-Homo-1α, 23,25-trihydroxyvitamin D ₃ (compound A) 2) 1α, 3-bis (trimethylsilyl) ether of compound A 3) 1α, 3-bis (t-butyldimethylsilyl) of compound A Ether 4) 1α, 3-bis (t-butyldiphenylsilyl) ether of compound A 5) 23,25-diacetyl ester of compound A 6) 23-acetyl ester of compound A 7) 1α, 3,23- of compound A Examples include, but are not limited to, tris (t-butyldimethylsilyl) ether.

Specific examples of the compound represented by the general formula [IB] include: 1) 26,26,26,27,27,27-hexafluoro-
24-homo-1α, 24,25-trihydroxyvitamin D ₃ (compound B) 2) 1α, 3,24-tris (trimethylsilyl) ether of compound B 3) 1α, 3,24-tris (t- Butyldimethylsilyl) ether 4) 1α, 3,24-tris (t-butyldiphenylsilyl) ether of compound B 5) 25-methoxymethyl ether of compound B 6) 1α, 3-bis (t-butyldimethyl) of compound B (Silyl) ether, but is not limited thereto.

Specific examples of the compound represented by the general formula [IC] include: 1) 26,26,26,27,27,27-hexafluoro-
24-homo-1α, 24-homo, 25-trihydroxyvitamin D ₃ (compound C) 2) 1α, 3-bis (trimethylsilyl) ether of compound C 3) 24-homo, 25-diacetyl ester of compound C 4) Examples include, but are not limited to, 24-homo-acetyl esters of compound C.

[0009]

The compound [I] of the present invention can be produced by various methods. One example of the best method is shown below. That is, the following general formula [IIA]:

Embedded image General formula [IIB]:

Embedded image Or the general formula [IIC]:

Embedded image Wherein R ¹ is OR ⁶ and R ² are hydrogen atoms, or R ¹ is a hydrogen atom and R ² is OR ⁶ ; R ⁵ and R ⁶ are each a hydrogen atom or a protecting group for a hydroxyl group. And a general formula [III]:

Embedded image [Wherein, R represents a hydroxyl-protecting group and Ph represents phenyl], which is subjected to a coupling reaction with an anion derived from a phosphine oxide represented by the following formula, and if necessary, deprotected. Can be As the base used to derive the anion of the phosphine oxide, an alkyl lithium such as n-butyl lithium is preferable.

Compounds [IIA] to [IIC] and compound [II]
The coupling reaction of I] is carried out at -80 ° C to 20 ° C,
In an inert atmosphere (eg, under an argon atmosphere), the reaction is performed in an ether solvent (eg, diethyl ether, tetrahydrofuran (THF), etc.) for 30 minutes to 2 hours. The obtained products [IA] to [IC] can be purified by a known method such as silica gel chromatography. Compound [IA]
~ [IC] is deprotected if necessary, but this can also be performed by a known method. The hydroxyl-protecting groups R ⁵ and R ⁶ in the general formulas [IIA] to [IIC] are preferably silyl-based protecting groups such as t-butyldimethylsilyl group and acyl-based protecting groups such as acetyl group. The hydroxyl-protecting group R in the general formula [III] is preferably a silyl-based protecting group such as a t-butyldimethylsilyl group.

The method for producing the starting compound [III] used in the above coupling reaction is described in Baggiolini et al. (EG Baggio).
lini et al.), J. Am. Chem. Soc., 104, 2945.
1982, and JP-A-2-250844. The other starting materials [IIA] to [IIC]
Can be produced, for example, by the method shown in the following reaction step.

When R ⁶ is acetyl and R ⁵ is hydrogen
Synthesis of Compound [IIA]

Embedded image (In the formula, Me is methyl, Bn is benzyl, Ph is phenyl, MOM is methoxymethyl, Ac is acetyl.) According to the above reaction steps, first, the aldehyde compound (1) is treated with (methoxymethyl) triphenylphosphonium chloride. Treatment converts to compound (2), which is treated with mercuric acetate to convert to compound (3). This is converted to a sulfone compound (3
4), followed by Swern oxidation,
Compound (4) is obtained. The compound (5) obtained by treating the compound (4) with samarium iodide is reduced to obtain a compound (6). The protecting group at the 25-position hydroxyl group is removed from compound (6), and the resulting compound (7) is protected at the 23-position hydroxyl group to give compound (8)
Get. Compound (8) is obtained by removing the benzyl protecting group.
Obtain (9). Oxidation of compound (9) with pyridinium chlorochromate gives the starting material [IIAa]. Detailed reaction conditions of the above reaction step are described in Reference Examples 1 to 9 below.

R ⁶ is t-butyldimethylsilyl, R ⁵ is water
Synthesis of compound [IIB] when it is element

Embedded image (In the formula, Me represents methyl, Bn represents benzyl, and TBDMS represents t-butyldimethylsilyl.) According to the above reaction step, first, the above-mentioned compound (3) is converted from the above-mentioned compound (1) to a compound (2) In the same manner as in the conversion to (3), the compound is converted to the compound (10).
Convert to (11). This is treated with methyl lithium to obtain a compound (12). The compound (12) is oxidized, and the obtained compound (13) is reacted with hexafluoroacetone to obtain a compound (14). Compound (14) is reduced to give compound (15)
Get. The 24-hydroxyl group of compound (15) is protected with a t-butyldimethylsilyl protecting group, and the benzyl protecting group of compound (16) is removed to obtain compound (17). Compound
Pyridinium chlorochromate oxidation of (17) gives the starting material [IIBb]. Detailed reaction conditions of the above reaction step are described in Reference Examples 10 to 18 described below.

When R ⁶ and R ⁵ are both acetyl
Synthesis of Compound [IIC]

Embedded image

Embedded image (Where MOM is methoxymethyl, TBDPS is t-butyldiphenylsilyl, Ms is methanesulfonyl, Ph
Represents phenyl, Bn represents benzyl and Ac represents acetyl.) According to the above reaction step, first, the compound (18) is reduced, and the obtained compound (19) is deprotected to obtain a compound (20). The diol compound (20) is oxidized to form an epoxy compound
(21) is obtained and reduced to obtain a triol compound (22). One terminal hydroxyl group of the compound (22) is protected with a t-butyldimethylsilyl group, and the resulting compound (23) is 2,2
Acetonide compound by reacting with dimethoxypropane
(24) is obtained. The compound (24) is deprotected, and the obtained compound (25) is converted into a methanesulfonate (26), which is then treated with a thiophenoxide anion to give a sulfide compound (27), which is oxidized to give a sulfone compound.
(28) is obtained. Compound (28) is reacted with aldehyde compound (1) to give compound (29). The compound (29) is reduced and the resulting compound (30) is deprotected to give a compound (31)
Get. The hydroxyl groups at the 24-homo position and the 25-position of compound (31) are protected with an acetyl group, and the benzyl protecting group of compound (32) is removed to obtain compound (33). Compound (33)
Is oxidized with pyridinium chlorochromate to give the starting material
[IICc] is obtained. Detailed reaction conditions of the above reaction step are described in Reference Examples 19 to 35 described later.

Hereinafter, the present invention will be described specifically with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto. Each compound described in Examples and Reference Examples is numbered, and this number corresponds to the compound number assigned to each compound in the reaction step.

[0017]

Examples Example 1-1 1-1 , 26,26,26,26 by a Wittig reaction of a compound [IIAa] and a compound [III] wherein R is TBDMS
27,27,27-hexafluoro-24-homo-1α,
1 of 23,25-trihydroxyvitamin D ₃ (compound A)
Synthesis of α, 3-bis (t-butyldimethylsilyl) ether: A solution of phosphine oxide [III] (750 mg) in anhydrous tetrahydrofuran (THF) (5 ml) at −78 ° C.
A 2.53 M solution of -butyllithium in hexane (0.5 ml) was added dropwise and stirred at the same temperature for 15 minutes. Compound in this solution
A solution of [IIAa] (59.2 mg) in anhydrous THF (5 ml) is added in one portion. After stirring for 10 minutes, the reaction mixture is warmed to room temperature and stirred for 1 hour. An aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate.
The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 10: 1) to give the title compound (88.45 mg, yield 87.9%) as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12H), 0.5
6 (s, 3H), 0.80-2.52 (m, 23H), 0.88 (s,
18H), 0.99 (d, J = 6.3 Hz, 3H), 2.75 −
2.90 (m, 1H), 3.72-3.90 (m, 1H), 4.13
-4.30 (m, 1H), 4.33-4.42 (m, 1H), 4.8
3-4.90 (m, 1H), 5.15-5.22 (m, 1H), 6.
02 (d, J = 11.2 Hz, 1H), 6.25 (d, J = 11.2)
(Hz, 1H), 6.45-6.52 (m, 1H). ¹⁹ F-NMR (CDCl ₃ ) ppm: −76.78 (q, J = 9.8)
(Hz, 3F), -78.57 (q, J = 9.8 Hz, 3F). IR (KBr): 3483, 2955, 1254, 121
5 cm ^-1 .

1-2, 26, 26, 26, by desilylation
27,27,27-hexafluoro-24-homo-1α,
Synthesis of 23,25-trihydroxyvitamin D ₃ (compound A): A solution of the compound (88.45 mg) obtained in Example 1-1 in methanol (5 ml) was added to a cationic ion exchange resin (5).
0W-X4) (1 g) is added and the suspension is stirred at room temperature for 16 hours. After filtration of the reaction mixture, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc).
c = 1: 1) to give the title compound A (58.6 mg, yield 9).
(3.5%) as colorless needles. 145.0-146.3 ° C (n-hexane / ether). ¹ H-NMR (CD ₃ OD) δ: 0.60 (s, 3H), 0.98
(d, J = 6.5 Hz, 3H), 1.10-2.35 (m, 25
H), 2.46-2.60 (m, 1H), 2.81-2.92 (m, 1H)
1H), 3.50-3.70 (m, 1H), 4.07-4.20
(m, 1H), 4.30-4.42 (m, 1H), 4.90-4.9
5 (m, 1H), 5.27-5.33 (m, 1H), 6.08 (d, J
= 11.3 Hz, 1 H), 6.33 (d, J = 11.3 Hz, 1)
H). IR (KBr): 3406, 2950, 1654, 121
0 cm ^-1 .

Example 2 2-1 26,26,26,26 by a Wittig reaction of a compound [IIBb] and a compound [III] wherein R is TBDMS
27,27,27-hexafluoro-24-homo-1α,
1 of 24,25-trihydroxyvitamin D ₃ (compound B)
Synthesis of α, 3,24-tris (t-butyldimethylsilyl) ether: To a solution of phosphine oxide [III] (550 mg, 0.94 mmol) in anhydrous THF (2 ml) was added n-butyllithium (−78 ° C.) (Hexane solution, 0.94 mmol) was added and the mixture was stirred at the same temperature for 5 minutes. Compound [IIBb] was added to this solution.
A solution of (25 mg, 0.05 mmol) in anhydrous THF (2 ml) is added. The temperature of the reaction mixture is gradually raised to room temperature, a saturated aqueous solution of ammonium chloride is added, and the mixture is extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc = 100:
Purification in 1) gave the title compound (35 mg, 85% yield) as a colorless viscous material.

[0020] 2-2. 26,26,26 by desilylation,
27,27,27-hexafluoro-24-homo-1α,
Synthesis of 24,25-trihydroxyvitamin D ₃ (compound B): A solution of the compound (35 mg) obtained in Example 2-1 in methanol (2 ml) was added to a cationic ion exchange resin (50 W-
X4) (0.5 g) is added and the suspension is stirred at room temperature for 6 days. After filtration of the reaction mixture, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc).
= 1: 1) to give the title compound B (16 mg, yield 72%).
Is obtained as amorphous crystals. IR (KBr) 3382, 2949, 2875, 120
9, 722 cm ^-1 . ¹ H-NMR (CD ₃ OD) δ: 0.58 (s, 3H), 0.96
(d, J = 6.9 Hz, 3H), 3.96-4.19 (m, 2H),
4.36 (t, J = 5.8 Hz, 1H), 4.91 (m, 1H), 5.
30 (m, 1H), 6.09 (d, J = 11.2 Hz, 1H), 6.
32 (d, J = 11.2 Hz, 1H).

Example 3 3-1 26,26,26,26 by a Wittig reaction of compound [IICc] and compound [III] wherein R is TBDMS
27,27,27-hexafluoro-24-homo-1α,
Synthesis of 1α, 3-bis (t-butyldimethylsilyl) ether of 24-homo, 25-trihydroxyvitamin D ₃ (compound C): phosphine oxide [III] (341.8 mg)
To an anhydrous THF solution (10 ml) was added dropwise a 2.5M hexane solution of n-butyllithium (0.244 ml) at -78 ° C, and the mixture was stirred at the same temperature for 5 minutes. The solution [II
Cc] (28.5 mg) in anhydrous THF (1 ml) is added in one portion. The reaction mixture is warmed to room temperature and stirred for 10 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of NaHCO ₃ and saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 20: 1) to obtain the title compound (21 mg, yield: 48.6%) as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12H), 0.5
3 (s, 3H), 0.88 (s, 18H), 0.94 (d, J = 6.0)
Hz, 3H), 1.03-2.10 (m, 20H), 2.13-
2.27 (m, 2H), 2.37-2.53 (m, 1H), 2.75
-2.88 (m, 1H), 3.87-4.04 (m, 1H), 4.1
0-4.26 (m, 1H), 4.34-4.45 (m, 2H), 4.
85-4.90 (m, 1H), 5.16-5.22 (m, 1H),
6.02 (d, J = 11.4 Hz, 1H), 6.23 (d, J = 1
1.4 Hz, 1H). IR (neat): 3422, 2954, 1632, 125
6, 1210 cm ^-1 .

[0022] 3-2. 26,26,26 by desilylation,
27,27,27-hexafluoro-24-homo-1α,
24- homo, 25-Synthesis of tri-hydroxyvitamin D ₃ (Compound C): The compound obtained in Example 3-1 (10.4 mg)
In a methanol solution of a cationic ion exchange resin (50
W-X4) (0.5 g) is added and the suspension is stirred at room temperature for 14 hours. After filtering the reaction mixture, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtO
Ac = 1: 1) and the title compound C (6.4 mg, yield 8).
6.9%) as a colorless viscous material. ¹ H-NMR (CD ₃ OD) δ: 0.58 (s, 3H), 0.97
(d, J = 6.5 Hz, 3H), 1.10-2.07 (m, 20
H), 2.26 (dd, J = 13.6, 6.6 Hz, 1H), 2.
48-2.58 (m, 1H), 2.81-2.92 (m, 1H),
3.81-3.90 (m, 1H), 4.05-4.19 (m, 1
H), 4.31-4.40 (m, 2H), 4.91 (m, 1H),
5.29 (m, 1H), 6.09 (d, J = 11.0 Hz, 1H),
6.32 (d, J = 11.0 Hz, 1H). IR (KBr): 3425, 2947, 1630, 121
0 cm ^-1 .

[0023]

[0024]

Reference Example 1 Synthesis of compound (2) from compound (1): (methoxymethyl) triphenylphosphonium chloride (6.78 g) was added to potassium
A solution of t-butoxide (2.02 g) in THF (10 ml) was added dropwise and stirred at 0 ° C. for 30 minutes. Compound (1) is added to this solution.
(1.80 g) in a solution of THF (3 ml) was added in one portion and
Stir for 0 minutes. The reaction mixture is added to an aqueous ammonium chloride solution and extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography.
(n-hexane: EtOAc = 100: 1)
(2) (E / Z = 2/3) (757.85 mg, yield 38.5%)
Is obtained as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 0.83-1.50 (m, 7
H), 0.97 (d, J = 6.7 Hz, 1.2 H), 0.99 (d, J
= 7.3 Hz, 1.8 H), 1.01 (s, 3 H), 1.50-1.
87 (m, 3H), 1.87-2.09 (m, 2.4H), 2.48
-2.73 (m, 0.6H), 3.46 (s, 1.2H), 3.54
(s, 1.8H), 3.65-3.76 (m, 1H), 4.16 (d-
d, J = 8.6, 6.5 Hz, 0.6 H), 4.36 (d, J = 13.
0 Hz, 1 H), 4.59 (dd, J = 13.0, 13.0 Hz,
0.4H), 4.62 (d, J = 13.0Hz, 1H), 5.72
(d, J = 6.5 Hz, 0.4 H), 6.24 (d, J = 13.0 H)
z, 0.6H), 7.15-7.39 (m, 5H). IR (neat): 2932, 1664, 1103 cm ^-1 .

Reference Example 2 Synthesis of Compound (3) from Compound (2): Compound (2) (806.55 mg) obtained in Reference Example 1 was added to THF (67 ml) and water (7 ml).
Was added, and mercuric acetate (1.576 g) was added, followed by stirring at room temperature for 3 hours. The reaction mixture is added to a 7% aqueous potassium iodide solution and extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and crude compound (3) (685.9 mg, yield 88.8) was obtained.
%).

Reference Example 3 Synthesis of Compound (4) from Compound (3): Sulfone Compound (3
4) (1.28 g) and 2.53 M n-butyllithium (2.2 ml)
Is reacted in THF (10 ml). To this reaction solution, a solution of the above crude compound (3) in THF (10 ml) is added all at once at -78 ° C, and the mixture is stirred for 30 minutes. The reaction mixture is heated to room temperature, added to an aqueous ammonium chloride solution, and extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off and the crude product (1.9
57 g) are obtained. Separately, oxalyl chloride (0.429m
l) in dichloromethane (10 ml) at −78 ° C. in dimethyl sulfoxide (0.7 ml) in dichloromethane (5 ml).
l) is added dropwise and stirred for 10 minutes. A solution of the above crude product (1.95 g) in dichloromethane (30 ml) was added dropwise to this solution,
After stirring at −78 ° C. for 10 minutes, triethylamine (1.
(714 ml) was added dropwise and stirred at the same temperature for 2 hours. The reaction mixture was warmed to room temperature and added to aqueous ammonium chloride solution.
Extract with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 10: 1) to give compound (4) (1.
296 g, yield of all three steps from Reference Example 2 59.2
%) As a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (d, J = 6.4 Hz,
1.5H), 0.98 (s, 1.5H), 1.00 (s, 1.5H),
1.01 (d, J = 6.4 Hz, 1.5 H), 1.03-1.56
(m, 6H), 1.56-1.92 (m, 3H), 1.92-2.1
2 (m, 3H), 2.22-2.70 (m, 2H), 2.70-2.
95 (m, 2H), 3.35 (s, 1.5H), 3.38 (s, 1.5
H), 3.68-3.76 (m, 1H), 4.31-4.40 (m,
1H), 4.40-4.50 (m, 1H), 4.62 (d, J = 1
(2.7Hz, 1H), 4.85-4.93 (m, 2H), 7.20
-7.40 (m, 5H), 7.55-7.82 (m, 5H). IR (neat): 2934, 1728, 1326, 121
7, 1153 cm ^-1 .

REFERENCE EXAMPLE 4 Synthesis of compound (5) from compound (4): To a methanol solution (5 ml) of compound (4) (1.296 g) obtained in Reference Example 3 was added -78.
At 0 ° C, 0.1M samarium iodide (100 ml) was added dropwise.
Stir for 30 minutes. After heating to 0 ° C. and stirring for another 15 minutes, the reaction mixture was added to an aqueous ammonium chloride solution,
Extract with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 40: 1) to give compound (5) (96).
(6.2 mg, 93.5% yield) as a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (d, J = 6.2 Hz, 3
H), 1.00 (s, 3H), 1.00-1.55 (m, 9H),
1.60-2.23 (m, 6H), 2.28-2.82 (m, 4
H), 3.45 (s, 3H), 3.67-3.75 (m, 1H),
4.36 (d, J = 12.6 Hz, 1H), 4.61 (d, J = 1
(2.6 Hz, 1H), 4.91 (s, 2H), 7.18-7.40
(m, 5H). IR (neat): 2935, 1719, 1213, 109
0 cm ^-1 .

Reference Example 5 Synthesis of Compound (6) by Reduction of Compound (5): Compound (5)
To a solution of ethanol (966.2 mg) in ethanol (10 ml) was added sodium borohydride (66.2 mg) at 0 ° C.
Stir for hours. The reaction mixture is added to an aqueous ammonium chloride solution and extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n
-Hexane: EtOAc = 10: 1) to give a colorless viscous compound (6) as a diastereomer having a small polarity.
(669.5 mg, 69.0% yield) and the more polar diastereomer (304.35 mg, 31.4% yield). Polar small diastereomer: ¹ H-NMR (CDCl ₃ ) δ: 0.85-1.92 (m, 16
H), 0.95 (d, J = 6.6 Hz, 3H), 0.99 (s, 3
H), 1.92-2.16 (m, 3H), 2.25-2.46 (m, 3H)
1H), 3.47 (s, 3H), 3.65-3.75 (m, 1H),
3.68 (bs, 1H), 4.36 (d, J = 12.6 Hz, 1H),
4.61 (d, J = 12.6 Hz, 1H), 4.95 (s, 2H),
7.18-7.42 (m, 5H). IR (neat): 3462, 2935, 1212, 103
5 cm ^-1 . Polar large diastereomer: ¹ H-NMR (CDCl ₃ ) δ: 0.85-2.20 (m, 19)
H), 0.96 (d, J = 6.2 Hz, 3H), 0.97 (s, 3
H), 2.25-2.45 (m, 1H), 3.47 (s, 3H),
3.62-3.80 (m, 2H), 4.35 (d, J = 12.6H
z, 1H), 4.61 (d, J = 12.6 Hz, 1H), 4.90 −
5.01 (m, 2H), 7.18-7.40 (m, 5H). IR (neat): 3440, 2935, 1212, 102
8 cm ^-1 .

Reference Example 6 Synthesis of Compound (7) by Deprotection of Compound (6): A solution of Compound (6) (669.5 mg) obtained in Reference Example 5 above in dioxane.
(10 ml) was added concentrated hydrochloric acid (1 ml) and stirred at 65 ° C. for 1 hour. After cooling, the reaction mixture is extracted with ether. The ether layer is washed with water, a saturated aqueous solution of NaHCO ₃ and saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 10: 1) to give compound (7) (41).
(1.4 mg, 66.8% yield) as colorless needles. mp 108.4-109.7 ° C (n-hexane / ether). ¹ H-NMR (CDCl ₃ ) δ: 0.90-2.15 (m, 18
H), 0.96 (d, J = 6.8 Hz, 3H), 0.98 (s, 3
H), 2.21-2.40 (m, 2H), 3.68-3.77 (m,
1H), 3.80 (bs, 1H), 4.36 (d, J = 12.3 Hz,
1H), 4.61 (d, J = 12.3 Hz, 1H), 6.54 (bs,
1H), 7.19-7.42 (m, 5H). IR (KBr): 3432, 2932, 1215 cm ^-1 .

Reference Example 7 Synthesis of compound (8) from compound (7): Compound (7) (164.24 mg) obtained in the above Reference Example 6, acetic anhydride (0.04 ml) and 4-dimethylaminopyridine (5 mg) ) Solution of pyridine
(1 ml) is stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ether, and the ether layer was washed with 2N hydrochloric acid, saturated NaHCO3.
₃ Wash with aqueous solution and saturated saline, and dry with magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 10: 1) to obtain compound (8) (124.7 mg, yield 70%) as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 0.85-1.55 (m, 11
H), 0.92 (d, J = 6.4 Hz, 3H), 0.95 (s, 3
H), 1.55-2.10 (m, 8H), 2.09 (s, 3H),
3.67-3.85 (m, 1H), 4.36 (d, J = 12.4H
z, 1H), 4.36 (s, 1H), 4.61 (d, J = 12.4H
z, 1H), 4.96-5.13 (m, 1H), 7.18-7.4
0 (m, 5H). IR (neat): 3355, 2935, 1738, 120
9 cm ^-1 .

Reference Example 8 Synthesis of Compound (9) by Deprotection of Compound (8): Reference Example 7
A suspension (15 ml) of the compound (8) (124.7 mg) and palladium carbon (100 mg) obtained in the above was stirred under a hydrogen atmosphere (1 atm) at room temperature for 23 hours. After filtering the reaction mixture, the solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 10: 1) to give compound (9) (79.5 mg, yield: 76.1%). Is obtained as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 0.90-2.05 (m, 20
H), 0.91 (d, J = 5.7 Hz, 3H), 0.92 (s, 3
H), 2.09 (s, 3H), 4.08 (bs, 1H), 4.53 (s,
1H), 4.96-5.10 (m, 1H). IR (KBr): 3513, 3184, 2994, 172
1,1272 cm ^-1 .

Reference Example 9 Synthesis of compound [IIAa] by oxidation of compound (9): Compound (9) (pyridinium chlorochromate (PCC) (140 mg) was added to a dichloromethane suspension (2.5 ml) at 0 ° C at 0 ° C. 6
A solution of 0.2 mg) in dichloromethane (2.5 ml) is added and stirred at room temperature for 2 hours. The reaction mixture was diluted with ether, filtered, the solvent was distilled off, and the residue was separated by florisil column chromatography (n-hexane: EtOAc = 3: 1) to give compound [IIAa] (59.2 mg, yield). 98.8%) as a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.64 (s, 3H), 0.80
-2.35 (m, 18H), 0.97 (d, J = 5.8, 3H),
2.10 (s, 3H), 2.38-2.52 (m, 1H), 4.31
(s, 1H), 4.98-5.13 (m, 1H). IR (neat): 3383, 2960, 1738, 171
2,1241 cm ^-1 .

Reference Example 10 Synthesis of compound (10) from compound (3): (methoxymethyl)
To a solution of potassium t-butoxide (2.7 g, 24.1 mmol) in THF (30 ml) was added to triphenylphosphonium chloride (8.5 g, 24.8 mmol) at room temperature, and the mixture was stirred for 30 minutes. The aldehyde (3) in THF was added to the reaction mixture.
After adding a solution (10 ml) and stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The ether layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The obtained residue is purified by column chromatography to obtain the enol ether compound (10) (2.59 g, yield 92%). IR (neat): 2932, 2864, 1654, 145
3, 1107, 735, 696 cm ^-1 . MS (EI): 342, 251, 163, 91, 81, 7
One.

Reference Example 11 Synthesis of Compound (11) from Compound (10): TH of enol ether (2.59 g, 7.6 mmol) obtained in Reference Example 10
F solution (200 ml), water (23 ml) and mercuric acetate
(7.2 g, 22.6 mmol) and stir at room temperature for 1 hour. The reaction mixture is added to a 7% aqueous potassium iodide solution,
Extract with benzene. The organic layer was washed with a 7% aqueous solution of potassium iodide and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude aldehyde compound.
(11) is obtained. This is used for the next reaction without purification.

Reference Example 12 Synthesis of compound (12) from compound (11): The above crude compound (1) was added to a 1.4 M methyllithium ether solution (17 ml).
A THF solution (10 ml) of 1) was added dropwise at -78 ° C, and after the addition was completed, the mixture was stirred for 30 minutes. The temperature of the reaction mixture was gradually raised to room temperature, and a saturated aqueous solution of ammonium chloride was added.
Extract with diethyl ether. The ether layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The obtained residue is purified by column chromatography to obtain alcohol compound (12) (1.56 g, yield 61%). MS (EI): 344 [M ⁺ ], 342, 301, 253,
217, 135, 107, 91, 81, 67.

REFERENCE EXAMPLE 13 Synthesis of compound (13) by oxidation of compound (12): 1 g of chromium (VI) oxide was dissolved in concentrated sulfuric acid (1.1 ml) and water (5 ml), and the alcohol ( 12) To a solution of 1.56 g (4.5 mmol) in ether (30 ml) at 0 ° C. After stirring at the same temperature for 3 hours, water is added. Water the ether layer,
Washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
Dry over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is purified by column chromatography to obtain a ketone compound.
(13) (1.0 g, yield 64%) is obtained. IR (neat): 2935, 2865, 1716, 145
3, 1356, 1164, 1097, 1071, 73
6,696 cm ^-1 . MS (EI): 342 [M ⁺ ], 299, 251, 97, 8
1, 67. ¹ H-NMR (CDCl ₃ ) δ: 0.89 (d, J = 6.4 Hz, 3
H), 0.95 (s, 3H), 2.14 (s, 3H), 3.71 (m,
1H), 4.35 (d, J = 12.0 Hz, 1H), 4.61 (d,
J = 12.0 Hz, 1H), 7.20-7.37 (m, 5H).

Reference Example 14 Synthesis of Compound (14) by Treatment of Compound (13) with Hexafluoroacetone: A solution of lithium diisopropylamide (LDA) (9.3 mmol) in THF (10 ml) was added to the ketone obtained in Reference Example 13
(13) (1.0 g, 2.9 mmol) in THF (10 ml)
The solution was added dropwise at -78 ° C, and after stirring for 30 minutes, further hexafluoroacetone (4 ml) was added at -78 ° C. -7
After stirring at 8 ° C. for 15 minutes, the temperature is gradually raised to room temperature, a saturated aqueous ammonium chloride solution is added, and the mixture is extracted with diethyl ether. The ether layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is distilled off to obtain a crude compound (14). This is used for the next reaction without purification.

Reference Example 15 Synthesis of compound (15) by reduction of compound (14): The above crude compound (14) was dissolved in ethanol (30 ml),
With sodium borohydride (300 mg, 7.9 mmol)
And stirred at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with diethyl ether. The ether layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is purified by column chromatography.
(15) (153 mg, yield 10.3%) is obtained. IR (neat): 3316, 2939, 2868, 127
8, 1207, 696 cm ^-1 . MS (EI): 510, 467, 419, 401, 38
3, 265, 211, 135, 91. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (d, J = 6.4 Hz, 3
H), 0.95 (s, 3H), 3.71 (m, 1H), 4.19 (br
s, 1H), 4.35 (d, J = 12.3 Hz, 1H), 4.61
(d, J = 12.3 Hz, 1H), 6.29 (brs, 1H), 7.2
0-7.36 (m, 5H).

Reference Example 16 Synthesis of Compound (16) from Compound (15): A solution of the alcohol (15) (32 mg, 0.06 mmol) obtained in Reference Example 15 in dichloromethane (2 ml) was added at 0 ° C. 6-lutidine (1
9 μl) and t-butyldimethylsilyl triflate (2
2 μl) and warm to room temperature. After stirring at the same temperature for 20 minutes, water is added, and the mixture is extracted with diethyl ether. The organic layer is washed with 2N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off to obtain a crude compound (16). This is used for the next reaction without purification.

REFERENCE EXAMPLE 17 Synthesis of compound (17) by deprotection of compound (16): The above crude compound (16) was converted to 5% palladium / carbon (5 m 2).
g) in methanol suspension (5 ml)
(Normal pressure) and stir at room temperature for 18 hours. The catalyst is filtered off and the solvent is distilled off. The obtained residue is purified by column chromatography to obtain compound (17) (27 mg, yield 81%). IR (neat): 3354, 2937, 2864, 125
9, 1065, 722 cm ^-1 . MS (EI): 533 (M-1), 501, 477, 45.
9, 363, 163, 149, 135. ¹ H-NMR (CDCl ₃ ) δ: 0.16 (s, 3H), 0.17
(s, 3H), 0.91 (d, J = 6.3 Hz, 3H), 0.91 (s, 3H)
6H), 0.91 (s, 3H), 0.94 (s, 3H), 4.09 (b
rs, 1H), 4.26 (m, 1H), 6.26 (s, 1 / 2H),
6.3 (s, 1 / 2H).

Reference Example 18 Synthesis of compound [IIBb] by oxidation of compound (17): P
Compound (17) (27 mg, obtained in Reference Example 17) was added to a suspension of CC (70 mg, 0.32 mmol) in dichloromethane (2 ml).
0.05 mmol) in dichloromethane (2 ml)
Stir at room temperature for 3 hours. After extraction with diethyl ether and concentration of the ether layer, the residue is purified by florisil column chromatography to obtain compound [IIBb] (25 mg, yield 93%).

Reference Example 19 Synthesis of Compound (19) by Reduction of Compound (18): Compound
(18) An ether solution (30 ml) of (10.876 g) was added dropwise to an ether suspension of lithium aluminum hydride (3.8 g) at 0 ° C., and the mixture was stirred under reflux for 4 hours. Under ice-cooling, water (7.2 ml) was added dropwise to the reaction mixture, and the insolubles were filtered through celite and washed with diethyl ether. The ether layers were combined, dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: Et.
OAc = 2: 1) and the allyl alcohol compound (1
9) (5.815 g, 53% yield) as a colorless oil. bp 98 ° C (9 mmHg). ¹ H-NMR (CDCl ₃ ) δ: 2.30 (bs, 1H), 3.47
(s, 3H), 4.25-4.40 (m, 2H), 4.90 (s, 2
H), 5.90 (dt, J = 16.4, 1.1 Hz, 1H), 6.
44 (dt, J = 16.4, 4.1 Hz, 1H). IR (neat): 3420, 1214, 1049 cm ^-1 .

Reference Example 20 Synthesis of compound (20) by deprotection of compound (19): To a methanol solution (60 ml) of allyl alcohol (19) (4.24 g) obtained in reference example 19 was added concentrated hydrochloric acid (10 drops). ) And stirred under reflux for 4 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc = 2:
The diol compound (20) (3.54 g, yield 1)
00%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.40 (bs, 1H), 3.35
(s, 1H), 4.20-4.38 (m, 2H), 5.97 (d, J =
15.6 Hz, 1 H), 6.52 (d-t, J = 15.6, 4.1 H)
z, 1H). IR (neat): 3441, 3096, 1225 cm ^-1 .

Reference Example 21 Synthesis of compound (21) by oxidation of compound (20): To a benzene solution (5 ml) of diol (20) (1.31 g) obtained in Reference Example 19 and vanadyl acetylacetonate (60 mg). , 80
At 3 DEG C., 3M t-butyl hydroperoxide (3 ml) was added dropwise and stirred for 2 hours. After cooling, the reaction mixture is diluted with diethyl ether, and the ether layer is washed with water, an aqueous solution of sodium sulfite and brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 1: 1) to obtain an epoxy compound (21) (1.015 g, yield 72.4).
%) As colorless needles. mp 67.1-67.7 ° C. ¹ H-NMR (CD ₃ COCD ₃ ) δ: 2.95 (bs, 2H),
3.30-3.39 (m, 1H), 3.50-3.59 (m, 1H)
H), 3.71 (dd, J = 13.0, 4.1 Hz, 1H), 3.
90 (dd, J = 13.0, 2.6 Hz, 1H). IR (KBr): 3418, 3048, 1234 cm ^-1 .

Reference Example 22 Synthesis of compound (22) by reduction of compound (21): THF of epoxy compound (21) (1.331 g) obtained in Reference Example 21
Lithium aluminum hydride (632 mg) was added to the solution (10 ml).
Was added dropwise to an ether suspension (10 ml) at 0 ° C.
Stir for 0 h and stir at room temperature for another 12 h. Under ice-cooling, 10% sulfuric acid is added to the reaction mixture, and the mixture is vigorously stirred and extracted with diethyl ether. Saturated ether layer
Wash with aHCO ₃ aqueous solution and saturated saline, and dry with magnesium sulfate. The solvent was distilled off to obtain a crude triol compound (22) (1.504 g) as a colorless viscous substance. ¹ H-NMR (CD ₃ COCD ₃ ) δ: 1.71-1.92 (m,
1H), 2.02-2.24 (m, 1H), 3.70-3.90
(m, 2H), 4.14 (bs, 1H), 4.23-4.40 (m, 1
H), 4.88 (d, J = 6.4 Hz, 1H), 6.61 (bs, 1
H). IR (neat): 3424 cm ^-1 .

Reference Example 23 Synthesis of compound (23) from compound (22): The above crude triol (22) was added to a solution of dimethylformamide (10 ml).
Add t-butyldiphenylsilane chloride (1.815 g) and imidazole (935 mg) and stir at room temperature for 7 hours.
The reaction mixture is diluted with diethyl ether, and the ether layer is washed with 10% hydrochloric acid and saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc = 10: 1).
To give a silyl ether compound (23) (2.28 g, yield of 86.4% in two steps from Reference Example 22) as colorless needle crystals. mp 60.8-62.0 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (s, 9H), 1.82
-2.13 (m, 2H), 3.80-4.03 (m, 2H), 4.0
5 (d, J = 4.3 Hz, 1 H), 4.28-4.42 (m, 1
H), 4.70 (s, 1H), 7.30-7.85 (m, 5H). IR (KBr): 3439, 1213 cm ^-1 .

Reference Example 24 Optical Resolution of Compound (23) The silyl ether (23) obtained in Reference Example 23 was optically resolved by derivatization with a camphoric acid ester. Silyl ether
(23) (3.29 g), (-)-camphanic acid chloride (5.88)
g), 4-dimethylaminopyridine (50 mg) and pyridine (3 ml) in dichloromethane (20 ml) are stirred at room temperature for 13 hours. Dilute the reaction mixture with diethyl ether,
The ether layer is washed with 5% hydrochloric acid, a saturated aqueous solution of NaHCO ₃ and saturated saline, and dried over magnesium sulfate. The solvent was distilled off, the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 5: 1), and the biscampanoic acid ester of colorless needle crystals was converted to a diastereomer of small polarity (2.21 g, yield 38.4%) and the more polar diastereomer (2.34 g, 40.6% yield). Polar small diastereomer: mp 127.7-129.4 ° C (n-hexane / ethyl acetate). ¹ H-NMR (CD ₃ COCD ₃ ) δ: 0.87 (s, 3H),
1.00 (s, 3H), 1.06 (s, 3H), 1.07 (s, 12
H), 1.11 (s, 3H), 1.12 (s, 3H), 1.55-
1.80 (m, 2H), 1.92-2.66 (m, 8H), 3.55
-3.70 (m, 1H), 3.78-3.91 (m, 1H), 6.8
4-6.97 (m, 1H), 7.35-7.54 (m, 6H), 7.
60-7.75 (m, 4H). IR (KBr): 2964, 1798, 1252, 121
9, 1104, 1060 cm ^-1 . Polar large diastereomer: mp 137.2-138.4 ° C (n-hexane / ethyl acetate). ¹ H-NMR (CD ₃ COCD ₃ ) δ: 0.87 (s, 3H),
1.02 (s, 3H), 1.07 (s, 3H), 1.08 (s, 9
H), 1.10 (s, 3H), 1.14 (s, 3H), 1.21 (s, 3H)
3H), 1.54-1.76 (m, 2H), 1.88-2.60
(m, 8H), 3.54-3.70 (m, 1H), 3.77-3.9
0 (m, 1H), 6.88-7.00 (m, 1H), 7.37-7.
55 (m, 6H), 7.60-7.77 (m, 4H). IR (KBr): 2968, 1795, 1254, 121
8, 1099, 1055 cm ^-1 . Bis camphoric acid ester (small polar diastereomer)
(2.80 g) and a suspension of lithium aluminum hydride (750 mg) in ether (150 ml) were stirred at room temperature for 3 hours. After adding 10% sulfuric acid to the reaction mixture and stirring, the mixture is extracted with diethyl ether. The ether layer is washed with a saturated aqueous solution of NaHCO ₃ and a saturated saline solution and dried over magnesium sulfate. The solution was distilled off, the residue, t-butyldiphenylsilane chloride (4.3 ml) and imidazole (2.8 g) were dissolved in dimethylformamide (20 ml), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with diethyl ether and the ether layer was
Wash with 0% hydrochloric acid and saturated saline and dry over magnesium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 5: 1) to obtain an optically active silyl ether compound (23) (1.17).
g, yield 73.2%). In the same manner, the other isomer of biscamphoric acid ester (a diastereomer having a large polarity) (2.3
0g) to give the other enantiomer of silyl ether compound (23) (1.22g, 92% yield).

Reference Example 25 Synthesis of Compound (24) from Compound (23): Silyl ether (23) (321.8 mg) from small polar diastereomer obtained by optical resolution in Reference Example 24 and p-toluene To a solution of sulfonic acid (39.3 mg) in benzene (2 ml) was added 2,2
-Dimethoxypropane (416 mg) was added dropwise at room temperature.
Stir for hours. The reaction mixture is diluted with diethyl ether, and the ether layer is washed with a saturated aqueous solution of NaHCO ₃ and brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-
Separation with hexane: EtOAc = 20: 1 gave the acetonide compound (24) (326 mg, 93.5% yield) as a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 1.05 (s, 9H), 1.48
(s, 3H), 1.53 (s, 3H), 1.83-2.23 (m, 2
H), 3.84 (d-d, J = 8.1, 3.4 Hz, 2H), 4.8
2-4.88 (m, 1H), 7.30-7.53 (m, 3H), 7.
55-7.80 (m, 2H). IR (neat): 2933, 1212, 1109 cm- ¹ .

Reference Example 26 Synthesis of compound (25) by deprotection of compound (24): THF solution of acetonide (24) (326 mg) obtained in Reference Example 25
(1 ml), 1M tetrabutylammonium fluoride (TH
(F solution) (1.5 ml) was added dropwise at 0 ° C. and stirred at the same temperature for 1 hour. The reaction mixture is added to a saturated aqueous ammonium chloride solution and extracted with diethyl ether. Saturated ether layer
Wash with aHCO ₃ aqueous solution and saturated saline, and dry with magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc = 5:
Separation in 1) gave alcohol compound (25) (164 mg, yield 93.5%) as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (s, 3H), 1.55
(s, 3H), 1.94 (bs, 1H), 1.98-2.13 (m, 2
H), 3.73-3.96 (m, 2H), 4.60-4.71 (m, 2H)
1H). IR (KBr): 3362, 2948, 1210, 110
5 cm ^-1 .

Reference Example 27 Synthesis of Compound (26) from Compound (25): Alcohol (25) (282 mg) obtained in Reference Example 26, methanesulfonyl chloride
(138 mg) and a solution of triethylamine (121 mg) in dichloromethane (2 ml) were stirred at 0 ° C. for 3 hours. The reaction mixture is diluted with diethyl ether, washed with 1% hydrochloric acid and saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the methanesulfonic acid ester compound (26) (365 m
g) is obtained as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.49 (s, 3H), 1.54
(s, 3H), 2.10-2.42 (m, 2H), 3.04 (s, 3
H), 4.31-4.52 (m, 2H), 4.52-4.56 (m,
1H). IR (KBr): 1354, 1211, 1183, 110
1 cm ^-1 .

Reference Example 28 Synthesis of compound (27) from compound (26): ethanol-water
To a thiophenoxide anion solution prepared from potassium hydroxide (73 mg) and thiophenol (121 mg) in a (1: 1) solution (1.5 ml) was added an ethanol solution of the methanesulfonic acid ester (26) obtained in Reference Example 27. (1 ml) at 0 ° C.
Stir at room temperature for 11 hours. The reaction mixture is diluted with diethyl ether, and the ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off to obtain a sulfide compound (27) (381 mg) as a colorless viscous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 3H), 1.53
(s, 3H), 1.93-2.30 (m, 2H), 2.98 (d-d-
d, J = 13.5, 9.3, 6.5 Hz, 1H), 3.25 (d−d−
d, J = 13.5, 7.1, 4.4 Hz, 1 H), 4.65-4.7
5 (m, 1H), 7.15-7.53 (m, 5H). IR (neat): 1210, 1103 cm ^-1 .

Reference Example 29 Synthesis of Compound (28) by Oxidation of Compound (27): To a suspension of sulfide (27) (381 mg) obtained in Reference Example 28 and sodium carbonate (1.272 g) in dichloromethane (4 ml). ,
Under ice-cooling, m-chloroperbenzoic acid (1.036 g) was added, and
Stir at C for 3 h and at room temperature for another 15 h. The insoluble material is filtered, washed with diethyl ether, and the combined organic layers are washed with a 10% aqueous sodium hydroxide solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc =
4: 1) to separate the sulfone compound (28) (366 mg, 3
(Yield of the process: 90.2%) as colorless needles. mp 60.7-68.9 ° C (hexane-ethyl acetate). ¹ H-NMR (CDCl ₃ ) δ: 1.42 (s, 3H), 1.50
(s, 3H), 2.10-2.40 (m, 2H), 3.24 (d-d-
d, J = 14.3, 7.3, 7.3 Hz, 1H), 3.37 (d−d−
d, J = 14.3, 8.4, 5.9 Hz, 1 H), 4.46-4.5
7 (m, 1H), 7.50-7.78 (m, 3H), 7.87-8.
00 (m, 2H). IR (KBr): 1310, 1213, 1151, 110
5 cm ^-1 .

Reference Example 30 Synthesis of compound (29) by reaction of compound (1) with compound (28): Sulfone compound (28) obtained in Reference Example 29 (447 m
To a solution of g) in THF (5 ml) was added dropwise 2.5 M n-butyllithium (0.44 ml) at -78 DEG C. and the mixture was stirred at the same temperature for 10 minutes. The aldehyde compound (1) (3) was added to the reaction mixture.
A solution of 30 mg) in THF (5 ml) is added at -78 ° C and stirred for 1 hour. The reaction mixture is added to a saturated aqueous ammonium chloride solution and extracted with diethyl ether. The ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off to obtain a crude product (821.6 mg). The above crude product
(821.6 mg), a pyridine solution (2 ml) of acetic anhydride (1.02 g) and 4-dimethylaminopyridine (40 mg) were stirred at room temperature for 20 hours. The reaction mixture is diluted with diethyl ether, and the ether layer is washed with a 10% aqueous solution of copper sulfate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off to obtain a crude product (1.06 g). The above crude product (1.0
6 g) and disodium hydrogen phosphate (1.78 g) in THF
To a suspension of (20 ml) -methanol (7 ml) was added 3% sodium amalgam (14.651 g), and the mixture was stirred at room temperature for 3 hours. Diethyl ether-water is added to the reaction mixture, insolubles are filtered, and the organic layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: EtOAc = 10:
Compound (29) (256.7 mg, 31.9% yield in 3 steps) was obtained as a colorless viscous substance by separation in 1). ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.86 (m, 11
H), 0.97 (s, 3H), 1.01 (d, J = 6.6 Hz, 3
H), 1.54 (s, 3H), 1.60 (s, 3H), 1.86-
2.20 (m, 2H), 2.30-2.62 (m, 2H), 3.65
-3.74 (m, 1H), 4.27-4.43 (m, 1H), 4.3
7 (d, J = 12.7Hz, 1H), 4.60 (d, J = 12.7H
z, 1H), 5.15-5.60 (m, 2H), 7.16-7.5
0 (m, 5H). IR (neat): 2937, 1457, 1387, 121
0, 1104 cm ^-1 .

Reference Example 31 Synthesis of compound (30) by reduction of compound (29): Compound (29) (16.14 mg) obtained in Reference Example 30 and platinum oxide
(0.5 mg) in ethyl acetate (1 ml) was stirred at room temperature under a hydrogen atmosphere (1 atm) for 10 hours. After removing the catalyst by filtration, the solvent was distilled off, and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 50: 1) to give compound (30) (14.11 mg, yield 87.1). %) As a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.57 (m, 12
H), 0.92 (d, J = 6.5 Hz, 3H), 0.95 (s, 3H),
1.47 (s, 3H), 1.54 (s, 3H), 1.57-1.10
(m, 7H), 3.66-3.77 (m, 1H), 4.30-4.4
3 (m, 1H), 4.36 (d, J = 12.7 Hz, 1H), 4.6
0 (d, J = 12.7 Hz, 1 H), 7.18-7.50 (m, 5
H). IR (neat): 2938, 1456, 1378, 121
^1, 1107 cm ^-1 .

Reference Example 32 Synthesis of compound (31) by deprotection of compound (30): To a methanol solution (20 ml) of compound (30) (166.46 mg) obtained in Reference Example 31 was added concentrated hydrochloric acid (10 drops). And add 5
Stir for days. The reaction mixture is diluted with diethyl ether, and the ether layer is washed with a saturated aqueous solution of NaHCO ₃ and brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-
Hexane: EtOAc = 10: 1) to separate compound (31)
(109.9 mg, 71.2% yield) as a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.80-2.20 (m, 20
H), 0.93 (d, J = 6.5 Hz, 3H), 0.96 (s, 3
H), 3.66-3.75 (m, 1H), 3.87-4.05 (m,
1H), 4.35 (bs, 1H), 4.36 (d, J = 12.8 Hz,
1H), 4.60 (d, J = 12.8 Hz, 1H), 7.17−
7.45 (m, 5H). IR (neat): 3422, 2936, 1210 cm ^-1 .

Reference Example 33 Synthesis of Compound (32) from Compound (31): Compound (31) (108.62 mg) obtained in Reference Example 32, acetic anhydride (0.5 ml),
4-dimethylaminopyridine (5 mg) and pyridine (1 m
A solution of l) in dichloromethane (3 ml) is stirred at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether, and the residue was subjected to silica gel column chromatography (n-hexane: EtO
Ac = 30: 1) to separate compound (32) (109.6 mg,
Yield 86.6%) as a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.85-1.53 (m, 11
H), 0.87 (d, J = 6.5 Hz, 3H), 0.94 (s, 3
H), 1.53-1.90 (m, 6H), 1.90-2.20 (m,
2H), 2.11 (s, 3H), 2.15 (s, 3H), 3.65−
3.75 (m, 1H), 4.35 (d, J = 12.6 Hz, 1H),
4.60 (d, J = 12.6 Hz, 1H), 6.10-6.23
(m, 1H), 7.15-7.36 (m, 5H). IR (neat): 2938, 1796, 1760, 121
5 cm ^-1 .

Reference Example 34 Synthesis of compound (33) by deprotection of compound (32): Compound (32) (104 mg) obtained in Reference Example 33 and 5% palladium / carbon (11 mg) were dissolved in methanol (10 ml). Stir at room temperature under a hydrogen atmosphere (1 atm) for 11 hours. After filtration of the catalyst, the solvent was distilled off and the residue was separated by silica gel column chromatography (n-hexane: EtOAc = 5: 1) to give compound (33) (90 mg, yield 100%) as a colorless viscous liquid. Get in substance. ¹ H-NMR (CDCl ₃ ) δ: 0.87 (d, J = 6.4 Hz, 3
H), 0.92 (s, 3H), 0.95-1.90 (m, 19H),
1.90-2.06 (m, 1H), 2.11 (s, 3H), 2.16
(s, 3H), 4.05-4.12 (m, 1H), 6.12-6.2
3 (m, 1H). IR (neat): 3448, 2940, 1797, 176
0, 1221 cm ^-1 .

Reference Example 35 Synthesis of Compound [IICc] by Oxidation of Compound (33): A dichloromethane solution (0.5 ml) of compound (33) (37.8 mg) obtained in Reference Example 34 was diluted with dichloromethane of PCC (49 mg). Add to the suspension and stir at room temperature for 3 hours. After diluting the reaction mixture with diethyl ether and removing insolubles by filtration, the ether layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the compound [IICc] (39.
(3 mg, 94.3% yield) as a colorless viscous material. ¹ H-NMR (CDCl ₃ ) δ: 0.60 (s, 3H), 0.90
(d, J = 5.7 Hz, 3H), 1.00-2.35 (m, 18
H), 2.09 (s, 3H), 2.13 (s, 3H), 2.35-
2.50 (m, 1H), 6.10-6.25 (m, 1H). IR (neat): 2959, 1794, 1762, 171
8, 1214 cm ^-1 .

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

Test Examples Test Example 1 Effect of the Compound of the Present Invention on Serum Calcium Concentration Test method: Wistar rats (male, Japan SLC), 3 weeks old, are bred on low calcium-low vitamin D ₃ diet made by CLEA Japan Then, a low calcium serum rat was prepared. The rats were subcutaneously administered 0.1 ml of the vehicle and the test compound for 5 days. From the day after the first administration to the next day, the calcium concentration in the serum was measured, and the control rat administered with the solvent alone and the rat administered with the solvent and the test compound were compared to assay the effect of increasing blood calcium. The increase in the calcium concentration was put on a dose-response curve of a standard product (1α, 25-dihydroxyvitamin D ₃ ), and expressed as a magnification relative to the standard product. Test compound: 1α, 25- (OH) ₂ D ₃ Compound A (compound of the present invention) Compound C (compound of the present invention) Test results: The test results are shown in Table 1 below.

[Table 1] As is clear from the above results, the compound A of the present invention
As compared with α, 25-dihydroxyvitamin D _3, it shows excellent suppression of increase in serum calcium concentration.

Test Example 2 Induction of Cell Differentiation Test Method: Human leukemia cells (HL-60) were inoculated at a density of 1.5 × 10 5 cells / ml into a 96-well plate for tissue culture, and 20 μl of the test compound was added. The cells were cultured for 3 days. Take 100 μl of the supernatant, add 100 μl of NBT reagent,
Incubate at 40 ° C for 40 minutes. The cells stained black were counted and the percentage of the whole was calculated. Test compound: The same compound as in Test Example 1 was used. Test results:

Table 2 Test compound concentration (M) Number of mucus-producing cells (%) 1α, 25- (OH) ₂ D ₃ 10-917 Compound A 10-945 Compound C 10-970 From the results in Table 2 above, Compounds A and C of the present invention
The standard 1α, 25-dihydroxyvitamin D ₃
It can be seen that more HL-60 cells are induced to differentiate as compared with. Furthermore, as is clear from the results of Tables 1 and 2, the compound A of the present invention has a low blood calcium-increasing effect and a high cell differentiation-inducing effect. In addition, the compound C of the present invention has a strong effect of inducing cell differentiation, although the effect of suppressing blood calcium rise is inferior. Therefore, the compounds of the present invention have desirable pharmacological actions as anticancer agents.

──────────────────────────────────────────────────続 き Continued on the front page (72) Katsuhiko Iseki, 3, Miyukigaoka, Tsukuba, Ibaraki Prefecture Inside Daikin Industries Co., Ltd. (72) Takafumi Nagai, 3, Miyukigaoka, Tsukuba, Ibaraki Prefecture, Daikin Industries, Ltd. (56) References European Patent Application Publication 529528 (EP, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 401/00 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound represented by the general formula [IA]: [Wherein R ¹ is OR ⁶ and R ² is a hydrogen atom, or R ¹ is a hydrogen atom and R ² is OR ⁶ ; R ³ , R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a protecting group for a hydroxyl group. Fluorinated vitamin D ₃ analog represented by the formula: 2. A compound represented by the general formula [IB]: [Wherein R ¹ is OR ⁶ and R ² is a hydrogen atom, or R ¹ is a hydrogen atom and R ² is OR ⁶ ; R ³ , R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a protecting group for a hydroxyl group. Fluorinated vitamin D ₃ analog represented by the formula: 3. A compound of the general formula [IC]: [Wherein R ¹ is OR ⁶ and R ² is a hydrogen atom, or R ¹ is a hydrogen atom and R ² is OR ⁶ ; R ³ , R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or a protecting group for a hydroxyl group. Fluorinated vitamin D ₃ analog represented by the formula: 4. The protecting group for a hydroxyl group is selected from the group consisting of methoxymethyl, ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and acetyl. The compound according to any one of the above.