JPH0873425A - Fluorinated vitamin d derivative and its production - Google Patents

Abstract

PURPOSE: To provide a new fluorinated vitamin D derivative free from side action when used as a remedy for osteoporosis and expected to have an improved bone-quantity improving action compared with conventional active vitamin D derivative. CONSTITUTION: This vitamin D derivative is 24,24-difluoro-1α-hydroxyvitamin D3 of formula I. The compound can be produced by reacting a compound of formula VI (R<1> and R<2> are each an alkylsulyl, an arylsilyl, acetoxy, tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl or ethoxyethyl; R<3> is an alkyl or an aryl) with a methyl metal compound, reacting the resultant compound of formula V with an alkyloxalyl chloride in an organic solvent in the presence of an amine to obtain a compound of formula IV, reacting the compound with a hydrogenated organic tin compound in the presence of a radical generating agent under heating, removing the protecting groups from the product, reacting the resultant compound of formula III with an alkali metal salt to obtain a compound of formula II, opening the ring of the produced compound and isomerizing by heating in an organic solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fluorinated vitamin D derivative and a method for producing the same. The present invention also relates to various synthetic intermediates for producing the vitamin D derivative and a method for producing the same. INDUSTRIAL APPLICABILITY The novel vitamin D derivative of the present invention is useful because it has an in vivo calcium regulating action and a tumor cell differentiation inducing action.

[0002]

PRIOR ART 1α-Hydroxyvitamin D ₃ and 1
α, 25-dihydroxyvitamin D ₃ is an active vitamin D ₃ having a high physiological action and is used as a therapeutic drug for renal failure rickets, osteoporosis and osteomalacia. Recently, treatment of psoriasis and its application as an anti-cancer agent have been attempted. Furthermore, it is known that vitamin D ₃ having fluorine also exhibits high activity, and the following are known as fluorinated vitamin D ₃ derivatives so far. Chemical formula (VII)

[0003]

[Chemical 7]

26, 26, 26, 27, 2 represented by
7,27-Hexafluoro-1α, 25-dihydroxyvitamin D ₃ [Chem. Pharm. Bull. , 3
0 , 4297 (1982)] and chemical formula (VIII)

[0005]

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24,24-difluoro-1 represented by
α, 25-dihydroxyvitamin D ₃ [Chem. Ph
arm. Bull. , 27 , 3196 (1979)] and the like. However, when these compounds are ingested in excess, they have a drawback of causing side effects such as hypercalcemia due to their strong physiological activity.

[0007]

Therefore, at present, there is a synthetic study on an active vitamin D derivative which has a bone mass improving effect comparable to or higher than that of active vitamin D ₃ and has less side effects and toxicity. It is being actively conducted. The present inventors have also synthesized a fluorinated vitamin D compound represented by the chemical formula (VIII) and confirmed that it has less side effects and an excellent bone mass improving effect as compared with conventional active vitamin D derivatives. ing. And although its analog can be expected to have a similar action, a compound in which the hydroxyl group at the 25-position is replaced by hydrogen, that is, the chemical formula (I)

[0008]

[Chemical 9]

1α-hydroxy-24,2 represented by
4-difluoromethoxy Vitamin D ₃ is not known conventionally difficulty and complexity of its synthesis.

Therefore, an object of the present invention is to provide a fluorinated vitamin D derivative [24,24-difluoro-1α-hydroxyvitamin D ₃ (I)] represented by the chemical formula (I) having a bone mass improving effect, and its synthesis. To provide an intermediate. Another object of the present invention is to provide a method for efficiently producing 24,24-difluoro-1α-hydroxyvitamin D ₃ (I).

[0011]

That is, the present invention relates to a fluorinated vitamin D derivative and a method for producing the same. More specifically, the chemical formula (I)

[0012]

[Chemical 10]

24,24-difluoro-1 represented by
α-Hydroxyvitamin D ₃ and its synthetic intermediate, chemical formula (II)

[0014]

[Chemical 11]

A compound represented by the general formula (III)

[0016]

[Chemical 12]

A compound represented by the formula (wherein R ³ represents an alkyl group or an aryl group), the general formula (IV)

[0018]

[Chemical 13]

(In the formula, R ¹ and R ² may be the same or different and each represents an alkylsilyl group, an arylsilyl group, an acetoxy group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a methoxymethyl group or an ethoxyethyl group. Where R ³ is as defined above and R ⁴
And R ⁵ may be the same or different and each represents an alkyloxalyl group) and a compound represented by the general formula (V)

[0020]

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A compound of the formula: wherein R ¹ , R ² and R ³ are as defined above. The present invention also provides a compound represented by the general formula (VI)

[0022]

[Chemical 15]

Starting from the provitamin D derivative represented by the formula: wherein R ¹ , R ² and R ³ are as defined above, the compounds of the general formula (V), of the general formula (IV) The present invention relates to a method for producing a fluorinated vitamin D derivative of the chemical formula (I) via a compound, a compound of the general formula (III) and a compound of the chemical formula (II).

The present invention will be summarized as follows. The 24,24-difluoro-1α-hydroxyvitamin D ₃ represented by the chemical formula (I) of the present invention can be obtained through the following reaction steps 1 to 5.

In the present invention, the organic solvent means an alcohol solvent, an ether solvent, an aprotic solvent, a halogen solvent, an aliphatic hydrocarbon solvent and an aromatic hydrocarbon solvent. The alcohol solvent is, for example, methanol or ethanol, and the ether solvent is, for example, an aliphatic ether such as ethyl ether or a heterocyclic ether such as tetrahydrofuran.

The aprotic polar solvent is, for example, dimethyl sulfoxide (DMSO), acetone, acetonitrile and the like, and the halogen type solvent is, for example, methylene chloride, chloroform and the like. Further, the aliphatic hydrocarbon solvent is, for example, pentane, hexane and the like, and the aromatic hydrocarbon solvent is, for example, benzene, toluene and the like. Further, in the present invention, the reaction is preferably carried out in an inert gas atmosphere, preferably an argon atmosphere. In all the reaction steps, isolation of the intermediate or the fluorinated vitamin D derivative of the formula (I) from the reaction mixture can be carried out by conventional purification means such as extraction column chromatography, recrystallization, preparative TLC, high performance liquid. It is performed by chromatography or the like.

Reaction Step 1: In producing the compound represented by the general formula (V), ethyl-24,24-difluoro-1α, 3 represented by the general formula (VI) in an organic solvent is used.
β-disubstituted oxy-5α, 8α- (3,5-dioxo-
4-Substituted-1,2,4-triazolidine-1,2-diyl) -23-hydroxyhomochol-6-ene-25-
A process for producing a compound of the general formula (V), which comprises reacting oate with a methyl metal compound. Here, the methyl metal compound is, for example, methyl magnesium halide (Grignard reagent), methyl lithium or the like.

Reaction step 2: In the production of the compound represented by the general formula (IV), the reaction step 1 is carried out in an organic solvent.
Is a process for producing a compound of the general formula (IV), which comprises reacting the compound represented by the general formula (V) described in 1) with an alkyloxalyl chloride in the presence of an amine. Here, the amine is, for example, triethylamine, pyridine,
4-dimethylaminopyridine, N, N-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] 7-
Such as Undecen. Alkyloxalyl chloride is
Preferred is methyloxalyl chloride.

Reaction step 3: In producing the compound represented by the general formula (III), the above-mentioned reaction step 2 is carried out in an organic solvent.
The compound represented by the general formula (IV) described in 1 above is reacted with an organotin hydride compound by heating in the presence of a radical generator to remove a hydroxyl group, and further deprotected with an organic acid or an inorganic acid in an organic solvent. Chemical formula (III) characterized by
Is a manufacturing process of the compound. Here, the radical generator is, for example, 2,2′-azobis (isobutylnitrile).
(AIBN), benzoyl peroxide and the like, and the hydrogenated organotin compound is, for example, trialkyltin hydride or triaryltin hydride. The organic acid or inorganic acid is, for example, p-toluenesulfonic acid, camphor-10-sulfonic acid, hydrochloric acid or the like.

Reaction Step 4: In the production of the compound represented by the chemical formula (II), the above Reaction Step 3 is carried out in an organic solvent.
In the process for producing the compound of the chemical formula (II), the compound represented by the general formula (III) described in 1) is reacted with an alkali metal salt or an aluminum hydride complex by heating. Here, the alkali metal salts are, for example, NaHC
O ₃ , K ₂ CO _{3 and the} like, and the aluminum hydride complexes are, for example, lithium aluminum hydride, diisobutylaluminum hydride and the like.

Reaction step 5: In producing the compound represented by the chemical formula (I), the reaction step 4 is carried out in an organic solvent.
In the process for producing a compound of the chemical formula (I), the compound represented by the chemical formula (II) described in 1 above is irradiated with light to open the ring, and further heated in an organic solvent for isomerization.
Here, the light irradiation is performed using a high-pressure mercury lamp, a medium-pressure mercury lamp, a low-pressure mercury lamp or the like as a light source.

A detailed description of each reaction step in the present invention will be described below.

In the reaction step 1, the step of producing the compound represented by the general formula (V) from the provitamin D derivative represented by the general formula (VI) is carried out in an ether type solvent by using the compound represented by the general formula (VI) as a starting material. It comprises reacting a compound with a methyl metal compound (eg, methyl magnesium halide, methyl lithium, etc.). Here, the methyl metal compound is 2 to 10 molar equivalents, preferably 6 to 8.5 molar equivalents, relative to the compound represented by the general formula (VI). The reaction temperature is -78 ° C to 50 ° C, preferably 0 ° C to room temperature,
The reaction time is 30 minutes to 4 hours, preferably 1 hour to 3 hours. The compound represented by the general formula (VI) as a raw material can be obtained by a known method [Chem. Pha
rm. Bull. , 40 , 1120 (1992)].

The step of producing the compound represented by the general formula (IV) from the compound represented by the general formula (V) in the reaction step 2 is represented by the general formula (V) in a halogen solvent, preferably methylene chloride. Consisting of reacting a compound with an alkyloxalyl chloride, preferably methyloxalyl chloride or ethyloxachloride, in the presence of an amine (eg triethylamine, pyridine, 4-dimethylaminopyridine, etc.). Here, the amine is 5 to 15 molar equivalents, preferably 8 to 12 molar equivalents with respect to the compound represented by the general formula (V), and methyloxalyl chloride or ethyloxachloride is represented by the general formula (V). It is 2 to 10 molar equivalents, preferably 4 to 8 molar equivalents, relative to the compound. Reaction temperature is -5
The temperature is 0 ° C to 50 ° C, preferably -10 ° C to room temperature, and the reaction time is 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

In the reaction step 3, the step of producing the compound represented by the general formula (III) from the compound represented by the general formula (IV) is carried out by using the general formula (IV) in an aromatic hydrocarbon solvent, preferably toluene. The compound represented is a radical generator [eg 2,2′-azobis (isobutylnitrile)]
(AIBN), benzoyl peroxide, etc.] in the presence of an organotin hydride compound (such as trialkyltin hydride or triaryltin hydride) to reduce the hydroxyl groups at the 23- and 25-positions. Here, the radical generator is 2 to 8 molar equivalents, preferably 4 to 6 molar equivalents, relative to the compound represented by the general formula (IV).
The reaction temperature is 70 ° C to 150 ° C, preferably 80 ° C to
It is 110 ° C., and the reaction time is 10 minutes to 2 hours, preferably 20 minutes to 60 minutes. After reduction of the hydroxyl group, the reaction product with an alcohol solvent, preferably methanol,
In a halogen solvent, preferably a 2: 1 to 1: 1 mixed solvent of chloroform, an organic acid or an inorganic acid [eg p-
[Toluenesulfonic acid or camphor-10-sulfonic acid, hydrochloric acid, etc.] to remove the protecting groups at the 1α and 3β positions. Here, the organic acid or inorganic acid is 1 to 5 molar equivalents, preferably 2 to 4 molar equivalents, relative to the compound represented by the general formula (IV). The reaction temperature is 0 ° C to 5 ° C.
The temperature is 0 ° C, preferably 10 ° C to room temperature, and the reaction time is 5 hours to 48 hours, preferably 8 hours to 24 hours.

In the reaction step 4, the step of producing the compound represented by the chemical formula (II) from the compound represented by the general formula (III) is carried out in an aprotic polar solvent, preferably dimethyl sulfoxide (DMSO). The compound represented by III) is converted to an alkali metal salt (for example, NaHC).
O ₃ , K ₂ CO _3, etc.) or aluminum hydride complexes [eg lithium aluminum hydride (LiAl
H _4), diisobutylaluminum hydride, etc.] are reacted, consists of elimination diene protecting group. Here, the alkali metal salt or aluminum hydride complex is 5 to 20 molar equivalents, preferably 10 to 15 molar equivalents, relative to the compound represented by the general formula (III). Reaction temperature is 70 ℃
To 150 ° C., preferably 80 to 110 ° C., and the reaction time is 5 hours to 48 hours, preferably 8 hours to 24 hours.

In the reaction step 5, the step of producing the compound represented by the chemical formula (I) from the compound represented by the chemical formula (II) is carried out by reacting the compound represented by the chemical formula (II) in an ether solvent, preferably ethyl ether. Preferably, the ring-opening is performed by irradiating with light, for example, by a high pressure mercury lamp under ice cooling. The reaction time is 3 minutes to 20 minutes, preferably 5 minutes to 10 minutes. Subsequently, it is heated in an alcoholic solvent, preferably ethanol, for isomerization. The reaction temperature is 60 ° C to 100 ° C, preferably 75 ° C to
It is 90 ° C., and the reaction time is 30 minutes to 120 minutes, preferably 40 minutes to 80 minutes.

As described above, 24,24-difluoro-1α-hydroxyvitamin D ₃ represented by the chemical formula (I) is obtained.

Starting from the compound represented by the general formula (VI) of the present invention, 24,24- represented by the chemical formula (I)
The synthetic route to obtain difluoro-1α-hydroxyvitamin D ₃ is shown in the following scheme.

[0040]

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Further, the novel fluorinated vitamin D ₃ of the present invention
Has no side effects when used as a remedy for osteoporosis,
In addition, a higher bone mass-improving action is expected as compared with the known active vitamin D derivatives.

[0042]

As described above, according to the present invention, a novel vitamin D derivative, 24,24-difluoro-1α, is obtained.
- hydroxyvitamin D _3, and can be relatively simple and efficient production of the intermediates.

Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

[0044]

【Example】

(1) 1α, 3β-di (t-butyldimethylsilyloxy) -24,24-difluoro-5α, 8α- (4-
Phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl) cholesta-6-ene-23,2
Preparation of 5-diol (V):

Under an argon atmosphere, 1α, 3β-di (t-
Butyldimethylsilyloxy) -24,24-difluoro-5α, 8α- (4-phenyl-3,5-dioxo-
Ethyl (1,2,4-triazolidine-1,2-diyl) cholesta-6-ene-24-carboxylate (VI) 63 mg
(0.071 mmol) was dissolved in 4 ml of dry ethyl ether, and methyl magnesium bromide (Et ₂ O) was added in an ice bath.
0.2 ml (0.60 mmol, 8.5 eq.) In 3M) was slowly added. The mixture was stirred at 0 ° C for 30 minutes, the ice bath was removed, and the mixture was further stirred at room temperature for 2 hours. It was quenched by adding water, extracted with ether, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 41 mg (yield 67%) of the compound of general formula (V).

¹ H-NMR (CDCl ₃ / TMS): δ
(Ppm) 0.06 (s, 3H), 0.88 (s, 3H), 0.0.
09 (s, 3H), 0.13 (s, 3H), 0.82 (s, 3
H), 0.88 (s, 9H), 0.89 (s, 9H), 0.92
(s, 3H), 1.07 (d, J = 6.7Hz, 3H), 1.8
8 (ddd, J = 2.4, 3.0, 10.1 Hz, 1H), 1.
95-2.12 (m, 5H), 2.43 (dd, J = 6.4,
12.2Hz, 1H), 2.45-2.59 (m, 2H), 2.
92-2.97 (m, 1H), 3.08-3.16 (m, 1
H), 3.23 (dd, J = 5.0, 13.7 Hz, 1H),
3.84 (t, J = 2.5Hz, 1H), 4.11 (dq, J
= 5.0, 10.1 Hz, 1H), 4.77 (tt, J = 5.
5,11.0Hz, 1H), 4.8 (s, 1H), 6.21
(D, J = 8.3Hz, 1H), 6.37 (d, J = 8.3H
z, 1H), 7.24-7.47 (m, 5H) IR (neat, cm ^-1 ): 3368, 1748, ¹
686, 1401 LR-MS: m / z 696 (M-PTAD), 63.
9 (M-PTAD-tBu), 564 (M-PTAD-
TBDMSOH), 507 (M-PTAD-TBDMS
OH-tBu) HR-MS: m / z (M-PTAD) C 39 H 70 O 4 S
i ₂ F ₂ theoretical value 696.4780 actual value 696.4778

(2) 1α, 3β-di (t-butyldimethylsilyloxy) -24,24-difluoro-23,
25-di (methyloxalyloxy) -5α, 8α-
(4-phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl) cholesta-6-ene-2
Production of 3,25-diol (IV):

Under an argon atmosphere, 1α, 3β-di (t-
Butyldimethylsilyloxy) -24,24-difluoro-5α, 8α- (4-phenyl-3,5-dioxo-
1,2,4-triazolidine-1,2-diyl) cholesta-6-ene-23,25-diol (V) 70.3 mg
(0.0348 mmol) and 4-dimethylaminopyridine (DMAP) 43.6 mg (0.357 mmol, 10e)
q. 2) dry methylene chloride (2 ml) and dissolved, and methyl oxalyl chloride 20 μl (0.217 mmol, 6
eq. ) Was added and the mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water, extracted with ether, and the organic layer was washed successively with saturated aqueous copper sulfate solution, water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography to give 18.1 mg (yield 5
0%) of the compound of general formula (IV) was obtained.

¹ H-NMR (CDCl 3 / TMS): δ
(Ppm) 3.84 (s, 3H), 3.91 (s, 3H)

(3) 24,24-difluoro-5α,
8α- (4-phenyl-3,5-dioxo-1,2,4
Preparation of -triazolidine-1,2-diyl) cholesta-6-ene-1α, 3β-diol (III):

1α, 3β-di (t-butyldimethylsilyloxy) -24,24-difluoro-23,25-di (methyloxalyloxy) -5α, 8α- (4-phenyl-3,5-dioxo-1) , 2,4-Triazolidine-1,2-diyl) cholesta-6-ene-23,25-
Diol (IV) 18.1 mg (0.0173 mmol) was dissolved in dry toluene 2.5 ml, and 2,2'-azobis (isobutyronitrile) (AIBN) 2.8 mg (0.017 m).
mol, 1 eq. ) And tributyltin hydride 19.0
μl (0.0706 mmol, 4 eq.) was added. Then, the atmosphere was replaced with argon and heated in an oil bath at 110 ° C. for 30 minutes. The reaction mixture was quenched with water, extracted with ether, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography, 7.2
Obtained mg of oil. This was further dissolved in 2 ml of a mixed solvent of chloroform-methanol 1: 1, a catalytic amount of camphorsulfonic acid was added, and the mixture was stirred at room temperature overnight. It was quenched by adding water, extracted with ethyl ether, and the organic layer was washed and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC, 3.1 mg
A compound of general formula (III) (yield 28%) was obtained.

[Α] _D = −33.6 ° (c1.00, CHCl ₃ ) ¹ H-NMR (CD ₃ OD / TMS): δ (ppm)
0.94 (s, 3H), 1.02 (s, 3H), 1.03 (d, J
= 6.6 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3
H), 2.61 (dd, J = 5.3, 12.7 Hz, 1H),
2.76 (dd, J = 7.0, 12.7Hz, 1H), 3.06
(Dd, J = 5.7, 14.1Hz, 1H), 3.90 (t,
J = 1.0 Hz, 1H), 4.77 (dd, J = 5.8, 11.
7Hz, 1H), 6.47 (d, J = 8.4Hz, 1H),
6.55 (d, J = 8.4 Hz, 1H), 7.36-7.52
(M, 5H) IR (neat, cm ⁻¹ ): 3420, 1744, ¹
682, 1412 LR-MS: m / z 436 (M-PTAD), 41.
_{8 (M-PTAD-H 2} O), 400 (M-PTAD-
2H ₂ O) HR-MS: m / z (M-PTAD) C ₂₇ H ₄₂ O ₂ F ₂
Theoretical value 436.3152 Measured value 436.3159

(4) Preparation of 24,24-difluorocholesta-5,7-diene-1α, 3β-diol (II):

24,24-Difluoro-5α, 8α-
(4-Phenyl-3,5-dioxo-1,2,4-triazolidine-1,2-diyl) cholesta-6-ene-1
α, 3β-diol (III) 20 mg (0.032 mmo
l) was dissolved in 3 ml of dimethyl sulfoxide, and 52.2 mg (0.378 mmol, 12 eq.) of potassium carbonate was added. The mixture was heated to 110 ° C. under an argon atmosphere and stirred overnight. Water was added thereto to quench the reaction, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Preparative T
Purified by LC, 14 mg (yield 98%) of general formula (II)
Was obtained.

[Α] _D = −53.3 ° (c1.00, CHCl ₃ ) UV (EtOH): λ _max 262 nm (sh), 270 n
m (ε6100), 281 nm (10500), 292
nm (9600) ¹ H-NMR (CDCl ₃ / TMS): δ (ppm)
0.64 (s, 3H), 0.95 (s, 3H), 0.96 (d, J
= 6.7 Hz, 3 H), 1.009 (d, J = 7.0 Hz, 3
H), 1.011 (d, J = 7.0Hz, 3H), 3.77
(Bs, 1H), 4.07 (ddd, J = 4.6, 11.3,
16.2Hz, 1H), 5.39 (quin, J = 2.4H
z, 1H), 5.74 (dd, J = 3.4, 5.5Hz, 1
H) IR (neat, cm ^-1 ): 3407, 1462, ¹
379 LR-MS: m / z 436 (M ⁺ ), 418 (M-).
H ₂ O), 400 (M-2H ₂ O) HR-MS: m / z (M ⁺ ) C ₂₇ H ₄₂ O ₂ F ₂ theoretical value 436.3153 measured value 436.3153

(5) 24,24-difluoro-1α-
Production of Hydroxyvitamin D ₃ (I):

24,24-Difluorocholesta-5,7
-Diene-1α, 3β-diol (II) 10 mg (0.0
2 mmol) was dissolved in 100 ml of dry ethyl ether and placed in a Pyrex photoreactor. Under an argon atmosphere, light irradiation was performed at 0 ° C. for 6 minutes with a high pressure mercury lamp (200 W) equipped with a Vycor filter. The solvent was distilled off under reduced pressure, 100 ml of ethanol was added, and the mixture was heated at 85 ° C. for 1 hour. After returning to room temperature, the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was dissolved in methylene chloride and subjected to high performance liquid chromatography (Lichrosor
b, 4x250mm, 8% i- PrOH-CH 2 C
I ₂ ) to obtain 2.7 mg (yield 27%) of the compound of general formula (I).

[Α] _D = + 75.6 ° (c0.15, CHCl ₃ ) UV (EtOH): λ _max 265 nm ¹ H-NMR (CDCl ³ / TMS): δ (ppm)
0.55 (s, 3H), 0.94 (d, J = 6.4Hz, 3
H), 1.00 (d, J = 7.0 Hz, 3H), 4.20-4.
25 (m, 1H), 4.43 (dd, J = 4.6, 7.6H
z, 1H), 5.00 (s, 1H), 5.33 (t, J = 1.7)
Hz, 1H), 6.02 (d, J = 11.5Hz, 1H),
6.38 (d, J = 11.5 Hz, 1H) IR (neat, cm ⁻¹ ): 3422, 1645, ¹
456 LR-MS: m / z 436 (M ⁺ ), 418 (M-).
H ₂ O), 400 (M-2H ₂ O), 152, 134 HR-MS: m / z (M ⁺ ) C ₂₇ H ₄₂ O ₂ F ₂ theoretical value 436.3153 measured value 436.3159

Claims (10)

[Claims] 1. A chemical formula (I): 24,24-difluoro-1α-hydroxyvitamin D ₃ represented by 2. A chemical formula (II): 24,24-difluorocholesta-5,7 represented by
-Diene-1α, 3β-diol. 3. A compound represented by the general formula (III): (In the formula, R ³ represents an alkyl group or an aryl group) 24,24-difluoro-5α, 8α- (3,
5-Dioxo-4-substituted-1,2,4-triazolidine-1,2-diyl) cholesta-6-ene-1α, 3β-
Diol. 4. A compound represented by the general formula (IV): (In the formula, R ¹ and R ² may be the same or different,
Each represents an alkylsilyl group, an arylsilyl group, an acetoxy group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a methoxymethyl group or an ethoxyethyl group,
R ³ represents an alkyl group or an aryl group, and R ⁴ and R ⁵ may be the same or different and each represents an alkyloxalyl group), 1α, 3β-disubstituted oxy-23,25-disubstituted Alkyl oxalyl-2
4,24-Difluoro-5α, 8α- (3,5-dioxo-4-substituted-1,2,4-triazolidine-1,2-
Jill) Cholesta-6-ene. 5. A compound represented by the general formula (V): (In the formula, R ¹ and R ² may be the same or different,
Each represents an alkylsilyl group, an arylsilyl group, an acetoxy group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a methoxymethyl group or an ethoxyethyl group,
R ³ represents an alkyl group or an aryl group) 1α, 3β-disubstituted oxy-24,24-difluoro-
5α, 8α- (3,5-dioxo-4-substituted-1,2,
4-triazolidine-1,2-diyl) cholesta-6-
En-23,25-diol. 6. In producing the compound represented by the chemical formula (I) according to claim 1, the compound represented by the chemical formula (II) according to claim 2 is irradiated with light in an organic solvent to ring-open, and A method for producing a compound of formula (I), which comprises heating in an organic solvent for isomerization. 7. In producing the compound represented by the chemical formula (II) according to claim 2, the compound represented by the general formula (III) according to claim 3 is mixed with an alkali metal salt or an aluminum hydride complex in an organic solvent. A method for producing a compound of the formula (II), which comprises reacting with a compound by heating. 8. When producing the compound represented by the general formula (III) according to claim 3, the compound represented by the general formula (IV) according to claim 4 in the presence of a radical generator in an organic solvent. A method for producing a compound of the chemical formula (III), which comprises heating and reacting with an organotin hydride compound to remove a hydroxyl group, and further deprotecting with an organic acid or an inorganic acid in an organic solvent. 9. When producing a compound represented by the general formula (IV) according to claim 4, the compound represented by the general formula (V) according to claim 5 is added to an alkyloxalyl in the presence of an amine in an organic solvent. A method for producing a compound of the general formula (IV), which comprises reacting with chloride. 10. When producing the compound represented by the general formula (V) according to claim 5, in the organic solvent, the compound represented by the general formula (VI): (In the formula, R ¹ and R ² may be the same or different,
Each represents an alkylsilyl group, an arylsilyl group, an acetoxy group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a methoxymethyl group or an ethoxyethyl group,
R ³ represents an alkyl group or an aryl group) 1α, 3β-disubstituted oxy-24,24-difluoro-
5α, 8α- (3,5-dioxo-4-substituted-1,2,
4-Triazolidine-1,2-diyl) -23-hydroxycholesta-6-ene-24-carboxylic acid alkyl ester and a methyl metal compound are reacted with each other to produce a compound of general formula (V). .