JPH08301842A - Fluorinated vitamin d derivative and its production - Google Patents

Abstract

PURPOSE: To obtain a new fluorinated vitamin D derivative having in vivo Ca controlling action or differentiating-inducing action of tumor cell and useful as a treating medicine for rickets having renal insufficiency, osteoporosis, etc., and psoriasis. CONSTITUTION: This fluorinated vitamin D derivative is expressed by formula I (R<1> is a 2-9C alkyl having an arbitrary substituent group; R<2> is H or hydroxyl group), e.g. (6S, 19R)-19-fluorinated vitamin D3 -SO2 adduct. The compound of formula I is obtained by carrying out reaction of a fluorinated vitamin D-SO2 adduct of formula II (R<2> is H or a protected hydroxyl group; R<5> is a protecting group of hydroxyl group; R<6> is F and R<7> is H or R<6> is H and R<7> is F) in the order of desulfonating step, a deprotecting group step and photoisomerization step. The compound of formula II is obtained by reacting a compound of formula III with N-fluorodibenzene-sulfonamide in an organic solvent in the presence of an alkali metal amide of formula IV (R<8> and R<9> are each trialkylsilyl, etc.; M is an alkali metal atom) and a base activating agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel vitamin D derivative and a method for producing the same. The vitamin D derivative has a calcium regulating action in vivo or a tumor cell differentiation inducing action, and is useful as a therapeutic drug for renal failure rickets, osteoporosis and the like and psoriasis.

[0002]

PRIOR ART 1α-Hydroxyvitamin D ₃ and 1
α, 25-dihydroxyvitamin D ₃ is currently used as an active vitamin D preparation for bone metabolic diseases such as renal insufficiency rickets, osteoporosis and osteomalacia. In addition, these active vitamin Ds were found to suppress the growth of keratinocytes in human epidermis (Endocrinology, 113, 1950 (198
3)), expectations for it as a drug for psoriasis are also increasing. On the other hand, as the vitamin D derivative in which the side chain portion of these compounds is modified with fluorine,

[Chemical 7] 26,26,26,27,27,27-hexafluoro-1α, represented by
25-dihydroxyvitamin D ₃ (Japanese Patent Publication No. 3-48903) or chemical formula (VII)

Embedded image 24,24-difluoro-1α, 25-dihydroxyvitamin D ₃ (Japanese Patent Publication No. 61-48501) and the like are known, both of which are extremely potent intestinal calcium compared with conventional active vitamin Ds. It is known to exhibit an absorption action and a differentiation inducing action of the human promyelocytic leukemia cell line HL-60.

Further, a compound in which the vitamin D conjugated triene moiety is modified with fluorine is represented by the chemical formula (VIII)

[Chemical 9] 6-fluorovitamin D ₃ represented by (J.Org.Chem., 5
0, 2007 (1985)), which is known to act as a vitamin D antagonist in vivo.

[0004]

The above chemical formula (VI),
Since the vitamin D derivatives shown in (VII) and (VIII) have various physiological activities, they are expected to be applied to various fields as therapeutic agents.
The compound of the general formula (I) in which the 19-position is modified with fluorine is difficult to synthesize, and thus far has not been produced. The object of the present invention is to provide a novel fluorinated vitamin D derivative represented by the general formula (I), which has been difficult to produce up to now.
It is an object of the present invention to provide an intermediate and a method for producing them.

[0005]

The present invention provides the following [1].
~ [11]. [1] General formula (I)

[Chemical 10] (In the formula, R ¹ represents an alkyl group having an arbitrary substituent and having 2 to 9 carbon atoms, and R ² represents a hydrogen atom or a hydroxyl group.) A fluorinated vitamin D derivative. [2] General formula (II)

[Chemical 11] (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms and having an arbitrary substituent, R ² is either a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ³ is a fluorine atom and R Fluorinated (5E) -vitamin D represented by ⁴ is a hydrogen atom, or R ³ is a hydrogen atom and R ⁴ is a fluorine atom, and R ⁵ is a hydrogen atom or a hydroxyl-protecting group.
Derivative. [3] General formula (III)

[Chemical 12] (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms having an arbitrary substituent, R ² is either a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ⁵ is a hydrogen atom or a hydroxyl group. R ⁶ is a fluorine atom and R ⁷
Is a hydrogen atom, or R ⁶ is a hydrogen atom and R ⁷ is a fluorine atom. ) Fluorinated vitamin D-SO ₂ adduct represented by [4] R ² is a hydrogen atom, a hydroxyl group, a trialkylsilyloxy group, a methoxymethoxy group, a methoxyethoxymethoxy group, or a tetrahydropyranyloxy group,
Fluorinated (5E) -vitamin D derivative represented by the general formula (II) according to [2], wherein R ⁵ is hydrogen atom, trialkylsilyl group, methoxymethyl group, methoxyethoxyethyl group or tetrahydropyranyl group. . [5] R ² is a hydrogen atom, a hydroxyl group, a trialkylsilyloxy group, a methoxymethoxy group, a methoxyethoxymethoxy group, or a tetrahydropyranyloxy group,
Fluorinated vitamin D-SO ₂ adduct represented by the general formula (III) according to [3], wherein R ⁵ is a hydrogen atom, a trialkylsilyl group, a methoxymethyl group, a methoxyethoxyethyl group, or a tetrahydropyranyl group. . [6] General formula (III ′)

[Chemical 13](In the formula, R¹Has 2 to 9 carbon atoms and has an arbitrary substituent
An alkyl group, R²Is a hydrogen atom, or is protected
Shows a hydroxyl group, R^FiveRepresents a protective group for hydroxyl group, R⁶Is
Fluorine atom and R⁷Is a hydrogen atom or R⁶Is a hydrogen atom
Tsu R⁷Represents a fluorine atom. ) Fluorinated vinyl represented by
Tamin D-SO₂Fluorinated bitters of general formula (I) derived from adducts
In a method for producing a Min D derivative, de-SO₂Chemical engineering
The deprotection group process and the photoisomerization process in this order.
Fluorinated vitamin D derivative of general formula (I) characterized by
Manufacturing method. [7] Fluorinated vitamin D represented by general formula (III ′)
-SO₂Induction of fluorinated vitamin D of general formula (I) from adduct
In the method for producing a conductor, a deprotecting group step, a de-SO ₂
It is characterized in that the reaction is carried out in the order of the photoisomerization step and the photoisomerization step.
Method for producing fluorinated vitamin D derivative of general formula (I)
Law. [8] In the photoisomerization step in an organic solvent in the presence of a photosensitizer,
Characterized by irradiating light to react [6] or
Fluorinated vitamin D derivative of the general formula (I) according to [7]
Body manufacturing method. [9] The deprotecting group step is performed in an organic solvent using a fluorine anion,
In the presence of acid or trialkylsilyl halide,
[6] or [7] characterized in that
A method for producing a fluorinated vitamin D derivative of the general formula (I). [10] De-SO₂Alkali metal salt in organic solvent
[6] characterized by reacting by heating in the presence of
Alternatively, the fluorinated vitamin of the general formula (I) according to [7]
Method for producing D derivative. [11] General formula (IV)

Embedded image (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms having an arbitrary substituent, R ² is a hydrogen atom or a protected hydroxyl group, and R ⁵ is a hydroxyl-protecting group.) The compound of formula (V)

[Chemical 15] (In the formula, R ⁸ and R ⁹ may be the same or different and each represents a trialkylsilyl group or an arbitrary alkyl group having 1 to 4 carbon atoms, and M represents an alkali metal atom.) A method for producing a fluorinated vitamin D-SO ₂ adduct of general formula (III '), which comprises reacting with N-fluorodibenzenesulfonamide in the presence of an amide and a base activator.

In the present invention, the general formulas (I), (II),
(III), (II '), (II''),(III') and (II
In the vitamin D derivative represented by I ″), R ¹ is an alkyl group having 2 to 9 carbon atoms and having an arbitrary substituent. The alkyl group having 2 to 9 carbon atoms is, for example, an ethyl group, a propyl group, a butyl group, an octyl group or a nonyl group. The optional substituent is, for example, a hydroxyl group, a halogen atom, a nitrile group or a formyl group. R ¹ may also be the side chain of vitamin D ₂ or vitamin D ₃ . In the description of the present invention, the compound (II ′) is a compound represented by the general formula (II) in which R ² is a hydrogen atom or a protected hydroxyl group and R ⁵ is a hydroxyl-protecting group. . The compound (II ″) is a compound represented by the general formula (II), R ²
Is a hydrogen atom or a hydroxyl group, and R ⁵ is a hydrogen atom. The compound (III ′) is a compound represented by the general formula (III) in which R ² is a hydrogen atom or a protected hydroxyl group and R ⁵ is a hydroxyl group-protecting group. The compound (III ″) is a compound represented by the general formula (III) in which R ² is a hydrogen atom or a hydroxyl group and R ⁵ is a hydrogen atom.

The manufacturing method [6] and [7] of the present invention comprises three steps including step 1 to step 3. Also [8]
The manufacturing method of [1] is step 1, the manufacturing method of [9] is step 2,
The manufacturing method [10] corresponds to step 3. Steps 1 to 3 are carried out in the order of step 3, step 2 and step 1 or in any order of step 2, step 3 and step 1. The manufacturing method of [11] corresponds to step 4.

The steps 1 to 4 will be described below. Process 1
Is a photoisomerization step, which is a step of producing a compound represented by the general formula (I) from the compound (II ″). This step is carried out by irradiating with light in the presence of a photosensitizer.
It is an EZ isomerization reaction step of the position double bond. Photosensitizers include, for example, anthracene, acridine, phenazine,
Eosin-Y and the like. Further, the wavelength at the time of light irradiation is visible to ultraviolet, and the light source is, for example, a halogen lamp, a xenon lamp, a high pressure mercury lamp or the like. The photosensitizer is used in 0.1-10 molar equivalents, preferably 0.5-5 molar equivalents, relative to compound (II ''). The reaction temperature is -20 ° C to room temperature, preferably 0 ° C to 5 ° C. The reaction time depends on the intensity of the light source, but it is 5 minutes to 1 hour, preferably 10 minutes to 30.
It's a minute. The organic solvent used in the reaction is preferably an aromatic hydrocarbon solvent or an alcohol solvent, and either a single solvent or a mixed solvent thereof can be used. In this step, both the 10 (E) -isomer and the 10 (Z) -isomer of compound (II ″) are converted into a single vitamin D derivative represented by the general formula (I) after irradiation with light. Become.

Step 2 is a step of deprotecting the hydroxyl-protecting group, which is a step of producing compound (II '') from compound (II ') or a compound (III'') from compound (III'). It is a process to do. The fluorine anion source used as the deprotecting agent is, for example, tetrabutylammonium fluoride, hydrofluoric acid, potassium fluoride, etc., and the acid is, for example, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, etc. . The trialkylsilyl halide is, for example, trimethyl bromide or trimethyl iodide. Deprotection base is raw material (compound (II ') or compound (III'))
To 1 to 20 molar equivalents, preferably 2 to 12 molar equivalents. The reaction temperature is -78 ° C to 50 ° C, preferably -40 ° C to room temperature. The reaction time is 30 minutes to 6 hours, preferably 1 hour to 4 hours. The organic solvent used in the reaction is preferably an anhydrous ether solvent or a halogen hydrocarbon solvent.

Step 3 is a step of removing SO ₂ by heating in the presence of an alkali metal salt. This step is compound (III ')
From the compound (II ′) or the compound (I
This is a step of producing compound (II '') from II ''). The alkali metal salt used in this step is, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like. The alkali metal salt is added in an amount of 1 to 20 molar equivalents, preferably 5 to 10 molar equivalents, based on the raw material (compound (III ') or compound (III'')). The reaction temperature is preferably in the range of 70 ° C to 120 ° C, and it is basically preferable to select an alcoholic solvent or an aprotic polar solvent having a boiling point within this range. The reaction time is 30 minutes to 3 hours, preferably 1 hour to 2 hours. The compound (III '), which is the starting material for this reaction, has four types of stereoisomers because it has asymmetric carbons at the 6- and 19-positions. It is derived from the vitamin D derivative represented by the general formula (I).

When the above-mentioned three steps are carried out, it may be carried out after purification by using a suitable purification means in each step, or may be carried out continuously without being purified.

The step 4 is carried out from the general formula (IV) to the general formula (II
I ') is a step for producing a compound, which is a fluorination reaction with N-fluorodibenzenesulfonamide under alkali metal amide and basic conditions. The compound of the general formula (IV) used as a raw material is a known method (Chem. Lett.
83 (1979), J.Org. Chem. 51, 1635 (1986) and J.Org.
Chem. 51, 4819 (1986)). The alkali metal amide of the general formula (V) is, for example, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, lithium tetramethylpiperidide lithium diisopropylamide. The base activator is, for example, hexamethylphosphoric triamide, N, N, N ',
Examples include N'-tetramethylethylenediamine. The alkali metal amide is 1 to 5 with respect to the raw material (general formula (IV)).
Add molar equivalents, preferably 1.5 to 3 molar equivalents. The base activator is added in an amount of 1 to 10 molar equivalents, preferably 3 to 6 molar equivalents, based on the raw material (general formula (IV)). N-fluorodibenzenesulfonamide is added in an amount of 1 to 5 molar equivalents, preferably 1.5 to 3 molar equivalents, based on the raw material (general formula (IV)). The reaction temperature is -100 ° C to -50 ° C, preferably -80 ° C to -60.
The reaction time is 5 minutes to 3 hours, preferably 10 minutes to 1.5 hours. The organic solvent used in the reaction is preferably an anhydrous ether solvent.

In the present invention, the ether solvent is, for example, diethyl ether, tetrahydrofuran or dioxane. The alcohol solvent is, for example, methanol or ethanol. The aromatic hydrocarbon solvent is
For example, benzene, toluene and the like. The aprotic polar solvent is, for example, dimethylformamide, dimethylsulfoxide or the like.

In the manufacturing method of the present invention, it is desirable to carry out all steps in an atmosphere of an inert gas such as argon gas. In addition, isolation of the intermediate and the vitamin D derivative of the general formula (I) from the general formula (I) from the reaction mixture can be carried out by a commonly used purification means such as extraction, recrystallization, column chromatography, separation through all the steps. It can be performed by preparative high performance liquid chromatography, preparative thin layer chromatography and the like.

[0015]

INDUSTRIAL APPLICABILITY The present invention uses a compound represented by the general formula (IV) obtained by a known method as a raw material to efficiently obtain a novel fluorinated vitamin D derivative represented by the general formula (I) in a short step. be able to. Furthermore, the present invention can provide a novel vitamin D preparation which is expected to be applicable to treatment of various diseases.

[0016]

EXAMPLES The present invention will be described more specifically with reference to Examples and Examples. The schemes below exemplify the embodiments of the synthetic routes of the general formulas (IV) to (I).

Embedded image The Greek numerals I to IV correspond to the respective general formulas, and the symbols a to b represent the embodiments of the general formula. Also,
(R, S) represents R-form and / or S-form. In addition, the Greek numeral of each compound in the present Reference Examples and Examples corresponds to the reaction scheme.

[0017] [Reference Example 1]: Vitamin D ₃ -SO ₂ adduct synthetic vitamin D ₃ of (IVa) (4.10g, 10.65mmol) and liquid sulfur dioxide (2
(0 ml) and stirred at room temperature for 30 minutes, excess liquid sulfur dioxide was blown off by blowing nitrogen gas, and the residue was dried under reduced pressure. The obtained crude SO ₂ adduct was dissolved in anhydrous dimethylformamide (10 ml), and imidazole (2.9
g, 42.64 mmol) and t-butyldimethylsilyl chloride (3.21 g, 21.32 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Water (150 ml) was added to the reaction mixture, and hexane (150 ml, 3 times) and ether (150 ml, 2 times) were added from the aqueous layer.
It was extracted in. The obtained organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (7.31 g). This was purified by silica gel column chromatography (150 g), and the (6S) -vitamin D ₃ -SO ₂ adduct (6S-IVa) (2.23) was obtained from the elution part of ethyl acetate: hexane (1: 9 (v / v)).
g), (6R) -vitamin D ₃ -SO ₂ adduct (6R-IVa) (1.94
g) and a mixture of both (1.50 g). Total yield 9
4.6%. The 6S: 6R ratio was about 1: 1 from the ¹ H-NMR spectrum measurement of the crude product.

6S-IVa: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.65 (3H, s,
H-18), 0.88 (9H, s, Si-tBu), 0.92 (3H, d, J = 6.5Hz, H-2
1), 0.8 to 2.3 (31H, m), 2.60 (1H, m), 3.65 (2H, m, H-19),
4.01 (1H, m, H-3), 4.52 and 4.78 (1H, d, J = 10.2Hz, H respectively)
-6,7)

6R-IVa: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.57 (3H, s, respectively)
H-18), 0.86 and 0.87 (3H, d, J = 6.3Hz, H-26,27),
0.88 (9H, s, Si-tBu), 0.93 (3H, d, J = 6.1Hz, H-21), 0.9〜
2.3 (25H, m), 2.57 (1H, m), 3.64 and 3.68 (each 1H, d, J =
16.0Hz, H-19), 3.97 (1H, m, H-3), 4.63 and 4.78 (1 each)
(H, d, J = 10.2Hz, H-6,7)

Reference Example 2 Vitamin D₂-SO₂Adduct
Synthesis of (IVb) Vitamin D₂Using the above as a raw material and the same operation as in Reference Example 1,
(6S) -Vitamin D₂-SO ₂Adducts (6S-IVb) and (6R)-
Vitamin D₂-SO₂An adduct (6R-IVb) was obtained.

6S-IVb: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.66 (3H, s,
H-18), 0.82 and 0.84 (each 3H, d, J = 7.0Hz, H-26,27),
0.88 (9H, s, Si-tBu), 0.92 (3H, d, J = 6.7Hz), 1.02 (3H, d, J
= 6.8Hz), 1.25 to 2.65 (21H, m), 3.65 (2H, m, H-19), 4.01
(1H, m, H-3), 4.52 and 4.69 (each 1H, d, J = 9.4Hz, H-6,
7), 5.19 (2H, m, H-22,23)

6R-IVb: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.57 (3H, s,
H-18), 0.82 and 0.84 (each 3H, d, J = 7.0Hz, H-26,27),
0.88 (9H, s, Si-tBu), 0.92 (3H, d, J = 7.1Hz,), 1.03 (3H, d,
J = 6.8Hz), 1.25 to 2.65 (21H, m), 3.64 and 3.69 (each 1
H, d, J = 15.8Hz, H-19), 3.97 (1H, m, H-3), 4.63 and 4.77
(1H, d, J = 10.4Hz, H-6,7), 5.20 (2H, m, H-22,23)

Reference Example 3 1α-hydroxyvitamin D ₃
Synthesis of -SO ₂ adduct (IVc) (5E) -1α- methoxymethoxy - vitamin D ₃ -3β-t- butyldimethylsilyl protecting body (830.0mg, 1.48mmol) liquid sulfur dioxide in anhydrous dichloromethane (5ml) of (About 15m
After refluxing with l) for 30 minutes at -10 ° C, the solvent and liquid sulfur dioxide were distilled off under reduced pressure. The crude product was purified by silica gel chromatography (100 g), and the (6S) -1α-hydroxyvitamin D ₃ -SO ₂ adduct (from the elution part of ethyl acetate: hexane (1: 5 (v / v)) was added ( 6S-IVc) (608.5
mg), (6R) -1α-hydroxyvitamin vitamin D ₃ -SO
₂ adduct (6R-IVc) (142.2 mg) was obtained. Total yield 8
1.1%.

6S-IVc: ¹ H-NMR (δ (ppm), CDCl _{3 /} TMS): δ; 0.06 and 0.07
(3H, s, 2 × Si-CH ₃ ), 0.66 (3H, s, H-18), 0.86 (3H, d, J
= 6.6Hz, H-26,27), 0.88 (9H, s, Si-tBu), 0.92 (3H, d, J = 6.
3Hz, H-21), 2.19 (1H, m), 2.61 (1H, m), 3.38 (3H, s, OC
H ₃ ), 3.66 and 3.98 (1H, d, J = 15.7Hz, H-19, respectively), 4.16 (1
H, m, H-3), 4.22 (1H, m, H-1), 4.59 and 4.72 (1H, d, respectively)
J = 7.0Hz, -OCH ₂ O-), 4.65 and 4.72 (1H, d, J = 9.6Hz, respectively)
H-6,7)

6R-IVc: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.07 (each 3H, s, 2 × Si-CH ₃ ), 0.56 (3H, s,
H-18), 0.88 (9H, s, Si-tBu), 0.93 (3H, d, J = 6.1Hz, H-2
1), 0.9 ~ 2.3 (25H, m), 2.35 (1H, m), 2.55 (1H, m), 3.39
(3H, s, OCH ₃ ), 3.68 (1H, dd, J = 16.1,2.9Hz, H-19), 3.96 (1
H, d, J = 16.1Hz, H-19), 4.12 (1H, m, H-3), 4.22 (1H, m, H-
1), 4.60 and 4.73 (each 1H, d, J = 7.0Hz, -OCH ₂ O-), 4.62
And 4.80 (1H, d, J = 10.2Hz, H-6,7 respectively)

[Example 1] 19-fluorination reaction of vitamin D-SO ₂ adduct (III ') Example 1-1: (6S-III'a) (6S) -obtained in Reference Example 1 Vitamin D ₃ -SO ₂ adduct (6S
-IVa) (225 mg, 0.40 mmol), hexamethylphosphoric triamide (139 μl, 0.80 mmol) and N-fluorodibenzenesulfonamide (151.4 mg, 0.48 mmol) were dissolved in anhydrous tetrahydrofuran (3 ml), and the solution was heated to -78 ° C. Cooled. Lithium bistrimethylsilylamide (1M tetrahydrofuran solution, 480 μl, 0.48 mmol) was added to this cooling and stirring solution, and the mixture was further stirred for 1 hour. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture and ether (3 x 30 ml) was added.
Times). The ether layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue (340.2 mg) was purified by silica gel column chromatography (50 g) using 3% ethyl acetate-containing hexane as an elution solvent to obtain (6S, 19R) -19-fluorinated vitamin D ₃ -SO ₂ adduct. (6S, 19R-III'a) (low polarity compound, 69.3 mg, yield 30.0%), (6S, 19S) -19-fluorinated vitamin D ₃ -SO ₂ adduct (6S, 19S-III'a) (Highly polar compound, 23.5 mg, yield 10.1%) and unreacted raw materials (47.
9 mg, recovery rate 21.3%) was obtained.

6S, 19R-III'a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.07 (3H, s, 2 × Si-CH ₃ ), 0.65 (3H, s,
H-18), 0.87 (9H, s, Si-tBu), 0.85 to 2.20 (29H, m), 0.93
(3H, d, J = 6.4Hz, H-21), 2.32 (2H, m), 2.60 (1H, m), 4.04
(1H, m, H-3), 4.66 (2H, m, H-6,7), 5.42 (1H, d, J = 56.9Hz, H
-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ; -165.20 (d, J = 56.4Hz) MS m / z (%): 516 (100, (M-SO ₂ ) ⁺ ), 496 (11), 459 (1
3), 439 (7), 431 (4), 403 (10), 384 (19), 364 (47), 362
(15), 349 (9), 309 (4), 271 (19), 259 (30), 251 (45), 2
47 (21), 211 (61), 197 (18), 157 (13), 155 (11), 136 (3
7), 135 (31), 117 (47)

6S, 19S-III'a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.07 (3H, s, 2 × Si-CH ₃ ), 0.66 (3H, s,
H-18), 0.87 (9H, s, Si-tBu), 0.92 (3H, d, J = 7.0Hz, H-2
1), 0.80 to 2.65 (32H, m), 4.04 (1H, m, H-3), 4.43 and
4.65 (1H, d, J = 9.6Hz, H-6,7), 5.35 (1H, d, J = 56.3Hz, H
-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ; -160.98 (d, J = 56.4Hz)

Example 1-2 (6R-III'a) Using the same reaction conditions as in Example 1-1, (6R) -vitamin D ₃ -SO ₂ adduct (6R-IVa) (2.64 g, 4.69mmol) 19-
Fluorinated, (6R, 19S) -19-Fluorinated Vitamin D
_3- SO ₂ adduct (6R, 19S-III'a) (744.3 mg, yield 27.4
%), (6R, 19R) -19-fluorinated vitamin D ₃ -SO ₂ adduct (6R, 19R-IIIa) (451.9 mg, yield 17.2%) and unreacted raw material (796.7 mg, recovery 30.2%) Got

6R, 19S-III'a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.56 (3H, s,
H-18), 0.87 (9H, s, Si-tBu), 0.93 (3H, d, J = 5.9Hz, H-2
1), 0.85 to 2.25 (29H, m), 2.33 (1H, m), 2.48 (1H, m), 2.5
5 (1H, m), 3.99 (1H, m, H-3), 4.74 (2H, s, H-6,7), 5.37 (1
H, d, J = 56.7Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ P
h): δ; -164.72 (d, J = 57.1Hz)

6R, 19R-III'a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.55 (3H, s,
H-18), 0.88 (9H, s, Si-tBu), 0.93 (3H, d, J = 6.0Hz, H-2
1), 0.85 to 2.10 (29H, m), 2.35 (2H, m), 2.57 (1H, m), 4.0
1 (1H, m, H-3), 4.50 and 4.69 (1H, d, J = 10.1Hz, H-6,
7), 5.40 (1H, d, J = 54.6Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ; -161.59 (d, J = 56.4Hz)

Example 1-3 (III'b) The 19-fluorination reaction was carried out using the same reaction conditions as in Example 1-1 to give a (6S) -vitamin D ₂ -SO ₂ adduct (6S- IVb)
From (6S, 19R) -19-fluorinated vitamin D ₂ -SO ₂ adduct (6
S, 19R-III'b) and (6R) -vitamin D ₂ -SO ₂ adduct (6R-IVb) to (6R, 19S) -19-fluorinated vitamin D ₂ -S
An O ₂ adduct (6R, 19S-III′b) was synthesized.

6S, 19R-III'b: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.66 (3H, s,
H-18), 0.82 and 0.84 (3H, d, J = 6.7Hz, H-26,27),
0.87 (9H, s, Si-tBu), 0.92 (3H, d, J = 7.1Hz,), 1.02 (3H, d,
J = 6.7Hz), 1.20-2.25 (18H, m), 2.31 (2H, m), 2.60 (1H, m)
m), 4.05 (1H, m, H-3), 4.65 (2H, m, H-6,7), 5.20 (2H, m, H-
22,23), 5.42 (1H, d, J = 57.0Hz, H-19) MS m / z (%): 528 (84, (M-SO ₂ ) ⁺ ), 471 (12), 451 (10) ，
403 (30), 271 (68), 251 (47), 211 (62), 137 (100), 117
(74)

6R, 19S-III'b: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.05 and 0.06 (3H, s, 2 × Si-CH ₃ ), 0.58 (3H, s,
H-18), 0.82 and 0.84 (3H, d, J = 6.6Hz, H-26,27),
0.88 (9H, s, Si-tBu), 0.92 (3H, d, J = 6.8Hz,), 1.03 (3H, d,
J = 6.6Hz), 1.20 ~ 2.20 (18H, m), 2.34 (1H, m), 2.50 (1H, m)
m), 2.55 (1H, m), 4.00 (1H, m, H-3), 4.75 (2H, br, H-6,
7), 5.20 (2H, m, H-22,23), 5.37 (1H, d, J = 56.7Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ -164.73 (d, J = 57.2Hz)

Example 1-4 (6R-III'c) Using the same reaction conditions as in Example 1-1, (6R) -1α-methoxymethoxy-3β-t-butyldimethylsilyloxyvitamin D _3-. SO ₂ adduct (6R-IVc) (41.3mg, 0.066mmo
l) 19-fluorination reaction of (6R, 19R) -1α-methoxymethoxy-3β-t-butyldimethylsilyloxy-19-fluorinated vitamin D ₃ -SO ₂ adduct (6R, 19R-III ' c) (10.2
mg, yield 24.0%) and unreacted raw material (16.1 mg, recovery rate 39.
0%) was obtained.

6R, 19R-III'c: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.06 and 0.07 (3H, s, 2 × Si-CH ₃ ), 0.57 (3H, 3H, s,
H-18), 0.88 (9H, s, Si-tBu), 0.93 (3H, d, J = 5.9Hz, H-2
1), 2.42 (1H, m), 2.54 (1H, m), 3.40 (3H, s, OCH ₃ ), 4.16
(1H, m, H-3), 4.44 (1H, br s, H-1), 4.67 and 4.76 (respectively
1H, d, J = 7.0Hz, -OCH ₂ O-), 4.78 (2H, m, H-6,7), 5.70 (1H,
d, J = 56.9Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ; -166.34 (d, J = 57.4Hz)

[Example 2]: 19-fluorinated vitamin D-S
De-SO ₂ conversion reaction of O ₂ adduct (III ′) Example 2-1: (6S, 19R) -19-fluorinated vitamin D ₃ —SO ₂ adduct (6S, 19R) obtained in Example 1-1. 19R-III'a) (84
2.5 mg, 1.45 mmol) and sodium hydrogen carbonate (609.2 mg,
After argon gas was passed through a suspension of 7.25 mmol) in ethanol (20 ml) for about 10 minutes, the mixture was heated in a sealed tube at 80 ° C. for 1.5 hours. After cooling the reaction solution, the insoluble matter was removed by filtration. Saturated saline (50 ml) was added to the filtrate, and ethyl acetate (3 x 100 m
It was extracted in l). The ethyl acetate layers were combined and washed with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained crude product (786.7 mg) was purified by silica gel column chromatography (80 g), and hexane containing 2% ethyl acetate was used as an eluent to extract (5Z, 10E) -3-t-butyldimethylsilyloxy-19-. Fluorovitamin D ₃ (hydroxyl protected form of Ia) (94.0 mg, yield 12.5%) and (5E, 10Z) -3-t
-Butyldimethylsilyloxy-19-fluorovitamin D ₃
(10Z-II'a) (447.2 mg, yield 59.7%) was obtained, and further 3%
Hexane containing ethyl acetate was added to the unreacted raw material (19
3.0 mg, recovery rate 22.9%) was recovered.

10Z-II'a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.06 and 0.07 (3H, s, 2 × Si-CH ₃ ), 0.56 (3H, s, respectively) H-1
8), 0.868 and 0.873 (3H, d, J = 6.6Hz, H-26, 27), 0.88
(9H, s, Si-tBu), 0.92 (3H, d, J = 6.4Hz, H-21), 2.26 (2H,
m), 2.64 (1H, m), 2.81 (1H, m), 3.84 (1H, m, H-3), 5.92 and 6.57 (1H, d, J = 11.5Hz, H-6,7), 6.48 (1H, d, J = 85.
7Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-135.92 (d, J = 86.5Hz) MS m / z (%): 516 (100, M ⁺ ) ， 496 (9) ， 459 (7) ， 455
(4), 439 (4), 403 (5), 384 (9), 364 (33), 362 (25), 349
(7), 309 (28), 271 (12), 259 (19), 251 (29), 247 (20),
211 (22), 197 (12), 157 (9), 155 (8), 136 (16), 135 (2
0), 117 (22) UV λmax (Hexane): 204,269nm

Ia (protected hydroxyl group): ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.069 and 0.073 (3H, s, 2 × Si-CH ₃ ), 0.55 (3H, s, respectively) , H-
18), 0.869 and 0.874 (3H, d, J = 6.6Hz, H-26,27), 0.8
9 (9H, s, Si-tBu), 0.92 (3H, d, J = 6.4Hz, H-21), 2.20 and
2.45 (1H, m, H-4), 2.72 (1H, m), 2.80 (1H, m), 3.81 (1
H, m, H-3), 5.92 and 6.21 (1H, d, J = 11.0Hz, H-6,
7), 6.49 (1H, d, J = 87.6Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-132.96 (d, J = 86.5Hz) MS m / z (%): 516 (44, M ⁺ ), 496 (7), 459 (18), 439 (1
0), 403 (6), 384 (23), 364 (20), 362 (13), 349 (4), 309
(5), 271 (13), 259 (9), 251 (17), 247 (27), 211 (100),
157 (12), 136 (81), 135 (54), 117 (22) UV λmax (Hexane): 211, 262nm

Example 2-2: Obtained in Example 1-1 (6
S, 19S) -19-Fluorinated vitamin D ₃ -SO ₂ adduct (6S, 19S-
The same operation as in Example 2-1 was carried out from a suspension of III'a) (206.7 mg, 0.36 mmol) and sodium hydrogen carbonate (149.4 mg, 1.78 mmol) in ethanol (20 ml). The crude product was purified by silica gel column chromatography (20 g) to give (5E, 10E) -3-t-butyldimethylsilyloxy-19-fluorovitamin D ₃ (10E-II′a) (111.5 mg, yield 60.6).
%). In this de-SO ₂ conversion reaction, (5Z) -vitamin D
The body did not produce at all.

10E-II'a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.06 and 0.07 (each 3H, s, 2 × Si-CH ₃ ), 0.55 (3H, s, H-1
8), 0.86 and 0.87 (3H, d, J = 6.6Hz, H-26,27), 0.88 (9
H, s, Si-tBu), 0.92 (3H, d, J = 6.3Hz, H-21), 2.25 (1H, m),
2.61 (2H, m), 2.81 (1H, m), 3.85 (1H, m, H-3), 5.81 and 6.
29 (1H, d, J = 11.4Hz, H-6,7), 6.66 (1H, d, J = 87.1Hz,
H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-137.15 (d, J = 87.0Hz) MS m / z (%): 516 (100, M ⁺ ), 496 (12), 459 (10), 455
(9), 439 (7), 403 (7), 384 (16), 364 (49), 362 (37), 34
9 (11), 309 (24), 271 (18), 259 (22), 251 (49), 247 (3
7), 211 (78), 197 (22), 157 (17), 155 (16), 136 (62), 1
35 (54), 117 (71)

Example 2-3: Obtained in Example 1-2 (6
R, 19S) -19-Fluorinated vitamin D ₃ -SO ₂ adduct (6R, 19S-
The same operation as in Example 2-1 was carried out from a suspension of III'a) (103.6 mg, 0.18 mmol) and sodium hydrogen carbonate (75.1 mg, 0.89 mmol) in ethanol (15 ml). The crude product was purified by silica gel column chromatography (10 g) to obtain (5Z, 10E) -3-t-butyldimethylsilyloxy-19-fluorovitamin D ₃ (hydroxyl-protected form of I) and (5E, 10Z).
-3-t-Butyldimethylsilyloxy-19-fluorovitamin D ₃ (10Z-II'a) (67.8 mg, total yield 73.7%, production ratio about 1: 8 to 1: 9) was obtained. The reaction raw material (8.9 mg) was recovered. The hydroxyl-protected compound of I and 10Z-II'a obtained here
The various spectral data of was in agreement with each compound obtained in Example 2-1.

Example 2-4: Obtained in Example 1-2 (6
R, 19R) -19-Fluorinated vitamin D ₃ -SO ₂ adduct (6R, 19R-
The same operation as in Example 2-1 was carried out from a suspension of III'a) (49.7 mg, 0.086 mmol) and sodium hydrogen carbonate (34.3 mg, 0.428 mmol) in ethanol (5 ml). The crude product was purified by silica gel column chromatography (5 g) to give (5E, 10E) -3-t-butyldimethylsilyloxy-19-fluorovitamin D ₃ (10E-II′a) (35.2 mg, yield 79.6).
%). Various spectral data of 10E-II'a obtained here were in agreement with the respective compounds obtained in Example 2-2.

Example 2-5: Obtained in Example 1-3 (6
S, 19R) -19-Fluorinated vitamin D ₂ -SO ₂ adduct (6S, 19R-
From III'b), the same procedure as in Example 2-1 was performed to remove SO _2.
Was carried out to synthesize (5E, 10Z) -3-t-butyldimethylsilyloxy-19-fluorovitamin D ₂ (10Z-II′b).

10Z-II'b: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.06 and 0.07 (each 3H, s, 2 × Si-CH ₃ ), 0.57 (3H, s, H-1
8), 0.83 and 0.84 (3H, d, J = 7.9Hz, H-26,27), 0.88 (9
H, s, Si-tBu), 0.92 (3H, d, J = 6.8Hz), 1.02 (3H, d, J = 6.4H
z), 2.25 (2H, m), 2.63 (1H, m), 2.82 (1H, m), 3.84 (1H, m,
H-3), 5.20 (2H, m, H-22,23), 5.92 and 6.57 (1H, d, J respectively)
= 11.6Hz, H-6,7), 6.48 (1H, d, J = 86.1Hz, H-19)

[Example 3]: Deprotection group reaction of (5E) -3-t-butyldimethylsilyloxy-19-fluorinated vitamin D (II ') Example 3-1: Obtained in Example 2-1. (5E, 10Z) -3-t-
Butyldimethylsilyloxy-19-fluorovitamin D ₃
(10Z-II'a) (27.6mg, 0.053mmol) was dissolved in anhydrous tetrahydrofuran (2ml) and tetra-n-butylammonium fluoride (1.0M tetrahydrofuran solution, 0.160m) was added.
mol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ether (50 ml), the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (5 g), and hexane containing 3% ethyl acetate was used as the eluent to obtain (5E, 10Z) -19-fluorovitamin D.
₃ (10Z-II ″ a) (20.1 mg, yield 93.6%) was obtained.

10Z-II''a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.56 (3H, s, H-18), 0.867 and 0.871 (3H, d, J = respectively) 6.6H
z, H-26,27), 0.92 (3H, d, J = 6.4Hz, H-21), 2.83 (2H, m),
3.86 (1H, m, H-3), 5.93 and 6.63 (1H, d, J = 11.5Hz, H-
6,7), 6.51 (1H, d, J = 86.6Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-134.81 (d, J = 85.5Hz) UV λmax (EtOH): 270nm

Example 3-2: (5E, 10E) -3-t-Butyldimethylsilyloxy-19-fluorovitamin D ₃ (10E-II′a) (100.0 mg, obtained in Example 2-2) 0.19mmol),
The same operation as in Example 3-1 was performed using a mixed solution of anhydrous tetrahydrofuran (5 ml) and tetra-n-butylammonium fluoride (3 equivalents). The crude product was purified by silica gel column chromatography (15g), (5E, 10
E) -19-Fluorovitamin D ₃ (10E-II ″ a) (68.2 mg,
Yield 87.5%) was obtained.

10E-II''a: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.55 (3H, s, H-18), 0.868 and 0.873 (3H, d, J = respectively) 6.6H
z, H-26,27), 0.92 (3H, d, J = 6.7Hz, H-21), 2.67 (1H, m),
2.82 (2H, m), 3.88 (1H, m, H-3), 5.83 and 6.35 (1H, each
d, J = 11.5Hz, H-6,7), 6.69 (1H, d, J = 86.7Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-135.42 (d, J = 86.6Hz) MS m / z (%): 402 (35, M ⁺ ), 384 (28), 364 (31), 362 (3
0), 347 (7), 317 (5), 299 (4), 289 (12), 271 (24), 251
(27), 247 (24), 223 (10), 195 (19), 176 (16), 154 (3
5), 135 (100) UV λmax (EtOH): 209, 269nm

Example 3-3: From (5E, 10Z) -3-t-butyldimethylsilyloxy-19-fluorovitamin D ₂ (10Z-II′b) obtained in Example 2-5, Example 3 was obtained. The deprotection reaction was carried out by the same operation as in -1, and (5E, 10Z) -19-fluorovitamin D ₂ (10Z-II ″ b) was synthesized.

10Z-II''b: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.58 (3H, s, H-18), 0.83 and 0.85 (3H, d, J = respectively) 6.5Hz, H
-26,27), 0.93 (3H, d, J = 6.8Hz, H-21), 1.02 (3H, d, J = 6.7H
z), 2.23 (2H, m), 2.83 (2H, m), 3.87 (1H, m, H-3), 5.20 (2
H, m, H-22,23), 5.93 and 6.64 (each 1H, d, J = 11.7Hz, H-6,
7), 6.51 (1H, d, J = 85.9Hz, H-19)

[Example 4]: Photosensitized isomerization reaction of (5E) -19-fluorinated vitamin D (II '') Example 4-1: Obtained in Example 3-1 (5E, 10Z). ) -19-
Fluorovitamin D ₃ (10Z-II ″ a) (20.0mg, 0.05mmo
l) and anthracene (44 mg, 0.25 mmol) are dissolved in a mixed solvent of benzene-ethanol (5:95 (v / v), 200 ml) and the mixture is cooled to 0 ° C.
Was irradiated with light (halogen lamp, 200 W). 5
The progress of the reaction was monitored by HPLC for each light irradiation for 15 minutes, and light irradiation was performed for 15 minutes in total. After distilling off the reaction solvent, the residue was subjected to silica gel column chromatography (5 g).
Purified by, and from the elution part of hexane containing 4% ethyl acetate
(10E) -19-Fluorovitamin D ₃ (Ia) (15.4 mg, yield
76.8%) was obtained.

Ia: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ0.53 (3H, s, H-18), 0.86 and 0.87 (3H, d, J = 6.6Hz, H respectively)
-26,27), 0.92 (3H, d, J = 6.4Hz, H-21), 2.56 (2H, m), 2.78
(1H, m), 3.93 (1H, m, H-3), 5.93 and 6.28 (1H, d, J = 1 respectively)
1.1Hz, H-6,7), 6.51 (1H, d, J = 87.4Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-132.50 (d, J = 86.5Hz) MS m / z (%): 402 (27, M ⁺ ), 384 (34), 362 (90), 360 (4
8), 347 (28), 289 (13), 271 (51), 249 (94), 247 (57), 2
23 (30), 195 (37), 179 (20), 154 (45), 135 (100) UV λmax (EtOH): 211, 260nm

Example 4-2: (5E, 10E) -19-fluorovitamin D ₃ (10E-II ″ a) obtained in Example 3-2 (4.
1 mg, 0.01 mmol), anthracene (9 mg, 0.05 mmol) and benzene-ethanol (5:95 (v / v), 100 ml) mixed solvent were used to perform the same operation as in Example 4-1. The crude product was purified by silica gel column chromatography (2g),
(10E) -19-Fluorovitamin D ₃ (Ia) (2.7 mg, yield 6
5.9%) was obtained. This compound completely coincided with the compound Ia obtained in Example 4-1 in NMR, MS and UV spectra.

Example 4-3: From (5E, 19Z) -19-fluorovitamin D ₂ (19Z-II ″ b) obtained in Example 3-3, light was applied in the same manner as in Example 4-1. A sensitized isomerization reaction was performed to synthesize (19E) -19-fluorovitamin D ₂ (Ib).

Ib: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ0.55 (3H, s, H-18), 0.82 and 0.83 (3H, d, J = 6.5Hz, H respectively)
-26,27), 0.91 (3H, d, J = 6.8Hz,), 1.01 (3H, d, J = 6.6Hz),
2.23 (2H, m), 2.56 (2H, M), 2.79 (1H, m), 3.94 (1H, m, H-
3), 5.20 (2H, m, H-22,23), 5.93 and 6.28 (1H, d, J = 1 respectively)
1.0Hz, H-6,7), 6.50 (1H, d, J = 87.3Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-132.48 (d, J = 87.4Hz) UV λmax (EtOH): 210, 260nm

[Example 5] 19-fluorinated vitamin D-S
Deprotection reaction of O ₂ adduct (III ′) (6R, 19R) -1α-methoxymethoxy-3β-t-butyldimethylsilyloxy-19-fluorinated vitamin D ₃ -SO obtained in Example 1-4 ₂ adduct (6R, 19R-III'c) (17.0mg, 0.
0265 mmol) in anhydrous dichloromethane (0.5 ml),
Trimethylsilyl bromide (7μl, 0.05
3 mmol) was added. After 2 hours, trimethylsilyl bromide (7 μl, 0.053 mmol) was added, and the mixture was further stirred at the same temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3 g) and deprotected (6R, 19R) -1α-hydroxy-19-fluorinated vitamin D ₃ -SO ₂ adduct (6R, 19R-
IIIc) (7.3 mg, yield 57.0%) was obtained.

6R, 19R-III''c: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ; 0.57 (3H, s, H-18), 0.867 and 0.873 (3H, d, respectively) J =
6.6Hz, -26,27), 0.93 (3H, d, J = 6.0Hz, H-21), 2.45-2.60
(2H, m), 4.28 (1H, m, H-3), 4.66 (1H, br s, H-1), 4.75 and 4.85 (1H, d, J = 10.0Hz, H-6,7), 5.78 (1H, d, J = 56.
5Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ; -165.94 (d, J = 56.6Hz) MS m / z (%): 418 (11, M ⁺ -SO ₂ ), 398 (16), 378 (25), 36
2 (14), 360 (10), 347 (6), 305 (5), 287 (7), 285 (9), 26
5 (20), 247 (30), 245 (15), 193 (15), 161 (18), 135 (5
6), 133 (48), 109 (39), 107 (43), 105 (58), 95 (67), 81
(55)

[Example 6]: 19-fluorinated vitamin D-S
De-SO ₂ conversion reaction and photosensitized isomerization reaction of O ₂ adduct (III ″) Deprotected (6R, 19R) -1α-hydroxy-19-fluorinated vitamin D ₃ obtained in Example 5 -SO ₂ adduct (6R, 19R-II
Ic) (7.0 mg, 0.0145 mmol), sodium hydrogen carbonate (2
A mixture of 4.3 mg, 0.29 mmol) and 95% ethanol (8 ml) was heated in a sealed tube at 80 ° C for 2 hours and then 90 ° C for 1 hour. The reaction solution was cooled to 0 ° C., diluted with ethyl acetate, and insoluble matter was removed by filtration. The filtrate was washed with saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was passed through silica gel column chromatography (2 g), ethyl acetate elution fractions were collected, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 10% benzene-containing ethanol (100 ml),
Anthracene (8.5 mg) was added, and light irradiation (halogen lamp, 200 W) was performed at 0 ° C. for 60 minutes. After evaporation of the solvent, the residue was subjected to silica gel column chromatography (3
(10E) -19-Fluoro-1α-hydroxyvitamin D from the hexane eluate containing 50% ethyl acetate.
₃ (Ic) (0.9 mg, yield 14.8%) was obtained.

Ic: ¹ H-NMR (δ (ppm), CDCl ₃ / TMS): δ 0.53 (3H, s, H-18), 0.863 and 0.867 (3H, d, J = 6.6H respectively)
z, H-26,27), 0.91 (3H, d, J = 6.3Hz, H-21), 2.19 (1H, m),
2.32 (1H, m), 2.68 (1H, m), 2.80 (1H, m), 4.18 (1H, m, H-
3), 5.09 (1H, m, H-1), 5.90 and 6.46 (1H, d, J = 11.1H respectively)
z, H-6,7), 6.50 (1H, d, J = 86.1Hz, H-19) ¹⁹ F-NMR (δ (ppm), CDCl ₃ / CF ₃ Ph): δ-129.82 (d, J = 85.9Hz) MS m / z (%): 418 (4, M ⁺ ), 400 (2), 380 (8), 378 (14),
376 (15), 362 (34), 360 (18), 347 (7), 305 (4), 287 (1
0), 252 (79), 250 (46), 247 (31), 245 (21), 235 (36), 2
19 (18), 207 (15), 195 (19), 178 (57), 135 (100), 133 (3
4), 109 (15), 107 (16), 105 (22), 95 (25), 81 (19) UV λmax (EtOH): 260nm

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07D 333/54 C07D 333/54

Claims (11)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ represents an alkyl group having an arbitrary substituent and having 2 to 9 carbon atoms, and R ² represents a hydrogen atom or a hydroxyl group.) A fluorinated vitamin D derivative. 2. A compound represented by the general formula (II): (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms and having an arbitrary substituent, R ² is either a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ³ is a fluorine atom and R Fluorinated (5E) -vitamin D represented by ⁴ is a hydrogen atom, or R ³ is a hydrogen atom and R ⁴ is a fluorine atom, and R ⁵ is a hydrogen atom or a hydroxyl-protecting group.
Derivative. 3. A compound represented by the general formula (III): (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms having an arbitrary substituent, R ² is either a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ⁵ is a hydrogen atom or a hydroxyl group. R ⁶ is a fluorine atom and R ⁷
Is a hydrogen atom, or R ⁶ is a hydrogen atom and R ⁷ is a fluorine atom. ) Fluorinated vitamin D-SO ₂ adduct represented by 4. R ² is a hydrogen atom, a hydroxyl group, a trialkylsilyloxy group, a methoxymethoxy group, a methoxyethoxymethoxy group or a tetrahydropyranyloxy group, and R ⁵ is a hydrogen atom, a trialkylsilyl group, methoxymethyl. Group, a methoxyethoxyethyl group or a tetrahydropyranyl group.
A fluorinated (5E) -vitamin D derivative represented by I). 5. R ² is a hydrogen atom, a hydroxyl group, a trialkylsilyloxy group, a methoxymethoxy group, a methoxyethoxymethoxy group or a tetrahydropyranyloxy group, and R ⁵ is a hydrogen atom, a trialkylsilyl group, methoxymethyl. Group, a methoxyethoxyethyl group, or a tetrahydropyranyl group, represented by the general formula (II
A fluorinated vitamin D-SO ₂ adduct represented by I). 6. A compound represented by the general formula (III ′): (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms having an arbitrary substituent, R ² is a hydrogen atom or a protected hydroxyl group, R ⁵ is a hydroxyl group-protecting group, and R ^{6 is} Is a fluorine atom and R ⁷ is a hydrogen atom, or R ⁶ is a hydrogen atom and R ⁷ is a fluorine atom, and a fluorinated vitamin D-SO ₂ adduct represented by the general formula (I) is used. A method for producing a fluorinated vitamin D derivative of the general formula (I), characterized in that the reaction is carried out in the order of deSO ₂ conversion step, deprotection group step, and photoisomerization step. 7. A fluorinated bitter represented by the general formula (III ').
Min D-SO₂Fluorinated vitamins of general formula (I) derived from adducts
In the method for producing a derivative of D.
SO ₂The reaction is carried out in the order of photopolymerization process and photoisomerization process.
Preparation of fluorinated vitamin D derivative of general formula (I)
Build method. 8. The photoisomerization step is characterized in that the reaction is carried out by irradiation with light in the presence of a photosensitizer in an organic solvent.
Alternatively, the method for producing the fluorinated vitamin D derivative represented by the general formula (I) according to the item 7: 9. The general formula (I) according to claim 6 or 7, wherein the deprotecting step is carried out in an organic solvent in the presence of a fluorine anion, an acid or a trialkylsilyl halide. A method for producing the fluorinated vitamin D derivative according to claim 1. 10. The fluorinated vitamin D of the general formula (I) according to claim 6 or 7, wherein the step of deSO ₂ conversion is carried out by heating in an organic solvent in the presence of an alkali metal salt. Method for producing derivative. 11. A compound represented by the general formula (IV): (In the formula, R ¹ is an alkyl group having 2 to 9 carbon atoms having an arbitrary substituent, R ² is a hydrogen atom or a protected hydroxyl group, and R ⁵ is a hydroxyl-protecting group.) The compound of formula (V) (In the formula, R ⁸ and R ⁹ may be the same or different and each represents a trialkylsilyl group or an arbitrary alkyl group having 1 to 4 carbon atoms, and M represents an alkali metal atom.) A method for producing a fluorinated vitamin D-SO ₂ adduct of general formula (III '), which comprises reacting with N-fluorodibenzenesulfonamide in the presence of an amide and a base activator.