JP3483155B2 - Method for producing 1α, 25-dihydroxyvitamin D4 and D7 - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 1α, 25-dihydroxyvitamin D ₄ and 1α, 25-dihydroxyvitamin D ₇ having excellent differentiation-inducing action and bone mass-improving action.

[0002]

PRIOR ART 1α-Hydroxyvitamin D ₃ and 1α,
25-dihydroxyvitamin D ₃ is an active vitamin D ₃ having high biological activity and is used as a therapeutic drug for osteoporosis. However, excessive intake of these compounds may cause side effects such as hypercalcemia due to their strong physiological activity.

At present, active research and development of active vitamin D derivatives having an effect of improving bone mass of active vitamin D ₃ or higher and having lower side effects and toxicity are being actively conducted. The present inventors have also synthesized various active vitamin D derivatives and investigated their physiological activity (Y. Tachibana, “Studies in Nat.
ural Products ", ed by A. Rahman, Elrevier (199
2), Vol 11, p379-p408).

As a result, the following equation (XV) or (XVI)

[Chemical 10] 1α, 25-dihydroxyvitamins D ₄ and D represented by
₇ was found to be less toxic and to have a bone mass improving effect comparable to or higher than that of active vitamin D ₃ (Bioc
him. Biophys, Acta, 1091 , 188 (1991)).

The present inventors succeeded in synthesizing the compounds (XV) and (XVI) using ergosterol as a starting material as shown in Schemes 1 and 2, but required a relatively long process (Y. Tachibana, Bull. Chem. Soc. Jpn.,
61 , 3915 (1988); see Japanese Patent Application No. 61-270951, Y. Tachiban.
a, Bull. Chem. Soc. Jpn., 63 , 2233 (1990);
1-78110; Japanese Patent Application No. 3-333057).

[Chemical 11]

[0006]

DISCLOSURE OF THE INVENTION The present invention was devised to improve the above-mentioned conventional techniques, and an object thereof is to provide a simpler method.

[0007]

[Means for Solving the Problems] In order to achieve the above object, as a result of extensive studies, 1α, 25-dihydroxyvitamin has been synthesized using an inexpensive stigmasterol as a starting material through a synthetic process not known so far. The present invention has been completed by newly developing a method for manufacturing D ₄ and D ₇ .

That is, according to the present invention, formula (I) obtained from stigmasterol through several steps

[Chemical 12] 22-alcohol derivative represented by (Tachibana, Nikkan, 19
92, 53 reference) was tosylated, then treated with sodium iodide following formula (II)

[Chemical 13] Then, the 22-iodo compound of the formula (II) is converted to the compound of the formula (III) or (IV)

[0009]

[Chemical 14] Derivatives of sulfone (Y. Tachibana, Bull. Che
m. Soc. Jpn., 62 , 3132 (1989)) to give a compound of formula (V) or (VI).

[Chemical 15] 23-phenyl sulfone derivative represented by the following formula, and then the compound of the formula (V) or (VI) is reduced with Na-Hg to obtain the following formula (VII) or (VIII)

[0010]

[Chemical 16] A compound of formula (VII) or (VII
The compound of I) is selectively epoxidized at the double bond at the 1-position to give the following formula (IX) or (X)

[Chemical 17] A compound of formula (IX) or (X)
The silyl group of the epoxy compound is eliminated using n-Bu ₄ NF to give the following formula (XI) or (XII)

[0011]

[Chemical 18] A diol compound represented by the formula (XI) or (XII) is then reduced to obtain the following formula (XIII) or (XI
V)

[Chemical 19] A 5,7-diene body represented by the formula (XII
Compound (I) or (XIV) is sequentially subjected to UV irradiation and thermal isomerization to obtain the compound of formula (XV) or (XVI)

[0012]

[Chemical 20] 1α, 25-dihydroxyvitamin D ₄ and 1 represented by
A method for producing α, 25-dihydroxyvitamin D ₇ is provided. The compound (I
I) to (XII) are novel compounds that have not been published in the literature.

In the specific reaction procedure of the above-mentioned method of the present invention, the starting compound, the compound of formula (I), is iodinated at the 22-position hydroxyl group to give the 22-iodo compound of formula (II). First, the compound of formula (I) is reacted with tosyl chloride in the presence of a basic compound in an organic solvent to tosylate the 22-position of the compound of formula (I). In this case, any organic solvent can be used, but a basic compound which itself functions as an acid binder such as pyridine can also be used as an organic solvent. When the tosyl product thus obtained is treated with sodium iodide in an organic solvent, a 22-iodo compound represented by the formula (II) is obtained.

The compound of the formula (II) thus obtained is then condensed with a phenyl sulfone derivative of the formula (III) or (IV) to give a compound of the formula (V) or (VI) having an extended side chain.
It is a 3-phenyl sulfone derivative. In this case, the reaction is carried out in a suitable organic solvent such as tetrahydrofuran in the presence of n-butyllithium.

Then, the sulfonyl group at the 23-position of the 23-phenyl sulfone derivative compound of the formula (V) or (VI) is reductively removed to convert it to the compound of the formula (VII) or (VIII). The compound of formula (V) or (VI) can be converted into Na as a reducing agent in a suitable organic solvent such as methanol.
-Reacted with Hg. The obtained formula (VII) or (V
The compound of III) is then selectively epoxidized at its double bond to form compound (IX) or (X),
At this time, peracetic acid and m-chloroperbenzoic acid are used as the epoxidizing agent. However, the preferred epoxidizing agent is m-
It is chloroperbenzoic acid (m-CPBA).

Then, the t-butyldimethylsilyloxy group at the 3-position and the triethylsilyloxy group at the 25-position are removed from the obtained epoxy compound of the formula (IX) or (X) to give the formula (XI) or (XII). It is converted into the diol compound of
Alternatively, it is carried out by treating the compound of (X) with n-tetrabutylammonium fluoride (n-Bu ₄ NF). The compound of formula (XI) or (XII) obtained is an alkali metal hydride or alkali metal borohydride such as LiAlH ₄ , NaAlH ₄ , KAlH.
Reduction with ₄ , LiBH ₄ , NaBH ₄ , KBH ₄ etc. gives the triol compound of formula (XIII) or (XIV). Of these reducing agents, LiAlH ₄ is preferred. In this case, the epoxy ring of the compound of formula (XI) or (XII) is converted to 1α-hydroxy, and 4-phenyl-1,2,4-triazoline-3, which is a protecting group of the 5,7-diene moiety, 5
-Zeon is also withdrawn. The obtained formula (XIII) or (XI
The triol of V) is converted into the desired 1α, 25-dihydroxyvitamin D ₄ or D ₇ by the conventional method of light irradiation with a high pressure mercury lamp and subsequent thermal isomerization.

The synthetic route from the 22-alcohol derivative (I) to the final products 1α, 25-dihydroxyvitamins D ₄ and D ₇ (compounds (XV) and (XVI)) in the production process of the present invention is as follows: An example of the reaction using a specific reaction reagent is as shown in the following scheme 3.

[0018]

[Chemical 21]

[0019]

[Chemical formula 22]

The present invention is described in detail below with reference to examples, but these are not intended to limit the present invention. Example 1 22-Iodo-5α, 8α- (4-phenyl-1,2-urazolo) -23,24-dinor-1,6-coradiene-3
β-ol 3β-t-butyldimethylsilyl ether (compound (II)) 22-alcohol derivative (I) (10.0 g) was dissolved in pyridine (50 ml), tosyl chloride (5.0 g) was added, and 0-5 Stir overnight at ° C. Extracted with ethyl acetate,
The extract was washed with saturated aqueous NaHCO ₃ , then brine, dried and concentrated. The residue (12.5 g) was dissolved in acetone (100 ml), NaI (12.0 g) was added, and the mixture was heated under reflux for 5 hours. After distilling off acetone, the mixture was extracted with chloroform, washed with brine, dried and concentrated.
The concentrate was crystallized from hexane to obtain 8.6 g of the title compound (II). Melting point 178-180 ° C ¹ H NMR (CDCl ₃ ) δ 0.90, 0.10 (each 3H, s), 0.78 (3H,
s), 0.90 (9H, s), 1.00 (3H, d, J = 6.1Hz), 1.04 (3H,
s), 3.29 (2H, m), 4.93 (1H, m), 5.65 (2H, m), 6.23,
6.41 (2H, ABq, J = 8.4Hz), 7.41 (5H, m).

Example 2 (24S) -5α, 8α- (4-phenyl-1,2-urazolo) -1,6-ergostadiene-3β, 25-diol 3β-t-butyldimethylsilyl ether 25-triethyl Silyl ether (compound (VII)) (R) -2,3-dimethyl-4-phenylsulfonyl-
2-Butanol triethylsilyl ether (III) (5.
0 g) was dissolved in THF (30 ml) and cooled to -20 ° C. 1.6N n-BuLi hexane solution (9.0 ml),
Then 1,3-dimethyl-2-imidazolidinone (4.0
ml) was added and the mixture was stirred at the same temperature for 30 minutes. A THF solution (50 ml) of 22-iodo derivative (II) (5.0 g) was added to -20
The mixture was added at 0 ° C., and the mixture was further stirred for 5 hours. Saturated aqueous NH ₄ Cl solution was added, extracted with ethyl acetate, washed with brine, dried and concentrated. The residue (V) (9.1 g) was dissolved in methanol (300 ml) and Na ₂ HPO ₄ (1.0 g), 5%
Na-Hg (50 g) was added, and the mixture was stirred overnight at room temperature. After removing mercury and concentrating methanol, extract with ethyl acetate,
Wash with brine, dry and concentrate, and purify the residue by silica gel chromatography to give the title compound (VII) 5.1.
g was obtained. ¹ H NMR (CDCl ₃ ) δ 4.47 (1H, m), 5.74 (2H, s), 6.21,
6.42 (2H, ABq, J = 8.3Hz), 7.30 ~ 7.45 (5H, m).

Example 3 (24R) -5α, 8α- (4-phenyl-1,2-urazolo) -1,6-ergostadiene-3β, 25-diol 3β-t-butyldimethylsilyl ether 25-triethyl Silyl ether (Compound (VIII)) Phenylsulfone derivative (IV) instead of Compound (III)
The same treatment as in Example 2 was carried out using (3.0 g) to obtain 3.5 g of the title compound (VIII).

Example 4 (24S) -5,7-Ergostadiene-1α, 3β, 2
5-triol (compound (XIII)) Compound (VII) (5.0 g) in chloroform (100 ml)
Dissolved in m-chloroperbenzoic acid (m-CPBA)
(5.0 g) was added and the mixture was stirred overnight at room temperature. 10% K ₂C
O₃After washing with brine, drying and concentration. Residue (I
X) (4.9g) with 1M Bu_FourNF THF solution (12m
l) was added, and the mixture was heated with stirring at 50 ° C. for 1 hour. Ethyl acetate
Extracted with, washed with brine, concentrated and the residue is silica
Purified by gel chromatography to give 2.6g of (XI)
It was Lithium in a THF solution (50 ml) of (XI) (2.6 g).
AlH_Four(1.3 g) was added and the mixture was refluxed for 3 hours. Add water
Excess LiAlH_FourTo decompose MgSO_FourAdd THF layer
Was separated and concentrated. Crystallize the residue from ethanol
This gave 1.1 g of the title compound (XIII). Melting point 231 ° C, λ_max 282nm (ε = 11,900, ethanol)¹ H NMR (CDCl₃＋ CD₃OD) δ 0.61 (3H, s), 0.84 (3H, d),
 0.86 (3H, s), 0.96 (3H, d), 1.07, 1.08 (each 3H, s), 3.
64 (1H, m), 3.94 (1H, m), 5.30 (1H, m), 5.55 (1H, m).

Example 5 (24R) -5,7-ergostadiene-1α, 3β, 2
5-Triol (Compound (XIV)) Compound (VIII) (3.0 g) was treated in the same manner as in Example 4 to obtain 71.0 mg of the title compound (XIV). Melting point 160-1
63 ° C.

Example 6 1α, 25-dihydroxyvitamin D ₄ (compound (XV)) 5,7-diene (XIII) (200 mg) was added to THF (500 m).
L), 450W high pressure mercury lamp (filter: 1.2
% KNO ₃ aqueous solution) for 3 minutes. After THF was concentrated, the residue was dissolved in ethanol and refluxed for 1 hour. Ethanol was distilled off, and the residue was purified by silica gel chromatography and then crystallized to obtain 35 mg of the title compound (XV). Melting point 147 to 148 ° C, λ _max 265 nm (ε = 17,100, ethanol) [α] _D ²⁰ + 35.4 ° (c = 0.5, ethanol) ¹ H NMR (CDCl ₃ ) δ 0.54 (3H, s), 0.90 (3H, d, J = 6.9H
z), 0.94 (3H, d, J = 6.3Hz), 1.16 (3H, s), 1.17 (3H,
s), 4.27 (1H, m), 4.43 (1H, m), 5.01 (1H, s), 5.33 (1
H, s), 6.02, 6.38 (2H, ABq, J = 11.2Hz).

Example 7 1α, 25-dihydroxyvitamin D ₇ (compound (XV
I)) 5,7-Diene (XIV) (100 mg) was treated in the same manner as in Example 6 to obtain 20 mg of the title compound (XVI). Melting point 175-177 ° C, λ _max 265nm (ε = 17,000, ethanol) [α] _D ²⁰ + 65.4 ° (c = 0.5, ethanol)

Continuation of the front page (56) Reference JP-A-4-300685 (JP, A) JP-A-5-163238 (JP, A) JP-A-3-141293 (JP, A) Bull. Chem. Soc. Jpn. , 1990, Vol. 63, No. 8, P 2233-38 Journal of the Chemical Society of Japan, 1992, No. 1, P53-62 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07C 401/00 C07J 9/00 REGISTRY (STN) CA (STN)

Claims (3)

(57) [Claims] 1. The following formula (I): The C-22 alcohol derivative represented by the following formula is tosylated and then treated with sodium iodide to give the following formula (II): Then, the 22-iodo compound of the formula (II) is converted to the compound of the formula (III) or (IV) By condensation with a sulfone derivative represented by the formula (V) or (VI) The compound of formula (V) or (VI) is then subjected to a reductive desulfurization reaction to give a 23-phenylsulfone derivative of formula (VII) or (VIII) A compound of formula (VII) or (VII
The compound of formula (I) is selectively α-epoxidized to give the following formula (I
X) or (X) The compound of formula (IX) or (X) is prepared by removing the protective group for the hydroxyl group of the compound of formula (IX) or (X).
I) [Chemical 29] A diol compound represented by the formula (XI) or (XI
The compound of I) is reduced to give the following formula (XIII) or (XIV): The compound of formula (XIII) or (XIV) is subjected to light irradiation and thermal isomerization by a conventional method, and is represented by the following formula (XV) or (XVI): 1α, 25-dihydroxyvitamin D ₄ (XV)
Alternatively, a method for producing 1α, 25-dihydroxyvitamin D ₇ (XVI). 2. The following formula (XI) or (XII): By reducing the diol compound represented by the following formula (XIII) or (XIV) The compound of formula (XIII) or (XIV) is subjected to light irradiation and thermal isomerization by a conventional method as a triol compound represented by the following formula (XV) or (XVI) 1α, 25-dihydroxyvitamin D ₄ (XV)
Alternatively, a method for producing 1α, 25-dihydroxyvitamin D ₇ (XVI). 3. The following formula (XI) or (XII): A diol compound represented by.