JP2953665B2 - Method for producing steroid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) And a process for producing cholesta-5,7-diene-1α, 3β, 25-triol.

The compounds obtained according to the present invention are powerful vitamins
It is a steroid derivative useful as an intermediate for the production of 1α, 25-hydroxyvitamin D ₃ having D ₃ activity.

(Conventional technology and its problems) Conventionally, as a method for producing cholesta-5,7-diene-1α, 3β, 25-triol, a method using DHRBarton et al. Using 25-hydroxycholesterol as a starting material (see “J. Chem. Soc. Chem. Commun., 1974 , 103) and 1,5,7-trienone which reacts by isomerizing 25-hydroxy-cholesta-1,4,6-trienone (III) with a base. And then cholesta-5,7-diene-1α, 3β,
A method for obtaining 25-triol (“J. Chem. Soc. Perkin
I ", 1979 , 165).

However, in the method of Barton et al., The target compound 5,
In addition to 7-diene, its isomer 4,6-diene is produced in large quantities, and its separation is also difficult. Furthermore, since a reaction reagent such as lithium metal or liquid ammonia which is difficult to handle is used, the method has high danger and cannot be said to be an excellent method as an industrial production method.

Also, according to the method of Ochi et al., When synthesizing the intermediate epoxide, unnecessary β-epoxide is generated,
As a result, the yield is low. Therefore, this method is not an excellent industrial method.

Thus, the present inventors have studied to avoid the above problems and to provide a novel production method for obtaining cholesta-5,7-diene-1α, 3β, 25-triol.As a result, 25-hydroxycholesterol was used as a starting material. And found a new production method which solved the above-mentioned problems via a new intermediate.

(Means for Solving the Problems) The above object of the present invention can be achieved by the synthetic route of the present invention shown in the following Scheme I.

The starting material of the present invention, 25-hydroxycholesterol (II), can be prepared by a method using stigmasterol as a starting material (A. Frst, Helv. Chim. Acta, 65 1499 (1982) or a method by Ikegawa et al. (Chem. Pharm). .Bull.) 21 , 2568 (1973)).

According to the invention, 25-hydroxycholesterol (II)
Is oxidized with 2,3-dichloro-5,6-dicyano-1,4-p-benzoquinone (DDQ) in dioxane to give 25-hydroxy-cholesta-1,4,
It is converted to 6-trien-3-one (III). Then, the hydroxyl group at the 25-position of the compound (III) thus obtained is protected. As the protecting group used herein, a protecting group that is not removed under the reaction conditions of the subsequent steps is used. As described later, those which can be removed by a reduction reaction which is a step of converting the compound (X) into the compound (I) are preferable. Protecting groups that form an ester bond, such as an acetyl group, a benzoyl group, a propionyl group, and a butyryl group, are generally used to satisfy such conditions. The reaction is carried out using the corresponding halide or acid anhydride in the presence of a base, as such, or in an organic solvent from 0 to 10
It can be performed at a temperature in the range of 0 ° C.

The resulting compound (IV) is reacted with isopropenyl acetate in the presence of an acid to give cholesta-1,3,5,7-tetraene-3.
-Il-acetate (V). The reaction at this stage is preferably carried out in the presence of an organic solvent, for example, a hydrocarbon such as n-hexane, benzene or toluene; a ketone solvent such as acetone or methyl ethyl ketone; an ester solvent such as ethyl acetate or butyl acetate. It is carried out in the presence of an acid catalyst at a temperature from normal temperature to reflux temperature, preferably 80 to 150 ° C. P-Toluenesulfonic acid as an acid catalyst,
Organic acids such as methanesulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid, and acidic potassium sulfate are used. These acid catalysts are generally used in an amount of 0.1 to 10 times the molar amount of the compound of the formula (IV). Isopropenyl acetate is used in an amount of 1 to 100 mol, preferably 10 to 50 mol, per mol of compound (IV). When isopropenyl acetate is used in a large excess, there is no need to add a separate solvent since it itself also functions as a reaction solvent.

The compound (V) thus obtained is then subjected to a reduction reaction. Examples of the reducing agent used in the reaction at this stage include lithium aluminum hydride (LiAlH ₄ ), sodium borohydride (NaBH ₄ ), calcium borohydride (Ca (BH ₄ ) ₂ ), and zinc borohydride (Zn (BH _{4) 2)}
And other metal hydrides. Among these metal hydrides, Ca (BH ₄ ) ₂ is particularly preferable. These metal hydrides are usually used in excess of the stoichiometric amount, for example, several times to several tens times. This reduction reaction is carried out in an organic solvent, for example in ether, at a temperature of -20 ° C to room temperature, preferably -5 ° C.
Performed at a temperature of 〜5 ° C. In this way, 25-
Acyloxycholesta-1,5,7-trien-3β-ol is obtained.

The resulting compound (VI) was then treated with 4-phenyl-1,2,4
-Reaction with triazoline-3,5-dione and Diels-Alder
It is converted to a compound of the formula (VII) which is a type addition reaction product. In this case, the reaction is carried out in the presence of a common organic solvent, for example, a hydrocarbon such as hexane, benzene, or toluene; a ketone solvent such as acetone or methyl ethyl ketone; an ester solvent such as ethyl acetate or butyl acetate.
It is carried out at a temperature between 0 ° C. and room temperature. In this case, the amount of 4-phenyl-1,2,4-triazoline-3,5-dione used is determined by the formula (V
1.0 to 1.5 times the molar amount of the compound of I) is sufficient.

This Diels-Alder type addition reaction product (VII) is then converted into a compound of formula (VIII) in which the 3-hydroxyl group is protected. The hydroxyl-protecting group is preferably a group which is sterically bulky and can be easily removed under mild conditions. As such, a silyl compound such as t-butyldimethylsilyl chloride is suitable. . In addition, diphenylmethylsilyl chloride and the like can be used. In introducing the protecting group, the reaction is preferably allowed to proceed in the presence of a base as an acid binding agent, for example, imidazole, triethylamine, diethylcyclohexylamine and the like.

The compound of formula (VIII) in which the 3-position hydroxyl group is protected is then converted to a compound of formula (I) in which the double bond at position 1 or 2 is epoxidized.
It is converted to the compound of X). Various peracids or metal oxide-hydrogen peroxide are used for this epoxidation. Suitable reagents include perbenzoic acid, m-chloroperbenzoic acid and the like. This epoxidation is carried out at a temperature in the range from 0 ° C. to room temperature, and an oxidizing agent is used in an amount of 1.5 to 10.0 times the theoretical amount of the compound of the formula (VIII).

The epoxidized compound of formula (IX) is then subjected to a deprotection reaction of its 3-position protecting group. This reaction is carried out, for example, using a solution of tetrabutylammonium fluoride in tetrahydrofuran. This deprotection reaction can also be performed using acetic acid / water. The reaction is performed at a temperature ranging from 0 ° C to room temperature.

The thus obtained compound of formula (X) in which the 3-position is a free hydroxyl group is then subjected to a reduction reaction to be converted to a compound of formula (I). This reduction reaction is
The reaction is performed under the same conditions as when the compound of the formula (V) is reduced to the compound of the formula (VI). As the reducing agent used here, lithium aluminum hydride is particularly preferable.

Starting material 25-hydroxycholesterol (II)
When the final product is obtained through a series of steps based on the total yield is 5 to 6%.

(Effects of the Invention) As described above, according to the present invention, starting from a known 25-hydroxycholesterol, cholester-5,7-diene- using a novel intermediate and a novel reaction route.
A novel method for producing 1α, 3β, 25-triol is provided.

According to the production method of the present invention, the yield is high, the reaction reagent used is easier to handle than the conventional method, and the purity of the target product is high.

Hereinafter, the present invention will be described with reference to examples, but these do not limit the scope of the present invention.

Example 1 Synthesis of 25-acetoxycholesta-1,4,6-trien-3-one (IV) 25-hydroxycholesterol (II) (8 g) DDQ (2 g)
A solution of 5) in dioxane (100 ml) was heated under reflux for 16 hours. The reaction solution was passed, the solution was concentrated, and the residue was subjected to silica gel chromatography (eluted with chloroform) to give 25-hydroxy-cholesta-1,4,6-triene-3.
-One (III) was obtained in a yield of 4.5 g. Then, acetic anhydride (5.0 ml) was added to a pyridine solution (30 ml) of the compound (III), and the mixture was reacted at 90 to 95 ° C. for 1 hour. The reaction was extracted with ethyl acetate, washed sequentially with dilute hydrochloric acid, aqueous NaHCO ₃ and brine, and dried (Na ₂ SO ₄ ). After the ethyl acetate was distilled off, the residue was purified by silica gel chromatography (chloroform / hexane = 1/1) to give 25-acetoxy-cholesterol.
4.3 g (49%) of 1,4,6-trien-3-one (IV) was obtained.

^{m / e 438 (M +)} , 378 (M + -CH 3 COOH) 1 H NMR (CDCl 3) δ 7.09 (1H, d, J = 10Hz, H-1), 5.97
6.26.26 (4H, m, H-2,4,6,7), 1.96 (3H, s, COCH ₃ ) λ _max 300 nm (ε = 9,800, ethanol) Example 2 25-acetoxy-cholesta-1,3,3 5,7-tetraene-3
Synthesis of -yl-acetate (V) 25-acetoxytrienone compound (IV) (3.0), p
-A mixture of toluenesulfonic acid (1.5 g), isopropenyl acetate (30 ml) and butyl acetate (30 ml) was heated at reflux for 5 hours. The reaction solution was washed with an aqueous solution of NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and evaporated to remove 3.1 g of crude (V).
(91%). The obtained (V) was used for the next reaction without purification.

^{m / e 480 (M +)} 1 H NMR (CDCl 3) 5.69~6.03 (m, 5H, H-1,2,4,6,7), 2.
10 (3H, s, COCH ₃ ), 1.98 (3H, s, COCH ₃ ) Example 3 25-acetoxy-cholesta-1,5,7-triene-3β-
All (VI) Diels-Alder addition reaction type compound (VI
Synthesis of I) An ether solution (50 ml) of a tetraenyl acetate compound (V) (3.1 g) was dissolved at −20 ° C. in a Ca (BH ₄ ) ₂ solution (30 g of calcium chloride) in methanol (150 ml). At 15 ° C., an ethanol solution (200 ml) of 15 g of NaBH ₄ was added dropwise thereto, and the mixture was stirred at the same temperature for 3 hours. Excess reagent was decomposed with 50% acetic acid and extracted with ethyl acetate. Extract is water, NaHC
The organic layer was washed with an aqueous solution of O ₃ and brine, and then dried (Na ₂ SO ₄ ). Then, 4-phenyl-1,2,4-triazoline-3,5-dione was added to the ethyl acetate solution until the red color disappeared. The ethyl acetate was concentrated and the residue was purified by silica gel chromatography (ethyl acetate / chloroform,
Eluted at 5/95). Thus, 1.2 g of the addition reaction product (VII)
(30%) obtained.

m / e 440 (M ⁺ -triazoline), 380 (440-CH ₃ COOH) ¹ H NMR δ (CDCl ₃ ), 7.43 (5H, m, C ₆ H ₅ ), 6.21, 6.43
(2H, ABq, J = 8Hz, H-6, H-7), 5.85 (2H, s, H-1, H-
2), 5.00 (1H, m , H-3), 1.98 (3H, s, COCH 3) Example 4 silyl derivative of Diels-Alder type addition reaction product (VIII)
To a solution of Diels-Alder type addition reaction product (VII) (1.0 g) in dimethylformamide (10 ml), t-butyldimethylsilyl chloride (0.5 g) and imidazole (0.5 g) were added, and the mixture was heated at 40 ° C. for 1 hour. Kept. Extracted with ether, washed with brine and dried (Na ₂ SO ₄ ). The ether was distilled off and the residue was crystallized from methanol to obtain (VIII) (0.95 g, 80%).

187-188 ° C m / e 554 (M ⁺ -triazoline), 494 (554-CH ₃ COOH) ¹ H NMR δ (CDCl ₃ ) 7.41 (5H, m, C ₆ H ₅ ), 6.23, 6.46 (2
H, ABq, J = 8Hz, H-6, H-7), 5.69 (2H, s, H-1, H-
2), 4.99 (1H, m, H-3), 1.97 (3H, s, COCH ₃ ) Elemental analysis C ₄₃ H ₆₃ N ₃ O ₅ Si Calculated C 70.73%, H 8.71%, N 5.75% Observed C 70.61%, H 8.68%, N 5.70% Example 5 Synthesis of 1,2-epoxide derivative (IX) Silyl derivative (VIII) (0.8 g) was added to chloroform (10 m
l), m-chloroperbenzoic acid (1.6 g) was added,
The reaction was performed at room temperature for 20 hours. The reaction solution was washed with a 10% aqueous potassium carbonate solution and brine, and then dried (Na ₂ SO ₄ ). 0.8 g of the compound (IX) from which chloroform was distilled off was obtained (98%).

m / e 570 (M ⁺ -triazoline) ¹ H NMR δ (CDCl ₃ ) 7.43 (5H, m, C ₆ H ₅ ), 6.19, 6.41 (2
H, ABq, J = 8Hz, H-6, H-7), 4.99 (1H, m, H-3), 3.2
0 (2H, m, H-1, H-2), 1.97 (3H, s, COCH ₃ ) Example 6 Synthesis of Epoxy Alcohol Derivative (X) Tetrahydrofuran solution (10 ml) of epoxide derivative (IX) (0.8 g) To the mixture was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (2 ml), and the mixture was reacted at room temperature for 6 hours. Extract with ethyl acetate, wash with brine, dry (Na ₂ SO ₄ ), evaporate the solvent and remove the residue on a silica gel chromatograph (ethyl acetate / chloroform,
1/9), and the eluate was crystallized from methanol.
0.57 g of compound (X) was obtained (75%).

Elemental analysis C ₃₇ H ₄₉ N ₃ O ₆ Calculated C 70.34%, H 7.82%, N 6.65% Actual C 69.91%, H 7.65%, N 6.35% Melting point 146-147 ° C m / e 457 (M ⁺ − Triazoline), 397 (M ⁺ -CH ₃ COOH) ¹ H NMR δ (CDCl ₃ ) 7.43 (5H, m, C ₆ H ₅ ), 6.19, 6.41 (2
H, ABq, J = 8Hz, H-6, H-7), 4.99 (1H, m, H-3), 3.2
0 (2H, s, H-1, H-2), 1.97 (3H, s, COCH ₃ ) Example 7 Synthesis of Cholesta-5,7-diene-1α, 3β, 25-triol (I) Epoxy alcohol ( X) (0.50 g) in tetrahydrofuran (10 ml) was added dropwise to a tetrahydrofuran solution (10 ml) containing LiAlH ₄ (1.0 g), and the mixture was refluxed for 2 hours. Water was added while cooling with ice water, to decompose excess LiAlH _4, followed by extraction with chloroform, then washed with brine, dried (Na ₂ SO _4). Chloroform was distilled off, and the residue was purified by silica gel chromatography (ethyl acetate / chloroform, 1/4) and crystallized from methanol-ether to obtain 0.24 g of compound (XI) (72%).

Mp _{210~212 ℃ λ max 282nm (ε =} 11,900, ethanol)

Claims (3)

(57) [Claims] (1) Expression (Wherein X represents a protected hydroxyl group) comprising reacting a compound of cholesta-1,4,6-trien-3-one with isopropenyl acetate in the presence of an acid. (Wherein X is as defined above) A method for producing cholesta-1,3,5,7-tetraen-3-yl-acetate represented by the formula: (2) Is converted to 2,3-dichloro-5,6-dicyano-1,4-p-benzoquinone (DD
Q) oxidize with formula To form a 25-hydroxy-cholesta-1,4,6-trien-3-one represented by Wherein X represents a protected hydroxyl group, and reacting with isopropenyl acetate in the presence of an acid in the presence of an acid. (Wherein X is as defined above) A method for producing cholesta-1,3,5,7-tetraen-3-yl-acetate represented by the formula: 3. The expression (Wherein X represents a protected hydroxyl group) by reacting a compound of cholesta-1,4,6-trien-3-one represented by the formula with isopropenyl acetate in the presence of an acid. (Where X is as defined above) to give cholesta-1,3,5,7-tetraen-3-yl-acetate represented by the formula: Wherein X is as defined above, to produce 25-acyloxycholesta-1,5,7-trien-3β-ol, which is then added to 4-phenyl-1,2,4-triazoline Reacting −3,5-dione with the formula (Wherein X is as defined above) as a Diels-Alder type addition reaction product represented by the following formula: Wherein X is as defined above and Y represents a protected hydroxyl group. The compound is converted to a compound represented by the formula: Wherein X and Y are as defined above, and the compound is subjected to a deprotection reaction of a 3-position protecting group to obtain a compound of the formula Wherein X is as defined above, and then subjecting the compound of formula (X) to a reduction reaction, A method for producing cholesta-5,7-diene-1α, 3β, 25-triol represented by the formula: