JP3492557B2 - How to synthesize steroids - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a simple method for producing a steroid compound such as β-cytosto-5-en-3-one.

Β-cytosto-5-en-3-one is the corresponding 3-
It can be produced by oxidizing the all-form, but when a normal oxidation reaction is carried out, rearrangement of the double bond occurs and a 4-en-3-one form is produced. Therefore, pyridinium chlorochromate etc. can be produced in the presence of anhydrous calcium carbonate. It is necessary to carry out the oxidation using chromic acid. When performing this oxidation reaction, the reaction mixture is treated with magnesium silicate (such as "Floridil" manufactured by Floridin Co., Ltd.) to remove chromic acid, water is added to the filtrate, and the desired product is extracted with dichloromethane or diethyl ether. In general, the residue obtained by concentrating the organic layer is purified by silica gel column chromatography to isolate the desired product. However, this method
Since the number of steps is large and complicated, it is not suitable for large-scale synthesis, and development of a method for efficiently separating and purifying a target product has been demanded.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention and Problems to be Solved by the Invention The problem of the present invention is to prepare a steroid compound such as β-cytosto-5-en-3-one and
It is an object of the present invention to provide a method for efficiently separating and purifying a target product from a reaction mixture obtained by oxidizing an all body. The inventors of the present invention have conducted diligent research to solve the above problems, and it is extremely easy to separate and purify a target substance by omitting a post-treatment step that was conventionally considered essential such as a product extraction and concentration operation. Moreover, it has been found that the yield of the target product can be significantly improved. The present invention has been completed based on the above findings.

That is, the present invention provides the following formula (I):

[Chemical 3] (In the formula, R represents a hydrogen atom or a lower alkyl group.) A steroid compound represented by the following formula (II) is obtained by chromic acid oxidation in the presence of anhydrous calcium carbonate:

[Chemical 4] (Wherein R has the same meaning as above)
A method for producing an on-form, comprising performing chromic acid oxidation in a halogenated hydrocarbon solvent, adsorbing a solute of the obtained reaction solution to an adsorbent having a magnesium silicate layer and a silica gel layer laminated, The present invention provides a method characterized by eluting a 5-en-3-one compound with a hydrogen solvent.

According to a preferred embodiment of the present invention, the above method wherein the chromic acid oxidation is carried out with pyridinium chlorochromate;
The above method wherein the halogenated hydrocarbon solvent used as the reaction solvent and the eluent is dichloromethane is provided; and the above method wherein R is a hydrogen atom, a methyl group, or an ethyl group.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, the above formula (I)
In producing the 5-en-3-one compound by chromic acid oxidation of the steroid compound represented by the formula (3) in the presence of anhydrous calcium carbonate, chromic acid oxidation is carried out in a halogenated hydrocarbon solvent. The type of chromic acid is not particularly limited as long as it can produce a 3-one form from a 3-ol form and does not isomerize a double bond in the oxidation process, but pyridinium chlorochromate is preferably used. it can. The combination of anhydrous calcium carbonate and pyridinium chlorochromate is particularly preferable, but chromic acid oxidation by this combination is well known and widely used in the field of steroid synthesis, and the conditions such as the concentration of each reagent, the reaction temperature, the reaction time, etc. are the same. It can be appropriately selected by a trader.

The halogenated hydrocarbon used as the reaction solvent is preferably a chlorinated solvent such as dichloromethane or chloroform, and dichloromethane is particularly preferable. You may use it in combination of 2 or more types of solvent.
The solvent needs to be anhydrous, but generally drying with molecular sieves or the like is sufficient. The amount of the solvent used is not particularly limited, but generally, about 10 to 100 ml may be used per 1 g of the compound represented by the formula (I). One kind or two or more kinds of molecular sieves, zeolite and the like may be added as a desiccant and an activator in the reaction system.

The reaction can be traced generally by silica gel thin layer chromatography, and a mixed solvent of hexane-ethyl acetate is usually used as a developing solvent. Further, a halogenated hydrocarbon solvent such as dichloromethane may be used as a developing solvent. When a halogenated hydrocarbon solvent such that the Rf of the target substance when used as a developing solvent is 0.2 to 0.5, preferably about 0.3, is used as a solvent for the oxidation reaction, this solvent is used as a solvent for elution in the next step. Therefore, the working process can be simplified. Further, the recovered elution solvent can be reused as a solvent for the reaction after being dried if necessary, which is also advantageous in terms of cost.

Then, the solute of the reaction solution after the reaction is adsorbed on an adsorbent having a magnesium silicate layer and a silica gel layer laminated, and the 5-en-3-one compound is eluted with a halogenated hydrocarbon solvent. The target substance can be separated and purified very efficiently. The adsorption on the adsorbent can be achieved by directly passing the reaction solution through the magnesium silicate layer and the silica gel layer in this order, and this operation is performed by ordinary column chromatography, preferably flash column chromatography. You can do it in the same way as. Usually, adsorption and elution can be performed using a single column in which the above two layers are stacked and packed.

If necessary, the reaction solution may be appropriately concentrated and then adsorbed on the adsorbent, but it is desirable to treat the reaction solution as it is in order to simplify the process. In the method of the present invention, it is not necessary to remove chromic acid from the reaction mixture using only magnesium silicate, and water is added to the reaction solution after removing chromic acid for extraction with an organic solvent, or There is no need to wash the layers with water and dry and concentrate the organic layers.

The magnesium silicate has a particle size of 15 for example.
For example, florisil (Floridin Co., Ltd.) having a particle size of 0 to 250 μm can be used, and as the silica gel, silica gel for ordinary column chromatography having a particle size of 40 to 100 μm can be used. Magnesium silicate can be used in an amount of about 10 to 50 ml, preferably about 20 ml, for 1 g of the compound of formula (I) used as a raw material, and silica gel is used for 1 g of the compound of formula (I) used as a raw material. 20-100 ml
Approximately 50 ml can be used. It is desirable to use silica gel in an amount of 1 to 5 times, preferably 2 to 3 times the volume of magnesium silicate.

In order to elute the target 5-en-3-one compound in a pure form from the solute of the reaction solution adsorbed on the adsorbent, a halogenated hydrocarbon solvent, preferably dichloromethane, is used as an elution solvent. Used as. Mixtures of two or more halogenated hydrocarbon solvents may be used. The solvent used for elution needs to be anhydrous, but in general, the one dried by molecular sieves is sufficient. Particularly preferably, it is desirable to use a halogenated hydrocarbon solvent as the elution solvent such that the Rf of the target substance is 0.2 to 0.5, preferably about 0.3. For example, a compound of formula (I) in which R is a hydrogen atom, a methyl group, or an ethyl group has an Rf of about 0.3 when silica gel thin layer chromatography uses dichloromethane as a developing solvent. Therefore, it is particularly preferable to use dichloromethane as a reaction solvent and an elution solvent for the production of this compound.

Following the halogenated hydrocarbon solvent, ethers such as diethyl ether are used as the elution solvent to reduce the adsorptive power of the adsorbent to give 5-ene-3.
A mixture containing an -one body, a 4-en-3-one body, a 4-ene-3,6-dione body and the like can be eluted with a minimum amount of solvent. However, if the elution solvent is changed to ethers before the elution of the 5-en-3-one compound is completed, the desired product in a pure form may not be obtained. The column filled with the adsorbent having the magnesium silicate layer and the silica gel layer laminated can be used several times as long as chromic acid does not flow out.

[0014]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples. Example 1 β-sitosterol (24.883 g: R = ethyl group) was dissolved in 2,000 ml of anhydrous dichloromethane (dried with molecular sieves, the same applies below), and anhydrous calcium carbonate (24.02 g) and molecular sieves were added under a nitrogen atmosphere. 4A (5.0 g) was added, and the mixture was stirred at room temperature for 15 minutes. Pyridinium chlorochromate (38.8 g) was added, and the mixture was reacted at room temperature for 45 minutes with stirring. The reaction was monitored by silica gel thin layer chromatography (the target β-cytosto-5-en-3-one was developed using dichloromethane as a developing solvent.
Rf = about 0.3).

Silica gel (Kanto Chemical Co., Ltd., 37561-85, Silica gel 60N, spherical, neutral, 40 to 10)
0 μm, 140 to 325 mesh) was filled, and Florisil (manufactured by Kanto Chemical Co., Ltd., 16230-08, 150 to 250 μm, 60 to 100 mesh) was laminated thereon at a height of 100 mm. After pouring the reaction solution into this layered column for adsorption, anhydrous dichloromethane 4.0 L,
Subsequently, it was eluted with 3.0 L of anhydrous ether. Chromic acid was almost completely retained by Florisil in the elution procedure. The desired product was contained as a single compound in the anhydrous dichloromethane fraction, and this product was concentrated and then recrystallized from the diethyl ether-petroleum ether mixture to give the desired product (15.5 g, yield). 62%). In addition, the diethyl ether fraction contained 5-ene-3-
The mixture of the on-form, 4-en-3-one form and 4-ene-3,6-dione form was contained. After concentrating this, the residue was purified again by silica gel column chromatography to obtain the desired product (2.5 g, yield 10%). By purifying this residue together with the following reaction product by silica gel chromatography, the target compound could be obtained more efficiently.

Example 2 Cholesterol (R = H) 11.6 as in Example 1 above
From 0 g, 9.4 g of the corresponding 5-en-3-one compound (81% yield) was obtained. In addition, campesterol (R = methyl group) 3.0 g
The corresponding 5-en-3-one derivative (2.4 g, yield 80%) was obtained.

[0017]

According to the method of the present invention, β-cytosto-5-
Steroid compounds such as en-3-one can be separated and purified from the reaction mixture very efficiently and easily. In addition, the same halogenated hydrocarbon solvent is used as the reaction solvent and the elution solvent, so that the working process can be simplified, and the cost can be reduced by reusing the recovered solvent.

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Claims (5)

(57) [Claims] 1. The following formula (I): A steroid compound represented by the formula (wherein R represents a hydrogen atom or a lower alkyl group) is oxidized with chromic acid in the presence of anhydrous calcium carbonate to give the following formula (II): (Wherein R has the same meaning as above)
In the method for producing an on-form, chromic acid oxidation is carried out in a halogenated hydrocarbon solvent, and the solute of the obtained reaction solution is adsorbed by an adsorbent having a magnesium silicate layer and a silica gel layer laminated to form a halogenated carbonization. A method comprising eluting a 5-en-3-one compound with a hydrogen solvent. 2. The method according to claim 1, wherein the chromic acid oxidation is carried out with pyridinium chlorochromate. 3. The method according to claim 1, wherein the halogenated hydrocarbon solvent used as the reaction solvent and the eluent is dichloromethane. 4. The method according to claim 1, wherein R is a hydrogen atom, a methyl group, or an ethyl group. 5. The method according to claim 4, wherein R is an ethyl group.