JPS6221358B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a Δ11-unsaturated steroid compound by desulfonating a steroid compound having an alkyl sulfone group at the 12-position, and in particular, it relates to a method for producing a △ ^11- unsaturated steroid compound by desulfonating a steroid compound having an alkyl sulfone group at the 12-position.
The present invention relates to a method characterized in that the desulfonation reaction is carried out in the coexistence of at least one ammonium salt or crown ether. The method of the present invention is used to synthesize various steroid compounds having an unsaturated bond at the 11th position, and is particularly useful for synthesizing chenodeoxycholic acid (CDC) from cholic acid. CDC is a useful substance as a drug such as a gallstone dissolving agent, and the development of an inexpensive synthesis method is expected in recent years. There are two main methods known for synthesizing CDC from cholic acid.
By esterifying the hydroxyl groups at positions 3α and 7α, respectively
This is a method in which methyl -diacetoxy-12α-hydroxycholanate is synthesized, then oxidized to form a 12-oxo form, and then the 12th position is substituted with hydrogen by Wolff or Chisner reduction or (Hamminlon reduction). The other method is to dehydrate the 12-position hydroxyl group of cholic acid to form a △ ¹¹ unsaturated bond, and then hydrogenate this. For example, the method described in U.S. Patent No. 3,998,859 is known. . That is, cholic acid was converted into methyl diacetoxycholanate, the hydroxyl group at the 12th position was converted to an alkylsulfone group, and this was desulfonated with acetate using hexamethylphosphotriamide (HMPT) as a ^solvent. An unsaturated steroid compound is obtained, then the unsaturated bond is hydrogenated, and the protecting group is removed by hydrolysis to obtain the desired product. Although this method is an excellent method with few side reactions, the HMPT used as a solvent is an expensive substance, and there have been recent reports that it may be carcinogenic, so it is not necessarily suitable as an industrial production method. It is hard to say that this is an appropriate method. In order to improve this method, the present inventors developed a steroid compound having an alkyl sulfone group at the 12-position using a material that is industrially relatively inexpensive and easily available and does not have harmful effects on the human body. As a result of various studies on methods for synthesizing steroid compounds having △ ¹¹ unsaturated bonds by desulfonation, it was found that the reaction was carried out using at least one combination of an alkali metal bicarbonate and a quaternary ammonium salt or a crown ether.
By conducting the experiment in the presence of the species, the desired product could be obtained in high yield, and the desired objective could be achieved successfully. The method of the present invention will be explained in more detail below. In the method of the present invention, the metal salt, quaternary ammonium salt, etc. have a function as a desulfonating agent, and lithium, sodium, or potassium bicarbonate, etc. are used as the metal salt. As the quaternary ammonium salt, a compound represented by the following general formula is used. (However, R ₁ , R ₂ , R ₃ and R ₄ each represent an alkyl group, an alkenyl group or an aryl group, and X represents an iodine atom, bromine atom, chlorine atom or fluorine atom.) Represented by the above general formula Especially among the quaternary ammonium salts, R ₁ , R ₂ and R ₃ each have 1 carbon number.
~8 chain or cyclic alkyl group, phenyl group, benzyl group, or phenyl group or benzyl group substituted with a lower alkyl group, and R ₄ is a chain or cyclic alkyl group having 1 to 18 carbon atoms, carbon number Compounds in which 2 to 4 lower alkenyl groups or benzyl groups and X is a chlorine atom or a bromine atom are the most practical from the viewpoints of ease of production and purification, economic efficiency, catalytic activity, stability, etc. I can say that. However, it is not necessarily limited to these. Some representative examples of quaternary ammonium salts used in the method of the present invention are as follows. Ammonium-tripropylmethyl iodide, -tripropylethyl chloride, -tetrapropyl bromide, -tripropyl butyl iodide, -
Tripropyloctyl iodide, -tripropylcyclohexyl chloride, -tripropylphenyl bromide, -tributylmethyl iodide, tributylmethyl bromide, tributyl ethyl bromide, tributylpropyl chloride, tritolylmethyl iodide, tricylylbenzyl bromide, tribenzyl Ethyl chloride, tricyclohexylmethyl iodide, tricyclobentyl isobutyl chloride, dimethylethyl phenyl iodide, dibutylmethyl phenyl iodide, tetrabutyl iodide, tributylamyl bromide, tributylhexyl chloride, tributyloctyl iodide, tributyl decyl Bromide, tributylcetyl iodide, tributylbenzyl chloride, tributylallyl chloride, tributylcyclohexyl bromide, triamylmethyl bromide,
Triheptylbutyl chloride, trihexylmethyl iodide, trihexylbutyl bromide, trihexyl octyl chloride, trioctyl, methyl iodide, trioctyl methyl bromide, trioctyl ethyl bromide, trioctylpropyl chloride, trioctyl butyl iodide, trioctyl amyl bromide,
Tetraoctyl chloride, trioctyl cetyl iodide, trioctyl benzyl chloride,
Triphenylmethyl iodide, triphenylpropyl bromide, triphenylbutyl iodide, triphenylheptyl bromide, triphenylbenzyl chloride, etc., and as a crown ether, 15-crown-5, 18-crown-
6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6, dibenzo-24-crown-8, dicyclohexyl-24-crown-8, etc. are used, especially in combination with the above metal salts, It is effective to use one that matches the ionic radius of the metal. The reaction is carried out in a liquid phase, but the 3α・7α-diacetoxy-12α- used as a raw material
Methyloxycholanate has a low melting point and can remain in a liquid state at the reaction temperature, so a solvent is not necessarily required. However, since side reactions generally increase when no solvent is used, it is usually preferable to use an appropriate solvent. As the solvent, a mixed solvent of water and an organic solvent or a non-aqueous organic solvent is used. The reaction rate varies depending on the type of solvent, but in principle there are no particular restrictions as long as it is stable under the reaction conditions, as long as it is liquid and does not react with or decompose with raw materials, target substances, catalysts, etc. Practically, for example, water-insoluble solvents such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, methyl isobutyl ketone, and butyl acetate, and water-soluble solvents such as tetrahydrofuran, dioxane, acetonitrile, propionitrile, and cyclohexanone are used. A solvent can be used as appropriate. As for the reaction conditions, there are no strict limitations, but the amount of metal salt used is usually 5 parts to 0.1 parts, preferably 2 parts to 1 part, per 1 part of the raw material compound.
About 0.2 part is appropriate, and the amount of quaternary ammonium salt or crown ether used is usually about 0.2 to 0.001 part, preferably about 0.1 part to 0.01 part, based on 1 part of the raw material compound. Although the optimum range of reaction temperature varies depending on the type of raw materials to be used, the combination of catalysts, solvents, etc., it is generally appropriate to carry out the reaction in the range of 80 to 150°C, preferably 110 to 130°C. Although it is difficult to specify a uniform reaction time, under normal conditions, 4 to 15 hours is appropriate. The method of the present invention uses cholic acid as described above.
In the process of synthesizing CDC, it is effectively applied to desulfonate methyl 3α・7α-diacetoxy-12α-mesyloxycholanate to convert it into a compound having an unsaturated bond at the 11-position. In this case, the alkyl sulfone group at the 12th position is not just arbitrary; for example, it has a strongly lipophilic group such as p-toluenesulfone group or benzenesulfone group, which is often used as a leaving group in organic synthesis reactions. In the case of anions, the released anions are unsuitable because they combine with quaternary ammonium salts and the like, making it impossible to transfer the metal salt residues necessary for the reaction to the oil phase. Therefore, a lower alkyl group such as methane-ethane- is suitable as the alkylsulfone group at the 12th position. However, the desulfonation reaction of the present invention is not affected by the substituents at the 3- and 7-positions. For example, the 3- and 7-positions are hydrogen atoms (unsubstituted), hydroxyl groups, alkoxy groups, acyloxy groups, alkyl Any group may be used, and the substituent at the 17th position is -CH(CH ₃ ), which corresponds to cholic acid.
It is not limited to CH ₂ CH ₂ CO ₂ H or its reactive derivatives such as esters, amides, acid chlorides, etc., but also other compounds such as -CH(CH ₃ )
_CH2CO2H −CH _{( CH3} ) _CO2H , _−CO2H−
It can be any group such as COCH ₃ , -CH ₂ CH ₃ , -CH(OH)CH ₃ , their homologues, or reactive derivatives, and can be widely applied to the synthesis of various △ ¹¹ unsaturated steroid compounds. can. Hereinafter, the method of the present invention will be described in more detail by showing examples, but these are merely representative examples of the method of the present invention, and it goes without saying that the present invention is not limited to these. Needless to say, there are no restrictions whatsoever. Example 1 100 g of methyl 3α・7α-diacetoxy-12α-mesyloxycholanate (), 50 ml of xylene,
150 g of potassium hydrogen carbonate, 100 ml of water, and 5 g of trioctylmethylammonium chloride as a catalyst were mixed and reacted at 110°C for 15 hours. After the reaction is completed, the potassium bicarbonate layer is separated and the organic layer is washed with water. Target 3,7-diacetoxy-△
¹¹ Since a portion of the hydrolyzate of methyl cholenate is formed, the resulting product is esterified and returned to the desired product.
After washing with water, xylene in the organic layer was distilled off under reduced pressure and recrystallized from methanol to obtain 72.3 g of a purified product. Example 2 The results of reacting 10 g of raw material (1) under various conditions are shown in the table.

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Claims (1)

[Claims] 1. A △ 11-unsaturated steroid characterized by subjecting a steroid compound having an alkyl sulfone group at the 12-position to a desulfonation reaction in the coexistence of an alkali metal bicarbonate and at least one quaternary ammonium salt or crown ^ether . Method of manufacturing compounds.