JPS6221357B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention 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, and particularly 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. carrying out a desulfonation reaction in the coexistence of a phase transfer catalyst comprising at least one carbonate, bicarbonate, sulfite, or hydroxide of the metal and at least one quaternary ammonium salt or crown ether; Relating to a method characterized by: 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-oxy compound, 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 ^Δ11 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 fewer 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. Therefore, the present inventors devised a method to improve this method by removing the steroid compound having an alkyl sulfone group at the 12-position using a material that is industrially relatively inexpensive, easily available, and has no harmful effects on the human body. As a result of various studies on the method of synthesizing steroid compounds having △ ¹¹ unsaturated bonds by sulfonation, it was found that the reaction was carried out using at least one kind of alkali metal fluorides or lower carboxylates and carbonates and bicarbonates of the metals. The desired product can be obtained in high yield by carrying out in the coexistence of a phase transfer catalyst consisting of at least one salt, sulfite or hydroxide and at least one quaternary ammonium salt or crown ether, succeeded in achieving the intended purpose. The method of the present invention will be explained in more detail below. In the method of the present invention, the metal salts and quaternary ammonium salts function as desulfonating agents, and the metal salts include fluorides, formates, and acetates of lithium, sodium, or potassium. , propionate, butyrate, etc. are used, and among them, sodium acetate, potassium acetate, sodium fluoride, potassium fluoride, etc. are practically preferred. In addition, alkaline substances such as carbonates, bicarbonates, sulfites, or hydroxides are useful in improving the action of the desulfonating agent and suppressing side reactions. 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 to 1 carbon atoms.
8 is a 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, or a chain or cyclic alkyl group having 2 carbon atoms. ~4 lower alkenyl group or benzyl group, and compounds in which X is a chlorine atom or a bromine atom are considered to be the most practical from the viewpoints of ease of production and purification, economic efficiency, activity as a catalyst, stability, etc. I can say it. 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, tributyl methyl bromide, tributyl Ethyl bromide, tributylpropyl chloride, tritolylmethyl iodide, tricylylbenzyl bromide, tribenzylethyl chloride, tricyclohexylmethyl iodide, tricyclopentyl isobutyl chloride, dimethylethylphenyl iodide, dibutylmethylphenyl iodide, tetrabutyl Iodide, tributyl amyl bromide, tributylhexyl chloride, tributyl octyl iodide, tributyl decyl bromide, tributyl cetyl iodide, tributyl benzyl chloride, tributyl allyl chloride, tributyl cyclohexyl bromide, triamyl methyl bromide, triheptyl butyl chloride, trihexyl methyl Iodide, trihexylbutyl bromide, trihexyl octyl chloride, trioctyl methyl iodide, trioctyl methyl bromide, trioctyl ethyl bromide, trioctyl propyl chloride, trioctyl butyl iodide, trioctyl amyl bromide, tetraoctyl chloride, tri- Octylcetyl iodide, trioctylbenzyl 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, and especially in combination with the above metal salts, the ionic radius of the metal It is effective to use the one that suits you. The reaction is carried out in liquid phase or solid-liquid phase, but
The methyl 3α·7α-diacetoxy-12α-mesyloxycholanate used as a raw material has a low melting point and can maintain 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. The reaction rate varies depending on the type of solvent, but in principle there are no particular restrictions as long as it is liquid under the reaction conditions and is stable as long as it does not react with or decompose the raw materials, target product, catalyst, etc. When the reaction is carried out in a liquid phase, organic solvents substantially immiscible with water such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, methyl isobutyl ketone, butyl acetate, etc. are used. In addition, in the case of solid-liquid phase systems, water-soluble solvents can be used in addition to the above, for example,
Tetrahydrofuran, dioxane, acetonitrile, propionitrile, cyclohexanone, etc. are used. 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 of the raw material compound.
Approximately 0.5 part is appropriate, and the alkaline substance is preferably 1 part to 0.01 part per 1 part of the raw material compound.
0.5 part to 0.05 part is appropriate, and the amount of quaternary ammonium salt or crown ether used is usually about 0.2 part to 0.001 part, preferably about 0.1 part to 0.01 part, based on 1 part of the raw material compound. . The optimal range of reaction temperature varies depending on the type of raw materials used, the combination of catalysts, solvents, etc., but it is usually 80 to 150.
It is appropriate to carry out the reaction at a temperature of 110 to 130°C. Although it is difficult to define the reaction time uniformly, it can be said that about 4 to 18 hours is appropriate under normal conditions. 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 alkylsulfone group at the 12th position is not arbitrary; for example, it may be a highly 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 an anion having , the desorbed anion will bond with the quaternary ammonium salt, etc., and the metal salt residue necessary for the reaction will not be transferred to the oil phase, which is inappropriate. Therefore, a lower alkyl group such as methane-ethane- is suitable as the alkylsulfone group at the 12th position. The desulfonation reaction of the present invention is not affected by substituents at the 3-position and 7-position, for example, hydrogen atoms (unsubstituted), hydroxyl group, alkoxy group, acyloxy group,
Any alkyl group may be used, and the substituent at position 17 is -CH(CH ₃ ) corresponding to cholic acid.
It is not limited to CH ₂ CH ₂ CO ₂ H or its reactive derivatives such as ethyl, amide, acid chloride, etc., but also other compounds such as -CH(CH ₃ )
_{CH2CH2H −} CH _{( CH3} ) _CO2HCO2H − _COCH3 ,
Any of groups such as CH ₂ CH ₃ -CH(OH)CH ₃ and their homologues and reactive derivatives may be used, and can be widely applied to the synthesis of various ^Δ11 unsaturated steroid compounds. 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,
180 g of potassium acetate, 20 g of soda carbonate, 100 ml of water, and 5 g of trioctylmethylammonium chloride as a catalyst were mixed and reacted by heating at 120°C for 10 hours. After the reaction is completed, the potassium acetate layer is separated and the organic layer is washed with water. After removing xylene in the organic layer under reduced pressure, the crude product was recrystallized with methanol to obtain purified products, 3α and 7α.
-Diacetoxy- ^Δ11 71.5 g of methyl cholate was obtained. Example 2 The table shows the product distribution when 10 g of raw material () was reacted for 8 hours under various conditions.

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Claims (1)

[Claims] 1 A steroid compound having an alkyl sulfone group at the 12-position is combined with at least one alkali metal fluoride or lower carboxylate salt and a carbonate of the metal;
At least one bicarbonate, sulfite or hydroxide
A method for producing a ^Δ11 unsaturated steroid compound, which comprises carrying out a desulfonation reaction in the coexistence of a phase transfer catalyst comprising at least one species and a quaternary ammonium salt or a crown ether.