JPS58178000A - Production of ketocholanic acid or ester thereof - Google Patents

Abstract

PURPOSE:A cholanic acid bearing hydroxyls or its ester is oxidized with an aqueous solution of an alkali or alkaline earth metal hypochlorite in a hydrophobic organic solvent to produce the titled compound used as an intermediate of drugs in high purity and high yield in low costs. CONSTITUTION:A cholanic acid bearing at least one of hydroxyl or its ester is treated with 1.1-1.3mol of an alkali or alkaline earth metal hypochlorite per mole of the hydroxyl in the cholanic acid, calculated as effective chlorine atoms, to oxidize at least one of hydroxyls, thus giving a ketocholanic acid or its ester. The reaction is carried out at 0-30 deg.C and less than 10 pH in the presence of a catalyst of a quaternary ammonium salt.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a method of oxidizing furan 1 wave or its esters having one or more hydroxyl groups using an alkali or alkaline earth metal hypochlorite to partially or completely oxidize the hydroxyl groups. The present invention relates to a method for producing ketocholanic acid or its esters.

The method of the present invention includes cosine 1 or its esters having a hydroxyl group, such as cole (bile acids, 3α, 7α,
It is used in the production of various ketocholanic acids or esters of ketocholanic acid by selectively or totally oxidizing the hydroxyl groups of 12α-trihydromylocanac) and its esters, excluding at least one hydroxyl group. These compounds are intermediates in the synthesis process of chenodeoxycholic acid (3α,7α-dihydroxycholanic acid) and ursodeoxycholic acid (3α,7β-dihydroxycholanic acid), which have recently attracted attention as pharmaceuticals such as gallstone dissolving agents. It is a useful substance as such.

Conventionally, as a method for selective oxidation of a part of hydroxyl groups or total oxidation of all hydroxyl groups of furanic acid or its esters having one or more hydroxyl groups, chromic acid, potassium dichromate, etc. were oxidized in an acetic acid solvent. Methods used (Journal of the American Chemical Society Vol. 72, 55)
30, 1950, etc.), but this method causes a large amount of harmful chromium to be mixed into the wastewater, requiring a large amount of cost to dispose of it, and also causing a layer of chromium to be mixed into the target product. Therefore, there were drawbacks such as requiring complicated labor to remove and purify it.

As a way to overcome these difficulties,
No. 493, No. 50-12434, No. 52-33638
The publication proposes a method using an aqueous solution of sodium hypochlorite as an oxidizing agent.

However, in these known methods, the selectivity of the singing reaction is low, the raw material compound does not dissolve in the reaction solution, and there are difficulties in reaction operation, and the method is not necessarily suitable as an industrial production method. It's hard to say.

For example, in Japanese Patent Publication No. 52-33638, lower fatty acids such as acetic acid or propionic acid or a mixture of these and lower alcohols such as methanol or ethanol are used as a solvent, and raw cholic acid esters are dissolved in this and hypochlorite is A method has been proposed for producing the desired ketocholanic acid esters with good selectivity by partially or completely oxidizing the hydroxyl groups using an alkaline aqueous solution of acid soda, but according to the experiments of the present inventors, the above-mentioned When the alkaline water f6d of sodium hypochlorite is added to the raw material solution, the raw material compound reacts and precipitates in the solution, so the subsequent reaction proceeds in a slurry state, making it difficult to stir the reaction solution uniformly.

However, using a large amount of acid such as acetic acid or propionic acid lowers the pH of the reaction solution, which promotes the decomposition of sodium hypochlorite, which is inconvenient for the reaction. Since they are all water-soluble in nature, it is difficult to separate the solvent and water, and whether they are recovered or disposed of, a great economic burden cannot be avoided.

The present inventors have completed the method of the present invention as a result of extensive studies aimed at solving the shortcomings of these known methods, synthesizing a highly pure target product with good selectivity, and carrying out the reaction economically. I ended up doing it.

That is, in the present invention, furanic acid or its derivatives having one or more hydroxyl groups, or esters thereof, are prepared by using an aqueous solution of an alkali or alkaline earth metal hypochlorite salt in a hydrophobic organic solvent. The present invention aims to provide a method for producing ketocholanic acid or its esters by oxidizing at least one hydroxyl group.

The method of the present invention will be explained in more detail below.

The hydrophobic organic solvent to be used in the method of the present invention is one that is substantially immiscible with water, does not react with or decompose with the raw material or product, and is ) and the desired product, ketocholanic acid (or ester), are not particularly limited.

Here, the meaning of "substantially immiscible with water" does not mean that there is no mutual solubility between the solvent and water;
In a two-component system of solvent and water, even if they have considerable solubility in each other, they can be used as long as they can be substantially separated into two phases, an organic layer and an aqueous layer, with the raw materials dissolved under the reaction conditions. It is something that can be done. Examples of such solvents include aliphatic, alicyclic, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, and more specifically, n-pefuran, n-hexane, n- Hebutane, nclohexane, be/ze/, toluene/, xylene, ethylbenzene/, chlorobenzene, dichlorobenzene, bromobenzene, dichlorometh/, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, dichlorobenzene, flom A suitable one is selected from benzene, inopropyl ether, tetrahydrofuran, dioxane, methyl ethyl ketone, and methyl isobutyl ketone. These solvents can be used alone or in mixtures. The reaction is carried out by adding the raw material hydroxycholanic acid (aqueous solution) to these organic solvents, preferably with sufficient stirring.

Although there are no strict restrictions on the reaction conditions, it is preferable to carry out the reaction at a temperature of about θ to 30°C, and if the pH of the reaction solution is too high, the reaction will be extremely slow.
It is desirable that the pH is preferably 10 or less. As the alkali metal salt of hypochlorite, sodium hypochlorite or potassium hypochlorite is usually used. It is used as an alkaline aqueous solution containing potassium, etc. Also, bleaching powder is usually used for the alkaline earth metal hypochlorite salt. The amount used is 10 to 1 chlorine available per mole of colanic acid (or ester) to be oxidized.
A suitable amount is about 5 mol, preferably about 11 to 1.3 mol. Similarly, the pH of the reaction solution depends on the alkalinity and amount of the alkali hypochlorite or alkaline earth metal salt bath solution used.
exceeds lO as described above, P l−
It is desirable to add an appropriate acid to the reaction solution for adjustment. In this case, the acid to be used is preferably a weak acid rather than a strong acid, but it must be compatible with the 5R bath in the reaction solution, be stable under the reaction conditions, and not react with or decompose with the raw materials and target product. It's good to have. Specifically, for example, acetic acid,
/Uric acid, citric acid, boric acid, S/acid, etc.

There is no strict limit to the lower limit of P tl, but it is preferably 4 or more, and it is appropriate to adjust the amount of acid within this range.

1^j. The reaction of the present invention can proceed satisfactorily without a catalyst and can achieve the intended purpose; however, in addition to this, it is possible to use at least 1 m of a phosphonium salt or macrocyclic ether (crown ether). It is effective in improving the reaction rate, and trioctylmethylammonium chloride, tributylbenzylammonium chloride, triethylbenzylammonium chloride, N-benzylpicolinium chloride, 18-crown-6, etc. are particularly good. These catalysts are effective when the pH of the reaction solution is alkaline. Therefore, when using a catalyst, it is desirable to adjust the pH of the reaction solution to 8 to 10, preferably around 9. There is no particular restriction on the amount of catalyst used, but it is usually o or o per 1 part (part by weight) of the raw material compound.
A suitable amount is approximately 0.2 parts, preferably 0.01 to 0.1 parts.

The optimum range of reaction time varies depending on the type of raw materials and solvent to be subjected to the reaction, reaction flow rate, PH, presence or absence of catalyst, type and amount thereof, etc., but under normal conditions it is carried out in about 10 minutes to 2 hours. .

According to the method of the present invention, the desired compounds can be economically produced with high purity and high selectivity in the production of the corresponding ketocola/acids and their esters by oxidation of the l-hydroxyl group in the molecule. can be obtained advantageously. Some typical examples of these applications include the following:

:+-from acid, 3α,12α-dihydroxy=7-
From kedocholanic acid, 3α-hydroxy-7゜12-diketocholanic acid or tehydrocholic acid, methyl cholate, 3α# 12α methyl dihydro-7-7-ketocholanate, methyl 3α-hydroxy-7-7.12-diketocholanate or tehydrocholanic acid Methyl, chenodeoxycholic acid to 3α-hydroxy/-7-ketochola/acid, or 3゜7-diketocholanic acid, methyl chenodeoxycholate to 3α-hydroxy-7-ketocholanic acid,
or methyl 3.7-diketocholanate, methyl 3α-acetoxy-7-kedo-12α-hydroxycholanate or methyl 3α-acetoxy7.12-diketocholanate, 3α-propionyloxy-7α,
Methyl 12α-dihydroxycholanate to methyl 3α-propionyloxy-7-keto-12α-hydroxycholanate, or 3α-propionylokine-7.12
-Methyl diketocholanate, 3α,7α-diacetoxy-12α-methyl dihydroxycholanate to 3α,7
Methyl α-diacetoxy-12-ketocholanate, 3α
, methyl 7α-dibu-pionyloxy-12α-dihydroxycholanate to methyl 3α,7α-dipropionyloxy-12-ketocholanate, and the like.

Hereinafter, typical examples of the method of the present invention will be shown and more specifically explained, but these are merely illustrative, and it goes without saying that the present invention is not limited to these.

Example 1 3α,7α-Diacetoxy-12α-hydroxy/methylfuranoate 10F is dissolved in 30 mlK of dichloromethane. Add 1.59 ior of acetic acid and 10 ior of water, then add sodium chlorate (available chlorine concentration 12.6%) to 13°32 to 10~
Add dropwise over 15 minutes while stirring at 15°C. After the dropwise addition was completed, the mixture was stirred for an additional hour at the same temperature.

Then, the organic layer was mixed with 5% aqueous sodium hydrogen carbonate solution and 10%
After washing with an aqueous sodium chloride solution and drying the organic layer, the solvent was distilled off under reduced pressure to obtain methyl 3α,7α-diacetoxy/-12-ketocholanate, melting point 180-2°C, 9.9 f/
(yield 99%).

Example 2 3α,7α-Diacetoxy-12α-hydroxy/methylcholanate 102 is dissolved in 100 rne of benzene. 50% benzyltributylammonium chloride 1. P 11 in a separate 10% phosphoric acid water bath solution.
Sodium chlorate water bath solution (available chlorine concentration 94%) prepared in 8.
Drip in minutes. After the addition was completed, the mixture was stirred for another hour at the same stirring temperature. Then, the organic layer was washed with an aqueous sodium bicarbonate solution and lθ% salted.) After washing with an aqueous solution of IJ and drying the organic layer, the solvent was distilled off under reduced pressure to obtain methyl 3α,7α-diacetoxy-12-ketocholanate. Melting point 180~2℃
9, 9? (yield: 99 cm).

Example 3 1 t of methyl cholate is dissolved in 4 rnl of dichloromethane. Add 6f of 10% acetic acid aqueous solution and heat 4.81 of sodium hypochlorite (available chlorine concentration 12.6t) at 10-15°C.
Add dropwise to the stopper while stirring. After dropping, add 1 more at the same temperature.
After stirring for an hour, the organic layer was washed with a 5% aqueous sodium bicarbonate solution and a 10% aqueous sodium chloride solution, and after drying, the solvent was distilled off under reduced pressure to obtain methyl tehydrocholate, melting point 240.
0962 (97% yield) was obtained at ~2°C.

Example 4 Methyl cholate 17 is dissolved in dichloromethane 4-. Add 4v of 10-thiacetic acid aqueous solution, and add 32v of sodium hypochlorite (126% available chlorine) dropwise into the stopper at 0 to 5°C with stirring. After the dropwise addition was completed, the mixture was stirred for another hour at the same temperature, and the organic layer was washed with a 5% aqueous sodium bicarbonate solution and a 10% aqueous sodium chloride solution, and after drying, the solvent was distilled off under reduced pressure.
methyl α-hydroxy7-7.12-diketocholanate,
Melting point 147-9℃, 0.9e? (yield 97%).

Example 5 3α-acetoquine-7α,12α-dihydroquine/methyl colanate 17 was converted to benzene xorn1. Dissolve in. Sodium hypochlorite aqueous solution adjusted to pH 8 with 10% acetic acid bath solution (available chlorine concentration 9.6 h) 1.57 to 0
Add dropwise to stoppers at 5°C while stirring. After the dropwise addition was completed, the mixture was stirred for an additional hour at the same temperature. 5% hydrogen carbonate to the organic layer) IJ
After washing the organic layer with a 10% sodium chloride aqueous solution and a 10% sodium chloride aqueous solution, the solvent was distilled off under reduced pressure to obtain 3α-acetoxy-7-keto-12α-hydroxy/methyl colanate,
It had a melting point of 154-6°C and a yield of 0.97 y (yield 97%).

Example 6 Chenodeoxy/cholic acid 2f was diluted with tetrahydrochloride 7/lO-
Dissolve in. Add 3 f of 10% acetic acid aqueous solution and add sodium hypochlorite (available chlorine 12.6%) 341 to 0-5℃.
Gradually add the mixture dropwise while stirring. After the dropwise addition was completed, the mixture was stirred for an additional hour at the same temperature. When the reaction solution is allowed to stand still, it separates into two layers: an organic layer and an aqueous layer.

The organic layer was washed with saturated brine, further dried, and the solvent was distilled off under reduced pressure to obtain 3α-hydroxy-7-ketocholanic acid, melting point 198.7201°C, 1. s s f (yield 93
%) was obtained.

Patent applicant: Showa Denko Co., Ltd.

Claims (1)

[Claims] 1) Collanic acid or colanic acid esters having one or more hydroxyl groups are dissolved in a hydrophobic organic bath medium using an aqueous solution of an alkali or alkaline earth metal salt of hypochloric acid to remove the hydroxyl groups in the molecule. A method for producing ketocholanic acid or its esters in which at least one is oxidized to form a 11 core.