JPS6354720B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides ursodeoxycholic acid (i.e. 3α,
7β-Dihydroxycholanic acid)) For details, please refer to the new method for producing 3α-hydroxy-7-ketocholanic acid in an organic solvent that dissolves alkali metals or alkaline earth metals and does not cause an alkoxidation reaction with these metals. Among them, the present invention relates to a method for producing a crude ursodeoxycholic acid product by hydrogenation using an alkali metal or an alkaline earth metal in the presence or absence of a proton source.

Hydrogenation of 3α-hydroxy-7-ketocholanic acid by conventional methods yields 3α,7β-dihydroxycholanic acid (also known as chenodeoxycholic acid),
Ursodeoxycholic acid is hardly obtained (for example, Hoshino et al.: Nippon Kagaku Zasshi, Vol. 76, p. 297;
(1955). Conventionally, methods for producing ursodeoxycholic acid using 3α-hydroxy-7-ketocholanic acid as a raw material include (1) hydrogenation method using metallic sodium in alcohol with a boiling point of 80 to 150°C (Japanese Patent Publication No. 33-9973); (2) Hydrogenation method using metallic potassium in t-butanol (Japanese Patent Publication No. 1983-
10062); and (3) a method of hydrogenation using lithium in the presence of a proton source in liquid ammonia (Japanese Unexamined Patent Publication No. 85600/1983).
The purity of the ursodeoxycholic acid crude product produced by these methods is said to be 82% or less for method (1), 96% or more for method (2), and about 90% for method (3), respectively. However, in method (2), which yields the most pure ursodeoxycholic acid crude product, hydrogenation is performed using potassium, but potassium is one of the most chemically reactive metals, and It may ignite; it reacts violently with water at room temperature and generates hydrogen, and the generated hydrogen ignites due to the heat of reaction. Method (2) cannot be called an industrial production method because potassium having such properties is used. On the other hand, (3)
This method requires cooling equipment because the reaction is carried out in liquid ammonia at -70 to -32°C, and the operation is complicated, which is disadvantageous as an industrial production method.

The inventor eliminates the manufacturing disadvantages of the above method,
As a result of research into a method for industrially easily producing a crude product of ursodeoxycholic acid with relatively high purity, it was found that 3α-hydroxy-7-ketocholanic acid was dissolved in alkali metals or alkaline earth metals and mixed with these metals. We have discovered that ursodeoxycholic acid crude products can be advantageously produced when hydrogenation is carried out using an alkali metal or alkaline earth metal in the presence or absence of a proton source in an organic solvent that does not cause an alkoxidation reaction, and the present invention Completed the invention.

As an organic solvent that dissolves the alkali metal or alkaline earth metal used in the method of the present invention and does not cause an alkoxidation reaction with these metals, amines such as hexamethylphosphoric acid triamide, ethylenediamine, methoxyethylamine, methylamine, and ethylamine are used. , glymes, propylene oxide cyclic tetramer, crown ether, and other ethers. The alkali metal or alkaline earth metal is preferably lithium, sodium or calcium, while the proton source includes lower alkyl alcohols such as methanol and t-butanol, acetic acid, and ammonium chloride.

When an organic solvent is used as the proton source in the method of the present invention, the proportion of the solvent in the mixture of the proton source and the solvent is 5 to 100%. Reaction conditions vary depending on the type of solvent used. When using a solvent with high solubility of alkali metals or alkaline earth metals, such as hexamethylphosphoric acid triamide, crown ether, etc., the amount of proton source should be at least 5 times the molar amount of 3α-hydroxy-7-ketocholanic acid. The amount is in large excess, for example up to 50 times the amount (v/w), and the reaction temperature is in the range from -80°C to the boiling point of the solvent. On the other hand, when using a solvent in which the alkali metal or alkaline earth metal has a rather low solubility, such as glymes or ethylenediamine, it is preferable to use a large excess amount of the proton source, and the reaction temperature is preferably near the boiling point of the solvent. The amount of alkali metal or alkaline earth metal added is in each case 3α-hydroxy-7-
The molar amount is 5 times or more relative to ketocholanic acid. Furthermore, when amines such as ethylenediamine, methoxyethylamine, methylamine, and ethylamine are used as a solvent in the method of the present invention, the reaction may be carried out in the absence of a proton source. In this case, the amount of solvent used is at least 5 times the amount (v/w) of 3α-hydroxy-7-ketocholanic acid, and the reaction temperature is -
The temperature is 50-100°C, preferably 10-40°C. Also,
Amines such as piperazine, morpholine, and ammonia can be present together.

Example 1 0.76 g of sodium metal was added to 26 ml of hexamethylphosphoric triamide under a nitrogen stream and stirred. The liquid took on a deep blue color. To this solution, 15 ml of anhydrous t-butanol was added at room temperature and stirred for 5 minutes. The color of the liquid was deep blue. A solution of 1.00 g of 3α-hydroxy-7-ketocholanic acid dissolved in 10 ml of hexamethylphosphoric acid triamide was gradually added to this solution, taking care not to lose the deep blue color. The sodium pieces remaining in the reaction solution were removed, water was added, and then concentrated hydrochloric acid was added to make the solution acidic, and the resulting precipitate was collected, washed with water, and dried to obtain 1.02 g of a crude ursodeoxycholic acid product. . Purity 92.6% (measured by gas chromatography; the same applies below), [α] _D = +56.88
(C=1%, ethanol).

Example 2 100 g of 3α-hydroxy-7-ketocholanic acid was mixed with 500 ml of ethylenediamine and 4.5 g of t-butanol.
Sodium metal is dissolved in a mixture of
370 g was added and heated under reflux to dissolve the sodium. The solution was cooled, water was added, concentrated under reduced pressure, and the residue was diluted with water. The diluted solution was made acidic with concentrated hydrochloric acid, and the resulting precipitate was collected, washed with water, and dried to produce 99 g of crude ursodeoxycholic acid.
I got it. Purity 90.5%, [α] _D = +55.70 (C = 1%,
ethanol).

Example 3 1 g of 3α-hydroxy-7-ketocholanic acid was dissolved in a mixture of 5 ml of ethylenediamine and 50 ml of t-butanol, and 2.95 ml of sodium metal was added to this solution.
g was added. While heating under reflux, 1.25 ml of methanol was gradually added to dissolve the metallic sodium. The solution was cooled, water was added, the solvent was distilled off, and the residue was diluted with water. This diluted solution was made acidic with 50% sulfuric acid, and the resulting precipitate was collected, washed with water, and dried to obtain 0.98 g of a crude product of ursodeoxycholic acid. Purity 90.0%, [α] _D = +55.56 (C = 1%, ethanol).

Example 4 5 ml of ethylenediamine and 50 ml of t-butanol
1.01 g of a crude ursodeoxycholic acid product was obtained in the same manner as in Example 3, except that 50 ml of dibrame and 32 ml of t-butanol were used in place of the 50 ml mixed solution, and 1 g of metallic sodium was used. purity
90.2%, [α] _D = +55.62 (C = 1%, ethanol).

Example 5 100g of 3α-hydroxy-7-ketocholanic acid was dissolved in 10% of ethylenediamine, and 36g of metallic lithium was added to this solution at room temperature, resulting in a deep blue color. Stirring was continued until the dark blue color disappeared, then water was added thereto, followed by 3N hydrochloric acid, and the resulting precipitate was collected, washed with water, and dried to obtain 99 g of a crude product of ursodeoxycholic acid. Purity 91.1%, [α] _D = +56.12 (C
= 1%, ethanol).

Example 6 10 g of 3α-hydroxy-7-ketocholanic acid was dissolved in a mixed solution of 750 ml of ethylenediamine and 250 g of piperazine at 40°C, and when 3.6 g of metallic lithium was added to this solution at the same temperature, the solution turned dark blue. After continuing to stir until the deep blue color disappeared, water was added, followed by 20% sulfuric acid, the resulting precipitate was collected, washed with water, and dried to obtain ursodeoxycholic acid crude product 9.8
I got g. Purity 90.1%, [α] _D = +55.56 (C = 1
%,ethanol).

Example 7 The same procedure as in Example 6 was repeated except that morpholine was used in place of piperazine to obtain 9.8 g of a crude ursodeoxycholic acid product. Purity 90.5%, [α] _D = +
55.68 (C=1%, ethanol).

Example 8 100 g of 3α-hydroxy-7-ketocholanic acid was dissolved in 5 parts of ethylenediamine, and a solution of 36 g of metallic lithium dissolved in 1 part of liquid ammonia was gradually added to this solution, resulting in a deep blue color. Stirring was continued until the deep blue color disappeared. Thereafter, the same procedure as in Example 6 was carried out to obtain 99.2 g of a crude ursodeoxycholic acid product. Purity 92.0%, [α] _D = +56.60 (C = 1%, ethanol).

Claims (1)

[Claims] 1 3α-Hydroxy-7-ketocholanic acid is dissolved in an alkali metal or alkaline earth metal in an organic solvent that dissolves the alkali metal or alkaline earth metal and does not cause an alkoxidation reaction with these metals, in the presence or absence of a proton source. A method for producing ursodeoxycholic acid, which comprises hydrogenation using an alkaline earth metal.