KR0130732B1 - Process for production of ursodeoxy cholic acid - Google Patents

Abstract

A high-purity title compound was prepared with safety by reacting 3- -hydroxy-7-oxo-5- -cholic acid which was obtained from kenodeoxycholic acid by oxidation and alkaline metal mixture containing at least 2 alkaline metal such as Li, Na, K, and Rb in a mixed solvent of t-butyl alcohol and t-amylalcohol, followed by reduction with hydrogen to give the titled compound.

Description

Method for preparing ursodeoxycholic acid

The present invention relates to a method for preparing ursodeoxycholic acid, and more particularly, a liquid alkali metal made by mixing at least two metal elements with 7-oxo groups of 3α-hydroxy-7-oxo-5β-cholanic acid. The present invention relates to a method for preparing ursodeoxycholic acid of high purity and high yield by reducing the mixture with hydrogen obtained by reacting an alcohol.

Ursodeoxycholic acid is a type of bile acid with hydroxyl groups at the positions of 3α and 7β of the steroid ring. It is a substance that binds with taurine in the bile of a bear and is present as bile acid. It is known to have excellent effects on the treatment of diseases, improvement of liver function of chronic liver disease, hyperlipidemia, gallstones and other small bowel sequelae and inflammatory small bowel disease and indigestion. I could not get a sheep. At present, most ursodeoxycholic acids are chemically produced, and therefore, there is a need to prepare ursodeoxycholic acid having higher stability, higher purity and higher yield.

The most common conventional method for preparing ursodeoxycholic acid is the process of ethyl estering phenolic acid (3α, 7α, 12α-trihydroxycholanic acid), and the hydroxyl group at 3α and 7α position using acetic anhydride. (3) oxidizing the hydroxyl group at position 12α with chromic acid to form carbonyl; (4) hydrolyzing to 12-oxykenodeoxycholic acid (3α, 7α-dihydroxy-12-oxycholate) Step (5) reducing carbonyl at position 12 to obtain kenodeoxycholic acid (3α, 7α-dihydroxycholanic acid), and (6) oxidizing the hydroxyl group at position 7α of kenodeoxycholic acid to carbonyl, A step of obtaining hydroxy-7-oxo-5β-cholanic acid, and a step of obtaining ursodeoxycholic acid (3α, 7β-dihydroxycholanic acid) by reducing the metal sodium in an alcohol. Among these processes, the reduction process from ketone intermediates in particular is a solvent and reactant with an alkali metal such as Li, Na, K, Rb, Cs and an alcohol such as first, second, third butyl alcohol, third amyl alcohol or propyl alcohol. The 7-oxo group of 3α-hydroxy-7-oxo-5β-cholanic acid obtained by oxidizing kenodeoxycholic acid with hydrogen generated by the reaction is reduced to stereoselectively with 7α-hydroxy group.

Reduction by reaction of metal sodium with alcohols used to produce large amounts of ursodeoxycholic acid, as is well known, has low stereoselectivity (generally, ursodeoxycholic acid: kenodeoxycholic acid = 80: 20). ), Economical losses caused by long reaction times, coloration, low purity, low yields, especially complex purification processes due to low purity, and many shortcomings due to loss of products and solvents.

However, reduction with metal potassium and alcohol has advantages such as high stereoselectivity (ursodeoxycholic acid: kenodeoxycholic acid = 94: 6), high yield, high purity, low coloration, and relatively simple purification process. Risk of ignition due to reactivity, difficulty in controlling reaction rate in reaction, difficulty in storage and handling, and expensive lighting disadvantages.

In the case of the alcohol used as a solvent and reactants in the reduction process, in particular when using a third butyl alcohol, a high freezing point (2,562 ℃) due to a lot of difficulties in the reaction and handling, and when using a third amyl alcohol Due to high boiling point, low reactivity, expensive point, there are many restrictions in actual use.

Accordingly, an object of the present invention is to provide a method for preparing ursodeoxycholic acid which is safe, inexpensive, and of high purity and high yield by solving the above disadvantages.

In order to achieve the above object, in the present invention, 7-oxo group of 3α-hydroxy-7-oxo-5β-cholanic acid is mixed with at least two alkali metals such as Li, Na, K, Rb, Cs, It is characterized by obtaining urethane deoxycholic acid of high purity and high yield by reducing the hydrogen obtained by reacting with an alcohol by making an alkali metal mixture. Potassium, which is used solely for the production of ursodeoxycholic acid among alkali metals, has a risk of explosion and is difficult to be used in the air. In addition, in the case of sodium, since it should be stored in a solvent, it is difficult to store and it is difficult to add to the reaction solution as well as the reaction time takes 24 hours up to 68 hours. In the present invention, this problem can be solved by mixing two or more alkali metals to make them in a liquid phase. Particularly, it is preferable to use an alkali metal mixture which is liquid at room temperature by mixing 40 to 90% of potassium.

Another feature of the present invention is to solve the problems of explosion risk, reaction rate, temperature, time, degree of coloring, yield, purity, etc. inevitably involved in the reaction of alcohol and liquid alkali metal mixture used as a solvent and reactant For this purpose, a liquid alkali metal mixture of at least two alkali metals and tertiary butyl alcohol, tertiary amyl alcohol or a mixed solvent thereof (mixing ratio of tertiary butyl alcohol with tertiary amyl alcohol = 2 to 8: 8 depending on the temperature) The above problems could be solved by using ˜2). Especially, the problems of reaction rate, low boiling point and high freezing point when the third butyl alcohol was used alone and the third amyl alcohol were used. High boiling point, low reactivity with metal, high price could solve the problems.

For example, the freezing point of the third butyl alcohol is 25 ℃ and the freezing point of the third amyl alcohol is 14 ℃, but when mixing them, the temperature varies depending on the mixing ratio according to the season as shown in Table 1 There is a feature that can be used in different ways.

TABLE 1

Therefore, as can be seen from the above table, for example, when the alcohol solvent is used to produce ursodeoxycholic acid in the summer when the temperature is high, the third butyl alcohol or the third amyl alcohol may be used as it is. In the case of using, it is very convenient to mix and use.

Another feature of the present invention is that despite the prolonged reaction when reducing the 7-oxo group of 3α-hydroxy-7-oxo-5β-cholanic acid with hydrogen obtained by reacting a liquid alkali metal mixture with an alcohol or mixed alcohol Although unreacted alkali metals remained, many treatments were involved, but in the present invention, after reacting a liquid alkali metal mixture with an alcohol or a mixed alcohol for a predetermined time, carbon or Ni (II), Mo ( A substance obtained by impregnating a porous anthracite, alone or in combination, with an oxide, such as Ⅵ), was added at most 10% based on the alkali metal mixture, and then heated and refluxed at 80 to 90 ° C. for about 2 to 4 hours to produce an unreacted metal. The residue can be completely removed. In addition, after the reduction reaction, water and methanol are generally added to decompose the unreacted alkali metals, thereby making it impossible to recover anhydrous solvents such as tertiary butyl alcohol, tertiary amyl alcohol, or mixtures thereof. In the case of using the catalyst according to the invention, there is no need to add water and methanol after the reaction, and thus there is an advantage in that anhydrous solvent can be recovered and reused.

Hereinafter, the present invention will be described in more detail with reference to examples, and the following examples are only illustrated for the present invention and do not limit the scope of the present invention.

Example 1

Tertiary butyl alcohol 3.5 To this, add 254.7 mmol of 3α-hydroxy-7-oxo-5β-cholanic acid, stir well while heating under reflux, and let nitrogen flow through. At this time, while heating and refluxing in the presence of nitrogen, 60 g of a liquid alkali metal mixture (Na: K = 22: 78) is added little by little over 2 hours. After adding all the alkali metal mixtures, the mixture was heated to reflux for another hour, and then visually checked for the presence of unreacted alkali metals. The solvent obtained at this time is anhydrous solvent and used for the next reaction. The solvent was separated by distillation under reduced pressure, water was added to the reaction, and the remaining solvent was distilled off under reduced pressure, and the pH was adjusted to 1-2 with concentrated hydrochloric acid solution. Acid was obtained at the ratio of 96: 4 (yield 99%).

Example 2

Tert-Butyl alcohol 2 254.7 mmol of 3α-hydroxy-7-oxo-5β-cholanic acid was added to the mixture, and the mixture was stirred while being heated to reflux, and passed through nitrogen. At this time, while heating and refluxing in the presence of nitrogen, 60 g of a liquid alkali metal mixture (Na: K = 22: 78) is added little by little over 3 hours. After all the alkali metal mixtures were added, 6 g of the catalyst prepared according to the present invention was added, and the mixture was heated to reflux for another hour, and then visually checked for the presence of unreacted alkali metal, and the solvent was distilled off under reduced pressure. The solvent obtained at this time is anhydrous solvent and used for the next reaction. The solvent was separated by distillation under reduced pressure, water was added to the reaction, and the remaining solvent was distilled off under reduced pressure, and the pH was adjusted to 1-2 with concentrated hydrochloric acid solution. Acid was obtained in 95: 5 ratio (yield 98.5%).

Example 3

Mixed solvent 2 in which tertiary butyl alcohol and tertiary amyl alcohol were mixed at a ratio of 6: 4. 254.7 mmol of 3α-hydroxy-7-oxo-5β-cholanic acid was added to the mixture, and the mixture was stirred while being heated to reflux, and passed through nitrogen. At this time, while heating and refluxing in the presence of nitrogen, 80 g of a liquid alkali metal mixture (Na: K = 40: 60) is added little by little over 4 hours. After all the alkali metal mixtures were added, 6 g of the catalyst prepared according to the present invention was added, and the mixture was heated to reflux for another hour, and then visually checked for the presence of unreacted alkali metal, and the solvent was distilled off under reduced pressure. The solvent obtained at this time is anhydrous solvent and used for the next reaction. The solvent was separated by distillation under reduced pressure, water was added to the reaction, and the remaining solvent was distilled off under reduced pressure, and the pH was adjusted to 1-2 with concentrated hydrochloric acid solution. Acid was obtained at the ratio of 94: 6 (yield 98%).

Example 4

Mixed solvent 2 in which tertiary butyl alcohol and tertiary amyl alcohol were mixed at a ratio of 4: 6. To this, add 254.7 mmol of 3α-hydroxy-7-oxo-5β-cholanic acid, stir well while heating under reflux, and let nitrogen flow through. At this time, while heating and refluxing in the presence of nitrogen, 80 g (Na: K = 60: 40) of the liquid alkali metal mixture is added little by little over 4 hours. After all the alkali metal mixtures were added, 6 g of the catalyst prepared according to the present invention was added, and the mixture was heated to reflux for another hour, and then visually checked for the presence of unreacted alkali metal, and the solvent was distilled off under reduced pressure. The solvent obtained at this time is anhydrous solvent and used for the next reaction. The solvent was separated by distillation under reduced pressure, water was added to the reaction, and the remaining solvent was distilled off under reduced pressure, and the pH was adjusted to 1-2 with concentrated hydrochloric acid solution. Acid was obtained at the ratio of 94: 6 (yield 98%).

Example 5

Tertiary Amyl Alcohol 2 To this, add 254.7 mmol of 3α-hydroxy-7-oxo-5β-cholanic acid, stir well while heating under reflux, and let nitrogen flow through. At this time, while heating and refluxing in the presence of nitrogen, 60 g of a liquid alkali metal mixture (Na: K = 22: 78) is added little by little over 5 hours. After all the alkali metal mixtures were added, 6 g of the catalyst prepared according to the present invention was added, and the mixture was heated to reflux for another hour, and then visually checked for the presence of unreacted alkali metal, and the solvent was distilled off under reduced pressure. The solvent obtained at this time is anhydrous solvent and used for the next reaction. The solvent was separated by distillation under reduced pressure, water was added to the reaction, and the remaining solvent was distilled off under reduced pressure, and the pH was adjusted to 1-2 with concentrated hydrochloric acid solution. Acid was obtained in 95: 5 ratio (yield 98.5%).

Example 6

After dissolving 50 g of sodium chloride-hexahydrate (acetate) in 300 ml of warm water, it was added to 500 g of anthracite in fine powder, heated and refluxed for 1 hour, and then dissolved in 300 ml of sodium molybdate and dihydrate in 300 ml of water. Warm at 90 ° C. for 1 hour. After standing at room temperature for 2 days, it is heated to 900 ℃ and cooled.

As described above, the high freezing point and the slow reaction rate of alkali metal and the third disadvantage of using tert-butyl alcohol by using the liquid alkali metal mixture, tert-butyl alcohol and tert-amyl alcohol mixed solution Solving the problems of high cost and reactivity with alkali metals, which are disadvantages of using amyl alcohol, could not only produce high-purity ursodeoxycholic acid in high yield, but also solve the problems mentioned above when using alkali metals alone. Could.

In addition, by using the catalyst according to the invention it was possible to shorten the reaction time and there was an advantage that can be reused in the next reaction to recover the solvent as an anhydrous solvent.

Claims (7)

Liquid alkali metal eutectic mixture of 7-oxo groups of 3α-hydroxy-7-oxo-5β-choline acid obtained by oxidizing kenodeoxycholic acid with at least two of alkali metals of Li, Na, K, Rb, and Cs And hydrogen reduced by reacting with a mixed solvent of tert-butyl alcohol and tertiary amyl alcohol. The method for producing ursodeoxycholic acid according to claim 1, wherein an alkali metal eutectic mixture containing 40 to 90% of potassium is a liquid at room temperature. The method for producing ursodeoxycholic acid according to claim 1, wherein up to 80% of third butyl alcohol is used. The method for producing ursodeoxycholic acid according to claim 1, wherein the third butyl alcohol or the third amyl alcohol is used alone according to the reaction temperature. The method for producing ursodeoxycholic acid according to claim 1, wherein a mixed solvent of the third butyl alcohol and the third amyl alcohol is used in combination according to the outside temperature. The method for producing ursodeoxycholic acid according to claim 1, wherein an oxide of carbon, nickel or molybdenum is impregnated with porous anthracite, alone or in combination, as a catalyst. 7. The process for producing ursodeoxycholic acid according to claim 6, wherein the catalyst is used up to 10% of the alkali metal mixture.