JPS58146597A - Separation of ulsodeoxycholic acid from kenodeoxycholic acid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for separating ursodeoxycholic powder from chenodeoxycholic acid.

Ursodeoxycholic acid is used in human medicine as a stone-dissolving agent. Ursodeoxycholic acid can be prepared either synthetically or by extraction;
That is, it must be separated from chenodeoxycholic acid.

Lumo (7), which has been described in publications as a method for separating ursodeoxycholic acid from chenodeoxycholic acid, includes derivatives of urtudeoxyfuric acid, such as esters (
Japanese Patent Application No. 78861/77, West German Patent Application No. 8019887) or the preparation of silyl derivatives (BP Application No. 24292). Separation of ursideoxycholic acid from chenodeoxycholic acid is carried out by crystallization of the intermediate in a suitable solvent. Hydrolysis of the crystallized product yields ursodeoxycholic acid.

Conventionally, only one of the two epimers was dissolved, and a simple 11
It was not possible to select methods and conditions that would allow separation by economical methods.

Surprisingly, a mixture of these beaks was suspended in a liquid in which both ursodeoxycholic acid and chenodeoxycholic acid were insoluble, and then N-alkylmorpholine was added to the resulting suspension to selectively induce It has been found that chenodeoxycholic acid can be dissolved in

According to the method of the invention, the liquid used for suspending the acid mixture is preferably selected from the group consisting of aromatic hydrocarbons, halogenated hydrocarbons, water or mixtures thereof.

A diluent is used in the appetizer to give the mixture a concentration of 0.2-40%.

N-alkylmorpholine is added to the suspension thus obtained in an amount of 1 to 10 mol per mol of chenodeoxycol. Preference is given to using N-alkylene or N-ethylmorpholine consisting of lower alkyl having 1 to 8 carbon atoms.

Alternatively, a mixture containing ursodeoxycholic acid and chenodeoxycholic acid is dissolved in a suitable solvent before or after adding the liquid in which both of these acids are insoluble, and then the N-alkylmorpholine is added.

The solvent and diluent are then removed using commonly used techniques. The oily residue thus obtained is treated with the liquid described above, which, due to the presence of the N-alkylmorpholine, is able to dissolve the chenodeoxycholic acid. The insoluble residue is ursodeoxycholic acid, which is separated and dried.

The above separation is preferably carried out at a concentration between -20° C. and the boiling point of the diluent.

The method of the present invention uses only insoluble ursodeoxycholic acid,
However, the method generally used provides further advantages in recovering 111° chenodeoxycholic acid from the mother liquor.

Hereinafter, the present invention will be explained in detail with reference to examples.

Example I N-methylmorpholine (1,562-1.7d J 1
5.4 mmol) was added to ursodeoxycholic acid (2,849,6 mmol) suspended in methylene chloride (715 g Lt) with stirring at 20°C. Added.

Stir the mixture overnight at 20°C. After filtration, the insoluble residue was washed with methylene chloride (15 g/) and dried to give urtudeoxyfurl containing 1.7% chenodeoxycholic acid! ! ! (7,929 J O mmol-I
IV rate of 66%).

Example 2 N-methylmorpholine (1,569-1, 寥's15.
4 mmol) was added to water (10 mmol) while stirring at 20°C.
Wurtudeoxyfur m (9,4o) suspended in
p.

24 mmol) and chenodeoxycol # (2,849
6 mmol) in suspension.

The insoluble residue was separated and dried, and the urtudeoxyfur containing 0.8% chenodeoxycholic acid (8,79,21
gives a millimolar Ie ratio of 70%).

After adjusting the pH of the mother liquor to 1 using 10% HOI, the suspension is filtered, the insoluble residue is washed with water and dried.

A mixture (89) containing 50.6% of ursodesoxifur and 49.4% of chenodeoxycholic acid is obtained. Example 8 Example 1 Repeatedly, N-ethylmorpholine was used instead of N-methylmorpholine. (1,71t & -1,589th 8 mmol) and filter the insoluble residue after 2 hours.

Ursodeoxycholic acid containing 8% of chenodeoxycholic acid (8.9g, 21 mmol + 3% yield 71%) is obtained.

Example 4 Practical Example 2 is repeated, but N-methylmorpholine is replaced by N-
Ethylmorpholine (1,7R&=1.58GI + 1
8 mmol).

Ursideoxycholic acid (7.77 g, 19 mmol, 66% yield) containing 1% chenodeoxycholic acid is obtained.

Example 6 A mixture (7,89° 20 mmol) consisting of ursodeoxycholic acid (80%) and chenodeoxycholic acid (20%) is suspended in methylene chloride (100 g ILt) and methanol (16 m) is added. N-methylmorpholine (1,]wu-19 was added to the solution thus obtained.
+ 10 mmol) at 2o"c. The mixture is evaporated under vacuum (100mH9) (external temperature 40"C) to give an oily residue (1o, sg).

Methylene chloride (60%) is added to the oily residue at 20°C. The mixture is stirred for 14 hours at go''c and then filtered. The crystalline insoluble residue is dissolved in methylene chloride (1
0m) and dry.

In this way, ursodeoxycholic acid (89%) and chenodeoxycholic l! ! A mixture consisting of (11%) (
4,849,12,4 mmol I (yield 62%) is obtained.

Example 6 Ursodeoxychole as (2,849,6 mmol) and chenodeoxycholic acid (1,569,4 mmol) were suspended in methylene chloride, and N-methylmorpholine (1,8S%/-1,2Gl + 11.9 mmol)
Add.

The suspension is stirred for 15 hours at 20°C and filtered.

The residue was washed with methylene chloride (8-) and dried.
．． Ursodeoxychole ii containing 5% chenodeoxycholic acid! (0.76 g, 1.9 mmol I yield 19
・Give 5%).

Example 7 Ursodeoxycholic II C9,49,24 mmol), chenodeoxycholic acid (2,849,6 mmol), water (45-) and methylene chloride (45 gLt)
) to a mixture of,! ! While stirring at .theta..degree. C., N-methylmorpholine (115.4 mmol of 1,71 t/-1,56 t) is added. Filter the suspension and remove the insoluble residue with water (
7@I! Wash with water and methylene chloride (7a/),
Urtudeoxyfuric acid containing 2.8% chenodeoxycholic acid (7,562,19 mmol ru ratio 6
5) will be given.

Example 8 Example 2 is repeated but with 600-g water as the diluent. Ursodeoxycholic acid containing 1.5% chenodeoxycholic acid (8,829,2 g mmol 8 yield 75%)
).

Example 9 Example 1 is repeated, but using chloroform instead of methylene chloride.

Urtudeoxyfuric acid containing 5% chenodeoxycholic acid (7,89,18,7 mmol/S'1JtY rate 62
．． 5%).

Example 10 Example 1 is repeated, but using toluene instead of methylene chloride.

Ursodeoxycholic containing 10% deoxycholic acid (10.8 g, 27.7 mm% A/IQ rate 9
2%).

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Claims (1)

[Claims] L A mixture of ursodeoxycholic acid and chenodeoxycholic acid is suspended in a liquid in which neither of these acids dissolves,
A method for separating ursideoxyfuric acid from chenodeoxycholic acid, which comprises adding N-alkylmorpholine and separating an insoluble acid. 2. A process according to claim 1, wherein the IN-alkylmorpholine is added in an amount of from 1 to 10 moles per mole of nochenodeoxycholic acid in the suspension. & The method according to claim 1 or 2, wherein the N-alkylmorpholine is N-methylmorpholine. 3. The method according to claim 1 or 2, wherein the 4LN-alkylmorpholine is N-ethylmorpholine.