JP3810610B2 - Tersamine amine salt of ursodeoxycholic acid and process for producing ursodeoxycholic acid using the same - Google Patents

Description

〔実施例１０〜１９〕
ウルソデオキシコール酸（ウルソデオキシコール酸９４．５％、ケノデオキシコール酸３．５％）１０．０ｇを用いて実施例１〜９と同様の操作をおこなった。結果を表２に示す。
【００１６】
【表２】

【００１７】
〔実施例２０〕 ウルソデオキシコール酸とトリエチルアミンとの２：１塩
ウルソデオキシコール酸（ウルソデオキシコール酸９４．５％、ケノデオキシコール酸３．５％）１０．０ｇをアセトン１００ｍＬに懸濁し、この懸濁液にトリエチルアミン７．１ｍＬ（２．０倍当量）を添加して加熱還流し、結晶を溶解させた。さらに加熱還流を続けると結晶が析出してきた。４０分間加熱還流してから放冷し、結晶を濾過した。濾過した結晶を再度アセトン２００ｍＬに加熱溶解し、徐冷した。析出した結晶を濾過して、ウルソデオキシコール酸とトリエチルアミンとの２：１塩を得た。
【００１８】
融点：２０２−２０５℃
熱分析：ＤＳＣ（5deg, 50sec）
１７０．６℃（トリエチルアミンの放出）
２０４．６℃（ウルソデオキシコール酸の融解）
元素分析：
計算値（Ｃ₅₅Ｈ₉₈ＮＯ₈として） Ｃ，73.18； Ｈ，10.80； Ｎ，1.58
実測値 Ｃ，73.36； Ｈ，11.06； Ｎ，1.48
ＩＲ（ＫＢｒ）：
３４４０，２９３０，２８６０，１７００，１５６０，１４５０ｃｍ^-1
1Ｈ−ＮＭＲ（２７０ＭＨｚ，ＣＤ₃ＯＤ）δｐｐｍ：
０．７１（３Ｈ，ｓ）、０．９６（６Ｈ，ｓ）、１．２９（９／２Ｈ，ｔ，Ｊ＝７．３Ｈｚ）、３．１６（６／２Ｈ，ｑ，Ｊ＝７．３Ｈｚ）、３．４８（２Ｈ，ｍ）
Ｘ線構造解析：
Ｃ₅₄Ｈ₉₅ＮＯ₈，ＦＷ＝８８６．３１，Ｏｒｔｈｏｒｏｍｂｉｃ，
Ｓｐａｃｅ ｇｒｏｕｐ Ｐ２（１）２（１）２（１），
ａ＝１１．０７８３（７）Å，ｂ＝１５．３３９０（１０）Å，
ｃ＝２９．９７７（２）Å，β=９０゜，Ｖ＝５０９４．０（６）＾３
Ｄｃ＝１．１５６ｃｍ＾−３，Ｚ＝４，Ｒ＝０．０５３７
【００１９】
【発明の効果】
本発明の塩及び製造方法により、非常に簡単な操作で収率良く、極めて高純度なウルソデオキシコール酸を得ることができる。
【図面の簡単な説明】
【図１】ウルソデオキシコール酸とトリエチルアミンとの２：１塩分子構造図[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a salt of ursodeoxycholic acid (chemical name: 3α, 7β-dihydroxy-5β-cholanic acid), a method for producing the same, and a method for producing ursodeoxycholic acid using the salt.
[0002]
[Prior art]
Ursodeoxycholic acid is produced from chenodeoxycholic acid (chemical name: 3α, 7α-dihydroxy-5β-cholanoic acid) via 3α-hydroxy-7-oxo-5β-cholanoic acid, but as an impurity, chenodeoxycholic acid, 3β, It contains 7β-dihydroxy-5β-cholanic acid, 3β, 7α-dihydroxy-5β-cholanic acid, cholic acid, etc., and its purity is usually 80-95%.
[0003]
As a method for increasing the purity of ursodeoxycholic acid, (1) a method of converting to a lower alkyl ester, recrystallization and hydrolysis with water-containing methanol (Japanese Patent Publication No. 53-10063), (2) methyl esterification, and alumina column A method of performing chromatography (Japanese Patent Publication No. 53-35946), (3) a method of precipitating crystals by adding an acid in a chloroform-containing aqueous solution as a sodium or lithium salt (Japanese Patent Laid-Open No. 55-154999), (4) A method of silylating in an organic solvent to precipitate crystals, followed by desilylation with hydrochloric acid and precipitation of crystals with ethyl acetate (JP-A-56-32500) and (5) Ursodeoxycholic acid and chenodeoxychol The mixture with acid is suspended in water or an organic solvent, and N-methylmorpholine is added thereto to remove insoluble acid. How to release (JP 58-146597 JP) it is known.
[0004]
[Problems to be solved by the invention]
The above methods (1) and (2) are complicated and require esterification and hydrolysis, and the method (1) has a disadvantage that the yield is low. The methods (2) and (3) are not suitable for operation on an industrial scale because a large amount of chloroform is used. In the method (4), the silylation must be carried out in a completely dehydrated state, which is industrially difficult.
[0005]
(5) When the method was operated in the same manner as that described in Example 2 in the publication, the purity did not increase at all. Specifically, 11.74 g of ursodeoxycholic acid (containing 82.3% ursodeoxycholic acid and 13.5% chenodeoxycholic acid) is suspended in 100 ml of water, and 1.7 ml of N-methylmorpholine is added to this suspension. Stir all day and night. The solution was colloidal and could not be filtered. Therefore, this was centrifuged to separate into a supernatant and a precipitate. The precipitate was dissolved in an aqueous sodium hydroxide solution and then neutralized with 25% sulfuric acid to obtain 7.7 g of crystals. When this crystal was analyzed by liquid chromatography, it contained 83.8% ursodeoxycholic acid and 12.7% chenodeoxycholic acid.
[0006]
As described above, since the conventional techniques have drawbacks, a simple and efficient method is desired.
[0007]
[Means for Solving the Problems]
Ursodeoxycholic acid is dissolved or suspended in an organic solvent, a tertiary amine is added thereto, and the precipitated salt of ursodeoxycholic acid and tertiary amine is separated. After that, the obtained ursodeoxycholic acid and tertiary amine salt is converted into a free acid according to a conventional method, so that the purity of ursodeoxycholic acid is higher than that of ursodeoxycholic acid used first. Can be obtained.
[0008]
As the organic solvent, acetic acid ester having 3 to 5 carbon atoms, ketone or ether, for example, ethyl acetate, acetone, dioxane and the like can be used, and the amount used is 2 to 10 times that of ursodeoxycholic acid (V / W) amount.
[0009]
As the tertiary amine, triethylamine or 4-dimethylaminopyridine is used, and the amount used is equivalent to 0.5 to 4 times equivalent to ursodeoxycholic acid.
[0010]
In order to convert a salt of ursodeoxycholic acid with a tertiary amine as a free acid, for example, a salt of ursodeoxycholic acid and a tertiary amine is dissolved in an appropriate solvent, and an acid is added thereto. It can be ursodeoxycholic acid which is a free acid. Here, the suitable solvent is preferably a solvent in which ursodeoxycholic acid is hardly soluble, for example, water.
[0011]
One reason why high-purity ursodeoxycholic acid can be obtained in the present invention is that a salt of ursodeoxycholic acid and a tertiary amine is difficult to dissolve in a solvent, while impurity acids such as chenodeoxycholic acid and tertiary acids It is considered that a salt with an amine is easily dissolved in a solvent.
[0012]
Furthermore, it is very interesting that in the case of a salt of ursodeoxycholic acid and triethylamine, the ratio is ursodeoxycholic acid: triethylamine = 2: 1. The carboxylic acid hydrogen of one molecule is detached and bonded to the nitrogen atom of triethylamine, the ursodeoxycholic acid molecule is negative, and the triethylamine molecule is positively charged. Furthermore, hydrogen was bonded to the other ursodeoxycholic acid molecule, and this ursodeoxycholic acid molecule had a structure having no charge. Such a crystal structure is a completely new one that has not been known so far, and the structure of the new salt is confirmed by elemental analysis, infrared absorption spectrum, nuclear magnetic resonance spectrum, and finally X-ray structure analysis. And solubility in solvents are considered to be closely related.
[0013]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described with reference to examples.
[0014]
【Example】
[Examples 1 to 9]
10.0 g of ursodeoxycholic acid (ursodeoxycholic acid 82.3%, chenodeoxycholic acid 13.5%) is suspended in an organic solvent, and a tertiary amine is added to the suspension and heated to reflux to obtain crystals. Dissolved. When heating and refluxing were continued, crystals were precipitated. The mixture was heated to reflux for 40 minutes, allowed to cool, and the crystals were filtered. The filtered crystals were suspended in 200 ml of water, diluted sulfuric acid was added, and the precipitated crystals were filtered to obtain high purity ursodeoxycholic acid. This was subjected to high performance liquid chromatography and the purity was measured. The results are shown in Table 1.
[0015]
[Table 1]

[Examples 10 to 19]
The same operations as in Examples 1 to 9 were performed using 10.0 g of ursodeoxycholic acid (ursodeoxycholic acid 94.5%, chenodeoxycholic acid 3.5%). The results are shown in Table 2.
[0016]
[Table 2]

[0017]
[Example 20] A 2: 1 salt of ursodeoxycholic acid and triethylamine 10.0 g of ursodeoxycholic acid (ursodeoxycholic acid 94.5%, chenodeoxycholic acid 3.5%) was suspended in 100 mL of acetone. To the suspension, 7.1 mL (2.0 times equivalent) of triethylamine was added and heated to reflux to dissolve the crystals. When heating and refluxing were continued, crystals were precipitated. The mixture was heated to reflux for 40 minutes, allowed to cool, and the crystals were filtered. The filtered crystals were dissolved again in 200 mL of acetone and cooled slowly. The precipitated crystals were filtered to obtain a 2: 1 salt of ursodeoxycholic acid and triethylamine.
[0018]
Melting point: 202-205 ° C
Thermal analysis: DSC (5deg, 50sec)
170.6 ° C (release of triethylamine)
204.6 ° C (melting of ursodeoxycholic acid)
Elemental analysis:
Calculated (as C ₅₅ H ₉₈ NO ₈ ) C, 73.18; H, 10.80; N, 1.58
Found C, 73.36; H, 11.06; N, 1.48
IR (KBr):
3440, 2930, 2860, 1700, 1560, 1450 cm ^-1
1 H-NMR (270 MHz, CD ₃ OD) δ ppm:
0.71 (3H, s), 0.96 (6H, s), 1.29 (9 / 2H, t, J = 7.3 Hz), 3.16 (6 / 2H, q, J = 7.3 Hz) ), 3.48 (2H, m)
X-ray structural analysis:
C ₅₄ H ₉₅ NO ₈ , FW = 886.31, Orthorobic,
Space group P2 (1) 2 (1) 2 (1),
a = 11.0783 (7) Å, b = 15.3390 (10) Å,
c = 29.977 (2) Å, β = 90 °, V = 5094.0 (6) ^ 3
Dc = 1.156 cm ^ -3, Z = 4, R = 0.0537
[0019]
【The invention's effect】
According to the salt and the production method of the present invention, ursodeoxycholic acid with very high purity and high purity can be obtained by a very simple operation.
[Brief description of the drawings]
FIG. 1 is a 2: 1 salt molecular structure diagram of ursodeoxycholic acid and triethylamine.

Claims (5)

A method for producing a salt of ursodeoxycholic acid and a tertiary amine, comprising dissolving or suspending ursodeoxycholic acid in an organic solvent, and adding triethylamine or 4-dimethylaminopyridine as a tertiary amine thereto. . A method for producing ursodeoxycholic acid, wherein a salt of ursodeoxycholic acid and triethylamine or 4-dimethylaminopyridine of a tertiary amine is dissolved in a solvent, and an acid is added thereto. Ursodeoxycholic acid is dissolved or suspended in an organic solvent, and the tertiary amine triethylamine or 4-dimethylaminopyridine is added thereto to separate the precipitated salt, which is further dissolved in a solvent, and then dissolved in an acid. A method for producing ursodeoxycholic acid having a purity higher than that of ursodeoxycholic acid used initially. The organic solvent is acetic ester having 3 to 5 carbon atoms, a ketone, or process according to claim 1 or claim 3 wherein the ether. The production method according to claims 1 to 3 , wherein the ratio of ursodeoxycholic acid to triethylamine is 2: 1.

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