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Method for preparing cholic acid conjugates

A technology of bile acid conjugates and conjugates, which is applied in the field of preparation of bile acid conjugates therapeutic drugs, can solve the problems of "three wastes" discharge, harsh reaction conditions, and low total yield, and achieve "three wastes" pollution less, mild reaction conditions, and easy operation

Inactive Publication Date: 2008-11-19
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The above-mentioned synthesis method has the disadvantages of using raw materials that are expensive and not easy to obtain (such as: EEDQ, DCC, DEPC, p-hydroxypropiophenone, etc.); the reaction conditions are harsh (absolutely anhydrous solvent is required); there are many reaction steps and the overall yield is low; The "three wastes" are seriously discharged during the preparation process; the reaction operation and post-treatment process are cumbersome and other deficiencies; the preparation cost of bile acid conjugate therapeutic drugs is relatively high, and the industrial scale preparation is limited

Method used

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  • Method for preparing cholic acid conjugates
  • Method for preparing cholic acid conjugates
  • Method for preparing cholic acid conjugates

Examples

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Effect test

Embodiment 1

[0038] The preparation of embodiment 1 taurodeoxycholic acid and its sodium salt

[0039] Add 39.26 g (0.1 mol) of deoxycholic acid, 13.77 g (0.11 mol) of taurine and 400 ml of isopropanol into the reaction flask, stir at room temperature until the solids are completely dissolved, add anhydrous K 2 CO 3 16.56 grams (0.12mol), after stirring evenly, add 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride in batches 35.98 gram (0.13mol), then stirred at room temperature and reacted for 12 hours. After the reaction, the insoluble matter was filtered off, and the filtrate was adjusted to pH 4-5 with 10% aqueous hydrochloric acid solution. Extract with 150 ml, separate the lower aqueous solution, cool in an ice bath, neutralize the aqueous solution with concentrated hydrochloric acid to strong acidity, continue stirring for 1 hour, filter the precipitated solid, and obtain 45.56 g of taurodeoxycholic acid white powder solid, mp183~ 185°C, (c=1.0, H 2 O), yield 88....

Embodiment 2

[0041] The preparation of embodiment 2 taurodeoxycholic acid and potassium salt thereof

[0042] The operation process is the same as in Example 1, except that isopropanol is replaced with deionized water, and chlorinated 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl Morpholine salt was replaced by 2-chloro-4,6-dimethoxy-1,3,5-triazine, anhydrous K 2 CO 3 Substitute 4-methylmorpholine to obtain 44.78 g of taurodeoxycholic acid white powder solid, mp182~186°C, (c=1.0, H 2 O), yield 86.5%. Take taurodeoxycholic acid and replace sodium hydroxide with potassium hydroxide to obtain potassium taurodeoxycholate with a yield of 92.5%.

Embodiment 3

[0043] Embodiment 3 Preparation of taurochenodeoxycholic acid and its sodium salt

[0044] The operation process is the same as in Example 1, except that deoxycholic acid is replaced by chenodeoxycholic acid, isopropanol is replaced by N,N-methylformamide, and anhydrous K 2 CO 3 Substituting triethylamine to obtain taurochenodeoxycholic acid as a white powder solid with a yield of 92.6%. The obtained taurochenodeoxycholic acid is salted with methanol solution of sodium methoxide to obtain sodium taurochenodeoxycholate, mp 180-182°C, yield 90.2%.

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Abstract

The invention provides a method for preparing a cholic acid coupler therapeutic medicine (I). The method adopts a taurine or glycinate compound as an initial material, and carries out a reaction to obtain the medicine (I) with the condensating agent of 2-chlorine-4,6-dimethoxy-1,3, 5-triazine or chloridized 4-(4,6- dimethoxy-1,3, 5-triazine-2-group)-4-methyl morpholine. The method has cheap and easily obtained raw material, gentle reaction conditions, solvent without water treatment, simple operation, high yield and friendly reaction environment. (in the formula, R1, R2, R3 represent H, alpha-OH, beta-OH, =O; R1, R2 and R3 can be the same or not the same; R represents CH2CH2SO3H, CH2COOH, CH2CH2SO3M, and CH2COOM; M represents metallic ions).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of bile acid conjugate therapeutic drugs (I). [0002] [0003] (where R 1 , R 2 , R 3 Represents H, α-OH, β-OH, =O; R 1 , R 2 and R 3 Can be the same or different; R means CH 2 CH 2 SO 3 H, CH 2 COOH, CH 2 CH 2 SO 3 M. CH 2 COOM; M means metal ion) Background technique [0004] Bile acids widely exist in the bile of humans and mammals, and are the main components of bile. The enterohepatic circulation of cholic acids can promote the absorption of fat and fat-soluble vitamins. In the human liver, bile acid compounds are synthesized from cholesterol. When the human enterohepatic circulation is disturbed by some diseases, the biological metabolism of bile acid compounds is hindered, which can cause a variety of hepatobiliary system diseases, such as: cholestasis , fatty liver, cholesterol stones, bile reflux gastritis, biliary pancreatitis, hy...

Claims

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Application Information

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IPC IPC(8): C07J43/00A61K31/58A61K31/185A61K47/48A61K47/54
Inventor 邓勇沈怡严忠勤钟裕国
Owner SICHUAN UNIV
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