Compound for preparing cholic acid conjugate, preparation and use thereof

A technology of compounds and conjugates, applied in the preparation of cholic acid conjugates therapeutic drugs, in the field of active thioesters of cholic acid compounds, can solve harsh reaction conditions, "three wastes" discharge, low total yield, etc. problems, to achieve the effect of mild reaction conditions, less pollution of "three wastes" and easy operation

Inactive Publication Date: 2009-08-12
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The above-mentioned synthesis method has the disadvantages of using raw materials that are expensive and difficult to obtain (such as: EEDQ, DEPC, p-hydroxypropiophenone, etc.); the reaction conditions are harsh (absolutely anhydrous solvent is required); there are many reaction steps and the total yield is low; the preparation process The discharge of "three wastes" is serious; 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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  • Compound for preparing cholic acid conjugate, preparation and use thereof
  • Compound for preparing cholic acid conjugate, preparation and use thereof
  • Compound for preparing cholic acid conjugate, preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Preparation of ursodeoxycholic acid-2-benzothiazole thioester

[0039] Add 15.7 grams (0.04mol) of ursodeoxycholic acid, 8.0 grams (0.048mol) of triethyl phosphite, 16.0 grams (0.048mol) of 2,2'-dithiodibenzothiazole and ethyl acetate in the reaction flask 100 ml, stirred at room temperature for 1 hour, added dropwise a solution of 7.0 ml of triethylamine dissolved in 20 ml of ethyl acetate, heated up to 35-40°C for 2.5 hours, cooled to room temperature, and evaporated under reduced pressure Remove the solvent and purify by column chromatography (eluent: chloroform: acetone: acetic acid = 20:1:1 (v / v)), to obtain the light yellow oily liquid 19.3 of ursodeoxycholic acid-2-benzothiazole thioester grams, yield 89.0%. 1 HNMR (CDCl 3 )δ: 8.03 (dd, J 1 = 0.8Hz,J 2 =8.0Hz, 1H, Ar-H 4 ), 7.91 (dd, J 1 = 0.8Hz,J 2 =7.2Hz, 1H, Ar-H 7 ), 7.52~7.41 (m, 2H, Ar-H 5 , Ar-H 6 ), 3.67~3.60 (m, 2H, C 7 -H,C 3 -H), 2.87~2.80(m, 1H, C 23 -H), 2.78~2.65(m, 1H, C 23 ...

Embodiment 2

[0040] Example 2 Preparation of Tauroursodeoxycholic Acid

[0041] Add 3.0 g (0.024 mol) of taurine, 0.88 g (0.024 mol) of sodium hydroxide and 40 ml of water into the reaction flask, stir evenly, cool in an ice-water bath to 0-10°C, add ursodeoxycholic acid-2 dropwise - A solution of 10.8 grams (0.02 mol) of benzothiazole thioester dissolved in 30 milliliters of tetrahydrofuran was stirred and reacted at room temperature for 8 hours. × 20 ml extraction, the resulting water layer was concentrated under reduced pressure to leave about 20 ml, adjusted to pH 1-2 with concentrated hydrochloric acid, added a small amount of seed crystals, stirred at 0-5°C for 2 hours, filtered with suction, washed the filter cake with a small amount of acetone, and then Recrystallize with acetone-water (12:1) to obtain 7.5 grams of tauroursodeoxycholic acid white powder solid, mp144~145°C, (c=2.0, EtOH), yield 78.6%. Purity 99.2% (HPLC normalization method). 1 HNMR (400MHz, D 2 O) δ: 3.65 ~ 3....

Embodiment 3

[0042] Example 3 Preparation of Glycoursodeoxycholic Acid

[0043] Add 3.35 g (0.024 mol) of glycine ethyl ester hydrochloride, 3.34 ml (0.024 mol) of triethylamine and 35 ml of ethyl acetate into the reaction flask, stir well, put in an ice-water bath to cool to 0-10°C, add dropwise 10.8 g (0.02 mol) of ursodeoxycholic acid-2-benzothiazole thioester was dissolved in 30 ml of ethyl acetate, stirred at room temperature and reacted overnight, after the reaction was completed, the insoluble matter was filtered off, and the ethyl acetate solution was sequentially used with 5% Wash with 36 ml of NaOH aqueous solution, 30 ml of 10% aqueous hydrochloric acid solution, 30 ml of saturated NaCl aqueous solution, anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain the crude ursodeoxycholoylglycine ethyl ester conjugate. The obtained crude product was dissolved in a mixed solution of 0.8 g (0.02 mol) of sodium hydroxide, 20 ml of water and 30...

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PUM

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Abstract

The invention discloses cholic acid compound activated thioester (1), also discloses s preparation method for the compound and the application thereof in the cholic acid conjugate therapeutic drug; (R 1, R2, and R3 in the formula express H, alpha-OH, beta-OH, =O ; R1, R2 and R3 can be same and can also be different; R4 presents 2- pyridil and 2- benzothiazolyl ).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to bile acid compound active thioester (I), its preparation method and its application in the preparation of bile acid conjugate therapeutic drugs. [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 4 represents 2-pyridyl, 2-benzothiazolyl). 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 gast...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00C07J33/00C07J75/00C07J41/00A61K31/575A61P1/16A61P1/18A61P3/06A61P1/04
Inventor 邓勇王海龙沈怡钟裕国
Owner SICHUAN UNIV
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