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Monomethoxy polyethylene glycol modified ezetimibe and preparation method thereof

A technology of polyethylene glycol and monomethoxy, which is applied in the fields of organic chemistry, organic chemistry, etc., can solve problems such as the preparation method of ezetimibe without polyethylene glycol modification, and achieve increased stability in vivo and extended half-life , the effect of excellent lipid-lowering effect

Inactive Publication Date: 2018-11-23
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There is no polyethylene glycol-modified ezetimibe drug and its preparation method in the prior art

Method used

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  • Monomethoxy polyethylene glycol modified ezetimibe and preparation method thereof
  • Monomethoxy polyethylene glycol modified ezetimibe and preparation method thereof
  • Monomethoxy polyethylene glycol modified ezetimibe and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: mPEG 2 - Preparation of ezetimibe

[0033] 10 mmol of methoxydicondensed polyethylene glycol (mPEG 2 -OH) was dissolved in toluene, 20 mmol of succinic anhydride was added, and the reaction was stirred at 110° C. for 12 h. After the reaction was completed, the temperature was lowered, the solvent was spin-dried, water was added, and stirred at 60° C. for 2 h. Dichloromethane extraction, phase separation, the lower organic phase was obtained, dried over anhydrous sodium sulfate, filtered, spin-dried solvent, and recrystallized to obtain the product methoxydiethylene glycol butyrate (mPEG 2 -COOH), 9.1 mmol, yield 91%. 1 HNMR (400MHz, CDCl 3 ) NMR data are as follows: δ=4.24~4.20(m, 2H); δ=3.65~3.63(m, 2H); δ=3.54(s, 4H); δ=3.30(s, 3H); δ=2.85~2.82 (m, 2H); δ = 2.76-2.72 (m, 2H).

[0034] Obtained mPEG 2 8.5mmol of -COOH was dissolved in dichloromethane, 8.5mmol of DCC, 8.5mmol of DMAP, and 17mmol of ezetimibe were added in sequence, and the reaction was...

Embodiment 2

[0035] Example 2: mPEG 4 - Preparation of ezetimibe

[0036] 10 mmol methoxy tetracondensed polyethylene glycol (mPEG 4 -OH) was dissolved in toluene, 30 mmol of succinic anhydride was added, and the reaction was stirred at 110° C. for 12 h. After the reaction was completed, the temperature was lowered, the solvent was spin-dried, water was added, and stirred at 60° C. for 2 h. Dichloromethane extraction, phase separation, the lower organic phase was obtained, dried over anhydrous sodium sulfate, filtered, spin-dried solvent, and recrystallized to obtain the product methoxytetraethylene glycol butyrate (mPEG 4 -COOH), 9.2 mmol, yield 92%. 1 HNMR (400MHz, CDCl 3 ) NMR data are as follows: δ=4.26~4.21(m, 2H); δ=3.67~3.62(m, 2H); δ=3.53(s, 12H); δ=3.30(s, 3H); δ=2.86~2.82 (m, 2H); δ = 2.73-2.70 (m, 2H).

[0037] Obtained mPEG 4 -COOH 8.5mmol was dissolved in dichloromethane, 17mmol DCC, 17mmol DMAP, 17mmol ezetimibe were added in sequence, and stirred at 30°C for 24h. Aft...

Embodiment 3

[0038] Example 3: mPEG 12 - Preparation of ezetimibe

[0039] 10 mmol of methoxydodecylpolyethylene glycol (mPEG 12 -OH) was dissolved in toluene, 40 mmol of succinic anhydride was added, and the reaction was stirred at 110° C. for 12 h. After the reaction was completed, the temperature was lowered, the solvent was spin-dried, water was added, and stirred at 60° C. for 2 h. Dichloromethane extraction, phase separation, the lower organic phase was obtained, dried over anhydrous sodium sulfate, filtered, spin-dried solvent, and recrystallized to obtain the product methoxy dodecyl glycol butyrate (mPEG 12 -COOH), 9.4 mmol, yield 94%. 1 HNMR (400MHz, CDCl 3 ) NMR data are as follows: δ=4.25~4.21(m, 2H); δ=3.67~3.60(m, 2H); δ=3.54(s, 44H); δ=3.31(s, 3H); δ=2.86~2.80 (m, 2H); δ = 2.75-2.70 (m, 2H).

[0040] Obtained mPEG 12 -COOH 8.5mmol was dissolved in dichloromethane, 17mmol EDC, 17mmol triethylamine, 17mmol ezetimibe were added sequentially, and stirred at 30°C for 24h. ...

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Abstract

The invention relates to monomethoxy polyethylene glycol modified ezetimibe and a preparation method thereof. The modified ezetimibe has the following general molecular formula as shown below in the specification, wherein n is the integer ranging from 1 to 24. The preparation method comprises the following steps of (1) adopting monomethoxy polyethylene glycol as a reactant to prepare a compound I;(2) carrying out condensation reaction on the compound I and the ezetimibe under the condition of the interaction of a filtrate reducer and alkali, and preparing the required modified ezetimibe. Thepreparation method is short in process flow, simple in reaction operation, less in side reaction, low in cost, high in reaction selectivity, and higher in yield.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a monomethoxy polyethylene glycol modified ezetimibe and a preparation method thereof. Background technique [0002] Ezetimibe is a new type of cholesterol antagonist jointly developed by Merck and Schering-Plough, and it is a new type of blood lipid-lowering drug. It was launched in Germany for the first time in 2002 and was launched in the United States at the same time. It is the first new type of blood lipid-lowering drug with selective cholesterol absorption inhibitory effect approved by the FDA. It has been widely used in more than 90 countries and regions. It has the advantages of small toxic and side effects, remarkable curative effect, etc., and has a broad market prospect. [0003] Ezetima acts partially on the epithelial cells of the small intestine, selectively inhibits the absorption of intestinal cholesterol and related sitosterol, reduces the cholesterol re...

Claims

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Application Information

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IPC IPC(8): C07D205/08
CPCC07D205/08C07B2200/07
Inventor 冯波
Owner 湖南华腾制药有限公司
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