Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom

A compound and chemical technology, applied in the field of pharmaceutical chemical synthesis, can solve the problems of inconvenient large-scale production and harsh storage conditions, and achieve the effects of shortening synthesis steps, reducing synthesis costs and mild synthesis reaction conditions.

Active Publication Date: 2006-09-06
天津泰普制药有限公司 +1
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  • Application Information

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Problems solved by technology

This method solves the technical difficulty that industrialized production cannot be realized in method 1, but the disadvantage is that diisopropylamide lithium must be used as an alkalizing reagent in the reaction preparation process of the alkylation, and it needs to be prepared at low temperature (-40°C) and absolutely without Operate under water conditions. At present, lithi

Method used

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  • Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom
  • Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom
  • Substituted benzyl ester and its preparation process and novel process for preparing substituted mopipe therefrom

Examples

Experimental program
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Example Embodiment

[0032] 1. Preparation Example 1: Preparation of (S)-2-halomethylphenylpropionyl-glycine benzyl ester

[0033] 1. Preparation of methyl 3-hydroxy-2-methylenyl-3-phenylpropionate

[0034] Add 67.3g of benzaldehyde, 60ml of methyl acrylate, and 13.5g of triethylenediamine into a 500ml reaction flask, stir at room temperature for 5 days, add 60ml of water, 60ml of concentrated hydrochloric acid, and 120ml of ethyl acetate. The organic layer was washed twice with 20 ml of water, the organic layer was dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 110.5 g of light yellow oil, which was distilled under reduced pressure to collect the 85-90℃ / 7-9mmHg fraction. 97.5 g of colorless liquid was obtained, the content was greater than 98% (GC method), and the yield was 80%.

[0035] 2. Preparation of 2-hydroxymethyl benzene acrylic acid

[0036] Dissolve 60g of 3-hydroxy-2-methylenyl-3-phenylpropionic acid methyl ester in 65ml...

Example Embodiment

[0053] 2. Preparation Example 2: Preparation of (+)-3R,4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine

[0054] 1. Preparation of 1,3-dimethyl-4-(3-isopropoxyphenyl)-4-hydroxypiperidine

[0055] Under nitrogen protection, 60g of 3-bromoisopropyloxybenzene was added to 150ml of THF, cooled to -72°C, and 150ml of n-butyllithium (2.5M) was slowly added dropwise. After dripping, stir at -60-70°C for 1 hour. Then, 30g of 1,3-dimethyl-4-piperidone was added dropwise, the reaction temperature was kept at about -60-70°C, and the mixture was stirred for 1 hour. Add 6N hydrochloric acid to the reaction solution under stirring, adjust the pH to 1-2, separate the water layer, adjust the pH to 12 with 20% sodium hydroxide, extract 3 times with ethyl acetate, combine the organic layers, and dry with anhydrous sodium sulfate overnight. After filtration, the filtrate was concentrated to dryness under reduced pressure, and n-heptane was recrystallized. After filtration, the product is dried to obtain ...

Example Embodiment

[0069] 3. Example 1:

[0070] 1. (+)-(3R, 4R)-[[2S-[[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-1-oxo Preparation of -3-phenylpropyl]amino]acetic acid-4′-bromobenzyl ester

[0071] Method A:

[0072] Add 10g(+)-3R,4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine, 25.9g(S)-2-methanesulfonylmethylphenacyl-4′-bromo -Glycine benzyl ester, 300ml of isopropanol, 9.6g of potassium carbonate, 0.1g of potassium iodide are added to a 500ml three-necked reaction flask, heated to reflux for 8 hours, TCL method detects that the reaction raw materials are basically complete (R f The value is about 0.4, ethyl acetate / petroleum ether = 1 / 15), cooled to room temperature, filtered, and concentrated under reduced pressure to obtain about 28.2 g of yellow oil. The content of the prepared product is about 80.4% (HPLC method), and the yield is 78.6%. It can be directly put into the next step for reaction.

[0073] Take 1 gram of the oily substance and pass it through column separation and purifi...

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Abstract

The invention discloses a (+)-(3R,4R)-[[2S-[[4-(3-hydroxyphenyl-3,4- dimethyl-1-nipecotic)-methyl]-1-oxo-3-phenylpropyl]amido]benzyl cetate compound and its process for preparing and a new technology for preparation of Mope by the said compound. The new technique of this invention changes the íŒone chainíŒ synthesis of the original patent method to the separate í‹two chainsíŒ preparation, by which the total compound steps are dramatically shortened, the compound cost is reduced to about one-half of the original patent method, and the method is more competitive on the market in price. Furthermore,the reaction condition is moderate, the operating procedure is simple, each reaction step is no need of given condition such as low temperature and absolute water-free, so it is more suitable for industrial production.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, more specifically (+)-(3R, 4R)-[[2S-[[4-(3-hydroxyphenyl-3,4-dimethyl-1-piper Pyridyl)-methyl]-1-oxo-3-phenylpropyl]amino]acetic acid substituted benzyl ester compound, a preparation method thereof and a new process for preparing avemopi from the compound. Background technique [0002] Avemopan (alvimopan) is a new type of selective opioid receptor antagonist, mainly used in the treatment of postoperative ileus. The preparation method of this product is currently reported to have two methods, the patented method 1 is based on (+)-3R, 4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine, 2-benzyl ethyl acrylate As the starting material, the target compound is prepared through five steps of addition, hydrolysis, carboxylation, chiral column chromatography, and hydrolysis (see patent CN1065455A); the disadvantage of this method is that the reaction products of each step are...

Claims

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Application Information

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IPC IPC(8): C07D211/10B01J23/44
Inventor 李祎亮田青松魏文涛朱红星杨胜利周学福瞿虹吴民义
Owner 天津泰普制药有限公司
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