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Preparation method of leucongen

A technology of Likejun and ethyl phenylacetate, which is applied in the technical field of synthesizing high-purity medicinal Likejun, to achieve the effect of simplifying the process and operation

Inactive Publication Date: 2013-05-15
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The currently disclosed processes include CN1872844A and CN1810791A. When these two patent documents synthesize ethyl α-formylphenylacetate, the reaction time is relatively long, both about 10h , and all are obtained by decompression distillation to remove the reaction solvent. On the one hand, the operation becomes complicated and the cost increases. When L-cysteine ​​hydrochloride was reacted to obtain Likejun product, it was found that it contained more than 0.1% methyl ester impurity (Ⅱ), which did not meet the requirements for pharmaceutical use

Method used

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  • Preparation method of leucongen
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  • Preparation method of leucongen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Synthesis of ethyl α-formylphenylacetate.

[0026] In a 50 L reactor, add 35 L of isopropyl ether and sodium tert-butoxide (586 g, 6.1 mol), start stirring, and mix well. Cool in a water bath, control the internal temperature below 10°C, weigh and mix evenly. A mixture of 1500 g (9.15 mol) of ethyl phenylacetate and 725 g (9.80 mol) of ethyl formate was added dropwise to control the internal temperature below 10°C. After the dropwise addition, raise the temperature, control the internal temperature to 15°C, and keep it warm for 5 hours. The reaction liquid is finally a milky white suspension. Add 20L of purified water to dissolve, extract twice with 20L of isopropyl ether, take the water phase, and adjust the pH with dilute hydrochloric acid. The value was 1.0, the temperature was lowered to 0-5° C. to crystallize, and 1350 g was obtained with a yield of 76.8%. Melting point: 58.6-60.7°C. 1 H-NMR (300MHz, DMSO-d6): δ: 10.95(1H,s,CHO), 7.86(1H,s,Ar-CH), 7....

Embodiment 2

[0027] Example 2: Synthesis of ethyl α-formylphenylacetate.

[0028] In a 50 L reactor, add 35 L of methyl tert-butyl ether and potassium tert-butoxide (784 g, 7.0 mol), start stirring, and mix well. Cool in a water bath, control the internal temperature below 10°C, weigh and mix evenly. A mixture of 1500 g (9.15 mol) of ethyl phenylacetate and 725 g (9.80 mol) of ethyl formate was added dropwise to control the internal temperature below 10°C. After the dropwise addition, raise the temperature, control the inner temperature to 20°C, and keep it warm for 4.5 hours. The reaction liquid is finally a milky white suspension. Add 20L of purified water to dissolve it, extract it twice with 20L of methyl tert-butyl ether, take the water phase, and use dilute Adjust the pH value to 2.0 with hydrochloric acid, cool down to 0-5 degrees to crystallize, and obtain 1280g with a yield of 72.9%. Melting point: 59.1-61.2 °C.

Embodiment 3

[0029] Example 3: Synthesis of ethyl α-formylphenylacetate.

[0030] In a 50 L reactor, add 15 L of isopropyl ether, 20 L of methyl tert-butyl ether and sodium tert-butoxide (586 g, 6.1 mol), start stirring, and mix well. Cool in a water bath, control the internal temperature below 10°C, weigh and mix evenly. A mixture of 1500 g (9.15 mol) of ethyl phenylacetate and 725 g (9.80 mol) of ethyl formate was added dropwise to control the internal temperature below 10°C. After the dropwise addition, raise the temperature, control the internal temperature to 15°C, and keep it warm for 5 hours. The reaction liquid is finally a milky white suspension. Add 20L of purified water to dissolve, extract twice with 20L of isopropyl ether, take the water phase, and adjust the pH with dilute hydrochloric acid. The value was 1.0, the temperature was lowered to 0-5° C. to crystallize, and 1310 g was obtained with a yield of 74.5%.

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Abstract

The invention belongs to the chemical pharmaceutical field and relates to a preparation method of leucongen. The preparation method comprises the following steps: performing a condensation reaction on ethyl phenylacetate and ethyl formate in the presence of a specific solvent and a condensing agent, extracting and purifying a reaction solution, then acidifying, then performing low-temperature devitrification to get a high-purity solid intermediate, namely ethyl a-formylphenylacetate, utilizing the intermediate and L-cysteine hydrochloride to perform a reaction to get the high-purity leucongen. The leucongen does not contain methyl ester impurity and is in line with the requirements of pharmaceutical purity; and furthermore, the operation is simple, and the preparation method is suitable for industrial production.

Description

Technical field: [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a process for synthesizing high-purity medicinal licoridine. Background technique: [0002] Hematological diseases are common and frequently-occurring diseases among clinical primary and secondary diseases. The common ones are leukopenia, agranulocytosis, thrombocytopenia, chronic systemic anemia, aplastic anemia, etc. Like Jun (I) is one of the effective drugs for the treatment and prevention of blood system diseases. [0003] [0004] Currently disclosed techniques include CN1872844A and CN1810791A. When these two patent documents are synthesizing ethyl α-formylphenylacetate, the reaction time is longer, all about 10h, and all are obtained by decompression distillation to remove the reaction solvent. On the one hand, the operation is complicated and the cost is increased. On the other hand, the inventor found through repeated experiments that there is a large...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/06
Inventor 储刚林辉王正泽霍立茹曾滢章郑俊范婧习超鹏
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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