Capecitabine impurity and preparation method thereof

A capecitabine and impurity technology, applied in the field of medicine, can solve the problems of capecitabine intermediate B not meeting quality standards, capecitabine being unable to continue production, affecting the normal production of capecitabine, and the like. The effect of increasing the washing time

Inactive Publication Date: 2019-04-19
山东安信制药有限公司
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  • Application Information

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Problems solved by technology

[0003] Capecitabine intermediate B, chemical name 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 -(Pentyloxycarbonyl)cytidine is synthesized by reacting 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (II) with n-pentyl chloroformate. During the synthesis process , an unknown impurity often appears at RRT=(0.27~0.30), the quality standard requires a single impurity not to be higher than 0.5%, and the impurity often exceeds the standard (attached figure 1 ), resulting in capecitabine intermediate B not meeting the quality standards, resulting in the inability to continue production of capecitabine (capecitabine intermediate B can be hydrolyzed to remove the acetyl group to obtain capecitabine), which seriously affected the production of capecitabine normal production of tabine

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  • Capecitabine impurity and preparation method thereof
  • Capecitabine impurity and preparation method thereof
  • Capecitabine impurity and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1: confirm target impurity I structure

[0028] The capecitabine intermediate B was detected by liquid chromatography-mass spectrometry, and the results were as follows: figure 2 As shown, after inferring the possible structure of the target impurity I, the inferred structure has the following types:

[0029]

[0030] According to the reaction process of capecitabine intermediate B from 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (II) with n-pentyl chloroformate in the presence of pyridine and conditions, acetic acid will be generated during the synthesis process, and then combined with image 3 The hydrogen spectrum of impurity Ⅰ shown (with Figure 4 Intermediate B for comparison), confirming that structure 3 is impurity I, the chemical name is 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 -(ethoxycarbonyl)cytidine.

Embodiment 2

[0032] Weigh 3.29g (0.01mol) of compound II into a 50ml three-neck flask, add 30ml of dichloromethane to dissolve, add 1.58g (0.02mol) of pyridine, cool down to 0°C, add 1.2g of glacial acetic acid (0.02mol) dropwise, During the addition process, the temperature should not exceed 5 ° C. After the dropwise addition, keep stirring for 1 hour. After the reaction is completed, add 10 ml of purified water and stir for 5 minutes. After standing still and layering, the obtained organic phase is subjected to vacuum distillation. After no liquid is evaporated, the obtained The oily substance is the impurity I, weighing 2.70 g, and the HPLC detection purity is 95.2%. Gained oil and intermediate A (used as a control) were added to the dichloride solution of capecitabine intermediate B, and the liquid phase was detected, and it was found that the content of impurity I (RRT=0.29) increased significantly (see attached Figure 5 ).

Embodiment 3

[0034] Weigh 3.29g (0.01mol) of compound II into a 50ml three-necked flask, add 30ml of dichloromethane to dissolve, add 2.37g (0.02mol) of pyridine, cool down to 0°C, add dropwise 0.9g of glacial acetic acid (0.015mol), dropwise During the addition process, control the temperature not to exceed 5°C. After the dropwise addition is completed, keep stirring for 1.5 hours. After the reaction is completed, add 10ml of purified water and stir for 5 minutes. Let stand and separate layers. The obtained organic phase is distilled under reduced pressure. After no liquid is evaporated, The obtained oily substance was impurity I, weighing 2.00 g, and its purity by HPLC was 93.2%.

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Abstract

The invention discloses a capecitabine impurity and a preparation method thereof. In the process of synthesizing a capecitabine intermediate B, an impurity of RRT=0.27-0.30 is subjected to structure inference and determination firstly, and it is determined that the impurity is 2', 3'-di-O-acetyl-5'-deoxygenation-5-fluorine-N4-(carbethoxy) cytidine (compound I). Then 2', 3'-di-O-acetyl-5'-deoxygenation-5-fluorine cytidine (compound II) is taken as a starting material, alkali is taken as an acid-binding agent, an acylation reagent is used for acylation and synthesizing of the impurity. Structuredetermination and preparation of the impurity play an important role in quality control over the capecitabine intermediate B and guidance for production of the capecitabine intermediate B.

Description

technical field [0001] The invention relates to a capecitabine impurity and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Capecitabine (Capecitabine) is an anti-metabolite fluoropyrimidine deoxynucleoside carbamate drug that can be converted into 5-FU in the body. It was developed by Roche and its trade name is Xeloda. It was first launched in May 1998. Listed in the United States, it is the only oral fluorouracil drug approved by the FDA so far, and it is also the most biologically active oral fluorouracil drug, which can reach or even exceed the curative effect of other intravenous fluorouracil drugs. It can inhibit cell division and interfere with RNA and protein synthesis. It is suitable for the further treatment of advanced primary or metastatic breast cancer that is ineffective in paclitaxel and chemotherapy regimens including anthracycline antibiotics. It is mainly used for advanced primary breast cancer. or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
CPCC07H1/00C07H19/06
Inventor 宇文礼李保勇赵旭东管清华杜云锋
Owner 山东安信制药有限公司
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