CN109796441B

CN109796441B - Preparation method of impurity A of tipyrimidine hydrochloride

Info

Publication number: CN109796441B
Application number: CN201910123807.7A
Authority: CN
Inventors: 刘云涛; 向松
Original assignee: Beijing Minkang Baocao Pharmaceutical Technology Co ltd
Current assignee: Beijing Minkang Baocao Pharmaceutical Technology Co ltd
Priority date: 2019-02-19
Filing date: 2019-02-19
Publication date: 2020-10-16
Anticipated expiration: 2039-02-19
Also published as: CN109796441A

Abstract

The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of an impurity A of tipyrimidine hydrochloride. The preparation method comprises a synthesis reaction, wherein the synthesis reaction is to perform hydrolysis reaction on 5-chloro-6- [ (2-imine-1-pyrrolidine) methyl ] uracil hydrochloride and an aqueous solution of alkali. The preparation method of the impurity A of the tipyrimidine hydrochloride can synthesize and prepare the impurity A of the tipyrimidine hydrochloride with simple operation, easily obtained raw materials, high yield and easy purification, so that the prepared impurity A is used as an impurity standard substance in the detection and analysis of finished products of the tipyrimidine hydrochloride and is used for the quality control of the tipyrimidine hydrochloride. According to the preparation method, after the impurity A of the Tibi pyrimidine hydrochloride is synthesized, a high-purity target product can be obtained only by simple filtration and washing.

Description

Preparation method of impurity A of tipyrimidine hydrochloride

Technical Field

The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of an impurity A of tipyrimidine hydrochloride.

Background

Trifluridine tipyrimidine (TAS-102), sold under the trade name Lonsurf, was a drug originally developed by japan megapenc drug agency, was approved by the FDA in the united states at 9 months 2015, by the european drug administration at 2016, and was later approved in 19 countries and regions, such as the uk, canada, and the like, for the treatment of refractory metastatic colorectal cancer (mCRC) patients who no longer respond to other therapies (chemotherapy and biological therapies). Due to high level evidence of evidence and good clinical experience, the drug has been listed in the clinical practice guidelines for NCCN colorectal cancer, the consensus on the management of ESMO metastatic colorectal cancer patients, the guidelines for the treatment of colorectal cancer by JSCR (Japanese society for colorectal cancer), and recommended for metastatic colorectal cancer patients (mCRC) who have previously received chemotherapy and targeted therapy with fluoropyrimidine, oxaliplatin and irinotecan.

The drug consists of the cytotoxin trifluridine (FTD) and thymidine phosphorylase inhibitor tippy-pyrimidine hydrochloride (TPI). Among them, trifluridine can substitute thymine and be directly incorporated into DNA double strand during DNA replication, resulting in DNA dysfunction and interfering with DNA synthesis of cancer cells. However, it is known that the effect of trifluridine is greatly reduced when it is orally administered. Tibipyrimidine hydrochloride can inhibit thymic phosphorylase related to the decomposition of trifluridine, reduce the degradation of trifluridine and improve the bioavailability of trifluridine. Moreover, the drug still has the anti-tumor effect on patients with drug resistance to fluorouracil drugs.

The chemical name of the Tibipyrimidine hydrochloride is 5-chloro-6- [ (2-imine-1-pyrrolidine) methyl ] uracil hydrochloride. The chemical name of the impurity A is 5-chloro-6- (2-pyrrolidone-1-yl) methyluracil, which is a degradation impurity of hydrochloric acid tipyrimidine, and the hydrochloric acid tipyrimidine is generated in the process of placing and can influence the quality of the hydrochloric acid tipyrimidine raw material medicine, so that the impurity A needs to be controlled. The structural formula of the impurity A is shown as follows.

However, no synthesis method of the impurity A of the tipyrimidine hydrochloride is reported in the prior art.

Disclosure of Invention

The invention aims to provide a preparation method of an impurity A of tipyrimidine hydrochloride, which is used for synthesizing the impurity A of tipyrimidine hydrochloride by being simple in operation, easy in raw material obtaining, high in yield and easy in purification, so that the prepared impurity A is used as an impurity standard substance in the detection and analysis of finished product of tipyrimidine hydrochloride and is used for the quality control of tipyrimidine hydrochloride.

To achieve this object, in a basic embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride, said process comprising a synthetic reaction of hydrolyzing 5-chloro-6- [ (2-imine-1-pyrrolidine) methyl ] ureidopyrimidine hydrochloride with an aqueous solution of a base.

The principle of the synthesis reaction of the present invention is as follows.

In a preferred embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride wherein the base is a strong inorganic base.

In a more preferred embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride, wherein the strong inorganic base is selected from sodium hydroxide and/or potassium hydroxide.

In a preferred embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride wherein the concentration of the aqueous solution of the base is from 0.6 to 1 mol/L.

In a preferred embodiment, the present invention provides a process for the preparation of impurity A, tipyrimidine hydrochloride, wherein the molar ratio of 5-chloro-6- [ (2-imine-1-pyrrolidine) methyl ] uracil hydrochloride to the base in the hydrolysis reaction is 1 (1.5-2).

In a preferred embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride wherein the temperature of the hydrolysis reaction is from 90 to 100 ℃.

In a preferred embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride wherein the hydrolysis reaction time is 4 to 5 hours.

In a preferred embodiment, the invention provides a preparation method of an impurity A of tipyrimidine hydrochloride, wherein the preparation method further comprises separation and purification after the synthesis reaction, and the separation and purification comprises the steps of filtering a product of the synthesis reaction, washing a filter cake with water and drying the filter cake.

In a more preferred embodiment, the invention provides a preparation method of impurity A of tipyrimidine hydrochloride, wherein the filtration is vacuum filtration, and the filter cake water washing is to wash the filter cake to be neutral.

In a more preferred embodiment, the present invention provides a process for the preparation of impurity a of tipyrimidine hydrochloride, wherein said drying is carried out at 50-60 ℃ for 8-10 hours under vacuum.

The method for preparing the impurity A of the tipyrimidine hydrochloride has the advantages that the method for preparing the impurity A of the tipyrimidine hydrochloride has simple operation, easily obtained raw materials, high yield and easy purification, and can be used for synthesizing and preparing the impurity A of the tipyrimidine hydrochloride, so that the prepared impurity A is used as an impurity standard substance in the detection and analysis of finished products of the tipyrimidine hydrochloride and is used for the quality control (the qualitative and quantitative control of the impurity A) of the tipyrimidine hydrochloride. According to the preparation method, after the impurity A of the Tibi pyrimidine hydrochloride is synthesized, a high-purity target product can be obtained only by simple filtration and washing.

Drawings

FIG. 1 is a high performance liquid chromatography detection profile of impurity A prepared in example 1.

FIG. 2 is an NMR hydrogen spectrum detection spectrum of impurity A prepared in example 1.

FIG. 3 is an NMR carbon spectrum detection chart of impurity A prepared in example 1.

Fig. 4 and 5 are mass spectrometric detection profiles of positive and negative ions, respectively, of impurity a prepared in example 1.

FIG. 6 is a high performance liquid chromatography detection profile of impurity A prepared in example 2.

FIG. 7 is an NMR hydrogen spectrum detection spectrum of impurity A prepared in example 2.

FIG. 8 is an NMR spectrum for carbon spectrum detection of impurity A prepared in example 2.

Fig. 9 and 10 are mass spectrometric detection profiles of positive and negative ions, respectively, of impurity a prepared in example 2.

Detailed Description

The following examples further illustrate embodiments of the present invention.

Example 1: preparation of impurity A of Tibipyrimidine hydrochloride

5.0g of hydrochloric acid substituted pyrimidine and 30mL of water are added into a reaction bottle, stirred and dissolved, then 1.1g of sodium hydroxide is added, stirred and heated (90 ℃) to reflux, and the temperature is kept for reaction for 5 hours. TLC monitors the reaction, cools to room temperature, filters under reduced pressure, leaches the filter cake with water three times, dries in vacuum at 50 ℃ for 10 hours to obtain 4.3g of white powdery solid product with the yield of 98.4 percent and the HPLC purity of 98.3 percent.

Example 2: preparation of impurity A of Tibipyrimidine hydrochloride

5.0g of tegaserod hydrochloride and 40mL of water are added into a reaction bottle, stirred and dissolved, then 1.4g of potassium hydroxide is added, stirred and heated (100 ℃) to reflux, and the reaction is kept for 4 hours. After the TLC monitoring reaction, the reaction was cooled to room temperature, filtered under reduced pressure, the filter cake was rinsed three times with water and dried under vacuum at 60 ℃ for 8 hours to obtain 4.2g of a white powdery solid product with a yield of 96.1% and an HPLC purity of 99.4%.

Example 3: examination of impurities A obtained in examples 1 and 2

The high performance liquid chromatography, the NMR hydrogen spectrum, the NMR carbon spectrum and the mass spectrum of the impurity A prepared in the example 1 and the example 2 are respectively detected to confirm the structure of the impurity A.

Wherein the NMR hydrogen spectrum and NMR carbon spectrum are detected by taking DMSO-d6 as a solvent; in mass spectrum detection, DMSO is used as a solvent for dissolution, and an excitation mode ESI is adopted; the detailed method of the high performance liquid chromatography detection is as follows:

according to high performance liquid chromatography (China pharmacopoeia 2015 edition four parts general rules 0512), octyl silane bonded silica gel is used as a stationary phase (Agela Venusil XBP C8, 250mm multiplied by 4.6mm, 5 mu m), a buffer salt solution (1.7 g of sodium heptanesulfonate, 1.36g of potassium dihydrogen phosphate are dissolved by adding 1000nl of water, the pH is adjusted to 2.7 by phosphoric acid) is used as a mobile phase A, methanol-acetonitrile (70:30) is used as a mobile phase B, and elution is carried out according to the following gradient program. The detection wavelength is 210 nm; the column temperature was 40 ℃.

The results of the tests are shown in FIGS. 1 to 10, respectively. The detection result shows that the impurity A of the target substance, namely the tipyrimidine hydrochloride, is prepared at high purity by using the preparation method.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is intended to include such modifications and variations. The foregoing examples or embodiments are merely illustrative of the present invention, which may be embodied in other specific forms or in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention should be indicated by the appended claims, and any changes that are equivalent to the intent and scope of the claims should be construed to be included therein.

Claims

1. A preparation method of an impurity A of tipyrimidine hydrochloride is characterized in that: the preparation method comprises a synthetic reaction, wherein the synthetic reaction is hydrolysis reaction of 5-chloro-6- [ (2-imine-1-pyrrolidine) methyl ] uracil hydrochloride and an aqueous solution of alkali, the alkali is inorganic strong alkali, and the inorganic strong alkali is selected from sodium hydroxide and/or potassium hydroxide,

the structural formula of the impurity A is shown as follows:

，

the temperature of the hydrolysis reaction is 90-100 ℃.

2. The method of claim 1, wherein: the concentration of the alkali aqueous solution is 0.6-1 mol/L.

3. The method of claim 1, wherein: the molar ratio of the 5-chloro-6- [ (2-imine-1-pyrrolidine) methyl ] uracil hydrochloride to the alkali in the hydrolysis reaction is 1 (1.5-2).

4. The method of claim 1, wherein: the time of the hydrolysis reaction is 4 to 5 hours.

5. The method of claim 1, wherein: the preparation method also comprises separation and purification after the synthesis reaction, wherein the separation and purification comprises the steps of filtering, washing and drying the filter cake of the product of the synthesis reaction in sequence.

6. The method of claim 5, wherein: the filtration is decompression filtration, and the filter cake washing is to wash the filter cake to be neutral.

7. The method of claim 5, wherein: the drying is vacuum drying at 50-60 ℃ for 8-10 hours.