Gefitinib intermediate impurity YKYZ-C-GF-3 as well as preparation method and control method thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly discloses a gefitinib intermediate impurity YKYZ-C-GF-3 and a preparation, analysis and control method thereof, the name of the impurity is 8-chlorine-N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine, the molecular formula is C15H10Cl2FN3O2, the molecular weight is 354.14, and the structure is confirmed by mass spectrum, 1H-NMR and 13C-NMR. The impurity is generated by the reaction of sulfonyl chloride in thionyl chloride, the structure of the impurity is similar to that of a gefitinib intermediate, and the impurity is difficult to remove by a general method, so that the invention provides a method for treating thionyl chloride by using activated carbon to reduce the content of sulfonyl chloride in thionyl chloride from the source, thereby reducing the generation of the impurity. And the quality of the final gefitinib finished product is ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and relates to quality control in a gefitinib synthesis process, and specifically relates to a gefitinib intermediate impurity YKYZ-C-GF-3 and a preparation, analysis and control method thereof. Background Art

[0002] Gefitinib is the first targeted therapy for NSCLC. It was developed by Astra-Zeneca, a joint venture pharmaceutical company between the United Kingdom and Sweden. It is currently used clinically to treat locally advanced or metastatic non-small cell lung cancer.

[0003] The synthesis of gefitinib uses 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-ol acetate (abbreviated as: oxoquinoline ethyl ester, YKYZ) as the raw material, and reacts with dichlorothionyl to obtain GF-1, GF-1 and 3-chloro-4-fluoroaniline are reacted by amination to obtain GF-2, which is hydrolyzed under sodium hydroxide conditions to obtain GF-3, and then alkylated with N-(3-chloropropyl)morpholine to obtain the product. The synthetic route is as follows:

[0004]

[0005] The currently disclosed impurities of gefitinib are:

[0006]

[0007]

[0008] The research on impurities with novel structures produced during the synthesis process of gefitinib is a dynamic and continuous process, which is crucial to improving the quality standards of gefitinib API and promoting the quality control of gefitinib API. Summary of the invention

[0009] In view of the deficiencies in the prior art, the object of the present invention is to provide a gefitinib intermediate impurity YKYZ-C-GF-3, which is generated by the reaction of sulfonyl chloride in thionyl chloride, and has a structure similar to that of the gefitinib intermediate, except that multiple chlorine is substituted at the 8th position of the quinazoline ring, and is difficult to be removed by a general refining method; another object of the present invention is to provide a preparation method, an analysis method and a control method for the impurity to ensure the quality of the final gefitinib product.

[0010] The present invention is achieved through the following technical solutions:

[0011] A gefitinib intermediate impurity YKYZ-C-GF-3, whose chemical name is 8-chloro-N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine, has the following structural formula:

[0012]

[0013] In the existing gefitinib preparation process, the chlorination reagent in the first step of the reaction is thionyl chloride, which is produced by the reaction of sulfur dioxide and chlorine. The process will produce byproducts such as sulfur dichloride, sulfur monochloride, and sulfonyl chloride. Among them, sulfonyl chloride has similar physical properties to thionyl chloride and has a stronger chlorination effect than thionyl chloride. It can react with oxyquinoline ethyl ester to generate the impurity YKYZ-C-GF-3 in GF-3. This impurity is similar in structure to the intermediate GF-3, except that it has multiple chlorine substitutions at the 8th position of the quinazoline ring. It is difficult to remove by general methods. It will continue to derive into YKYZ-C-GF-4 in the alkylation reaction, affecting the quality of the final product.

[0014]

[0015] A further improvement of the present invention is:

[0016] A method for preparing gefitinib intermediate impurity YKYZ-C-GF-3, comprising the following steps:

[0017] 1) Chlorination reaction: ethyl oxaquinate, sulfonyl chloride and DMF are mixed and reacted, and then distilled and concentrated to obtain the impurity intermediate YKYZ-C-GF-1;

[0018] 2) Amination reaction: Freeze YKYZ-C-GF-1 to below 0°C, add isopropanol precooled to -20 to 0°C, add isopropanol solution of 3-chloro-4-fluoroaniline in batches, react at controlled temperature, filter after the reaction, and vacuum dry the filter cake to obtain light brown solid powder YKYZ-C-GF-2;

[0019] 3) Hydrolysis reaction: Add methanol and 10% NaOH solution to YKYZ-C-GF-2, stir and react at room temperature, adjust the solution pH to 6-7 with dilute hydrochloric acid, filter, wash with methanol, and dry to obtain impurity YKYZ-C-GF-3, a yellow powdery solid;

[0020] The reaction equation is as follows:

[0021]

[0022] Furthermore, in step 1), the volume ratio of oxaquinone, sulfonyl chloride and DMF is 1:3-20:0.01-0.5.

[0023] Preferably, the volume ratio of oxaquinoxaline, sulfonyl chloride and DMF is 1:10:0.1.

[0024] Furthermore, in step 1), the reaction temperature is 50-80° C. and the reaction time is 1-6 hours.

[0025] Preferably, the reaction temperature is 70-80°C and the reaction time is 4-6 hours.

[0026] Furthermore, in step 2), the molar ratio of YKYZ-C-GF-1 to 3-chloro-4-fluoroaniline is 1:1.0-2.0.

[0027] Furthermore, in step 2), the temperature of the temperature-controlled reaction is 0 to 10° C., and the time is 25 to 35 hours.

[0028] Furthermore, in step 3), the reaction time is 2 to 5 hours under stirring at room temperature.

[0029] Sulfonyl chloride: molecular formula SOCl2, colorless or yellow liquid, boiling point 78.8°C; sulfonyl chloride: molecular formula SO2Cl2, colorless liquid, boiling point 69.1°C. In the prior art, to obtain thionyl chloride of higher purity, sulfur powder needs to be used for reflux reaction, and qualified products can only be obtained after multiple distillations. The processing process is relatively complicated, and multiple distillations will affect the product yield, and will also significantly increase the operation and labor costs of the product. In view of this problem, the further improvement scheme of the present invention is:

[0030] A method for controlling the impurity YKYZ-C-GF-3 in a gefitinib intermediate comprises the following steps: taking thionyl chloride, an initial raw material of gefitinib, adding activated carbon, heating and refluxing, and filtering to obtain qualified thionyl chloride, wherein the content of sulfonyl chloride in the qualified thionyl chloride is less than or equal to 0.05wt%, and the yield of the treatment can reach more than 95%.

[0031] Furthermore, the amount of the activated carbon is 0.1-5% of the mass of thionyl chloride.

[0032] Preferably, the amount of activated carbon is 2% of the mass of thionyl chloride.

[0033] Furthermore, the heating reflux time is 0.5-5h.

[0034] Preferably, the heating reflux time is 2 h.

[0035] The beneficial effects of the present invention are:

[0036] The present invention first confirms the influence of sulfonyl chloride in thionyl chloride on the synthesis of gefitinib, and uses sulfonyl chloride to react with oxaquinoxaline, obtains the intermediate impurity YKYZ-C-GF-3 through amination and hydrolysis, and provides an analysis method and a structure confirmation spectrum of the impurity. The influence of sulfonyl chloride in thionyl chloride on the synthesis of gefitinib and the structure of the impurity disclosed in the present invention have not been reported in the literature. Studies have shown that controlling the content of sulfonyl chloride can significantly improve the quality of gefitinib, providing a guarantee for safe medication.

[0037] The thionyl chloride treatment method provided by the present invention comprises the following steps: adding activated carbon to thionyl chloride for reflux, filtering, and obtaining thionyl chloride with a low sulfonyl chloride content to meet production needs. Compared with the existing process of adding sulfur powder for reflux and multiple distillation, the method has small product loss, high yield, convenient operation, and reduced cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the mass spectrum of the intermediate impurity YKYZ-C-GF-3;

[0039] Figure 2 It is the intermediate impurity YKYZ-C-GF-3 1 H-NMR spectrum;

[0040] Figure 3 is the carbon NMR spectrum of YKYZ-C-GF-3;

[0041] Figure 4 It is the nuclear magnetic resonance DEPT135 spectrum of YKYZ-C-GF-3;

[0042] Figure 5 is the HPLC spectrum of YKYZ-C-GF-3;

[0043] Figure 6 This is the HPLC spectrum of GF-3 prepared in Comparative Example 1;

[0044] Figure 7 The HPLC spectrum of gefitinib prepared in Comparative Example 1;

[0045] Figure 8 This is the HPLC spectrum of GF-3 prepared in Example 3;

[0046] Fig. 9 The HPLC spectrum of gefitinib prepared in Example 3 is shown. DETAILED DESCRIPTION

[0047] The present invention is described in detail below in conjunction with specific embodiments.

[0048] Example 1: Confirmation of intermediate impurity YKYZ-C-GF-3

[0049] Name: 8-chloro-N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazolin-4-amine;

[0050] structure:

[0051] Molecular formula: C 15 H 10 Cl2FN3O2;

[0052] Molecular weight: 354.14

[0053] Figure 1 This is the mass spectrum of the intermediate impurity YKYZ-C-GF-3.

[0054] Mass spectrometry results:

[0055]

[0056] The mass-to-charge ratio in the mass spectrum is 354.0215, corresponding to [M+H] + . With the sample molecular formula C 15 H 10 Cl2FN3O2 (precise molecular weight is 353.0134; [M+H] + The molecular formula is C 15 H 11 Cl2FN3O2 + , the exact molecular weight is 354.0207). There are peaks with mass-to-charge ratios of +2 and +4 next to the main peak, and the abundance ratio between the main peak and the peak is about 9:6:1, indicating the presence of 2 Cl atoms, which is consistent with the molecular formula C 15 H 10 Cl2FN3O2 is consistent.

[0057] Figure 2 It is the intermediate impurity YKYZ-C-GF-3 1 H-NMR spectrum.

[0058]

[0059] like Figure 2 As shown, the hydrogen spectrum of gefitinib impurity YKYZ-C-GF-3 has 8 component peaks, and its integration ratio (from low field to high field) is 1:1:1:1:1:1:1:1:3, with a total of 10 protons, which is consistent with the theoretical proton number of gefitinib impurity YKYZ-C-GF-3. The attribution of each hydrogen is as follows:

[0060]

[0061] Figure 3 , Figure 4 for 13 C-NMR test spectrum, as can be seen from the figure, there are 15 resonance absorption peaks in the figure, that is, the 15 carbons contained in the molecule of gefitinib impurity YKYZ-C-GF-3. The attribution analysis of each carbon is as follows:

[0062]

[0063]

[0064] Combined with NMR 1 H NMR,13 C NMR, the NMR data of gefitinib impurity YKYZ-C-GF-3 are completely consistent with the chemical structure formula.

[0065] Example 2: Preparation of impurity YKYZ-C-GF-3

[0066] (1) Synthesis of YKYZ-C-GF-1:

[0067]

[0068] Oxoquinoline ethyl ester (5 g, 21.3 mmol), sulfonyl chloride (50 ml) and DMF (0.5 ml) were mixed, reacted at 70-80°C for 5 hours, and distilled and concentrated to dryness to obtain the impurity intermediate YKYZ-C-GF-1, 6.2 g.

[0069] (2) Synthesis of YKYZ-C-GF-2:

[0070]

[0071] YKYZ-C-GF-1 (6.2 g, 21.6 mmol) was taken and frozen to below 0°C. Isopropanol (50 ml) precooled to -20 to 0°C was added. A solution of 3-chloro-4-fluoroaniline (5 g, 34.4 mmol) in isopropanol (20 ml) was added in batches. The reaction liquid temperature was controlled to be below 10°C. The reaction was stirred at 0-10°C for 30 hours. The mixture was filtered and the filter cake was dried under vacuum to obtain a light brown solid powder YKYZ-C-GF-2 (7.2 g).

[0072] (3) Synthesis of YKYZ-C-GF-3

[0073]

[0074] YKYZ-C-GF-2 (7.0 g, 20.2 mmol), methanol (50 ml), 10% NaOH solution (25 ml), stirred at room temperature for 4 hours, diluted hydrochloric acid adjusted the solution pH = 6-7, filtered, washed with methanol, dried to obtain impurity YKYZ-C-GF-3, 5.3 g, yellow powdery solid, HPLC purity: 99.2% (HPLC spectrum see Figure 5 ). HPLC analysis method is as follows:

[0075] Take an appropriate amount of this product, weigh it accurately, dissolve it with 0.2% trifluoroacetic acid-acetonitrile (6:4) and dilute it to make a solution containing about 0.5 mg per 1 ml as the test solution. According to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 Edition Part Four General Rules 0512), use octadecylsilane bond and silica gel as fillers; ammonium acetate solution (take 3.854g of ammonium acetate, dissolve it in water and dilute it to 1000ml)-acetonitrile (60:40) as the mobile phase; the flow rate is 1.0ml / min; the column temperature is 35℃; the detection wavelength is 247nm. Accurately measure 5μl of the control solution and the test solution and inject them into the liquid chromatograph, record the chromatogram to 3 times the retention time of the main component peak, and calculate it by the area normalization method.

[0076] Comparative Example 1

[0077] Industrial thionyl chloride was taken without treatment and detected by conventional titration method in the prior art. The content of sulfonyl chloride was measured to be about 0.5%. GF-3 was synthesized by the existing process in the background technology. The content of impurity YKYZ-C-GF-3 in the GF-3 obtained by the reaction was about 0.276% (see Figure 6 ), which is difficult to remove later. The YKYZ-C-GF-4 impurity in the finished gefitinib product is 0.163%, exceeding the standard of 0.1% (see Figure 7 ).

[0078] Example 3

[0079] Take 500ml of the same batch of thionyl chloride as Comparative Example 1, add 10g of activated carbon, reflux for 2 hours, filter to obtain qualified thionyl chloride, and detect that the content of sulfonyl chloride can be reduced to about 0.05%. Use the treated thionyl chloride as raw material, and also use the existing process in the background technology to synthesize GF-3. The content of impurity YKYZ-C-GF-3 in the GF-3 obtained by the reaction is 0.012% (see Figure 8 ), the YKYZ-C-GF-4 in the prepared gefitinib product is 0.01% (see Fig. 9 ), which meets the standards.

[0080] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A gefitinib intermediate impurity YKYZ-C-GF-3, characterized in that: The chemical name is 8-chloro-N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazolin-4-amine, and the structural formula is:

2. A method for preparing a gefitinib intermediate impurity YKYZ-C-GF-3 as claimed in claim 1, characterized in that: The following steps are involved: 1) Chlorination reaction: ethyl oxaquinate, sulfonyl chloride and DMF are mixed and reacted, and then distilled and concentrated to obtain the impurity intermediate YKYZ-C-GF-1; 2) Amination reaction: Freeze YKYZ-C-GF-1 to below 0°C, add isopropanol precooled to -20 to 0°C, add isopropanol solution of 3-chloro-4-fluoroaniline in batches, react at controlled temperature, filter after the reaction, and vacuum dry the filter cake to obtain light brown solid powder YKYZ-C-GF-2; 3) Hydrolysis reaction: Add methanol and 10% NaOH solution to YKYZ-C-GF-2, stir and react at room temperature, adjust the solution pH to 6-7 with dilute hydrochloric acid, filter, wash with methanol, and dry to obtain impurity YKYZ-C-GF-3, a yellow powdery solid; The reaction equation is as follows:

3. A method for preparing a gefitinib intermediate impurity YKYZ-C-GF-3 according to claim 2, characterized in that: In step 1), the volume ratio of oxaquinoxaline, sulfonyl chloride and DMF is 1:3-20:0.01-0.

5.

4. A method for preparing a gefitinib intermediate impurity YKYZ-C-GF-3 according to claim 2, characterized in that: In step 1), the reaction temperature is 50-80° C. and the reaction time is 1-6 hours.

5. A method for preparing a gefitinib intermediate impurity YKYZ-C-GF-3 according to claim 2, characterized in that: In step 2), the molar ratio of YKYZ-C-GF-1 to 3-chloro-4-fluoroaniline is 1:1.0-2.

0.

6. A method for preparing a gefitinib intermediate impurity YKYZ-C-GF-3 according to claim 2, characterized in that: In step 2), the temperature of the temperature-controlled reaction is 0 to 10° C. and the time is 25 to 35 hours.

7. A method for preparing a gefitinib intermediate impurity YKYZ-C-GF-3 according to claim 2, characterized in that: In step 3), the reaction time is 2 to 5 hours under stirring at room temperature.

8. A method for controlling the impurity YKYZ-C-GF-3 in the gefitinib intermediate as claimed in claim 1, characterized in that: The following steps are involved: Take thionyl chloride, the initial raw material of gefitinib, add activated carbon, heat and reflux, and filter to obtain qualified thionyl chloride, in which the content of sulfonyl chloride is less than or equal to 0.05wt%.

9. The method for controlling the impurity YKYZ-C-GF-3 in the gefitinib intermediate according to claim 8, characterized in that: The amount of the activated carbon used is 0.1-5% of the mass of the thionyl chloride.

10. The method for controlling the impurity YKYZ-C-GF-3 in the gefitinib intermediate according to claim 8, characterized in that: The heating reflux time is 0.5-5h.

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