Novel method for synthesizing imrecoxib oxide impurity

Abstract

The invention discloses a preparation method of an imrecoxib oxide impurity (compound 1). The preparation method comprises the following steps: carrying out oxidation one-step reaction on imrecoxib under the action of alkali; and synthesizing to obtain the target product imrecoxib oxide impurity (compound 1). The route provides a simple and effective method for preparing the imrecoxib oxide impurity (compound 1). Compared with a conventional synthesis route, the method has the advantages that the reaction route is shorter, the reaction is more economical, expensive reagents are not needed, and the like.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a new method for preparing oxidized impurities of erlotinib. Background Art

[0002] Imrecoxib is the first COX-2 selective inhibitor with independent intellectual property rights in my country and belongs to non-steroidal anti-inflammatory drugs (NSAIDs). Traditional NSAIDs are prone to cause gastrointestinal adverse reactions due to excessive inhibition of COX-1, while highly selective COX-2 inhibitors (such as rofecoxib and valdecoxib) may increase cardiovascular risks. Imrecoxib was created based on the concept of "moderate inhibition". While exerting anti-inflammatory and analgesic effects, it can maintain the balance of prostaglandins in the body, thereby reducing the risk of gastrointestinal and cardiovascular adverse reactions. The chemical structure of Imrecoxib is as follows:

[0003]

[0004] Irecoxib is prone to generate oxidative impurities (Compound 1) during storage and synthesis. The structure is as follows:

[0005]

[0006] Irecoxib oxidized impurity (Compound 1) is one of the most important impurities in the quality study of Irecoxib. Studies have found that Irecoxib tablets are prone to produce this oxidized impurity when they are improperly stored. Therefore, the synthesis study of this oxidized impurity is of great significance for the quality control of Irecoxib tablets.

[0007] Compound 1 is a substituted maleimide derivative. The usual synthesis method is to first synthesize substituted maleic anhydride, then aminize and N-substitute to obtain the corresponding maleimide derivative. Intermediate 1 obtained in the synthesis of Erelcoxib is used as a raw material, and intermediate 2 is obtained by oxidation reaction. Intermediate 2 reacts with hexamethyldisilazane to generate intermediate 3; intermediate 3 then reacts with bromopropane to obtain compound 1.

[0008]

[0009] The disadvantages of this method are that the synthetic route is long, the process is unstable, and expensive reagents such as hexamethyldisilazane are used. In particular, the anhydride structure in intermediate 2 is particularly active, and separation and purification are very difficult. Summary of the invention

[0010] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a simple and easy-to-operate method for synthesizing erlotoxib oxidized impurities (compound 1). Using erlotoxib as a starting material, erlotoxib oxidized impurities (compound 1) are synthesized through a one-step oxidation reaction.

[0011] Specifically, the purpose of the present invention is achieved through the following technical solutions:

[0012]

[0013] In the presence of an organic base, in an organic solvent, ericoxib reacts with an oxidant to generate ericoxib oxidized impurity compound 1.

[0014] As an embodiment, the molar ratio of erlotinib to the organic base is 1:1-4.

[0015] Furthermore, the molar ratio of erlotinib to the organic base is 1:2.

[0016] As an embodiment, the organic base is triethylamine, diisopropylethylamine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

[0017] Furthermore, the organic base is preferably triethylamine.

[0018] As an embodiment, the oxidant is oxygen, air, etc.

[0019] Furthermore, the oxidant is preferably oxygen.

[0020] As an embodiment, the organic solvent is acetonitrile, ethyl acetate, dichloromethane, chloroform, acetone, etc.

[0021] Furthermore, the organic solvent is preferably acetonitrile.

[0022] The advantages of the present invention are: providing a simple and effective method for preparing the oxidized impurity of erlotinib (compound 1). Compared with the conventional synthesis route, the route provided by the present invention has the advantages of being shorter, more convenient to operate, more economical, and not requiring the use of the expensive reagent hexamethyldisilazane. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0024] Figure 1 NMR spectrum of compound 1; DETAILED DESCRIPTION

[0025] The synthetic route of the erecoxib oxidized impurity compound 1 of the present invention is as follows:

[0026]

[0027] The present invention is described in detail below in conjunction with embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, some adjustments and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0028] Embodiment 1:

[0029] Synthesis of 3-(4-(methylsulfonyl)phenyl)-1-propyl-4-(p-tolyl)-1H-pyrrole-2,5-dione (Compound 1)

[0030] Method A:

[0031] Install a magnetic stirrer and a gas tube in a three-necked reaction bottle. Add 2 g of Irecoxib, 1.11 g of triethylamine and 20 ml of acetonitrile at room temperature. Maintain the reaction temperature at 25-30°C and allow oxygen to react for 6-8 hours.

[0032] TLC (petroleum ether: ethyl acetate = 2:1) showed that the raw material Erelcoxib had reacted completely. Pour 52ml 3mol / l hydrochloric acid into the reaction solution and stir for 15 minutes. Filter to obtain the crude product. The crude product was purified by column with petroleum ether: ethyl acetate (4:1) to obtain 1.52g of yellow solid; yield 73.5%. HPLC purity 95.94%. 1 H NMR (400MHz, DCCl3): δ7.93(d,2H),7.68(d,2H),7.34(d,2H),7.18(d,2H),3.62(t,2H),3.08(s,3H),2.38(s,3H),1.74(m,2H),0.97(t,3H).

[0033] Method B:

[0034] Install a magnetic stirrer and a gas tube in a three-necked reaction bottle. Add 2 g of Irecoxib, 2.48 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile at room temperature. Maintain the reaction temperature at 25-30°C and allow oxygen to react for 6-8 hours.

[0035] TLC (petroleum ether: ethyl acetate = 2:1) showed that the raw material ericoxib had reacted completely. Pour 52ml of 3mol / l hydrochloric acid into the reaction solution and stir for 15 minutes. Filter to obtain the crude product. The crude product was purified by column with petroleum ether: ethyl acetate (4:1) to obtain 1.01g of yellow solid; yield 48.6%.

[0036] Method C:

[0037] Install a magnetic stirrer and an air guide tube in a three-necked reaction bottle. Add 2 g of Irecoxib, 1.11 g of triethylamine and 20 ml of dichloromethane at room temperature. Maintain the reaction temperature at 25-30°C and allow air to flow for 6-8 hours.

[0038] TLC (petroleum ether: ethyl acetate = 2:1) showed that the raw material ericoxib had reacted completely. The reaction solution was poured into 54 ml of 3 mol / l hydrochloric acid and filtered to obtain a crude product. The crude product was purified by column with petroleum ether: ethyl acetate (4:1) to obtain 1.05 g of a yellow solid; the yield was 50.5%. Comparative Example 1:

[0039] The erlotinib oxidized impurity compound 1 was prepared by the synthesis method mentioned in the background technology.

[0040] Synthesis of Intermediate 2 (3-(4-(methylsulfonyl)phenyl)-4-(p-tolyl)furan-2,5-dione)

[0041] Install a magnetic stirrer and a gas tube in a three-necked reaction bottle. Add 1.64 g of intermediate 1, 2.28 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile at room temperature. Maintain the reaction temperature at 25-30°C and allow oxygen to react for 6-8 hours.

[0042] Post-treatment: TLC (petroleum ether: ethyl acetate = 2:1) showed that the raw intermediate 1 had reacted completely. 46 ml of 3 mol / l hydrochloric acid was added to the reaction solution and the crude product was filtered. No intermediate 2 was obtained by column chromatography with petroleum ether: ethyl acetate (4:1).

[0043] The crude product was tried to be used directly in the subsequent reaction, but compound 1 was not obtained.

[0044] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A novel method for synthesizing an oxidized impurity compound 1 of Erelcoxib, characterized in that: The method comprises the following steps: In the presence of an organic base, in an organic solvent, ericoxib reacts with an oxidant to generate ericoxib oxidized impurity compound 1.

2. The novel method for synthesizing oxidized impurities of Erelcoxib according to claim 1, characterized in that: The molar ratio of erecoxib to the organic base is 1:1-4.

3. The novel method for synthesizing oxidized impurities of Erelcoxib according to claim 2, characterized in that: The molar ratio of erecoxib to the organic base is 1:

2.

4. The novel method for synthesizing oxidized impurities of Erelcoxib according to claim 1, characterized in that: The organic base is any one of triethylamine, diisopropylethylamine, diisopropylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

5. The novel method for synthesizing oxidized impurities of Erelcoxib according to claim 1, characterized in that: The oxidant is any one of oxygen and air.

6. The novel method for synthesizing oxidized impurities of Irecoxib according to claim 1, characterized in that: The organic solvent is any one of acetonitrile, ethyl acetate, dichloromethane, chloroform and acetone.

7. The novel method for synthesizing oxidized impurities of Erelcoxib according to claim 1, characterized in that: The organic base is triethylamine, the oxidant is oxygen, and the organic solvent is acetonitrile.

8. The novel method for synthesizing oxidized impurities of Irecoxib according to claim 1, characterized in that: The reaction is carried out at 10-50°C and the reaction time is 6-12 hours.

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