A method for synthesizing sunitinib pyrrole intermediate 2,4-dimethylpyrrole-3-carboxylate

Abstract

The present invention belongs to the field of chemical pharmacy, and discloses a method for synthesizing 2,4-dimethylpyrrole-3-carboxylate, comprising the following steps: (1) preparing MOF material UiO-66-NH2; (2) using UiO-66-NH2 as a catalyst, adding the catalyst to a mixed solution of hydroxyacetone and 3-aminocrotonate, and stirring the reaction under a protective atmosphere; (3) after the reaction is completed, 2,4-dimethylpyrrole-3-carboxylate can be separated from the reaction solution. The present invention provides a more convenient and feasible synthesis method for synthesizing sunitinib key intermediate 2,4-dimethyl-3-pyrrole carboxylate by improving the reagents (especially catalysts) used in the synthesis method, the synthesis reaction mechanism, etc.

Description

Technical Field

[0001] The invention belongs to the field of chemical pharmacy, and more specifically, relates to a method for synthesizing sunitinib pyrrole intermediate 2,4-dimethylpyrrole-3-carboxylate. Background Art

[0002] Sunitinib (Sunitinib, Sutent) is a new multi-targeted oral drug for the treatment of tumors. It can inhibit multiple signaling pathways and has anti-angiogenesis and anti-tumor proliferation activities. It can inhibit tyrosine kinase receptors including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell growth factor receptor (KIT), FMA-like tyrosine kinase (FLT3), colony stimulating factor (CSF-1) and glial cell-derived neurotrophic factor receptor (RET) and other tyrosine kinases. These proteins are involved in the occurrence and development of some malignant tumors, including small cell lung cancer, gastrointestinal stromal tumors, breast cancer, acute myeloid leukemia, etc. Sunitinib can cut off the blood and nutrients needed for tumor growth and kill cancer cells. It is clinically used to treat gastrointestinal stromal tumors and advanced renal cancer.

[0003] 2,4-dimethyl-3-pyrrolecarboxylic acid ethyl ester is an important intermediate for the synthesis of the anti-tumor drug Sunitinib. 2,4-dimethyl-3-pyrrolecarboxylic acid ethyl ester is also known as Sunitinib intermediate 3 [Sunitinib intermediate 3; 1H-pyrrole-3-carboxylic acid, 2,4-dimethyl-, ethyl ester; 2,4-dimethylpyrrole-3-carboxylic acid ethyl ester; 2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester; Sunitinib malate intermediate 3, English name Ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate; 2,4-Dimethylpyrrole-3-carboxylic acid ethyl ester.], its molecular formula: C 9 H 13 NO 2 ; Molecular mass: 167.21; CAS: 2199-51-1; Structural formula: The appearance is light yellow to brown crystalline powder.

[0004] 2,4-Dimethyl-1H-pyrrole-3-carboxylic acid methyl ester is also known as 2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester [2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester; 2,4-dimethyl-3-pyrrole carboxylic acid methyl ester; 3-pyrrole carboxylic acid, 2,4-dimethyl-, methyl ester, English name: 1H-Pyrrole-3-carboxylicacid, 2,4-dimethyl-, methylester.], its molecular formula: C 8H 11 NO 2 ; Molecular mass: 153.18; CAS: 52459-90-2; Structural formula: Appearance is yellow to brown solid.

[0005] The currently reported preparation method of 2,4-dimethyl-3-pyrrole carboxylate mainly uses acetoacetate as raw material, obtains 2,4-dimethylpyrrole-3,5-dicarboxylic acid diester after multi-step reaction, and then selectively decarboxylates the 2,4-dimethylpyrrole-3,5-dicarboxylic acid diester after hydrolysis, which is easy to generate double decarboxylation by-products, and at least five steps of reaction are required to obtain the target product. The cumbersome steps increase the process flow and generate high additional costs. In addition, the traditional route uses a large amount of controlled reagent hydrochloric acid, which adds certain obstacles to the industrial production of the product. The use of ice water in the production process is easy to generate a large amount of wastewater, which increases the burden on subsequent environmental protection treatment.

[0006] The existing technical routes are as follows:

[0007] Traditional Route 1:

[0008]

[0009] Traditional Route 2:

[0010] Summary of the invention

[0011] In view of the above defects or improvement needs of the prior art, the purpose of the present invention is to provide a method for synthesizing sunitinib pyrrole intermediate 2,4-dimethylpyrrole-3-carboxylate, wherein by improving the reagents (especially catalysts) used in the synthesis method, the synthesis reaction mechanism, etc., a simpler and more feasible synthesis method is provided for synthesizing sunitinib key intermediate 2,4-dimethyl-3-pyrrole carboxylate compared with the prior art. In addition, the raw materials used in the method of the present invention are easy to obtain, the synthesis is one-step, and the catalyst can be reused multiple times, which can greatly reduce the cost.

[0012] To achieve the above object, the present invention provides a method for synthesizing 2,4-dimethylpyrrole-3-carboxylate, characterized in that it comprises the following steps:

[0013] (1) Preparation of MOF material UiO-66-NH 2 ;

[0014] (2) UiO-66-NH 2 as a catalyst, adding the catalyst into a mixed solution of hydroxyacetone and 3-aminocrotonate, and stirring the mixture under a protective atmosphere for reaction;

[0015] (3) After the reaction is completed, 2,4-dimethylpyrrole-3-carboxylate can be separated from the reaction solution.

[0016] As a further preferred embodiment of the present invention, the step (3) further comprises the operation of separating the catalyst from the reaction liquid system, and the separated catalyst can be recycled for the synthesis of 2,4-dimethylpyrrole-3-carboxylate.

[0017] As a further preferred embodiment of the present invention, in the step (2), the stirring reaction is carried out at a temperature of 20° C. to 100° C., and the reaction time is 8 to 24 hours.

[0018] As a further preferred embodiment of the present invention, in the step (2), the molar ratio of hydroxyacetone to 3-aminocrotonate is (1-2):(1-2).

[0019] As a further preferred embodiment of the present invention, in the step (2), the 3-aminocrotonate is specifically 3-aminocrotonate methyl ester or 3-aminocrotonate ethyl ester;

[0020] Correspondingly, in the step (3), the 2,4-dimethylpyrrole-3-carboxylate is specifically 2,4-dimethylpyrrole-3-carboxylic acid methyl ester or 2,4-dimethylpyrrole-3-carboxylic acid ethyl ester.

[0021] As a further preferred embodiment of the present invention, in the step (2), for the mixed solution of hydroxyacetone and 3-aminocrotonate, the solvent used in the mixed solution is nitromethane and / or trifluoroethanol;

[0022] Preferably, the solvent used in the mixed solution is trifluoroethanol, or a mixed solvent of nitromethane and trifluoroethanol, wherein the mixed solvent of nitromethane and trifluoroethanol is obtained by mixing nitromethane and trifluoroethanol in a volume ratio of 2:1 to 0:1.

[0023] As a further preferred embodiment of the present invention, the step (1) further comprises the MOF material UiO-66-NH 2 The preparation steps are as follows:

[0024] ZrCl 4 , N, N-dimethylformamide (DMF), and 2-aminoterephthalic acid are used as raw materials, and the three raw materials are mixed in a molar ratio of 1:10:1 to 1:20:1, and then stirred at 120°C to 150°C for 6 hours to 12 hours; after the reaction, the product is separated to obtain UiO-66-NH 2 Material.

[0025] As a further preferred embodiment of the present invention, in the step (3), the separation is specifically to first filter out the catalyst from the reaction liquid system, then concentrate the reaction liquid by distillation, and separate by column chromatography to obtain 2,4-dimethylpyrrole-3-carboxylate;

[0026] The distillation is vacuum distillation or rotary distillation.

[0027] As a further preferred embodiment of the present invention, in the step (2), the protective atmosphere is nitrogen or an inert gas.

[0028] Through the above technical scheme conceived by the present invention, compared with the prior art, the present invention provides a simpler and more feasible synthesis method for synthesizing the key intermediate of sunitinib 2,4-dimethyl-3-pyrrole carboxylate, which uses amino-functionalized metal organic framework materials (MOFs) as catalysts, and under protective atmosphere conditions, MOF catalysts, hydroxyacetone, and 3-aminocrotonate are mixed and stirred for reaction (heating may be combined), thereby synthesizing 2,4-dimethyl-3-pyrrole carboxylate, and the synthesis steps are simple. By using amino-functionalized MOF materials as catalysts, the reaction is carried out under multiphase conditions, and hydroxyacetone and 3-aminocrotonate are used to synthesize 2,4-dimethyl-3-pyrrole carboxylate in one step, the yield can be as high as 60%, and the catalyst can be filtered and recovered and used multiple times.

[0029] The reaction of the present invention can be carried out at a temperature of 20°C to 100°C, and the reaction conditions are mild. In addition, the reaction of the present invention can be carried out in a mixed solvent environment of nitromethane and trifluoroethanol, and the volume ratio of the two can be 2:1 to 0:1, and a good yield can be obtained. The catalyst UiO-66-NH 2 , is a MOF catalyst that has been reported many times. Any one of them satisfies the existing UiO-66-NH 2 Chemical structure and composition of UiO-66-NH 2 All materials can be used in the present invention. 2 The chemical structure of the material is shown below:

[0030]

[0031] In addition, the present invention also further comprises UiO-66-NH 2 The synthesis method was improved by using a specific molar ratio of ZrCl 4 , N, N-dimethylformamide (DMF), and 2-aminoterephthalic acid as raw materials, and stirred at 120°C to 150°C for 6 hours to 12 hours to obtain UiO-66-NH 2 Material.

[0032] Compared with Route 1 and Route 2 in the conventional technology, the present invention utilizes a different reaction route and adopts a one-step synthesis method, thereby avoiding cumbersome reaction processes, saving time and labor costs, and reducing the use of a large number of consumables (such as water, strong acid, and strong base), which is more environmentally friendly.

[0033] The present invention can overcome the problem of self-polymerization of hydroxyacetone and 3-aminocrotonate, and utilize the pore confinement effect of MOF itself to inhibit the self-polymerization of the reactants, so that the reaction proceeds in the direction of generating 2,4-dimethylpyrrole-3-carboxylate. The difficulty of this reaction lies in the need to adopt a suitable pore size to inhibit the occurrence of side reactions. The present invention uses UiO-66-NH 2 As a catalyst, UiO-66-NH 2 It is of the right size for this reaction, and contains -NH 2 , which can promote the formation of target products.

[0034] In summary, compared with the traditional synthesis method of 2,4-dimethylpyrrole-3-carboxylate, the synthesis method of the present invention is simple, the required raw materials are easily available, the catalyst is easy to recover and can be recycled multiple times, the reaction conditions are easy to operate, it is not easy to produce by-products, it is easy to purify, and it is suitable for industrial production. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0036] In general, the synthetic route of the preparation method of 2,4-dimethyl-3-pyrrolecarboxylate in the present invention is as follows:

[0037]

[0038] After the reaction is completed, the catalyst is filtered, and the reaction solution is concentrated after distillation under normal pressure and reduced pressure; and the target product 2,4-dimethyl-3-pyrrolecarboxylate is obtained after separation through a silica gel column.

[0039] In addition, UiO-66-NH 2 The material was prepared as follows: 15 mL ZrCl 4(1.2g) of N, N-dimethylformamide (DMF) solution and 15mL of 2-aminoterephthalic acid (0.9g) in DMF solution. Then seal (of course, not sealing does not affect the reaction), and react at 120°C for 6 hours under stirring. The product is separated by centrifugation and rinsed with DMF and methanol. Finally, UiO-66-NH 2 Dry under vacuum at 80 °C overnight. 2 The yield is 96% (based on ZrCl 4 By this method, UiO-66-NH can be synthesized quickly and efficiently in large quantities. 2 .

[0040] The following are specific embodiments:

[0041] Example 1

[0042] The preparation method of the embodiment of the present invention is as follows: under nitrogen protection (of course, it can also be other inert gases such as argon), hydroxyacetone (750 mg, 20 mmol), 3-amino ethyl crotonate (2.0 g, 30 mmol), UiO-66-NH 2 1.0 g of catalyst, 50 mL of nitromethane and 25 mL of trifluoroethanol were mixed and stirred for 24 hours under heating (80° C.). After the reaction was completed, the catalyst was filtered and the reaction solution was distilled under normal pressure and reduced pressure to obtain 2.0 g of ethyl 2,4-dimethyl-3-pyrrolecarboxylate (total yield 60%).

[0043] Example 2

[0044] The preparation method of the embodiment of the present invention is as follows: under nitrogen protection (of course, it can also be other inert gases such as argon), hydroxyacetone (750 mg, 20 mmol), 3-aminocrotonic acid methyl ester (1.5 g, 30 mmol), UiO-66-NH 2 1.0 g of catalyst, 50 mL of nitromethane and 25 mL of trifluoroethanol were mixed and stirred for 24 hours under heating (80° C.). After the reaction was completed, the catalyst was filtered and the reaction solution was distilled under normal pressure and reduced pressure to obtain 2.3 g of methyl 2,4-dimethyl-3-pyrrolecarboxylate (total yield 64%).

[0045] Embodiments 3 to 5

[0046] The preparation method of the embodiment of the present invention is as follows: under nitrogen protection (of course, other inert gases such as argon can also be used), hydroxyacetone (750 mg, 20 mmol), 3-amino crotonic acid ethyl ester (2.0 g, 30 mmol), different MOF materials as catalysts 1.0 g, 50 mL nitromethane, 25 mL trifluoroethanol, mixed and stirred for 24 hours under heating (80 ° C). After the reaction is completed, the catalyst is filtered, and the reaction solution is distilled under normal pressure and reduced pressure to obtain 2,4-dimethyl-3-pyrrolecarboxylic acid ethyl ester product.

[0047] The specific results corresponding to different catalysts are shown in the following table:

[0048]

[0049] From the comparison between Example 1 and the above table, it can be seen that the present invention uses UiO-66-NH 2 As a catalyst, it can greatly improve the yield and has a good effect.

[0050] Embodiment 6-11

[0051] Similar to Example 1, Examples 6-11 are based on MOF (UiO-66-NH 2 ) as catalyst, using different solvent ratios (except for the solvent conditions, other conditions are consistent with those in Example 1), the synthetic reaction results are shown in the following table:

[0052]

[0053]

[0054] The reaction solvent can be either nitromethane or trifluoroethanol, or a mixed solvent of nitromethane and trifluoroethanol. The volume ratio of nitromethane to trifluoroethanol can be 1:0 to 0:1 (corresponding to any ratio of mixing); of course, when the volume ratio of nitromethane to trifluoroethanol is 2:1, the effect is better.

[0055] Examples 12-16

[0056] Similar to Example 1, Examples 12-16 are based on MOF (UiO-66-NH 2 ) is used as the catalyst and is reused after filtration. The synthetic reaction results are shown in the following table:

[0057]

[0058] Examples 17-21

[0059] Similar to Example 1, Examples 17-21 are based on MOF (UiO-66-NH 2) as catalyst, using different reaction temperatures (except temperature conditions, other conditions are consistent with Example 1), the synthesis reaction results are shown in the following table:

[0060]

[0061] The above embodiments are merely examples. For example, in addition to using nitrogen as the protective atmosphere, other inert gases (such as argon and helium) may also be used as the protective gas.

[0062] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 2,4-dimethylpyrrole-3-carboxylate, characterized in that: The steps include: (1) Prepare MOF material UiO-66-NH2; (2) using UiO-66-NH2 as a catalyst, adding the catalyst to a mixture of hydroxyacetone and 3-aminocrotonate, and stirring the mixture under a protective atmosphere for reaction; (3) After the reaction is completed, 2,4-dimethylpyrrole-3-carboxylate can be separated from the reaction solution; In the step (2), the solvent used in the mixed solution of hydroxyacetone and 3-aminocrotonate is trifluoroethanol or a mixed solvent of nitromethane and trifluoroethanol; wherein the mixed solvent of nitromethane and trifluoroethanol is obtained by mixing nitromethane and trifluoroethanol in a volume ratio of 2:1 to 0:1; In the step (2), the 3-aminocrotonate is methyl 3-aminocrotonate or ethyl 3-aminocrotonate; correspondingly, in the step (3), the 2,4-dimethylpyrrole-3-carboxylate is methyl 2,4-dimethylpyrrole-3-carboxylate or ethyl 2,4-dimethylpyrrole-3-carboxylate.

2. The method according to claim 1, characterized in that: The step (3) also includes the operation of separating the catalyst from the reaction liquid system, and the separated catalyst can be recycled for synthesizing 2,4-dimethylpyrrole-3-carboxylate.

3. The method according to claim 1, characterized in that: In the step (2), the stirring reaction is carried out at a temperature of 20° C. to 100° C., and the reaction time is 8 to 24 hours.

4. The method according to claim 1, characterized in that: In the step (2), the molar ratio of hydroxyacetone to 3-aminocrotonate is (1-2): (1-2).

5. The method according to claim 1, characterized in that: The step (1) also includes the preparation step of the MOF material UiO-66-NH2: Using ZrCl4, N,N-dimethylformamide (DMF) and 2-aminoterephthalic acid as raw materials, these three raw materials are mixed in a molar ratio of 1:10:1 to 1:20:1, and then stirred at 120°C to 150°C for 6 hours to 12 hours; after the reaction, the product is separated to obtain the MOF material UiO-66-NH2.

6. The method according to claim 1, characterized in that: In the step (3), the separation is specifically to first filter out the catalyst from the reaction liquid system, then concentrate the reaction liquid by distillation, and separate by column chromatography to obtain 2,4-dimethylpyrrole-3-carboxylate; The distillation is a reduced pressure distillation.

7. The method according to claim 1, characterized in that: In the step (2), the protective atmosphere is an inert gas.

8. The method according to claim 1, characterized in that: In the step (2), the protective atmosphere is nitrogen.

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