Preparation method and production process of a six-membered aromatic ring fused pyrrole compound
By using a mixed solvent of toluene and water and an optimized post-treatment method, six-membered aromatic ring pyrrole compounds were efficiently synthesized under normal pressure, solving the problems of long reaction time under negative pressure and difficulty in solvent removal in the prior art, and achieving high yield and good product properties.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI LINKCHEM TECHNOLOGY CO LTD
- Filing Date
- 2023-12-19
- Publication Date
- 2026-06-23
AI Technical Summary
Existing methods for synthesizing six-membered aromatic ring pyrrole compounds require negative pressure conditions, which result in long reaction times and difficulties in removing the solvents used, thus affecting production efficiency.
A mixed solvent of toluene and water was used, and the reaction was carried out under normal pressure. The post-treatment process was optimized by combining washing with sodium chloride aqueous solution and pulping with tert-butyl methyl ether.
Achieving high-yield synthesis of six-membered aromatic ring pyrrole compounds under normal pressure simplifies the solvent removal process, improves production efficiency, and enhances product properties.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, specifically to a method and process for preparing a six-membered aromatic ring pyrrole compound. Background Technology
[0002] Six-membered aromatic ring pyrrole compounds have wide applications in the pharmaceutical field. For example, Chinese patent CN102574799A discloses that pyridinopyrrole compounds can be used to synthesize the drug dabrafenib, which can be used to treat melanoma skin cancer. Chinese patent CN110903254A discloses that pyrazinopyrrole compounds can be used to synthesize the JAK1 inhibitor uroxitinib, which is used to treat diseases such as rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), and psoriatic arthritis (PsA).
[0003] In the prior art, several patents, such as CN1095751019 A and CN 102574799A, reported the following methods for synthesizing six-membered aromatic ring pyrrole compounds.
[0004]
[0005] However, the reactions reported in both of the above-mentioned literatures need to be carried out under negative pressure conditions, and the reaction time is as long as 15-20 hours.
[0006] Furthermore, the reaction solvents used in the two aforementioned articles are N-methylpyrrolidone and ethylene glycol, respectively. Both of these solvents have boiling points of around 200°C, making them difficult to remove using conventional methods. Summary of the Invention
[0007] This invention is made to solve the above-mentioned problems, and aims to provide a method and process for preparing six-membered aromatic ring pyrrole compounds that can be obtained in high yield even under normal pressure using a low-boiling-point solvent.
[0008] This invention provides a method for preparing a six-membered aromatic ring pyrrole compound, characterized by the following steps:
[0009]
[0010] Compound 1 reacts in the presence of a base and a solvent to give compound 2.
[0011] In the above formula, X is H or a halogen, and A1 and A2 are independently selected from CH or N.
[0012] The alkali is sodium hydroxide and / or potassium hydroxide.
[0013] The solvent is a mixture of toluene and water.
[0014] This invention provides a process for producing six-membered aromatic ring pyrrole compounds, characterized by the following steps:
[0015]
[0016] In the above formula, X is H or a halogen, and A1 and A2 are independently selected from CH or N.
[0017] Compound 1 reacts in the presence of a base and a solvent to give a reaction solution, wherein the solvent is a mixed solvent composed of toluene and water;
[0018] An organic solvent was added to the reaction solution for extraction, and the organic phase was collected.
[0019] The organic phase was washed with an aqueous sodium chloride solution and concentrated to obtain a crude product.
[0020] Add tert-butyl methyl ether to the crude product, slurry, filter, and dry to obtain compound 2.
[0021] In one embodiment of the invention, the reaction is carried out at 0.1 bar to 1.01 bar.
[0022] In one embodiment of the invention, the reaction is carried out at 0.40 bar to 0.90 bar.
[0023] In one embodiment of the present invention, when the reaction is carried out under reduced pressure, the corresponding reaction time is 5-8 hours; specifically, 6.5 hours.
[0024] In one embodiment of the present invention, when the reaction is carried out under normal pressure, the corresponding reaction time is 10-20 hours; specifically, 15 hours may be selected.
[0025] In one embodiment of the present invention, the molar ratio of the base to compound 1 is (2-8):1.
[0026] In one embodiment of the present invention, the volume ratio of toluene to water in the mixed solvent is (0.9-4):1.
[0027] In one embodiment of the present invention, the concentration of compound 1 relative to the mixed solvent is 0.05-0.5 g / mL.
[0028] In one embodiment of the present invention, the organic solvent is ethyl acetate.
[0029] In one embodiment of the present invention, the concentration of the sodium chloride aqueous solution is 15wt%-26.5wt%.
[0030] In one embodiment of the present invention, the volume-to-mass ratio of the tert-butyl methyl ether to the crude product is (3-5):1, mL / g.
[0031] The role and effect of the invention:
[0032] According to the method for preparing six-membered aromatic ring pyrrole compounds of the present invention, since a mixed solvent composed of toluene and water is used, the present invention can achieve ideal reaction yields even under normal pressure.
[0033] The production process of the six-membered aromatic ring pyrrole compounds according to the present invention, because the washing with sodium chloride aqueous solution and the pulping with tert-butyl methyl ether are used in sequence, can not only effectively remove by-products in the post-processing, but also improve the product properties. Detailed Implementation
[0034] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments.
[0035] In the following embodiments, unless otherwise stated, the raw materials used in each embodiment are commercially available products.
[0036] <Example 1>
[0037] Preparation method of compound 2a
[0038] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:
[0039]
[0040] Includes the following steps:
[0041] 70g of compound 1a was added to a reaction vessel, along with 700mL of toluene and 280mL of water. The temperature was raised to 80℃, and the pressure inside the reaction vessel was reduced to 0.9 bar. 60.1g of NaOH dissolved in 420mL of water was added dropwise to the reaction vessel. After the addition was complete, the mixture was stirred for 6.5h. The reaction was confirmed to be complete by HPLC.
[0042] Add 700 mL of ethyl acetate to the reaction system, extract, take the organic phase, wash once with 700 mL of 20 wt% sodium chloride aqueous solution, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and obtain the crude product. Add 250 mL of tert-butyl methyl ether and stir for 30 min to obtain 45.9 g of compound 2a, a yellow solid, with a yield of 84.9% and a purity of 99%.
[0043] <Example 2>
[0044] Preparation method of compound 2a
[0045] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:
[0046]
[0047] Includes the following steps:
[0048] 70g of compound 1a was added to a reaction vessel, along with 700mL of toluene and 280mL of water. The temperature was raised to 80℃, and 60.1g of NaOH dissolved in 420mL of water was added dropwise to the reaction vessel. After the addition was complete, the mixture was stirred at atmospheric pressure for 15h, and the reaction was confirmed to be complete by HPLC.
[0049] Add 700 mL of ethyl acetate to the reaction system, extract, take the organic phase, wash once with 700 mL of 20 wt% sodium chloride aqueous solution, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and obtain the crude product. Add 250 mL of tert-butyl methyl ether and stir for 30 min to obtain 46.6 g of compound 2a, a yellow solid, with a yield of 86.1% and a purity of 99%.
[0050] <Example 3>
[0051] Screening of reaction solvents
[0052] In this embodiment, the reaction solvent was screened under both reduced pressure and normal pressure conditions, and the reaction formula is as follows:
[0053]
[0054] The reaction conditions are as follows:
[0055] Reaction condition A:
[0056] 3g of compound 1a was added to the reaction vessel and solvent. The temperature was raised to 80℃, and the pressure inside the reaction vessel was reduced to 0.9 bar. 3.62g of NaOH was dissolved in 9.3mL of water to prepare an aqueous sodium hydroxide solution. This aqueous sodium hydroxide solution was added dropwise to the reaction system. After the addition was complete, the reaction was stirred for 6.5h. The reaction solution was then analyzed by HPLC.
[0057] Reaction condition B:
[0058] 3g of compound 1a was added to the reaction vessel and solvent, and the temperature was raised to 80℃. 3.62g of NaOH was dissolved in 9.3mL of water to prepare an aqueous sodium hydroxide solution. The aqueous sodium hydroxide solution was added dropwise to the reaction system. After the addition was complete, the reaction was stirred at normal pressure for 15h. The reaction solution was then analyzed by HPLC.
[0059] The reaction results are shown in Table 1.
[0060] Table 1 Screening of reaction solvents
[0061] Serial Number reaction solvent HPLC yield of compound 2a HPLC yield of compound 3a Reaction conditions 1 12mL toluene + 3mL water 82.0％ 6.6％ B 2 12mL glycerol + 3mL water 70.8％ 11.2％ B 3 12mL DMF + 3mL water 17.1％ 81.3％ B 4 12mL NMP + 3mL water 66.0％ 11.8％ B 5 12mL DMAC + 3mL water 48.3％ 47.4％ B 6 12 mL 1,4-dioxane + 3 mL water 45.6％ 13.1％ B 7 15mL toluene 36.8％ 13.3％ B 8 12mL n-Butanol + 3mL Water Trace(<5%) Trace(<5%) B 9 15mL water 75.1％ 8.1％ A 10 12mL NMP + 3mL water 73.0％ 7.2％ A 11 12mL toluene + 3mL water 87.9％ 6.8％ A
[0062] As shown in Table 1, the reaction solvent has a significant impact on the reaction in this embodiment.
[0063] When toluene and water are used as a mixed reaction solvent, the reaction can achieve a good conversion rate of over 80% regardless of whether it is carried out under normal pressure or reduced pressure. In particular, the reaction can be completed within 6.5 hours under 0.9 bar conditions, which greatly shortens the reaction time while ensuring the yield.
[0064] When DMAC / water or DMF / water is used as the reaction solvent, the reaction produces a large amount of byproducts such as compound 3a. In particular, when DMF / water is used as the solvent, compound 3a even becomes the main product.
[0065] <Example 4>
[0066] Screening of NaOH dosage
[0067] This embodiment screened the amount of NaOH used, and the reaction formula is as follows:
[0068]
[0069] The reaction conditions are as follows:
[0070] Reaction condition A:
[0071] 3g of compound 1a was added to a reaction vessel, along with 12mL of toluene and 3mL of water. The temperature was raised to 80℃, and the pressure inside the reaction vessel was reduced to 0.9 bar. NaOH was dissolved in 9.3mL of water to prepare an aqueous sodium hydroxide solution. This aqueous sodium hydroxide solution was added dropwise to the reaction system. After the addition was complete, the mixture was stirred for 6.5 hours. The reaction solution was then analyzed by HPLC.
[0072] The reaction results are shown in Table 2.
[0073] Table 2 Screening of NaOH dosage
[0074] Serial Number NaOH dosage HPLC yield of compound 2a HPLC yield of compound 3a 1 2.58g 84.7％ 6.3％ 2 1.64g 83.3％ 6.2％ 3 0.94g 82.4％ 5.1％
[0075] As shown in Table 2, in the reaction system with toluene / water as the solvent, the amount of NaOH used has little effect on the reaction yield, and even using only 2.0 eq can achieve a satisfactory yield.
[0076] <Comparative Example>
[0077] Preparation method of compound 2a
[0078] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:
[0079]
[0080] Includes the following steps:
[0081] 70g of compound 1a was added to a reaction vessel, along with 700mL of toluene and 280mL of water. The temperature was raised to 80℃, and the pressure inside the reaction vessel was reduced to 0.9 bar. 60.1g of NaOH dissolved in 420mL of water was added dropwise to the reaction vessel. After the addition was complete, the mixture was stirred for 6.5h. The reaction was confirmed to be complete by HPLC.
[0082] Add 700 mL of ethyl acetate to the reaction system, extract, take the organic phase, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and obtain the crude product. Add 250 mL of tert-butyl methyl ether and stir for 30 min to obtain 34.9 g of compound 2a, a black mud-like substance, with a yield of 64.5% and a purity of 93.3%.
[0083] The difference between this comparative example and Example 1 lies in the post-treatment. When the washing step with sodium chloride aqueous solution is omitted in the post-treatment steps, the pulping of tert-butyl methyl ether cannot improve the properties of the product, and the by-products of the reaction will undergo polymerization with the target product during the post-treatment process, thereby further reducing the yield.
[0084] The role and effect of the embodiments
[0085] According to the preparation method of the six-membered aromatic ring pyrrole compound involved in Example 2, because a mixed solvent composed of toluene and water is used, the present invention can achieve ideal reaction yields even under normal pressure. Furthermore, since toluene and water are chosen as reaction solvents, both of which have boiling points of around 100°C, the solvents can be removed relatively easily, avoiding solvent residues from affecting subsequent reactions.
[0086] Furthermore, according to the method for preparing the six-membered aromatic ring pyrrole compound involved in Example 1, the reaction yield is effectively improved because the reaction is carried out under a reaction condition of 0.9 bar.
[0087] According to the production process of the six-membered aromatic ring pyrrole compounds involved in the above embodiments, because the washing with sodium chloride aqueous solution and the pulping with tert-butyl methyl ether are used in sequence, the by-products can be effectively removed in the post-processing, and the product properties can also be improved.
[0088] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of the present invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the present invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims of the present invention.
Claims
1. A method for preparing a six-membered aromatic ring pyrrole compound, characterized in that, Includes the following steps: Compound 1 reacts in the presence of a base and a solvent to give compound 2. In the above formula, X is H or a halogen, and A1 and A2 are independently selected from CH or N. The alkali is sodium hydroxide and / or potassium hydroxide. The solvent is a mixture of toluene and water; the volume ratio of toluene to water is (0.9-4):
1. The reaction was carried out at 0.9 bar–1.01 bar.
2. The method for preparing a six-membered aromatic ring pyrrole compound according to claim 1, characterized in that: in, X is bromine, and A1 and A2 are both N.
3. The method for preparing a six-membered aromatic ring pyrrole compound according to claim 1, characterized in that: in, The molar ratio of the base to compound 1 is (2-8):
1.
4. A production process for a six-membered aromatic ring pyrrole compound, characterized in that, Includes the following steps: In the above formula, X is H or a halogen, and A1 and A2 are independently selected from CH or N. Compound 1 reacts in the presence of a base and a solvent to give a reaction solution, wherein the base is sodium hydroxide and / or potassium hydroxide, and the solvent is a mixed solvent of toluene and water; the volume ratio of toluene to water is (0.9-4):
1. The reaction was carried out at 0.9 bar–1.01 bar; After the reaction is complete, an organic solvent is added to the reaction solution for extraction, and the organic phase is collected; the organic solvent is ethyl acetate. The organic phase was washed with an aqueous sodium chloride solution and concentrated to obtain a crude product. Add tert-butyl methyl ether to the crude product, slurry, filter, and dry to obtain compound 2.
5. The production process of the six-membered aromatic ring pyrrole compound according to claim 4, characterized in that: in, The mass concentration of the sodium chloride aqueous solution is 15%-26.5%.
6. The production process of the six-membered aromatic ring pyrrole compound according to claim 4, characterized in that: in, The volume-to-mass ratio of tert-butyl methyl ether to the crude product is (3-5):1, mL:g.