Preparation method and application of 1, 3-bis (2-methoxy-5-(trifluoromethyl) phenyl) urea
By using triphosgene to react step by step with amine raw materials, the synthesis of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea in the prior art was solved by using highly toxic phosgene to synthesize 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea in the prior art was solved by using highly toxic phosgene to synthesize 1,3-bis( The problem of this paper realizes an efficient, safe and low-cost synthesis process, and improves the yield and purity of the product.
Patent Information
- Application Number
- CN202411527379.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-30
- Publication Date
- 2025-02-07
AI Technical Summary
The existing synthesis method of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea uses highly toxic phosgene, and has low yields and difficult product purity to meet application requirements.
Triphosgene is used as raw material and reacts with amine raw materials in step. Through pre-reaction and subsequent reaction steps, 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea is prepared.
Achieve efficient and safe synthesis of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, reducing production costs, improving product yield and purity, and complying with green and efficient processes Requirements.
Smart Images
Figure CN119390612A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a preparation method and application of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea. Background Art
[0002] The cardiac action potential is generated by the coordinated action of different ion channels and transporters. Dysfunction of any of these membrane proteins can cause arrhythmias, especially the repolarizing potassium channel. Increasing the repolarizing current may be a new antiarrhythmic principle because it may attenuate afterdepolarization, ischemic leak current, and reentry. It has been reported that the diphenylurea compound 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea (NS1643) is an active substance that regulates ion channels. It can activate HERG channels and increase repolarization reserves, and is expected to become a new antiarrhythmic method.
[0003] At present, the process for synthesizing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea is to use phosgene, which is highly toxic and has a strong pungent or suffocating odor. It is a severe suffocating gas. Inhalation of phosgene may cause pulmonary edema, pneumonia, etc., and is fatal. In addition, the current production of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea using phosgene has a low yield, and the purity of the obtained product is difficult to meet the subsequent application requirements.
[0004] Therefore, how to provide a green and efficient method for synthesizing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea has become a problem that needs to be solved urgently. Summary of the invention
[0005] In order to solve the above technical problems, the present invention provides a preparation method and application of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, which uses triphosgene as a raw material and reacts with amine raw materials in a specific manner, replacing the phosgene production method in the prior art. The amount of triphosgene used is small, the reaction yield is high, the process cost is low, and it is green and efficient, which is in line with the concept of the development of modern organic chemistry.
[0006] To achieve this object, the present invention adopts the following technical solutions:
[0007] In a first aspect, the present invention provides a method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, the preparation method comprising the following steps:
[0008] The first 2-methoxy-5-trifluoromethylaniline is pre-reacted with triphosgene to remove impurities, and then reacted with the second 2-methoxy-5-trifluoromethylaniline to obtain the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea.
[0009] The method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea provided by the present invention first reacts triphosgene with an amine raw material to generate the corresponding chloroformic acid amide, then filters out impurities, and then adds the other half of the raw material amine to react to prepare the product. The present invention uses triphosgene, which is called solid phosgene, as a raw material to make the reaction safer and more controllable, and in a reaction that is exactly the same as phosgene, the amount of triphosgene can usually be reduced to one-third of the amount of phosgene. The preparation method provided by the present invention has simple experimental operation, high product yield and purity, and saves costs, providing a new green and efficient path for the production of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea.
[0010] In the present invention, the reaction of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea is as follows:
[0011]
[0012] Preferably, the molar ratio of the total amount of triphosgene to 2-methoxy-5-trifluoromethylaniline is 1:(4.5-6.5), wherein the specific value of (4.5-6.5) can be, for example, 4.8, 5, 2.5, 5.5, 5.8, 6 or 6.2, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
[0013] Preferably, the molar ratio of the first 2-methoxy-5-trifluoromethylaniline to the second 2-methoxy-5-trifluoromethylaniline is 1:(0.5-1.5), wherein the specific value of (0.5-1.5) can be, for example, 0.6, 0.8, 1, 1.2 or 1.4, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range, and further preferably 1:(0.9-1.1).
[0014] In the present invention, the ratio of 2-methoxy-5-trifluoromethylaniline used in the two-step reaction is close to 1:1, which is conducive to the generation of a symmetrical structure product, namely 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, and the product obtained thereby has a higher yield and good purity.
[0015] Preferably, the pre-reaction comprises a pre-reaction of a first 2-methoxy-5-trifluoromethylaniline solution with a triphosgene solution.
[0016] Preferably, the solvent of the first 2-methoxy-5-trifluoromethylaniline solution comprises toluene.
[0017] In the present invention, toluene is used as a reaction solvent. Toluene has relatively stable chemical properties and a moderate boiling point, and is therefore often used as a chemical reaction medium. In the preparation method provided by the present invention, toluene as a solvent can effectively increase the reaction rate and the purity of the product.
[0018] Preferably, the concentration of 2-methoxy-5-trifluoromethylaniline in the first 2-methoxy-5-trifluoromethylaniline solution is 0.05-0.5 mmol / mL, for example, 0.08 mmol / mL, 0.1 mmol / mL, 0.15 mmol / mL, 0.2 mmol / mL, 0.3 mmol / mL or 0.4 mmol / mL, and specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
[0019] Preferably, the solvent of the triphosgene solution comprises toluene.
[0020] Preferably, the concentration of triphosgene in the triphosgene solution is 0.01-0.1 mmol / mL, for example, it can be 0.015 mmol / mL, 0.02 mmol / mL, 0.03 mmol / mL, 0.04 mmol / mL, 0.05 mmol / mL, 0.06 mmol / mL or 0.08 mmol / mL, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
[0021] Preferably, the pre-reaction is carried out in the presence of a basic substance.
[0022] Preferably, the alkaline substance comprises triethylamine.
[0023] The alkaline substance in the present invention is triethylamine. Since there are two ethyl groups (C2H5) in the triethylamine molecule, the carbon-hydrogen bonds contained in these groups can stabilize protons and further increase the alkalinity of the solution.
[0024] Preferably, the molar ratio of the alkaline substance to triphosgene is (5-10):1, wherein the specific value of (5-10) can be, for example, 5.5, 6, 7, 8 or 9, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range, and further preferably is 5.88:1.
[0025] The present invention uses a slightly excessive amount of alkaline substances because most of the amines exist in the form of hydrochloride, so an excessive amount of base needs to be added for neutralization, thereby improving the purity of the product and reducing the purification cost.
[0026] Preferably, the temperature of the pre-reaction is 15-30°C, for example, 18°C, 20°C, 22°C, 25°C or 28°C, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
[0027] Preferably, the pre-reaction time is 10-60 min, for example, it can be 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min or 55 min, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
[0028] Preferably, the method of removing impurities comprises filtration and / or centrifugation.
[0029] Preferably, the reaction temperature is 100-150°C, for example, it can be 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C or 145°C, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
[0030] Preferably, the reaction time is 16-18 h, for example, it can be 16.2 h, 16.5 h, 16.8 h, 17 h, 17.2 h, 17.5 h or 17.8 h.
[0031] Preferably, the reaction is monitored by thin layer chromatography (TLC).
[0032] In the present invention, the reaction is terminated when the raw materials are completely reacted as observed by thin layer chromatography.
[0033] Preferably, the solvent for thin layer chromatography comprises petroleum ether (PE) and / or diethyl ether (EA).
[0034] Preferably, the volume ratio of petroleum ether to ethyl ether is (1-5):1, wherein the specific value of (1-5) can be, for example, 1.5, 2, 2.5, 3, 3.5, 4 or 4.5, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
[0035] Preferably, post-treatment is performed after the reaction is completed.
[0036] Preferably, the post-treatment includes filtration and drying.
[0037] Preferably, the preparation method comprises the following steps:
[0038] The alkaline substance is mixed with the first 2-methoxy-5-trifluoromethylaniline solution, and pre-reacted with the triphosgene solution at 15-30° C. for 10-60 min to remove impurities to obtain a pre-product;
[0039] The pre-product is reacted with a second 2-methoxy-5-trifluoromethylaniline at 100-150° C. for 16-18 hours to obtain the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea;
[0040] The molar ratio of the first 2-methoxy-5-trifluoromethylaniline, the alkaline substance and the triphosgene is (1-5): (1-10): 1; the concentration of the first 2-methoxy-5-trifluoromethylaniline solution is 0.05-0.5 mmol / mL, and the concentration of the triphosgene solution is 0.01-0.1 mmol / mL;
[0041] The molar ratio of the first 2-methoxy-5-trifluoromethylaniline to the second 2-methoxy-5-trifluoromethylaniline is 1:(0.5-1.5).
[0042] In a second aspect, the present invention provides an application of the preparation method described in the first aspect in drug synthesis.
[0043] Compared with the prior art, the present invention has at least the following beneficial effects:
[0044] The present invention uses triphosgene, which is called solid phosgene, as a raw material, and reacts it with amine raw materials in steps to obtain a 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea product. The overall reaction operation is simple, safe and controllable, the amount of triphosgene used is only one-third of the amount of phosgene used, the production cost is reduced, and the obtained 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea product has a high yield and high purity. In some preferred technical solutions, the yield is greater than 30% and the purity is greater than 99%, which meets the development needs of green and efficient modern processes. BRIEF DESCRIPTION OF THE DRAWINGS
[0045] Figure 1 The results obtained by detecting the reaction progress by TLC in Example 1;
[0046] Figure 2 This is the NMR spectrum of 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea obtained in Example 1. DETAILED DESCRIPTION
[0047] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.
[0048] The materials used in the following examples are all commercially available products.
[0049] In the present invention, LC-MS was used to detect the purity of the product, and the area normalization method was used to calculate the substance content. The LC-MS test conditions were:
[0050] The detection instrument was Agilent 1290IIUPLCMS, the chromatographic column was ZORBAX Eclipse Plus C18, 2.1x50m, the injection volume was 10 μL, the column temperature was 35°C, the mobile phase flow rate was 0.4 mL / min, the mobile phase A was a 0.025% by volume formic acid aqueous solution, the mobile phase B was a 0.025% by volume formic acid acetonitrile solution, and the gradient elution program was shown in Table 1.
[0051] Table 1
[0052]
[0053]
[0054] Example 1
[0055] A method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, wherein the reaction of the preparation method is as follows:
[0056]
[0057] The materials involved in the preparation method are shown in Table 2:
[0058] Table 2
[0059]
[0060] The preparation method comprises the following steps:
[0061] Toluene (50 mL) and triphosgene (0.53 g, 1.779 mmol) were added to a 250 mL round-bottom flask in sequence and mixed; in addition, raw materials 2-methoxy-5-trifluoromethylaniline (1 g, 5.23 mmol), triethylamine (1.06 g, 10.463 mmol) and toluene (30 mL) were weighed in a 100 mL flask, mixed evenly, and the prepared solution was added dropwise to the reaction solution in the round-bottom flask; after the addition, the mixture was stirred at room temperature for 30 min, and the white solid precipitate was filtered out; raw material 2-methoxy-5-trifluoromethylaniline (1 g, 5.23 mmol) was added to the filtrate, and the reaction solution was transferred to 120 ° C for reflux reaction for 17 h, and solid precipitation was observed in the system. After the reaction was completed, the reaction solution was cooled, and the reaction progress was observed by TLC detection (PE to EA volume ratio of 3), and the reaction was completed (such as Figure 1As shown), filter, dry the filter cake to obtain a light yellow solid, namely 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea. The product H NMR spectrum is as follows Figure 2 As shown, the yield was 30.13% and the purity was 99% as determined by LC-MS.
[0062] Example 2
[0063] A method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, which differs from Example 1 only in that the amount of triphosgene used is 0.46 g (the feed ratio is 0.15 eq.), and the other preparation steps and parameters are the same as those in Example 1.
[0064] LC-MS detection revealed that the purity of the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea product was reduced to 82%. The clean target product could be obtained by pulping purification, but the yield was reduced to 15%.
[0065] Example 3
[0066] A method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, which differs from Example 1 only in that the amount of triethylamine used is 0.848 g (the feed ratio is 0.8 eq.), and the other preparation steps and parameters are the same as those in Example 1.
[0067] LC-MS detection revealed that the purity of the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea product was reduced to 64% and was difficult to purify.
[0068] Example 4
[0069] A method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, which differs from Example 1 only in that triethylamine is replaced by an equal molar amount of pyridine, and other preparation steps and parameters are the same as those in Example 1.
[0070] After reflux reaction at 120°C for 17 hours, TLC detection showed that the product had not reacted completely. The reaction time was extended to 20 hours, but the raw material still had difficulty in reacting completely.
[0071] Comparative Example 1
[0072] A method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, which differs from Example 1 only in that a step-by-step experiment is not used. Specifically, the preparation method comprises the following steps:
[0073] Toluene (50 mL) and triphosgene (0.53 g, 1.779 mmol) were added to a 250 mL round-bottom flask in sequence and mixed; in addition, raw materials 2-methoxy-5-trifluoromethylaniline (2 g, 10.46 mmol), triethylamine (1.06 g, 10.463 mmol) and toluene (30 mL) were weighed in a 100 mL flask and mixed evenly, and the prepared solution was added dropwise to the reaction solution in the round-bottom flask; after the addition, the reaction solution was transferred to 120°C and refluxed for 17 h. No target product was generated by TLC detection.
[0074] It can be seen from the test results that the preparation method provided by the present invention first reacts triphosgene with an amine raw material to obtain a chloroformic acid amide compound, then filters out impurities, and then adds the other half of the raw material amine to react to obtain a 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea product. The synthesis process has a high yield and a high product purity. The amount of triphosgene required for the reaction is small, which saves production costs and meets the requirements of a green and efficient process.
[0075] By comparing Example 1 with Examples 2-4, it can be seen that the present invention further improves the yield and purity of the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea product by limiting the ratio of triphosgene to amine monomers, the type and amount of alkaline substances, and shortens the reaction time.
[0076] By comparing Example 1 with Comparative Example 1, it can be seen that when triphosgene directly reacts with all amine monomers, the reaction is difficult to proceed, and the generation of the target product cannot be detected by TLC detection. This is because the reaction of triphosgene and amine monomers cannot be generated in one step, and the amine needs to be synthesized first and then reacted with the other half of the product to generate a urea product.
[0077] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.
Claims
1. A method for preparing 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea, characterized in that: The preparation method comprises the following steps: The first 2-methoxy-5-trifluoromethylaniline is pre-reacted with triphosgene to remove impurities, and then reacted with the second 2-methoxy-5-trifluoromethylaniline to obtain the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea.
2. The preparation method according to claim 1, characterized in that: The molar ratio of triphosgene to the total amount of 2-methoxy-5-trifluoromethylaniline is 1:(4.5-6.5); Preferably, the molar ratio of the first 2-methoxy-5-trifluoromethylaniline to the second 2-methoxy-5-trifluoromethylaniline is 1:(0.5-1.5), and more preferably 1:(0.9-1.1).
3. The preparation method according to claim 1 or 2, characterized in that: The pre-reaction comprises a first pre-reaction of a 2-methoxy-5-trifluoromethylaniline solution with a triphosgene solution; Preferably, the solvent of the first 2-methoxy-5-trifluoromethylaniline solution comprises toluene; Preferably, the concentration of 2-methoxy-5-trifluoromethylaniline in the first 2-methoxy-5-trifluoromethylaniline solution is 0.05-0.5 mmol / mL; Preferably, the solvent of the triphosgene solution comprises toluene; Preferably, the concentration of triphosgene in the triphosgene solution is 0.01-0.1 mmol / mL.
4. The preparation method according to any one of claims 1 to 3, characterized in that The preliminary reaction is carried out in the presence of an alkaline substance; Preferably, the alkaline substance comprises triethylamine; Preferably, the molar ratio of the alkaline substance to triphosgene is (5-10):
1.
5. The preparation method according to any one of claims 1 to 4, characterized in that: The temperature of the pre-reaction is 15-30°C; Preferably, the pre-reaction time is 10-60 min.
6. The preparation method according to any one of claims 1 to 5, characterized in that: The method of removing impurities includes filtration and / or centrifugation.
7. The preparation method according to any one of claims 1 to 6, characterized in that: The reaction temperature is 100-150°C; Preferably, the reaction time is 16-18 hours.
8. The preparation method according to any one of claims 1 to 7, characterized in that: The reaction progress is detected by thin layer chromatography; Preferably, after the reaction is completed, post-treatment is performed; Preferably, the post-treatment includes filtration and drying.
9. The preparation method according to any one of claims 1 to 8, characterized in that: The preparation method comprises the following steps: The alkaline substance is mixed with the first 2-methoxy-5-trifluoromethylaniline solution, and pre-reacted with the triphosgene solution at 15-30° C. for 10-60 min to remove impurities to obtain a pre-product; The pre-product is reacted with a second 2-methoxy-5-trifluoromethylaniline at 100-150° C. for 16-18 hours to obtain the 1,3-bis(2-methoxy-5-(trifluoromethyl)phenyl)urea; The molar ratio of the first 2-methoxy-5-trifluoromethylaniline, the alkaline substance and the triphosgene is (1-5): (1-10): 1; the concentration of the first 2-methoxy-5-trifluoromethylaniline solution is 0.05-0.5 mmol / mL, and the concentration of the triphosgene solution is 0.01-0.1 mmol / mL; The molar ratio of the first 2-methoxy-5-trifluoromethylaniline to the second 2-methoxy-5-trifluoromethylaniline is 1:(0.5-1.5).
10. Use of the preparation method according to any one of claims 1 to 9 in drug synthesis.