A kind of 4-(2-butyl)aminoaniline and preparation method thereof
By performing the steps of amine group protection, coupling and deprotection of halogenated aniline as raw material, the problems of easy explosive raw materials and precious metal catalysts in the prior art are solved, and the efficient, economical and environmentally friendly preparation of 4-(2-butyl)aminoaniline is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411935586.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-04-04
AI Technical Summary
The existing methods for preparing 4-(2-butyl)aminoaniline are easy to produce raw materials, difficult to commercially purchase or use precious metal catalysts, resulting in high industrial costs and high risks.
Using parahalogenin as raw material, 4-(2-butyl)aminoaniline is prepared by amine group protection, coupling and deprotection steps, avoiding the use of easily explosive raw materials and precious metal catalysts.
It realizes a preparation method of easy-to-get raw materials, environmentally friendly, and no precious metals. It has high purity and high yield, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to 4-(2-butyl)aminoaniline and a preparation method thereof. Background Art
[0002] 4-(2-Butyl)aminoaniline is an important chemical raw material and a key intermediate for a variety of pharmaceutical intermediates. Currently, there are not many reports on the invention routes of 4-(2-butyl)aminoaniline (Compound A), mainly the following:
[0003] Route 1: Woo Bae, Jong; et al Perkin 1 (2000), (2), 145-146 reported the use of p-nitroaniline as a raw material for reductive amination with butanone to prepare intermediate 1, which was then reduced by nitro group to obtain compound A. This invention has a shorter route and a high yield, but the raw material p-nitroaniline is explosive and difficult to purchase commercially. In addition, the precious metal palladium is used as a catalyst, which greatly increases the cost of industrialization.
[0004]
[0005] Route 2: L'Oreal France, FR2913015 A12008-08-29, reported that p-fluoronitrobenzene was used as a raw material, coupled with n-butylamine to prepare intermediate 1, and then reduced by nitro group to obtain compound A. This invention also has the following problems: the raw material p-fluoronitrobenzene is explosive, and the coupling yield of this step is only 66%, the total yield is less than 40%, and the product purity is not reported, so the industrialization cost is high and the risk is great.
[0006]
[0007] In summary, it is found that the current invention routes for preparing 4-(2-butyl)aminoaniline are very short, but the raw materials are explosive and difficult to purchase commercially, or precious metals are used, which increases the cost. These factors make it difficult to industrialize. Therefore, it is urgent to develop a preparation method for 4-(2-butyl)aminoaniline in which the raw materials and reagents are easy to obtain or prepare and no precious metals are used. Summary of the invention
[0008] 1. Technical issues to be solved
[0009] In view of the deficiencies in the prior art, the present invention provides a 4-(2-butyl)aminoaniline and a preparation method thereof, which solves the technical problem that the raw materials required by the prior preparation method are explosive or precious metals, which makes the raw materials difficult to purchase commercially and the cost is high.
[0010] (II) Technical solution
[0011] To achieve the above objectives, the present invention is implemented through the following technical solutions:
[0012] In a first aspect, the present invention provides a method for preparing 4-(2-butyl)aminoaniline (Compound A), which uses p-haloaniline as a raw material and obtains Compound A through amino protection, coupling, and deprotection.
[0013] Its synthetic route is:
[0014]
[0015] X is one of chlorine, bromine and iodine,
[0016] The present invention provides a method for preparing 4-(2-butyl)aminoaniline, comprising the following steps:
[0017] S1, take p-haloaniline and solvent and stir evenly, add acid binding agent, add di-tert-butyl dicarbonate solution dropwise at temperature T1, react at temperature T2, after the reaction is complete, add ethyl acetate, wash with water, concentrate, cool, crystallize, filter, and dry to obtain compound 1;
[0018] S2, nitrogen protection, take the solvent, compound 1, 2-butylamine, alkali, salt, and catalyst, stir evenly, react at temperature T3, after the reaction is complete, cool to room temperature, extract, adjust pH, wash with water, and concentrate the organic layer to dryness to obtain compound 2;
[0019] S3, under nitrogen protection, take compound 2 and the solvent, stir evenly, cool to T4, add 1M hydrochloric acid solution dropwise, control the temperature to T5 for reaction, after the reaction is complete, wash with sodium bicarbonate solution, wash with water, combine the organic layers, dry, and concentrate to dryness to obtain compound A.
[0020] Furthermore, in S1, the p-haloaniline is selected from p-chloroaniline, p-bromoaniline, and p-iodoaniline, preferably p-bromoaniline;
[0021] Furthermore, in said S1, the solvent is selected from one of methanol, tetrahydrofuran, and 1,4-dioxane, preferably methanol;
[0022] Furthermore, in S1, the acid binding agent is selected from one of triethylamine, sodium bis(trimethylsilyl)amide (NaHMDS), and 4-dimethylaminopyridine (DMAP), preferably triethylamine;
[0023] Furthermore, in the S1, the mass ratio of the p-haloaniline to the acid-binding agent is 1:1-4, preferably 1:1-2;
[0024] Furthermore, in the S1, the temperature T1 is -10 to 20°C, preferably -5 to 5°C;
[0025] Furthermore, in the S1, the mass ratio of p-haloaniline to di-tert-butyl dicarbonate (Boc2) is 1:1-3, preferably 1:1.2-2;
[0026] Furthermore, in the S1, the temperature T2 is 10 to 60°C, preferably 20 to 40°C;
[0027] Further, in said S2, the solvent is selected from one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP), preferably DMF;
[0028] Furthermore, in the S2, the mass ratio of compound 1 to 2-butylamine is 1:1-5, preferably 1:1.5-2.5;
[0029] Furthermore, in the S2, the base is selected from one of potassium carbonate, sodium carbonate and cesium carbonate, preferably potassium carbonate;
[0030] Furthermore, in the S2, the mass ratio of compound 1 to the alkali is 1:1-8, preferably 1:2-4;
[0031] Furthermore, in S2, the salt is selected from cuprous bromide, cuprous chloride, and cupric iodide, preferably cuprous bromide;
[0032] Furthermore, in the S2, the mass ratio of compound 1 to salt is 1:0.1-1, preferably 1:0.2-0.5;
[0033] Further, in said S2, the catalyst is selected from 2-isobutylcyclohexanone, 2-isopropylcyclohexanone, and 2-acetylcyclohexanone;
[0034] Furthermore, in said S2, the mass ratio of compound 1 to catalyst is 1:0.1-1, preferably 1:0.2-0.4;
[0035] Further, in said S2, the temperature of T3 is 100-160°C, preferably 120-140°C;
[0036] Furthermore, in S3, the solvent is selected from one of ethyl acetate, isopropyl acetate and dichloromethane, preferably ethyl acetate;
[0037] Furthermore, in said S3, the temperature of T4 is -10 to 20°C, preferably -5 to 5°C;
[0038] Furthermore, in S3, the mass ratio of compound 2 to 1M hydrochloric acid is 1:1-5, preferably 1:1.6-2.5;
[0039] Furthermore, in said S3, the temperature of T5 is 0 to 80°C, preferably 20 to 30°C;
[0040] In a second aspect, the present invention further provides a 4-(2-butyl)aminoaniline obtained by the preparation method described in the first aspect, wherein the structure of the 4-(2-butyl)aminoaniline is
[0041] The formula is as follows:
[0042]
[0043] (III) Beneficial effects
[0044] The present invention provides a 4-(2-butyl)aminoaniline and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:
[0045] The present invention uses p-haloaniline as a raw material, and undergoes amine protection, coupling, and deprotection to obtain compound A. Compared with the prior art, the present invention has a novel synthesis route, and the raw materials and reagents used are easy to obtain or prepare, and no precious metal reagents are used, which is safe and environmentally friendly, and the reaction conditions are mild, and the operation is convenient and controllable. The prepared 4-(2-butyl)aminoaniline has good purity and high yield, and is suitable for industrial production. The present invention has broad prospects and industrial application value. DETAILED DESCRIPTION
[0046] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0047] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.
[0048] Example 1
[0049] A method for preparing 4-(2-butyl)aminoaniline (compound A), specifically comprising the following steps:
[0050]
[0051] S1. Synthesis of Compound 1
[0052] Into the reaction flask, add p-bromoaniline (86 g, 0.5 mol), 250 ml methanol, cool to 0 ° C, add triethylamine (50.6 g, 0.5 mol), add Boc2-methanol solution (131 g, 0.6 mol) dropwise, react at 25 ° C for 5 h, remove the solvent, add 400 mL ethyl acetate, stir and dissolve, wash with water, remove part of the solvent, cool to 5 ° C, crystallize, filter, and obtain compound 1, 134.7 g, yield 99%, purity 99.6%;
[0053] S2. Synthesis of Compound 2
[0054] Under nitrogen protection, 300 mL of DMF, compound 1 (136 g, 0.5 mol), 2-butylamine (55 g, 0.75 mol), potassium carbonate (138 g, 1.0 mol), and cuprous bromide (14.3 g, 0.1 mol) were added to the reaction bottle, stirred evenly, and 2-isobutylcyclohexanone (15.4 g, 0.1 mol) was added. The mixture was reacted at 120 ° C for 14 h. After the reaction was complete, the mixture was cooled to room temperature, water was added, and 300 mL*2 of isopropyl acetate was used for extraction. The organic layers were combined, and the organic layers were adjusted to pH = 8 using citric acid. The organic layers were concentrated to dryness to obtain compound 2, 132.2 g, with a yield of 92% and a purity of 98.5%;
[0055] S3. Synthesis of Compound A
[0056] Under nitrogen protection, compound 2 (132.2 g, 0.5 mol) and 400 mL of ethyl acetate were added to the reaction bottle, the temperature was lowered to 0°C, 1 M hydrochloric acid solution (29.2 g, 0.8 mol) was added dropwise, the temperature was raised to 20°C, and the mixture was stirred for 1 h. When the reaction was completed, the mixture was washed with sodium bicarbonate solution and water, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound A, 78.1 g, with a yield of 95% and a purity of 99.1%.
[0057] Example 2
[0058] A method for preparing 4-(2-butyl)aminoaniline (compound A), specifically comprising the following steps:
[0059]
[0060] S1. Synthesis of Compound 1
[0061] To the reaction flask, add p-chloroaniline (63.8 g, 0.5 mol), 600 ml THF, cool to -5 ° C, add NaHMDS (183.4 g, 1.0 mol), add Boc2-methanol solution (218.3 g, 1.0 mol) dropwise, react at 40 ° C for 3 h, remove the solvent, add 500 mL ethyl acetate, stir and dissolve, wash with water, remove part of the solvent, cool to 0 ° C, crystallize, filter, and obtain compound 1, 111.6 g, yield 98%, purity 99.2%;
[0062] S2. Synthesis of Compound 2
[0063] Under nitrogen protection, 400 mL of DMAC, compound 1 (113.9 g, 0.5 mol), 2-butylamine (91.6 g, 1.25 mol), sodium carbonate (212 g, 2.0 mol), and cuprous chloride (24.8 g, 0.25 mol) were added to the reaction bottle, stirred evenly, and 2-isopropylcyclohexanone (28 g, 0.2 mol) was added. The mixture was reacted at 140 ° C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, water was added, and 400 mL*2 isopropyl acetate was used for extraction. The organic layers were combined, and the organic layers were adjusted to pH = 8 using citric acid. The organic layers were concentrated to dryness to obtain compound 2, 119 g, with a yield of 90% and a purity of 98.7%;
[0064] S3. Synthesis of Compound A
[0065] Under nitrogen protection, compound 2 (132.2 g, 0.5 mol) and 400 mL of isopropyl acetate were added to the reaction bottle, the temperature was lowered to 5°C, 1 M hydrochloric acid solution (45.6 g, 1.25 mol) was added dropwise, the temperature was raised to 30°C, and the mixture was stirred for 0.5 h. When the reaction was completed, the mixture was washed with sodium carbonate solution and water, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound A, 75.6 g, with a yield of 92% and a purity of 98.4%.
[0066] Example 3
[0067] A method for preparing 4-(2-butyl)aminoaniline (compound A), specifically comprising the following steps:
[0068]
[0069] S1. Synthesis of Compound 1
[0070] Into the reaction bottle, add p-iodoaniline (109.5 g, 0.5 mol), 400 ml 1,4-dioxane, cool to 5 ° C, add DMAP (91.6 g, 0.75 mol), add Boc2-methanol solution (174.6 g, 0.8 mol) dropwise, react at 25 ° C for 2 h, remove the solvent, add 500 mL ethyl acetate, stir and dissolve, wash with water, remove part of the solvent, cool to 0 ° C, crystallize, filter, and obtain compound 1, 158 g, yield 99%, purity 99.0%;
[0071] S2. Synthesis of Compound 2
[0072] Under nitrogen protection, 600 mL of NMP, compound 1 (159.6 g, 0.5 mol), 2-butylamine (73.1 g, 1.0 mol), cesium carbonate (260.7 g, 0.8 mol), and copper iodide (38.3 g, 0.2 mol) were added to the reaction bottle, stirred evenly, and 2-acetylcyclohexanone (21 g, 0.15 mol) was added. The mixture was reacted at 130 ° C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, water was added, and 500 mL*2 of isopropyl acetate was used for extraction. The organic layers were combined, and the organic layers were adjusted to pH = 8 using citric acid. The organic layers were concentrated to dryness to obtain compound 2, 119 g, with a yield of 90% and a purity of 99.4%;
[0073] S3. Synthesis of Compound A
[0074] Under nitrogen protection, compound 2 (132.2 g, 0.5 mol) and 300 mL of dichloromethane were added to the reaction bottle, the temperature was lowered to -5°C, 1 M hydrochloric acid solution (36.5 g, 1.0 mol) was added dropwise, the temperature was raised to 30°C, and the mixture was stirred for 0.5 h. When the reaction was completed, the mixture was washed with sodium bicarbonate solution and water, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound A, 75.9 g, with a yield of 92.4% and a purity of 98.6%.
[0075] Comparative Example 1
[0076] The difference between this comparative example and Example 1 is that triethylamine is not added to S1, and Boc2-methanol solution (181.6 g) is added dropwise. The other conditions are the same as Example 1, and compound A (68.2 g) is obtained with a yield of 83% and a purity of 92.7%.
[0077] In summary, compared with the prior art, the present invention has the following beneficial effects:
[0078] The invention provides a method for preparing 4-(2-butyl)aminoaniline (compound A). The method has readily available raw materials, is environmentally friendly, has a novel route, does not use precious metals, and under the action of an acid binding agent, the prepared 4-(2-butyl)aminoaniline has good purity and high yield, and is suitable for industrial production.
[0079] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.
[0080] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
[0081] The present invention illustrates the detailed process flow of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed process flow, that is, it does not mean that the present invention must rely on the above-mentioned detailed process flow to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.
Claims
1. A method for preparing 4-(2-butyl)aminoaniline, characterized in that: Using p-haloaniline as the raw material, 4-(2-butyl)aminoaniline is obtained through amine protection, coupling, and deprotection. The synthetic route is: X is one of chlorine, bromine and iodine.
2. The preparation method according to claim 1, characterized in that The following steps are involved: S1, take p-haloaniline and solvent and stir evenly, add acid binding agent, add di-tert-butyl dicarbonate solution dropwise at temperature T1, react at temperature T2, after the reaction is complete, add ethyl acetate, wash with water, concentrate, cool, crystallize, filter, and dry to obtain compound 1; S2, nitrogen protection, take the solvent, compound 1, 2-butylamine, alkali, salt, and catalyst, stir evenly, react at temperature T3, after the reaction is complete, cool to room temperature, extract, adjust pH, wash with water, and concentrate the organic layer to dryness to obtain compound 2; S3, under nitrogen protection, take compound 2 and the solvent, stir evenly, cool to T4, add 1M hydrochloric acid solution dropwise, control the temperature to T5 for reaction, after the reaction is complete, wash with sodium bicarbonate solution, wash with water, combine the organic layers, dry, and concentrate to dryness to obtain 4-(2-butyl)aminoaniline.
3. The preparation method according to claim 2, characterized in that: S1 satisfies at least one of the following conditions: The p-haloaniline is selected from p-chloroaniline, p-bromoaniline and p-iodoaniline, preferably p-bromoaniline; The acid binding agent is selected from one of triethylamine, sodium bis(trimethylsilyl)amide and 4-dimethylaminopyridine, preferably triethylamine; The solvent is selected from one of methanol, tetrahydrofuran and 1,4-dioxane, preferably methanol.
4. The preparation method according to claim 2, characterized in that: S1 satisfies at least one of the following conditions: T1 temperature is -10 to 20°C, preferably -5 to 5°C; T2 temperature is 10-60°C, preferably 20-40°C; The mass ratio of the p-haloaniline to the acid binding agent is 1:1-4, preferably 1:1-2; The mass ratio of p-haloaniline to di-tert-butyl dicarbonate is 1:1-3, preferably 1:1.2-2.
5. The preparation method according to claim 2, characterized in that: S2 satisfies at least one of the following conditions: The base is selected from potassium carbonate, sodium carbonate and cesium carbonate, preferably potassium carbonate; The mass ratio of compound 1 to the alkali is 1:1-8, preferably 1:2-4.
6. The preparation method according to claim 2, characterized in that: S2 satisfies at least one of the following conditions: The salt is selected from cuprous bromide, cuprous chloride, and cupric iodide, preferably cuprous bromide; The mass ratio of compound 1 to the salt is 1:0.1-1, preferably 1:0.2-0.
5.
7. The preparation method according to claim 2, characterized in that: S2 satisfies at least one of the following conditions: The catalyst is selected from 2-isobutylcyclohexanone, 2-isopropylcyclohexanone, and 2-acetylcyclohexanone; The mass ratio of compound 1 to catalyst is 1:0.1-1, preferably 1:0.2-0.
4.
8. The preparation method according to claim 2, characterized in that: S2 satisfies at least one of the following conditions: T3 temperature is 100-160°C, preferably 120-140°C; The mass ratio of compound 1 to 2-butylamine is 1:1-5, preferably 1:1.5-2.5; The solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably DMF.
9. The preparation method according to claim 2, characterized in that: S3 satisfies at least one of the following conditions: The solvent is selected from one of ethyl acetate, isopropyl acetate and dichloromethane, preferably ethyl acetate; T4 temperature is -10 to 20°C, preferably -5 to 5°C; The mass ratio of compound 2 to 1M hydrochloric acid is 1:1-5, preferably 1:1.6-2.5; The T5 temperature is 0 to 80°C, preferably 20 to 30°C.
10. 4-(2-butyl)aminoaniline obtained by the preparation method according to any one of claims 1 to 9, characterized in that: Its structural formula is as follows: