Preparation method of N-BOC-aniline derivative

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of an N-BOC-aniline derivative, which takes an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as a reaction reagent, 4-dimethylaminopyridine as a catalyst and tetrahydrofuran solvent as a solvent to carry out amino acylation reaction to obtain the N-BOC-aniline derivative. In the amino acylation reaction process, the temperature is controlled to be 20-30 DEG C, the rotating speed is controlled to be 400-500 r / min, the obtained reaction liquid is purified to finally obtain the N-BOC-aniline derivative, the aniline derivative is 2-bromine-5-chloroaniline, 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyl aniline, 3-carboxyl aniline or 4-bromine-6-carboxyl aniline, and the N-BOC-aniline derivative is 2-bromine-5-chloroaniline, 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyl aniline, 3-carboxyl aniline or 4-bromine-6-carboxyl aniline. The preparation method has the characteristics of simple preparation process, low preparation cost and high yield and purity of the final N-BOC-aniline derivative, the final yield can reach 84-93%, and the purity can reach 98.98-100%.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and more specifically, to a method for preparing an N-BOC-aniline derivative. Background Art

[0002] The market demand for aniline and aniline derivatives mainly comes from dyes, medicines, pesticides and polyurethane industries. With the continuous development of these industries, the demand for aniline and aniline derivatives is also growing steadily. Especially in Asia, due to the rapid development of textile, construction and automobile industries, the market demand for aniline and aniline derivatives has grown significantly.

[0003] At present, the Boc synthesis method based on the amino group on aniline or aniline derivatives has a complicated reaction process and the purity of the final product is low. As disclosed in the synthesis example of KR102107018.2020.B1, 2-bromo-5-chloroaniline is reacted with saturated sodium bicarbonate aqueous solution and 1,4-dioxane and dibutyl dicarbonate, and then purified and separated to obtain (2-bromo-5-chlorophenyl)carbamic acid tert-butyl ester, and the yield after purification is 84.9%. Summary of the invention

[0004] The purpose of the present application is to solve the technical problems of the above-mentioned N-BOC-aniline derivatives, such as the complicated preparation process and the low purity of the final product, and to provide a preparation method of N-BOC-aniline derivatives, which has the characteristics of simple preparation process, high product yield and high purity, and at the same time, the preparation method has the advantages of low preparation cost and safe and reliable preparation process.

[0005] The technical solution of this application In the first aspect, the present application provides a method for preparing N-BOC-aniline derivatives, using the following technical scheme A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as a reaction reagent, and 4-dimethylaminopyridine as a catalyst to carry out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative of the aniline derivative; The aniline derivative is 2-bromo-5-chloroaniline, 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyaniline, 3-carboxyaniline or 4-bromo-6-carboxyaniline; The N-BOC-aniline derivatives corresponding to the above-mentioned aniline derivatives of 2-bromo-5-chloroaniline, 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyaniline, 3-carboxyaniline and 4-bromo-6-carboxyaniline are tert-butyl (2-bromo-5-chlorophenyl)carbamate, N-BOC-4-hydroxyaniline, N-BOC-3-hydroxyaniline, N-BOC-4-aminobenzoic acid, N-BOC-3-aminobenzoic acid and N-BOC-5-bromoanthranilic acid, respectively.

[0006] The above technical scheme is adopted, with aniline derivatives and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as reaction reagent (the role of the sodium hydride is to make the amino group on the aniline derivative easily form amino anions, so that the aniline derivative is more easily aminoamidated), and 4-dimethylaminopyridine as catalyst, and an aminoacylation reaction is carried out in tetrahydrofuran solvent to prepare N-BOC-aniline derivatives, that is, for the first time, the N-BOC-aniline derivative compound is safely and efficiently synthesized using sodium hydride.

[0007] Preferably, in the preparation method of the above-mentioned N-BOC-aniline derivative, when the aniline derivative used in the preparation process is 2-bromo-5-chloroaniline, the amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the preparation process, calculated by molar ratio, are aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine in the ratio of 1:1.2:1.5:0.1.

[0008] By adopting the above technical scheme, the N-BOC-aniline derivative (tert-butyl (2-bromo-5-chlorophenyl) carbamate) was successfully prepared with the aniline derivative 2-bromo-5-chlorobenzene in a molar ratio of 1:1.2:1.5:0.1 for aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine.

[0009] Preferably, in the above-mentioned method for preparing an N-BOC-aniline derivative, when the aniline derivative used in the preparation process is 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyaniline, 3-carboxyaniline or 4-bromo-6-carboxyaniline, the amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the preparation process are calculated in molar ratios of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine in the ratio of 1:1.2:2.5:0.1.

[0010] The above technical scheme is adopted, and aniline derivatives 2-bromo-5-chloroaniline, 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyaniline, 3-carboxyaniline or 4-bromo-6-carboxyaniline and di-tert-butyl dicarbonate are used as reaction substrates. When the molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine is 1:1.2:2.5:0.1, N-BOC-4-hydroxyaniline, N-BOC-3-hydroxyaniline, N-BOC-4-aminobenzoic acid, N-BOC-3-aminobenzoic acid and N-BOC-5-bromo-o-aminobenzoic acid are successfully prepared.

[0011] Preferably, the aminoacylation reaction process is controlled at a temperature of 20-30°C and a rotation speed of 400-500 r / min; Preferably, in the above-mentioned method for preparing an N-BOC-aniline derivative, the order of adding the aniline derivative, di-tert-butyl dicarbonate, sodium hydride, 4-dimethylaminopyridine and tetrahydrofuran solvent during the preparation process is: First, tetrahydrofuran solvent and aniline derivative are added to the reactor, and sodium hydride is added at a stirring speed of 400-500 r / min and a temperature of 0-5° C. After the addition of sodium hydride, the temperature is controlled at 20-30° C. and the speed is 400-500 r / min and stirring is continued for 25-35 minutes; Then, the temperature is controlled at 0-5° C., and 4-dimethylaminopyridine and di-tert-butyl dicarbonate are added dropwise in sequence. After the addition of 4-dimethylaminopyridine and di-tert-butyl dicarbonate, the temperature is controlled at 20-30° C. and the rotation speed is 400-500 r / min to carry out aminoacylation reaction. The aniline derivative is used as a reference. During the aminoacylation reaction, TLC monitors the complete reaction of the aniline derivative to obtain a reaction solution. The dropping rate of the above-mentioned 4-dimethylaminopyridine is controlled at 1-3 g / min, and the dropping rate of di-tert-butyl dicarbonate is controlled at 5-10 mL / min.

[0012] By adopting the above technical scheme, the yield and purity of the final N-BOC-aniline derivative are synergistically enhanced by controlling the addition order of reactants and catalysts, the dripping rate of 4-dimethylaminopyridine and di-tert-butyl dicarbonate, and the control parameters of the process.

[0013] Preferably, in the above-mentioned method for preparing an N-BOC-aniline derivative, the process of extracting the reaction solution obtained after the aminoacylation reaction with ethyl acetate is as follows: That is, under the condition of a rotation speed of 400-500r / min and a temperature of the reaction liquid of 5-10°C, water of 5 times the volume of the reaction liquid and ethyl acetate of 5 times the volume of the reaction liquid are added to the reaction liquid in sequence, the dropping rate of water is 3-5mL / min, and the dropping rate of ethyl acetate is 20-30mL / min. After the dropwise addition, the mixture is allowed to stand for stratification, and the obtained aqueous phase is extracted 2-3 times with 5 times the volume of ethyl acetate, and the obtained organic phases are combined to serve as the first organic phase; Then, 5 times the volume of saturated salt water was added to the first organic phase, stirred and mixed, and allowed to stand for stratification, and the obtained organic phase was used as the second organic phase; Then, the second organic phase is absorbed with anhydrous sodium sulfate and filtered using a filter medium with a pore size of 20-25 μm. The obtained filtrate is spin-dried at a controlled speed of 30-40 r / min and a temperature of 45° C. to obtain an N-BOC-aniline derivative.

[0014] By adopting the above technical scheme and through specific purification conditions, the yield and purity of the final N-BOC-aniline derivative are further guaranteed to be high, with a yield of 84-93% and a purity of 98.98-100%.

[0015] In order to better reflect the innovation of the present application, the inventors of the present application have conducted some experiments in the process of realizing the present application, but encountered some problems in the process and were unable to achieve the preparation of high-yield and high-purity N-BOC-aniline derivatives, as follows: 1. According to the synthesis example of paragraph 0458-0464 of KR1021070180000B1, an experiment was conducted to prepare N-BOC-aniline derivatives. Most of the raw material 2-bromo-5-chloroaniline used in the reaction did not react, and the yield of the target product of the N-BOC-aniline derivative finally obtained was only 20-30%; 2. Using 2-bromo-5-chloroaniline and di-tert-butyl dicarbonate as raw materials, methanol as solvent, and stirring overnight at room temperature (internal temperature of about 20° C.) to react and prepare N-BOC-aniline derivatives, but the raw material 2-bromo-5-chloroaniline is not consumed in the preparation process; 3. Using 2-bromo-5-chloroaniline and di-tert-butyl dicarbonate as raw materials, 4-dimethylaminopyridine as catalyst, and tetrahydrofuran as solvent, and stirring overnight at room temperature (internal temperature of about 20° C.) to react and prepare N-BOC-aniline derivatives, but the raw material 2-bromo-5-chloroaniline is not consumed in the preparation process, and more by-products are generated, resulting in a low yield of the final target product; 4. Using 2-bromo-5-chloroaniline and di-tert-butyl dicarbonate as raw materials and dioxane as solvent, stirring overnight at a temperature of 20°C ± 1°C to react and prepare N-BOC-aniline derivatives. However, the yield of the final target product is low due to the incomplete reaction of the raw material 2-bromo-5-chloroaniline during the preparation process.

[0016] The above-mentioned methods for preparing N-BOC-aniline derivatives all have technical problems such as incomplete reaction of raw materials and low reaction yield, and the yield of the final target product is less than 60%, and the results are not as ideal as the technical solution of the present application.

[0017] Beneficial technical effects of this application The present invention discloses a method for preparing N-BOC-aniline derivatives, which uses aniline derivatives and di-tert-butyl dicarbonate as reaction substrates, sodium hydride and 4-dimethylaminopyridine as catalysts, and is the first method to successfully prepare N-BOC-aniline derivatives in a safe and feasible manner in tetrahydrofuran solvent.

[0018] Furthermore, in the preparation method of an N-BOC-aniline derivative of the present application, the use of sodium hydride during the preparation process can allow all aniline derivatives to form amine anions, making the aminoacylation reaction easier to proceed. At the same time, by controlling the addition order of reactants and catalysts, the dripping rate of 4-dimethylaminopyridine and di-tert-butyl dicarbonate, and the control parameters of the process, the yield of the final N-BOC-aniline derivative product is increased.

[0019] Furthermore, in the method for preparing an N-BOC-aniline derivative of the present application, the sodium hydride used in the preparation process is widely available, thereby relatively reducing the preparation cost of the N-BOC-aniline derivative.

[0020] Furthermore, in the preparation method of an N-BOC-aniline derivative of the present application, specific purification conditions are used after the aminoacylation reaction in the preparation process to further ensure the yield and purity of the final N-BOC-aniline derivative. The final yield of the N-BOC-aniline derivative product reaches 84-93%, and the purity reaches 98.99-100%. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 , HNMR diagram of the white solid product (CAS: 384793-17-3) obtained in Example 1; Figure 2a , Page 1 in the LCMS data spectrum of the white solid product (CAS: 384793-17-3) obtained in Example 1 ； Figure 2b , Page 2 in the LCMS data spectrum of the white solid product (CAS: 384793-17-3) obtained in Example 1 ； Figure 2c , Page 3 in the LCMS data spectrum of the white solid product (CAS: 384793-17-3) obtained in Example 1; Figure 3 , HNMR chart of the white solid product (CAS: 54840-15-2) obtained in Example 2; Figure 4a , Page 1 in the GCMS data spectrum of the white solid product (CAS: 54840-15-2) obtained in Example 2; Figure 4b , Page 2 in the GCMS data spectrum of the white solid product (CAS: 54840-15-2) obtained in Example 2; Figure 5 , HNMR chart of the white solid product (CAS: 19962-06-2) obtained in Example 3; Figure 6a , Page 1 in the LCMS data spectrum of the white solid product (CAS: 19962-06-2) obtained in Example 3; Figure 6b , Page 2 in the LCMS data spectrum of the white solid product (CAS: 19962-06-2) obtained in Example 3; Figure 7 , HNMR chart of the white solid product (CAS: 66493-39-8) obtained in Example 4; Figure 8a , Page 1 in the LCMS data spectrum of the white solid product (CAS: 66493-39-8) obtained in Example 4; Figure 8b , Page 2 in the LCMS data spectrum of the white solid product (CAS: 66493-39-8) obtained in Example 4; Fig. 9 , HNMR chart of the white solid product (CAS: 111331-82-9) obtained in Example 5; Fig.10a , Page 1 in the LCMS data spectrum of the white solid product (CAS: 111331-82-9) obtained in Example 5; Fig.10b , Page 2 in the LCMS data spectrum of the white solid product (CAS: 111331-82-9) obtained in Example 5; Fig.10c , Page 3 in the LCMS data spectrum of the white solid product (CAS: 111331-82-9) obtained in Example 5; Fig.10d , Page 4 in the LCMS data spectrum of the white solid product (CAS: 111331-82-9) obtained in Example 5; Fig.11, HNMR chart of the white solid product (CAS: 306937-20-2) obtained in Example 6; Fig.12a , Page 1 in the LCMS data spectrum of the white solid product (CAS: 306937-20-2) obtained in Example 6; Figure 12b , Page 2 in the LCMS data spectrum of the white solid product (CAS: 306937-20-2) obtained in Example 6. DETAILED DESCRIPTION

[0022] The technical solution of the present application is described in detail below through specific embodiments and in combination with the accompanying drawings, but the present application is not limited thereto.

[0023] The raw materials used in the examples of this application are all commercially available.

[0024] The instrument BRUKER used for hydrogen spectrum determination of N-BOC-aniline derivatives obtained in each example of the present application is AVANCE NEO 400M, produced by Bruker (Beijing) Technology Co., Ltd. The GCMS data spectra of the N-BOC-aniline derivatives obtained in each example were measured using the following instrument: gas chromatography-mass spectrometry, model 8890-5977B, produced by Agilent Technologies, Inc.; The LCMS data spectra of the N-BOC-aniline derivatives obtained in each example were measured using a liquid chromatography-mass spectrometer, model 1260-G6125C, produced by Agilent Technologies; The purity of the N-BOC-aniline derivative product finally obtained in each embodiment is determined by using the above-mentioned model 8890-5977B, Agilent Technologies, Inc. gas chromatography-mass spectrometer or model 1260-G6125C, Agilent Technologies, Inc. liquid chromatography-mass spectrometer to obtain the GCMS data spectrum or LCMS data spectrum; The calculation formula of the yield of the N-BOC-aniline derivative product obtained in each example = (actual mass × product purity) / theoretical mass × 100%; The above actual mass is the mass of the N-BOC-aniline derivative product in the white solid substance finally obtained after purification in each embodiment of the present application; The above theoretical mass is the mass of the N-BOC-aniline derivative product that should be obtained by 100% amination reaction of the aniline derivative used in each example of the present application.

[0025] Example 1 A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as a reaction reagent, and 4-dimethylaminopyridine as a catalyst, and carries out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative corresponding to the aniline derivative, wherein the aniline derivative is 2-bromo-5-chloroaniline; The reaction equation for the preparation process of the above-mentioned N-BOC-aniline derivative is as follows: The amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the above preparation are calculated in a molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine of 1:1.2:1.5:0.1.

[0026] The preparation method of the above-mentioned N-BOC-aniline derivative comprises the following specific steps: Tetrahydrofuran (2000 mL) and aniline derivative (200 g, 968.678 mmol) were added to the reaction vessel in sequence, and then sodium hydride (34.87 g, 1453.017 mmol) was added to the reaction vessel under the conditions of controlling the stirring speed at 450 r / min and the temperature at 5°C. After the addition of sodium hydride, the temperature was controlled at 25°C and the speed was 450 r / min, and stirring was continued for 30 min; Then the temperature was controlled at 5°C and the speed was 450r / min, 4-dimethylaminopyridine (11.83g, 96.868mmol) and di-tert-butyl dicarbonate (253.70g, 1162.413mmol) were added dropwise to the reaction container at the dropping rates of 2g / min and 8mL / min respectively. After the addition of 4-dimethylaminopyridine and di-tert-butyl dicarbonate was completed, the temperature was controlled at 25°C and the speed was 450r / min to react for 4.5h. During the reaction, TLC detected that the raw material 2-bromo-5-chlorobenzeneamine was completely reacted to obtain a reaction solution; Then, the temperature of the reaction solution was controlled to be 10° C., and water 5 times the volume of the reaction solution and ethyl acetate 5 times the volume of the reaction solution were sequentially added dropwise to the reaction solution. After stirring and mixing, the mixture was allowed to stand for separation. The obtained aqueous phase was extracted twice with 5 times the volume of ethyl acetate, and the obtained organic phases were combined to serve as the first organic phase. Then, 5 times the volume of saturated salt water was added to the first organic phase, stirred and mixed, and allowed to stand for stratification, and the aqueous phase was removed to obtain an organic phase as the second organic phase; Then, the second organic phase was dried with anhydrous sodium sulfate and filtered through a filter medium with a pore size of 20-25 μm (the filter paper with a pore size of 20-25 μm was used in Example 1 of the present application), and the filtrate was spin-dried at a controlled temperature of 45°C and a rotation speed of 35 r / min, and then purified by silica gel column chromatography to obtain a white solid substance.

[0027] The hydrogen spectrum of the white solid substance obtained above was detected, and the obtained nuclear magnetic hydrogen spectrum, i.e., HNMR spectrum, was as follows: Figure 1 As shown, the H NMR spectrum data are as follows: 1H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.40 (d, J = 8.5Hz, 1H), 7.01 (s, 1H), 6.88 (d, J = 8.5Hz, 1H), 1.53 (d, J = 0.9Hz, 9H). The liquid chromatography-mass spectrometry of the white solid substance obtained above was detected, and Pages 1-3 of the obtained liquid chromatography-mass spectrometry were as follows: Figure 2a , 2b , 2c, from Figure 2a , 2b , 2c shows MS m / z: 249.9 / 251.9 [M-56] + m / z:327.9 / 330.0[M+23] + , its purity is 99.35%; Based on the above-mentioned white solid substance's nuclear magnetic hydrogen spectrum and liquid chromatography-mass spectrometry Figure 2a , 2b , 2c show that the final white solid substance has the structural formula That is tert-butyl (2-bromo-5-chlorophenyl)carbamate, the product with CAS number 384793-17-3.

[0028] The yield of the white solid substance (2-bromo-5-chlorophenyl)carbamic acid tert-butyl ester obtained above was 84%.

[0029] Example 2 A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as a reaction reagent, and 4-dimethylaminopyridine as a catalyst to carry out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative corresponding to the aniline derivative, wherein the aniline derivative is 4-hydroxyaniline; The preparation method of the above-mentioned N-BOC-aniline derivative has the following reaction equation for the preparation process: The amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the above preparation are calculated in a molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine of 1:1.2:2.5:0.1.

[0030] The above-mentioned method for preparing an N-BOC-aniline derivative is different from the above-mentioned method in that 2-bromo-5-chlorobenzeneamine in Example 1 is replaced by 4-hydroxyaniline, the amount of sodium hydride is changed to 58.08 g (2421.695 mmol), and the other raw materials and amounts are the same as those in the specific steps of Example 1, and a white solid substance is finally obtained.

[0031] The hydrogen spectrum of the white solid substance obtained above was detected, and the obtained nuclear magnetic hydrogen spectrum, i.e., HNMR spectrum, was as follows: Figure 3 As shown, the H NMR spectrum data are as follows: 1H NMR (400MHz, CDCl3) δ: 7.17 (d, J = 8.8Hz, 2H), 6.74 (d, J = 8.8Hz, 2H), 6.36 (s, 1H), 1.50 (s, 9H). The gas chromatography-mass spectrometry of the white solid substance obtained above was detected, and Pages 1-2 of the obtained gas chromatography-mass spectrometry were as follows: Figure 4a , 4b As shown, from Figure 4a , 4b It can be seen that MS m / z:109[M-100] + m / z:153[M-56] + , its purity is 99.89%; Based on the above-mentioned white solid substance, the nuclear magnetic hydrogen spectrum Figure 3 Gas chromatography-mass spectrometry Figure 4a , 4b , indicating that the structural formula of the white solid substance finally obtained is That is N-BOC-4-hydroxyaniline, the product with CAS number 54840-15-2.

[0032] The yield of the white solid N-BOC-4-hydroxyaniline obtained above was 91%.

[0033] Example 3 A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as a reaction reagent, and 4-dimethylaminopyridine as a catalyst to carry out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative corresponding to the aniline derivative, wherein the aniline derivative is 3-hydroxyaniline; The reaction equation for the preparation process of the above-mentioned N-BOC-aniline derivative is as follows: The amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the above preparation are calculated in a molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine of 1:1.2:2.5:0.1.

[0034] The above-mentioned method for preparing an N-BOC-aniline derivative is different from the above-mentioned method in that 2-bromo-5-chlorobenzeneamine in Example 1 is replaced by 3-hydroxyaniline, the amount of sodium hydride is changed to 58.08 g (2421.695 mmol), and the other raw materials and amounts are the same as those in the specific steps of Example 1, and a white solid substance is finally obtained.

[0035] The hydrogen spectrum of the white solid substance obtained above was detected, and the obtained nuclear magnetic hydrogen spectrum, i.e., HNMR spectrum, was as follows: Figure 5 As shown, the H NMR spectrum data are as follows: 1H-NMR (400MHz, CDCl3) δ7.12(m,2H),6.99(m,1H),6.53(m,1H),6.45(m,1H)1.53(s,9H). The liquid chromatography-mass spectrometry of the white solid substance obtained above was detected, and Page 1-2 of the obtained liquid chromatography-mass spectrometry were as follows: Figure 6a , 6b As shown, from Figure 6a , 6b It can be seen that MS m / z:154[M-56+1] + m / z:208[M-1] - , its purity is 98.98%; Based on the above-mentioned white solid substance, the nuclear magnetic hydrogen spectrum Figure 5 HPLC-MS Figure 6a , 6b It can be concluded that the structural formula of the white solid substance finally obtained is That is N-BOC-3-hydroxyaniline, the product with CAS number 19962-06-2.

[0036] The yield of the white solid N-BOC-3-hydroxyaniline obtained above was 89%.

[0037] Example 4 A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as reaction reagents, and 4-dimethylaminopyridine as a catalyst, and carries out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative corresponding to the aniline derivative, wherein the aniline derivative is 4-carboxyaniline; The reaction equation for the preparation process of the above-mentioned N-BOC-aniline derivative is as follows: The amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the above preparation are calculated in a molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine of 1:1.2:2.5:0.1.

[0038] The above-mentioned method for preparing an N-BOC-aniline derivative is different from the above-mentioned method in that 2-bromo-5-chlorobenzeneamine in Example 1 is replaced by 4-carboxyaniline, the amount of sodium hydride is changed to 58.08 g (2421.695 mmol), and the other raw materials and amounts are the same as those in the specific steps of Example 1, and a white solid substance is finally obtained.

[0039] The hydrogen spectrum of the white solid substance obtained above was detected, and the obtained nuclear magnetic hydrogen spectrum, i.e., HNMR spectrum, was as follows: Figure 7 As shown, the H NMR spectrum data are as follows: 1H NMR (DMSO-d6, 400MHz): 12.62 (s, 1H), 9.73 (s, 1H), 7.82 (d, 2H, J = 8.4Hz), 7.55 (d, 2H, J = 8.8Hz), 1.50 (s, 9H). The liquid chromatography-mass spectrometry of the white solid substance obtained above was detected, and Page 1-2 of the obtained liquid chromatography-mass spectrometry were as follows: Figure 8a , 8b As shown, from Figure 8a , 8b It can be seen that MS m / z:182[M-56+1] + m / z:236[M-1] - , its purity is 100%; Based on the above-mentioned white solid substance, the nuclear magnetic hydrogen spectrum Figure 7 HPLC-MS Figure 8a , 8b It can be concluded that the structural formula of the white solid substance obtained in Example 4 is That is N-BOC-4-aminobenzoic acid, the product with CAS number 66493-39-8.

[0040] The yield of the white solid N-BOC-4-aminobenzoic acid obtained above was 93%.

[0041] Example 5 A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as reaction reagents, and 4-dimethylaminopyridine as a catalyst, and carries out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative corresponding to the aniline derivative, wherein the aniline derivative is 3-carboxyaniline; The reaction equation for the preparation process of the above-mentioned N-BOC-aniline derivative is as follows: The amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the above preparation are calculated in a molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine of 1:1.2:2.5:0.1.

[0042] The above-mentioned method for preparing an N-BOC-aniline derivative is different from the above-mentioned method in that 2-bromo-5-chlorobenzeneamine in Example 1 is replaced by 3-carboxyaniline, the amount of sodium hydride is changed to 58.08 g (2421.695 mmol), and the other raw materials and amounts are the same as those in the specific steps of Example 1, and a white solid substance is finally obtained.

[0043] The hydrogen spectrum of the white solid substance obtained above was detected, and the obtained nuclear magnetic hydrogen spectrum, i.e., HNMR spectrum, was as follows: Fig. 9 As shown, the H NMR spectrum data are as follows: 1H NMR(400MHz,DMSO-d6)δ12.90(brs,1H),9.55(s,1H), 8.13(s,1H),7.61(dd,1H,J=0.8Hz,J=8Hz),7.54-7.52(m, 1H),7.32(t,1H,J=7.6Hz),1.46(s,9H) The liquid chromatography-mass spectrometry of the white solid substance obtained above was detected, and Page 1-2 of the obtained liquid chromatography-mass spectrometry were as follows: Fig.10a , 10b , 10c, 10d, from Fig.10a , 10b10c, 10d, it can be seen that MS m / z: 182 [M-56+1] + m / z:236[M-1] - , its purity is 99.59%; Based on the above-mentioned white solid substance, the nuclear magnetic hydrogen spectrum Fig. 9 HPLC-MS Fig.10a , 10b , 10c, 10d, it can be concluded that the structural formula of the white solid substance obtained in Example 5 is N-BOC-3-aminobenzoic acid, product with CAS number 111331-82-9.

[0044] The yield of the white solid N-BOC-3-aminobenzoic acid obtained above was 92%.

[0045] Example 6 A method for preparing an N-BOC-aniline derivative, which uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as reaction reagents, and 4-dimethylaminopyridine as a catalyst, and carries out an aminoacylation reaction in a tetrahydrofuran solvent to obtain an N-BOC-aniline derivative corresponding to the aniline derivative, wherein the aniline derivative is 4-bromo-6-carboxyaniline; The reaction equation for the preparation process of the above-mentioned N-BOC-aniline derivative is as follows: The amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the above preparation are calculated in a molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine of 1:1.2:2.5:0.1.

[0046] The above-mentioned method for preparing an N-BOC-aniline derivative is different from the above-mentioned method in that 2-bromo-5-chlorobenzeneamine in Example 1 is replaced by 4-bromo-6-carboxyaniline, the amount of sodium hydride is changed to 58.08 g (2421.695 mmol), and the other raw materials and amounts are the same as those in the specific steps of Example 1, and a white solid substance is finally obtained.

[0047] The hydrogen spectrum of the white solid substance obtained above was detected, and the obtained nuclear magnetic hydrogen spectrum, i.e., HNMR spectrum, was as follows: Fig.11 As shown, the H NMR spectrum data are as follows: 1H-NMR (400MHz, CDCl3) δ7.12(m,2H),6.99(m,1H),6.53(m,1H),6.45(m,1H)1.53(s,9H). The liquid chromatography-mass spectrometry of the white solid substance obtained above was detected, and Page 1-2 of the obtained liquid chromatography-mass spectrometry were as follows: Fig.12a , 12b As shown, from Fig.12a , 12b It can be seen that MS m / z:316[M-1] - , its purity is 100%; Based on the above-mentioned white solid substance, the nuclear magnetic hydrogen spectrum Fig.11 HPLC-MS Fig.12a , 12b It can be concluded that the structural formula of the white solid substance obtained in Example 6 is N-BOC-5-bromo-anthranilic acid, CAS No. 306937-20-2 The yield of the white solid N-BOC-5-bromo-anthranilic acid obtained above was 92%.

[0048] Example 7 A method for preparing N-BOC-aniline derivative (2-bromo-5-chlorophenyl) carbamic acid tert-butyl ester, wherein the amount of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride, 4-dimethylaminopyridine as a catalyst and tetrahydrofuran solvent used in the preparation is the same as that in Example 1, except that the preparation process is different as follows, and the other preparation processes are the same as those in Example 1: Tetrahydrofuran and aniline derivatives are sequentially added to a reaction container, and then sodium hydride is added to the reaction container under the conditions of controlling the stirring speed to 400 r / min and the temperature to 5°C. After the sodium hydride is added, the temperature is controlled to be 20°C and stirring is continued for 35 minutes; then the speed is controlled to be 400 r / min and the temperature is 5°C, 4-dimethylaminopyridine and di-tert-butyl dicarbonate are sequentially added dropwise to the reaction container at a dropping rate of 1 g / min and 5 mL / min, and after the addition of 4-dimethylaminopyridine and di-tert-butyl dicarbonate is completed, the temperature is continued to be controlled to be 0°C and the speed is 400 r / min to react for 5 hours. During the reaction, TLC detects that the raw material 2-bromo-5-chlorobenzeneamine is also completely reacted to obtain a reaction solution; Then, the temperature of the reaction solution was controlled to be 8° C., and water 5 times the volume of the reaction solution and ethyl acetate 5 times the volume of the reaction solution were sequentially added dropwise to the reaction solution. After stirring and mixing, the mixture was allowed to stand for separation. The obtained aqueous phase was extracted twice with 5 times the volume of ethyl acetate, and the obtained organic phases were combined to serve as the first organic phase. Add 5 times the volume of saturated brine to the first organic phase, mix well and let stand for separation, remove the aqueous phase, and use the obtained organic phase as the second organic phase, which is dried with anhydrous sodium sulfate and filtered with a filter medium with a pore size of 20-25 μm. The obtained filtrate is spin-dried at a temperature of 45°C and a rotation speed of 30-40 r / min, and then purified by silica gel column chromatography to obtain a white solid substance.

[0049] The white solid obtained above was tested and found to have a purity of 98.99% and a yield of 90%.

[0050] Example 8 A method for preparing N-BOC-aniline derivative (2-bromo-5-chlorophenyl) carbamic acid tert-butyl ester, wherein the amount of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride, 4-dimethylaminopyridine as a catalyst and tetrahydrofuran solvent used in the preparation is the same as that in Example 1, except that the preparation process is different as follows, and the other preparation processes are the same as those in Example 1: Tetrahydrofuran and aniline derivatives were added to the reaction container in sequence, and then sodium hydride was added to the reaction container under the conditions of controlling the stirring speed to 500 r / min and the temperature to 2.5°C. After the addition of sodium hydride, the temperature was controlled to be 20°C and stirred for 25 minutes; Then, the speed was controlled to be 500 r / min and the temperature was 2.5° C., and 4-dimethylaminopyridine and di-tert-butyl dicarbonate were added dropwise to the reaction container at the dropping rates of 3 g / min and 10 mL / min, respectively. After the addition of 4-dimethylaminopyridine and di-tert-butyl dicarbonate, the temperature was continued to be controlled to be 25° C. and the speed was continued to be 500 r / min to react for 4.5 hours. During the reaction, TLC detected that the raw material 2-bromo-5-chlorobenzeneamine was completely reacted to obtain a reaction solution; Then, the temperature of the reaction solution was controlled to be 5° C., and water 5 times the volume of the reaction solution and ethyl acetate 5 times the volume of the reaction solution were sequentially added dropwise to the reaction solution. After stirring and mixing, the mixture was allowed to stand for separation. The obtained aqueous phase was extracted twice with 5 times the volume of ethyl acetate, and the obtained organic phases were combined to serve as the first organic phase. Add 5 times the volume of saturated brine to the first organic phase, mix well and let stand to separate the liquids, remove the aqueous phase, and use the obtained organic phase as the second organic phase, which is dried with anhydrous sodium sulfate and filtered with a filter medium with a pore size of 20-25 μm. The filtrate is spin-dried at a controlled temperature of 45°C and a rotation speed of 35 r / min, and then purified by silica gel column chromatography to obtain a white solid substance.

[0051] The white solid substance (2-bromo-5-chlorophenyl)carbamic acid tert-butyl ester obtained above was detected and its purity was 99.64% and the yield was 90%.

[0052] The by-products, product yields and purity results of the N-BOC-aniline derivatives prepared in the above-mentioned Example 1 and Examples 2-6 are listed in the following table: Example Yield (%) purity(%) Example 1 84 99.35 Example 2 91 99.89 Example 3 89 98.98 Example 4 93 100 Example 5 92 99.59 Example 6 92 100 Example 7 90 98.99 Example 8 90 99.64 As can be seen from the above table, the preparation method of an N-BOC-aniline derivative of the present application uses an aniline derivative and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as a reaction reagent, 4-dimethylaminopyridine as a catalyst, and an aminoacylation reaction in tetrahydrofuran solvent to obtain N-BOC-aniline derivatives corresponding to different aniline derivatives. The preparation process is safe and controllable, and the yield and purity of the final product N-BOC-aniline derivative are very high, with a yield of 84-93% and a purity of 98.98-100%.

[0053] The specific embodiments of the present application are merely explanations of the present application and are not limitations of the present application. After reading this specification, those skilled in the art may make modifications to the embodiments without any creative contribution as needed. However, as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A method for preparing an N-BOC-aniline derivative, characterized in that The preparation process uses aniline derivatives and di-tert-butyl dicarbonate as reaction substrates, sodium hydride as reaction reagent, 4-dimethylaminopyridine as catalyst, and carries out aminoacylation reaction in tetrahydrofuran solvent to obtain N-BOC-aniline derivatives of aniline derivatives; The aniline derivative is 2-bromo-5-chloroaniline, 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyaniline, 3-carboxyaniline or 4-bromo-6-carboxyaniline.

2. A method for preparing an N-BOC-aniline derivative as claimed in claim 1, characterized in that When the aniline derivative used in the preparation process is 2-bromo-5-chloroaniline, the amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the preparation process are calculated by molar ratio of aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine to be 1:1.2:1.5:0.

1.

3. A method for preparing an N-BOC-aniline derivative as claimed in claim 1, characterized in that When the aniline derivative used in the preparation process is 4-hydroxyaniline, 3-hydroxyaniline, 4-carboxyaniline, 3-carboxyaniline or 4-bromo-6-carboxyaniline, the amounts of the aniline derivative, di-tert-butyl dicarbonate, sodium hydride and 4-dimethylaminopyridine used in the preparation process are calculated in molar ratio as follows: aniline derivative: di-tert-butyl dicarbonate: sodium hydride: 4-dimethylaminopyridine: 1:1.2:2.5:0.

1.

4. A process for preparing an N-BOC-aniline derivative as claimed in claim 1, 2 or 3, characterized in that The aminoacylation reaction process is controlled at a temperature of 20-30°C and a rotation speed of 400-500 r / min.

5. A method for preparing an N-BOC-aniline derivative as claimed in claim 4, characterized in that The order of adding aniline derivative, di-tert-butyl dicarbonate, sodium hydride, 4-dimethylaminopyridine and tetrahydrofuran solvent in the preparation process is as follows: First, add aniline derivatives and tetrahydrofuran solvent into the reactor, control the stirring speed to 400-500 r / min, and add sodium hydride at a temperature of 0-5°C. After adding sodium hydride, control the temperature to 20-30°C and the speed to 400-500 r / min and continue stirring for 25-35 minutes; Then, the temperature is controlled at 0-5°C, and 4-dimethylaminopyridine and di-tert-butyl dicarbonate are added dropwise in sequence. After the addition of 4-dimethylaminopyridine and di-tert-butyl dicarbonate, the temperature is controlled at 20-30°C and the rotation speed is 400-500 r / min, and the stirring is continued to carry out aminoacylation reaction. The aniline derivative is used as a reference. During the aminoacylation reaction, TLC is monitored to monitor the complete reaction of the aniline derivative, and a reaction solution is obtained; The dropping rate of the above-mentioned 4-dimethylaminopyridine is controlled at 1-3 g / min, and the dropping rate of di-tert-butyl dicarbonate is controlled at 5-10 mL / min.

6. The method for preparing an N-BOC-aniline derivative according to claim 5, characterized in that The dosage of the tetrahydrofuran solvent is 1 mol: 1.5-2.5 L based on the ratio of aniline derivative to tetrahydrofuran solvent.

7. The method for preparing an N-BOC-aniline derivative according to claim 6, characterized in that After the aminoacylation reaction, the obtained reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, filtered, and spin-dried to obtain the corresponding N-BOC-aniline derivative.

8. A method for preparing an N-BOC-aniline derivative as claimed in claim 7, characterized in that: The process of extracting the reaction solution with ethyl acetate is as follows: That is, under the condition of a rotation speed of 400-500r / min and a temperature of the reaction liquid of 5-10°C, water of 5 times the volume of the reaction liquid and ethyl acetate of 5 times the volume of the reaction liquid are added to the reaction liquid in sequence, the dropping rate of water is 3-5mL / min, and the dropping rate of ethyl acetate is 20-30mL / min. After the dropwise addition, the mixture is allowed to stand for stratification, and the obtained aqueous phase is extracted 2-3 times with 5 times the volume of ethyl acetate, and the organic phases are combined as the first organic phase; Then, 5 times the volume of saturated salt water was added to the first organic phase, stirred and mixed, and allowed to stand for stratification, and the obtained organic phase was used as the second organic phase; Then, the second organic phase is filtered after being absorbed with anhydrous sodium sulfate, and the obtained filtrate is spin-dried at a speed of 30-40 r / min and a temperature of 45° C. to obtain an N-BOC-aniline derivative.

9. A method for preparing an N-BOC-aniline derivative as claimed in claim 8, characterized in that: The filtration medium used in the filtration has a filtration pore size of 20-25 μm.

Images