A method for synthesizing imide derivatives

Abstract

The invention discloses a method for synthesizing an imide derivative, comprising: (1) dissolving carboxylic acid A and carboxylic acid B in an organic solvent, performing an intermolecular dehydration reaction, separating the dehydrating agent A after the reaction, and then performing extraction separation to obtain an inorganic extract and an organic raffinate containing anhydride C; (2) reacting the organic raffinate containing anhydride C obtained in step (1) with an ammonia source at low temperature first and then at high temperature, and after the reaction, separating the inorganic phase to obtain an organic solution containing imide D; (3) adding an appropriate amount of halogenated hydrocarbon to the organic solution containing imide D to perform a nucleophilic substitution reaction, washing and extracting to obtain an organic extract phase after the reaction, removing the solvent by reduced pressure distillation, and drying to obtain an imide derivative product. The method has mild reaction conditions, safety and environmental protection, high reaction yield, and low cost. The functional functional groups of the imide derivative molecules can be flexibly regulated according to the use characteristics, and the application range is wide.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for synthesizing an imide derivative. Background Art

[0002] Imide derivatives are widely used in drug synthesis, organic optoelectronics, molecular catalysis, chemical synthesis and other fields due to their rigid conjugated skeleton structure, controllable functional groups in the molecule, and electron-deficient properties.

[0003] Direct oxidative coupling between CH bonds and NH bonds is a commonly used method in the prior art for the construction of CN bonds. The main NH nucleophiles used are amine compounds or specific amides (such as pyridine amides or primary amides, etc.). Wang Long et al. (Chem. Eur. J. 2008, 14, 10722-10726) used amide compounds and aldehyde compounds as raw materials, and carried out amidation reaction of aldehyde compounds under NBS / Cu catalytic system to prepare imide derivatives. The reaction formula is as follows:

[0004]

[0005] CN104788336B also uses amide compounds and aldehyde compounds as raw materials, realizes the above reaction under the conditions of an iron salt / auxiliary agent composite catalytic system, and prepares imide derivatives.

[0006] Bian Yongjun et al. (Synthesis of Imides by Palladium-Catalyzed C-HFunctionalization of Aldehydes with SecondaryAmides. Chemistry, 2013, 19(3):1129-33) used N-substituted N-aromatic-2-formamide and an aldehyde compound as raw materials and synthesized a secondary imide compound under the catalysis of precious metal palladium. The reaction formula is as follows:

[0007]

[0008] At present, the synthesis of imide derivatives is mainly based on the aldehyde-amidation synthesis method.

[0009] The main technical features are as follows: (1) The economic cost of reactants and catalyst raw materials is relatively high, which affects the economic practicality of this technical route; (2) The conversion rate of the amidation reaction of aldehyde substances is relatively low, resulting in a low product yield of imide derivatives. If the yield is to be improved, it must be carried out under harsh reaction conditions, which further affects the industrial-scale production of this process; (3) Since the variety of amide reactant raw materials is relatively small, α-unsaturated aldehydes above C3 are generally present as mixed α-unsaturated aldehydes, and the raw material purity is relatively low, it is difficult to flexibly control the functional groups of the imide derivative molecules, and the application range is relatively narrow. Summary of the invention

[0010] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing an imide derivative. The method has mild reaction conditions, is safe and environmentally friendly, has a high reaction yield, and is low in cost. The functional groups of the imide derivative molecules can be flexibly regulated according to the usage characteristics, and has a wide range of applications.

[0011] The synthesis method of the imide derivative of the present invention comprises the following steps: (1) dissolving carboxylic acid A and carboxylic acid B in an organic solvent, carrying out an intermolecular dehydration reaction under the conditions of catalyst A, dehydrating agent A and high temperature, separating the dehydrating agent A after the reaction, and then extracting and separating to obtain an inorganic extract and an organic raffinate containing an acid anhydride C; (2) reacting the organic raffinate containing an acid anhydride C obtained in step (1) with an ammonia source under the action of catalyst B and dehydrating agent B, first at low temperature for a period of time, and then at high temperature for a period of time, separating the inorganic phase after the reaction to obtain an organic solution containing an imide D; (3) adding an appropriate amount of halogenated hydrocarbon to the organic solution containing the imide D, carrying out a nucleophilic substitution reaction under weak or strong alkaline conditions, washing and extracting to obtain an organic extract phase after the reaction, removing the solvent by reduced pressure distillation, and drying to obtain an imide derivative product.

[0012] In the method of the present invention, step (1) is to form a polymer anhydride C with different structural functional groups by intermolecular dehydration of carboxylic acid A and carboxylic acid B containing different or same structural functional groups.

[0013] In the method of the present invention, the intermolecular dehydration reaction formula in step (1) is as follows:

[0014] .

[0015] In the method of the present invention, in the carboxylic acid A (R1COOH) and the carboxylic acid B (R2COOH) described in step (1), R1 is one of furan, an aromatic hydrocarbon substituent, a benzyl group or an alkane substituent; R2 is one of furan, an aromatic hydrocarbon substituent, a benzyl group or an alkane substituent, wherein the furan, aromatic hydrocarbon substituent, benzyl group or an alkane substituent may further contain one or more functional groups selected from the group consisting of an alkyl group, an alkoxy group and an ester group.

[0016] In the method of the present invention, the organic solvent in step (1) is selected from one or more of xylene, trimethylbenzene, chlorobenzene, N,N-dimethylformamide (DMF), ethyl acetate or pyridine; the ratio of the organic solvent to the carboxylic acid is 2-10 mL / g, preferably 3-6 mL / g.

[0017] In the method of the present invention, the catalyst A in step (1) is an aqueous solution of sodium methoxide and an iron salt, the molar concentrations of which are 0.01-5 mol / L and 0.1-10 mol / L, respectively, and the dehydrating agent A is P2O5;

[0018] In the method of the present invention, the molar ratio of carboxylic acid A:carboxylic acid B:catalyst A:dehydrating agent A in step (1) is 1:1:0.15-0.5:0.5-5.

[0019] In the method of the present invention, the dehydration reaction conditions of step (1) are: reaction at normal pressure and 40-80°C for 18-25 hours. During the reaction, a layer-by-layer analysis method (ethyl acetate: n-hexane = 2:1) is used to select 300-400 mesh silica gel, and the reaction process of the target product is tracked and monitored by TCL. After the reaction is completed, the reaction mixture is washed 3 times with deionized water, and then extracted with dichloromethane to obtain an organic extract phase, and the solvent is removed by vacuum distillation, and the product is placed in an oven for drying to obtain a white solid target product.

[0020] In the method of the present invention, the catalyst B and the dehydrating agent B in step (2) are a mixed solution of triethylamine and potassium carbonate, the molar concentrations of the two are 0.01-2 mol / L and 0.5-10 mol / L, respectively, and the molar ratio of triethylamine to potassium carbonate is 1:0.6-2.5.

[0021] In the method of the present invention, the ammonia source in step (2) is ammonia gas, ammonia water, ammonium bicarbonate or urea, preferably ammonia gas or ammonia water, and the molar ratio of the ammonia source to the anhydride C is 1.2-10:1.

[0022] In the method of the present invention, the pressure in step (2) is 0.1-0.5 MPa.

[0023] In the method of the present invention, the low-temperature reaction conditions of step (2) are: reaction at 25-50°C for 2-5 hours; and the high-temperature reaction conditions are: reaction at 110-120°C for 1-1.5 hours.

[0024] In the method of the present invention, in step (2), preferably during the high temperature reaction, vacuum dehydration conditions are set, and the vacuum degree is -0.01 to -0.1 MPa.

[0025] In step (2) of the method of the present invention, the reaction is firstly carried out under low temperature conditions of 25-50°C for pre-hydrolysis reaction, and after the reaction substrate is activated in the catalytic system, an ammonolysis reaction is carried out under high temperature conditions of 210-230°C.

[0026] In the method of the present invention, the aminolysis reaction formula of step (2) is as follows:

[0027] .

[0028] In the method of the present invention, in step (2), the organic raffinate containing the acid anhydride C is preferably added to the mixed solution of the catalyst B and the dehydrating agent B (triethylamine and potassium carbonate) in batches or by slow titration, and the addition time is preferably 25 to 35 minutes.

[0029] In step (3) of the method of the present invention, the hydrogen halide generated by the nucleophilic substitution reaction (β-elimination reaction) is dissolved in an alkaline aqueous solution, and the target main product is dissolved in an organic solvent.

[0030] In the method of the present invention, the reaction equation of step (3) is as follows (taking bromoalkane as an example):

[0031]

[0032] In the method of the present invention, the reaction conditions of step (3) are: reaction at 25-50° C. for 8-15 hours.

[0033] In the method of the present invention, the drying conditions in step (3) are: drying at normal pressure and a temperature of 120-140° C. for 12-24 hours.

[0034] In the method of the present invention, the washing in step (3) is generally performed by washing the reaction mixture 2 to 4 times with deionized water.

[0035] In the method of the present invention, the halogenated alkane in step (3) is a brominated alkane, a chloroalkane, etc., preferably a brominated alkane, and the molar ratio of the halogenated alkane to the carboxylic acid A is 1.2-1.5:1.

[0036] The method of the present invention can prepare imide derivative products with different functional groups according to actual needs, and can be widely used in the fields of drug intermediate synthesis, chemical raw material synthesis, photoelectric molecular catalysis, etc. DETAILED DESCRIPTION

[0037] The present invention is further described below in conjunction with specific preferred embodiments, but the protection scope of the present invention is not limited thereby. The percentage contents described in the embodiments of the present invention are all weight percentage contents.

[0038] Example 1

[0039] Take the synthesis process of N-isopentyl 1-isopropyl-2-tert-butylimide as an example

[0040]

[0041] In a 500 mL reactor, 88.1 g of tert-butyric acid, 74.5 g of propionic acid, 71 g of P2O5, and 30 mL of a mixture of sodium methoxide and iron salts (including 5.4 g of sodium methoxide and 9.1 g of ferrous nitrate) were added at once. The system temperature was raised to 50°C, and the reaction was terminated after constant temperature reaction for 20 hours. The P2O5 powder was filtered out, and the reaction solution was transferred to a separatory funnel and washed three times with deionized water to separate the inorganic aqueous solution; the organic raffinate was returned to the reactor, and a mixture of 45-50 wt% potassium carbonate and triethylamine was added at once, and a mixed gas of ammonia and nitrogen was filled into the reaction system, and the pressure was increased to 0.25-0.3 MPa. The reaction was carried out at 30°C for 2 hours, and then the system temperature was increased to 120°C for 1.5 hours. After the system was cooled to room temperature, the inorganic phase in the mixture was separated; 165 g of 1-Bromopentane, 35°C for 12 hours, layer-by-layer analysis (ethyl acetate: n-hexane = 2:1) was used with 300-400 mesh silica gel, and the composition of the raw materials and products in the reaction system was monitored by TCL tracking. After the reaction, the reaction product was washed with deionized water for 3 times, washed with dichloromethane, and the solvent was distilled under reduced pressure. The product was placed in an oven and dried for 4 hours to finally obtain a white crystalline product. The obtained product was confirmed to be N-isopentyl 1-isopropyl-2-tert-butylimide structure by 1HNMR and MS spectral analysis, and the yield was 95.6% (based on the raw material carboxylic acid, the same below).

[0042] 1H NMR (500MHz, CDCl3) δ=0.95~1.10 (m, 18H), 2.07~2.17 (m, 1H), 2.25~2.4 (m, 2H), 2.5~2.55 (m, 2H), 3.45~3.55 (s, 2H);

[0043] MS[M+H] + :241.3.

[0044] Example 2

[0045] Take the synthesis process of N-tert-butyl di-tert-butylimide as an example

[0046]

[0047] In a 500 mL reactor, 176.2 g of tert-butyric acid, 75 g of P2O5, and 50 mL of a mixture of sodium methoxide and iron salts (including 6.8 g of sodium methoxide and 10 g of ferrous nitrate) were added at once. The system temperature was raised to 65°C. The reaction was terminated after 20 hours of constant temperature reaction. The P2O5 powder was filtered out, and the reaction solution was transferred to a paging funnel and washed three times with deionized water to separate the inorganic aqueous solution. The organic raffinate was returned to the reactor, and a mixed gas of ammonia and nitrogen was filled into the reaction system. The pressure was increased to 0.25-0.3 MPa, and the reaction was carried out at 35°C for 2 hours. During the reaction, 50 mL of a mixture of 45-50 wt.% potassium carbonate and triethylamine was pumped into the reaction system for 20 min, and the system temperature was then increased to 120 ℃ for 1.5 hours, and after the system is cooled to room temperature, the inorganic phase in the mixed solution is separated; 165g of 1-bromobutane is added to the remaining organic phase reaction solution, and the reaction is carried out at 35℃ for 12 hours. The layer-by-layer analysis method (ethyl acetate: n-hexane = 2:1) is used to select 300-400 mesh silica gel, and the composition of the raw materials and products in the reaction system is tracked and monitored by TCL. After the reaction, the reaction product is washed with deionized water for 3 times, and the reaction solution is vacuum dehydrated under a vacuum condition of -0.6~-0.75MPa, and the product is washed with dichloromethane, and the solvent is distilled under reduced pressure. The product is placed in an oven and dried for 4 hours, and finally N-n-butyl di-tert-butyl imide white crystals are obtained. The obtained product is confirmed to be N-n-butyl di-tert-butyl imide by 1H NMR and MS spectral analysis, and the total yield is 95.6%.

[0048] 1H NMR (500MHz, CDCl3) δ=0.9~1.0 (m, 18H), 1.9~2.05 (m, 1H), 2.05~2.15 (m, 2H), 2.25~2.4 (m, 4H), 3.4~3.45 (s, 2H);

[0049] MS[M+H] + :241.7.

[0050] Embodiment 3~5

[0051] The preparation methods of the following examples are the same as those of Example 2, except that corresponding carboxylic acids and halogenated alkane raw materials are selected according to the functional groups (R1, R2, R3) of different target products.

[0052] Among them, Example 3 uses tert-butyric acid, alkoxypropionic acid, and butyl bromide as raw materials, Example 4 uses acetic acid, propionic ester, and pentane bromide as raw materials, and Example 5 uses formic acid, benzoic acid, and propylene chloride as raw materials.

[0053] The specific properties of the target products of Examples 1 to 5 are shown in Table 1, and the evaluation results are shown in Table 2.

[0054] Example 6

[0055] 225mL C9 aromatics, 75mL of the solvent to be tested (such as N-tert-butyl di-tert-butylimide) and 45g of 2-ethylanthraquinone were fully mixed to form a working solution; 4.5g of hydrogenation catalyst was loaded into a transparent visual fixed bed reactor. The catalyst used was a conventional palladium catalyst (Pd / Al2O3) in the hydrogen peroxide industry, with a catalyst particle size of 0.4~0.5mm and a pore volume of 0.6~0.8cm 3 / g, specific surface area 150~180m 2 / g, Pd content is 0.25~0.30wt.%.

[0056] The 2-ethylanthraquinone working solution was pumped into the fixed bed reactor using a metering pump at a temperature of 55°C, a pressure of 0.25 MPa, and a space velocity of 15 h -1 The working solution was subjected to hydrogenation reaction under the following conditions, during which the flow state of the working solution was detected by laser tracking. When the working solution in the bed reached the critical turbidity state (i.e., the 2-ethylanthraquinone reaction carrier reached the critical state of precipitation), the hydrogenation reaction was stopped. The 2-ethylanthraquinone working solution was taken out from the bottom of the bed, and the composition of the working solution was analyzed by high performance liquid chromatography, and the hydrogenation efficiency of the working solution was determined by potassium permanganate titration. Under the condition that no obvious degradation products were detected by high performance liquid chromatography results, the solubility of hydroanthraquinone in the solvent system (a mixture of aromatic hydrocarbons and imide target products) was calculated by the hydrogenation efficiency. The solubility of hydroanthraquinone in the working solution of different target products is shown in Table 2

[0057] Comparative Example 1

[0058] CN 104788336 B Implementation scheme:

[0059]

[0060] 1 mol of the compound of formula (I) and 0.06 mol of FeCl2 were added to a mechanically stirred reactor, and nitrogen was introduced to maintain a nitrogen atmosphere. Then 6 L of solvent toluene was added to the system, and 3 mol of the compound of formula (II), 2.2 mol of TBHP and a mixture of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 1,10-phenanthroline and I2O5 in a mass ratio of 1:0.4:0.2 (total mass of 10 g) were added under stirring, and nitrogen was continued to be introduced and then sealed. The temperature was raised to 50°C for reaction for 14 hours. After the reaction was completed, water was added to quench the reaction, and ether was used for extraction. After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain the compound of formula (III) with a yield of 93.8% and a purity of 98.9% (HPLC).

[0061] 1HNMR(400MHz, CDCl3)δ=7.62-7.49(m,5H),3.21(s,3H),2.33(s,3H);

[0062] MS[M+H] + :177.07.

[0063] Table 1 Properties of target products in various examples

[0064] Example <![CDATA[R1]]> <![CDATA[R2]]> <![CDATA[R3]]> Appearance Yield purity Example 1 <![CDATA[C3H7]]> <![CDATA[C4H9]]> <![CDATA[C5H 11 ]]> White crystal 95.6 98.2% Example 2 <![CDATA[C4H9]]> <![CDATA[C4H9]]> <![CDATA[C4H9]]> White crystal 96.7 99.3% Example 3 <![CDATA[CH3]]> <![CDATA[C3H7O-]]> <![CDATA[C4H9]]> White crystal 96.1 98.1% Example 4 <![CDATA[C2H5]]> <![CDATA[C3H7COO-]]> <![CDATA[C5H 11 ]]> White crystal 95.9 99.5% Example 5 <![CDATA[CH3]]> <![CDATA[CH3C6H5-]]> <![CDATA[C3H7]]> White crystal 97.2 98.8% Comparative Example 1 <![CDATA[CH3]]> <![CDATA[CH3]]> <![CDATA[C6H5]]> White crystal 93.8 98.9%

[0065] Table 2 Evaluation results of the products of various examples

[0066] Example <![CDATA[R1]]> <![CDATA[R2]]> <![CDATA[R3]]> 2-Ethylhydroanthraquinone Solubility Water content Example 1 <![CDATA[C3H7]]> <![CDATA[C4H9]]> <![CDATA[C5H 11 ]]> 108.3 0.15wt% Example 2 <![CDATA[C4H9]]> <![CDATA[C4H9]]> <![CDATA[C4H9]]> 116.5 0.13wt% Example 3 <![CDATA[CH3]]> <![CDATA[C3H7O-]]> <![CDATA[C4H9]]> 83.8 0.15wt% Example 4 <![CDATA[C2H5]]> <![CDATA[C3H7COO-]]> <![CDATA[C5H 11 ]]> 97.9 0.19wt% Example 5 <![CDATA[CH3]]> <![CDATA[CH3C6H5-]]> <![CDATA[C3H7]]> 86.7 0.17wt% Comparative Example 1 <![CDATA[CH3]]> <![CDATA[CH3]]> <![CDATA[C6H5]]> 75.4 0.24wt%

Claims

1. A method for synthesizing an imide derivative, characterized in that: The steps include: (1) dissolving carboxylic acid A and carboxylic acid B in an organic solvent, carrying out an intermolecular dehydration reaction in the presence of catalyst A, dehydrating agent A and high temperature, separating the dehydrating agent A after the reaction, and then extracting and separating to obtain an inorganic extract and an organic raffinate containing anhydride C; (2) reacting the organic raffinate containing anhydride C obtained in step (1) with an ammonia source under the action of catalyst B and dehydrating agent B, first at low temperature for a period of time, then at high temperature for a period of time, and after the reaction is completed, separating the inorganic phase to obtain an organic solution containing imide D; (3) adding an appropriate amount of halogenated hydrocarbon to an organic solution containing imide D, carrying out a nucleophilic substitution reaction under weak or strong alkaline conditions, washing and extracting after the reaction to obtain an organic extract phase, removing the solvent by vacuum distillation, and drying to obtain an imide derivative product; The carboxylic acid A and the carboxylic acid B described in step (1) are tert-butyric acid; and the halogenated alkane described in step (3) is bromobutyl.

2. The method according to claim 1, characterized in that: The organic solvent in step (1) is selected from one or more of xylene, trimethylbenzene, chlorobenzene, N,N-dimethylformamide, ethyl acetate or pyridine.

3. The method according to claim 1, characterized in that: The ratio of the organic solvent to the carboxylic acid in step (1) is 2 to 10 mL / g.

4. The method according to claim 3, characterized in that: The ratio of the organic solvent to the carboxylic acid in step (1) is 3-6 mL / g.

5. The method according to claim 1, characterized in that: The catalyst A described in step (1) is an aqueous solution of sodium methoxide and iron salt, the molar concentrations of the two are 0.01-5 mol / L and 0.1-10 mol / L respectively, and the dehydrating agent A is P2O5.

6. The method according to claim 1, characterized in that: The molar ratio of carboxylic acid A:carboxylic acid B:catalyst A:dehydrating agent A in step (1) is 1:1:0.15-0.5:0.5-5.

7. The method according to claim 1, characterized in that: The dehydration reaction conditions of step (1) are: reaction at normal pressure and 40-80° C. for 18-25 hours.

8. The method according to claim 1, characterized in that: The catalyst B and the dehydrating agent B in step (2) are a mixed solution of triethylamine and potassium carbonate, the molar concentrations of the two are 0.01-2 mol / L and 0.5-10 mol / L respectively, and the molar ratio of triethylamine to potassium carbonate is 1:0.6-2.

5.

9. The method according to claim 1, characterized in that: The ammonia source in step (2) is ammonia gas, ammonia water, ammonium bicarbonate or urea; the molar ratio of the ammonia source to the acid anhydride C is 1.2 to 10:

1.

10. The method according to claim 1, characterized in that: The pressure in step (2) is 0.1-0.5 MPa.

11. The method according to claim 1, characterized in that: The low temperature reaction conditions of step (2) are: 25-50°C for 2-5 hours; the high temperature reaction conditions are: 110-120°C for 1-1.5 hours.

12. The method according to claim 1, characterized in that: In step (2), during the high temperature reaction, vacuum dehydration conditions are set, and the vacuum degree is -0.01 to -0.1 MPa.

13. The method according to claim 1, characterized in that: Step (2) adding the organic raffinate containing the acid anhydride C into the mixed solution of the catalyst B and the dehydrating agent B in batches or by slow titration.

14. The method according to claim 13, characterized in that: The time for adding the organic raffinate containing anhydride C in step (2) is 25 to 35 minutes.

15. The method according to claim 1, characterized in that: The reaction conditions of step (3) are: reaction at 25-50° C. for 8-15 hours.

16. The method according to claim 1, characterized in that: The drying conditions in step (3) are: drying at normal pressure and a temperature of 120 to 140° C. for 12 to 24 hours.

17. The method according to claim 1, characterized in that: The molar ratio of the halogenated alkane to the carboxylic acid A in step (3) is 1.2-1.5:

1.

18. An imide derivative product prepared by any one of the methods of claims 1 to 17 is used as a solvent for 2-ethylanthraquinone in the palladium catalyst reduction industry.

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